... Electrophysiologic Evaluation in Otolaryngology

Transcription

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2 ... Electrophysiologic Evaluation in Otolaryngology..

3 ... Advances in Oto-Rhino-Laryngology Vol. 53 Series Editor W. Arnold, München

4 ... Electrophysiologic Evaluation in Otolaryngology Volume Editors B.R. Alford, Houston, Tex. J. Jerger, Houston, Tex. H.A. Jenkins, Houston, Tex. 73 figures and 14 tables, 1997

5 ... Advances in Oto-Rhino-Laryngology Library of Congress Cataloging-in-Publication Data Electrophysiologic evaluation in otolaryngology / volume editors, B.R. Alford, J. Jerger, H.A. Jenkins. (Advances in oto-rhino-laryngology; vol. 53) Includes bibliographical references and indexes. 1. Audiometry, Evoked response. 2. Auditory evoked response. I. Alford, Bobby R. (Bobby Ray), II. Jerger, James. III. Jenkins, H.A. (Herman A.) IV. Series. [DNLM: 1. Audiometry, Evoked Response methods. 2. Evoked Potentials, Auditory. W1 AD701 v / WV 272 E ] RF16.A38 vol. 53 [RF294.5.E87] s dc21 [ ] ISBN (hardcover: alk. paper) Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents Ô and Index Medicus. Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Ó Copyright 1997 by S. Karger AG, P.O. Box, CH 4009 Basel (Switzerland) Printed in Switzerland on acid-free paper by Thür AG Offsetdruck, Pratteln ISBN

6 ... Contents VII Preface Electrophysiologic Evaluation in Otolaryngology 1 Electrocochleography Kumagami, H.; Nakata, T.; Hirano, Y.; Tsukazaki, N. (Nagasaki) 21 Auditory Brainstem Response: Recent Developments in Recording and Analysis Hall, J.W., III; Rupp, K.A. (Nashville, Tenn.) 46 Hearing as Reflected by Middle and Long Latency Event-Related Potentials Jacobson, G.P. (Detroit, Mich.); Kraus, N.; McGee, T.J. (Evanston, Ill.) 85 Objective Measurements and the Audiological Management of Cochlear Implant Patients Shallop, J.K. (Englewood, Colo.) 112 Electroneuronography Dennis, J.M. (Oklahoma City, Okla.); Coker, N.J. (Houston, Tex.) 132 Testing the Vestibulo-Ocular Reflex Halmagyi, G.M.; Yavor, R.A.; McGarvie, L.A. (Camperdown, N.S.W.) 155 Vestibular Evoked Potentials Trinus, K.F. (Kyiv) 182 Otoacoustic Emissions Probst, R.; Harris, F.P. (Basel) 205 Author Index 206 Subject Index

7 ... Preface The past decade has seen an explosive growth in the application of electrophysiologic measurement techniques to the evaluation of patients with hearing and balance disorders. In long-established areas, like electrocochleography, electroneuronography, electronystagmography, and the auditory brainstem response, advances in computer technology have generated new and exciting applications. In addition, new areas of exploration are being developed. The late auditory and event-related potentials, for example, are being successfully applied to the evaluation of patients both before and after cochlear implant surgery. Within the past decade, moreover, we have seen the development of an entirely new clinical tool, the measurement of otoacoustic emissions, which has already had a significant impact on the evaluation of auditory function. Finally, the successful recording of evoked potentials in response to stimulation of the vestibular system promises the possibility of substantially more sophisticated methods for studying the dizzy patient. In this volume we have attempted to bring to the reader the current thinking of recognized leaders in their respective areas of this rapidly burgeoning technological revolution in otologic evaluation. Houston, Tex., August 1996 Bobby R. Alford, MD James Jerger, PhD Herman A. Jenkins, MD

8 Alford BR, Jerger J, Jenkins HA (eds): Electrophysiologic Evaluation in Otolaryngology. Adv Otorhinolaryngol. Basel, Karger, 1997, vol 53, pp Electrocochleography Hidehaku Kumagami, Takashige Nakata, Yasuhiro Hirano, Naoki Tsukazaki Department of Otolaryngology, School of Medicine, Nagasaki University, Nagasaki, Japan In clinical electrocochleography (ECoG), particularly the transtympanic electrode technique using needle electrodes, we record the cochlear microphonic (CM), the summating potential (SP) and the compound cochlear nerve action potential (APN 1 ). This chapter considers how certain aspects of the ECoG, particularly the pathophysiology of a widened AP-SP complex (abnormally broad wave), interact with audiometric parameters. We present separate sections on (1) ECoG study of the AP-SP complex, and (2) the diagnostic significance of ECoG in patients with acute low-frequency sensorineural hearing loss. There have been many reports that a widened AP-SP complex is observed in retrolabyrinthine deafness but the cause has been controversial. In this report we have attempted to evaluate the broad ECoG wave in patients with cerebellopontine (CP) angle tumor and with inner ear disorders. Methods for Recording and Categorizing the ECoG Response For the measurement of AP, we have used a click produced by 1 cycle of a 4-kHz sinusoid. For the measurement of CM, we have used short tone bursts (3 ms duration at 8 and 4 khz, 4 ms duration at 2 khz, 6 ms duration at 1 and 0.5 khz). At all frequencies the rise-decay time was 1 ms. All signals are delivered by a shielded loudspeaker located 50 cm lateral to the tested ear. The AP-SP complex wave was recorded in response to click stimulation at 90 dbnhl. We defined a broad AP-SP complex as a waveform in which the width between the rising portion of the negative wave and the baseline crossing was 1.50 ms or more. Abnormal waves were further subdivided into an AP-SP mixed type, which is usually observed, and a dissociated type which shows a two-peak waveform (fig. 1).

9 Fig. 1. Width of the AP-SP complex wave and classification of the abnormally broad wave. The latter was defined as an AP-SP complex wave width of 1.50 ms or more, and was divided into an AP-SP mixed type and a dissociated type. Subjects We report results on a total of 109 individuals: 18 normal controls, 35 patients with CP angle tumors, and 56 patients with presumed cochlear disorders. Patients were divided into three major groups: (1) hair cell damage (H type); (2) retrocochlear damage (R type), and (3) mixed (M type). The mixed type was further subdivided into M-H type (more H than R) and M-R type (more R than H). The H type represents cases in which the AP and CM detection thresholds are almost identical to the pure-tone audiometric level. The R type represents cases in which the CM detection threshold is close to normal, and inner ear hair cells are fairly well preserved. The M type represents cases of probable damage to both inner ear hair cells and retrolabyrinthine pathways. Results Normal Control Group Average ECoG findings at 90 dbnhl in 18 normal hearing subjects were as follows: The click AP(N 1 ) latency was ms, the output potential was approximately 80 μv. For the negative SP the output potential was SP 15 μv ( SP/AP ratio 19%). The width of AP-SP complex wave was ms. The mean CM output potentials at 0.5, 1 and 4 khz were 66, 83 and 85 μv, respectively. The detection thresholds of the CM at 0.5 and 4 khz were approximately 20 and 40 dbnhl, respectively. The threshold at 1 khz was detectable up to the same level as the pure-tone audiometric threshold. A SP/AP ratio of 30% or more defined a dominant negative summating potential [Kumagami et al., 1982]. Kumagami/Nakata/Hirano/Tsukazaki 2

10 Table 1. Relationship between the ECoG classification and the abnormally broad wave in 35 CP angle tumor cases AP-SP width AP-SP width Total 1.50 ms 1.50 ms (broad wave) Hair cell damage (H) type WWWWWXX WWWWX 12 Mixed (M) type 19 M-H type WWWW WWXX 8 M-R type WWWWWWXp 11 Retrocochlear damage (R) type X WWX 4 Total W>Acoustic neurinoma; X>meningioma; >cerebellar astrocytoma; >medulloblastoma; p>prepontine pseudocyst. Table 2. Relationship between the ECoG classification and each type of loss in broad waves in CP angle tumor cases AP-SP mixed type Dissociated type Total Hair cell damage (H) type WWWX WWX 7 Mixed (M) type 7 M-H type WWW W 4 M-R type 3 Retrocochlear damage (R) type X 1 Total W>Acoustic neurinoma; X>meningioma; >cerebellar astrocytoma; >medulloblastoma. Results in Patients with Cerebellopontine Angle Tumor (n>35) The relationship between the ECoG classification and the abnormally broad wave is summarized in table 1. There were 12 H type cases, 19 M type cases (8 M-H and 11 M-R type cases) and 4 R type cases. An abnormally broad wave was observed in 15 cases (42.9%). Of these 15 cases, 7 were H type cases, 7 were M type cases (4 M-H and 3 M-R cases) and 1 was an R type case. R types were relatively infrequent. Most cases showed hair cell damage. The relationship between the ECoG classification and the type of abnormally broad wave is shown in table 2. Nine cases were of the AP/ SP mixed type and 6 cases were of the dissociated type. Electrocochleography 3

11 Table 3. Mean values of the detection thresholds of AP(N 1 ) and CM, output amplitudes of AP(N 1 ) and the width of the AP-SP complex wave at the stimulus intensity of 90 dbnl No. SP AP(N 1 ) Width CM det.thres. 1 Hearing level 2 μv ms latency ampl. det.thres. 0.5 khz 1 khz 4 khz 0.5 khz 1 khz 4 khz ms μv dbnhl (dbnhl) (db) (db) (db) 1 Normal hearing (n>18) CP angle tumors (n>35) Broad wave AP-SP mixed type (1) (4) (5) (5) Dissociated type Not broad wave (5) (5) (5) 3 Cochlear disorders (n>56) Broad wave AP-SP mixed type (1) Dissociated type (2) Flat moderate SHL Low tone losses Ménière s disease Low tone (Williams) No response at 90 dbnhl. 2 Beyond equipment limits. 3 Excludes endolymphatic hydrops. 4 Williams endolymphatic hydrops without vertigo. The mean values of the various parameters by each type are shown in table 3. Many of the CP angle tumor cases showed good agreement between the AP(N 1 ) detection thresholds, the CM response, and the pure-tone audiometric threshold. Five of these cases, though profoundly deafened, showed satisfactory AP(N 1 ) and CM responses. In the SP/AP mixed type, the detection thresholds for both the CM at 4 khz and for click AP(N 1 ) were high. Click AP(N 1 ) showed prolongation of latency and small amplitude. In the dissociated type, the CM detection threshold was high at 4 khz but satisfactory as in the normal group at 1 khz. The detection threshold of the click AP and its latency were close to normal. Illustrative Cases In the following section we discuss ECoG findings in various illustrative patients. Case 1: 69-year-old male, right acoustic schwannoma, abnormally broad wave, AP/ SP mixed type (fig. 2). The pure-tone audiogram for the right ear showed a profound Kumagami/Nakata/Hirano/Tsukazaki 4

12 Fig. 2. Audiogram, ECoG waveform, and input-output curves in a 69-year-old male with right acoustic schwannoma (AP-SP mixed type). sensorineural loss. The click AP(N 1 ) latency was prolonged to 2.00 ms and its amplitude was only 4 μv. The width of the AP/ SP complex wave was 2.00 ms (an abnormally broad wave). The detection threshold of the click-evoked AP(N 1 ) was 60 dbnhl. One- and 4-kHz tone burst AP(N 1 ) thresholds were 60 and 90 dbnhl, respectively. The SP amplitude was low. The CM amplitude was low and was particularly remarkable at 4 khz. The CM detection threshold was somewhat better than the pure-tone audiometric level. These ECoG findings indicated profound inner ear hair cell damage mostly in the high-frequency area (H type). Case 2: 51-year-old female, right acoustic schwannoma, broad wave, dissociated type (fig. 3). The pure-tone audiogram for the right ear showed a severe high-frequency sensorineural loss. The click AP(N 1 ) latency was prolonged to 1.56 ms and its output amplitude was only 6.8 μv. The width of the complex wave was 2.50 ms showing an abnormally broad wave of the dissociated type. The 4-kHz pure-tone audiometric threshold and the AP detection threshold were almost identical, 70 dbnhl. The threshold for click stimulation was even better, 50 dbnhl. The SP amplitude was only 5.9 μv but the SP was dominant with reference to the SP/AP ratio. (What was the ratio?) The CM detection threshold was almost identical to the pure-tone audiometric level. These findings indicated profound hair cell damage (H type) in the high-frequency region. Case 3: 40-year-old female, right acoustic schwannoma, normal AP/SP complex, retrocochlear damage type (fig. 4). In this case, the pure-tone audiogram showed total loss of hearing in the right ear. The click AP(N 1 ) latency was 1.22 ms with minimal prolongation but a high amplitude of 107 μv. The width of the complex wave was 1.20 ms, almost within the normal range. The detection threshold for click AP(N 1 ) was 10 dbnhl, and 1- and 4- khz tone burst AP(N 1 ) thresholds were 20 and 10 dbnhl, respectively, well within the normal range. The SP amplitude and the SP/AP ratio were also within the normal range. CM responses at 4 khz were generally satisfactory although the amplitude at 90 dbnhl was somewhat low (23 μv) and the detection threshold was 50 dbnhl showing a slight increase. In view of the above ECoG findings, this case reflected typical retrocochlear damage type (R type). Electrocochleography 5

13 Fig. 3. Audiogram, ECoG waveform, and input-output curves in a 51-year-old female with right acoustic schwannoma (dissociated type). Deafness due to Cochlear Disorder (n>56) Of the 56 patients in this group there were 49 cases showing an abnormally broad wave, 38 cases were of the AP/ SP mixed type and 11 cases were of the dissociated type. In the AP/ SP mixed type, the mean hearing levels at 0.5, 1 and 4 khz were 57, 55 and 73 db, respectively. The mean detection threshold for click AP(N 1 ) were 57 dbnhl 55, 51 and 74 dbnhl, respectively, excluding 1 case of no response. Thus, profound hair cell damage was noted in the highfrequency area. The click AP(N 1 ) latency was ms, showing a marked prolongation. The amplitude was only 14 μv. To investigte the relationship between the abnormally broad wave and inner ear hair cell damage in the high-frequency region, we reviewed results in various types of hearing disorder. In 16 cases of flat, moderate sensorineural loss (2 cases of sudden loss, 1 case of acute trauma, 2 cases of familial loss, and 11 cases of sensorineural loss of unknown etiology), the mean detection threshold of the CM at 0.5 and 1 khz was approximately 50 dbnhl, almost identical to results in the AP/ SP mixed group. At 4 khz, it was 60 dbnhl, Kumagami/Nakata/Hirano/Tsukazaki 6

14 Fig. 4. Audiogram, ECoG waveform, and input-output curves in a 40-year-old female with right acoustic schwannoma. significantly better than the former group (p=0.0001). The click AP(N 1 ) latency was ms with little prolongation, and the width of the complex wave was ms with no increase. In 19 cases of low-frequency sensorineural loss with almost normal responses in the high-frequency region (12 cases of familial loss, 7 cases of sensorineural loss of unknown etiology, excluding cases of endolymphatic hydrops), there was no prolongation of the click AP(N 1 ) latency and no increase of the width of the complex wave at the stimulus level of 90 dbnhl. In 10 cases of Ménière s disease, the SP was 24.1 μv, a high value. The width of the complex wave was slightly increased but was not abnormally broad. Electrocochleography 7.

15 Fig. 5. Audiogram, ECoG waveform, and input-output curves in a 48-year-old female with left Ménière s disease (AP-SP mixed type). In 11 cases of low-frequency sensorineural loss, the so-called endolymphatic hydrops without vertigo, the click AP(N 1 ) latency was 1.14 ms without notable prolongation, and the SP showed a high amplitude of 24.1 μv. The width of the complex wave was slightly increased to 1.23 ms but an abnormally broad wave was not observed in any case. Among 11 cases with a dissociated-response type, the slope of the sensorineural loss was either abrupt or gradual in as many as 8 cases. The click AP(N 1 ) showed a prolonged latency and a low amplitude. In comparison with the 4-kHz pure-tone audiometric level and the mean detection threshold of the AP, the 4-kHz threshold level was 69 db and the 4-kHz tone burst was 62 dbnhl, nearly identical to results in the former group. The threshold for click stimulation was 40 dbnhl. Illustrative Cases Case 4: 48-year-old female, left Ménière s disease, type III [Kumagami et al., 1982], abnormally broad wave, AP/ SP mixed type (fig. 5). The pure-tone audiogram shows a severe sensorineural loss with a somewhat gradual sloping audiometric contour. The click AP(N 1 ) shows a marked prolongation of latency (1.88 ms) and a low amplitude of 16.4 μv. The width of the AP/ SP complex wave was 2.40 ms, a broad wave. The detection threshold was 60 dbnhl for the click AP(N 1 ), and 60 and 80 dbnhl, respectively, for the AP(N 1 )at1 and 4 khz. The amplitude of SP was 8.8 μv, well within the normal range. The SP/AP ratio was 54%, indicating a dominant SP. The CM showed a low amplitude at 4 khz, but was normal in the medium-low frequency region. The detection thresholds of the CM at 0.5, 1 and 4 khz were 40, 60 and 90 dbnhl, respectively, somewhat better than the pure-tone threshold levels in the medium-low frequency region, but profound inner ear hair cell damage was indicated in the high-frequency region. Kumagami/Nakata/Hirano/Tsukazaki 8

16 Fig. 6. Audiogram, ECoG waveform, and input-output curves in a 12-year-old male with familial hearing loss (dissociated type). Case 5: 12-year-old male, familial loss, abnormally broad wave, dissociated type (fig. 6). The pure-tone audiogram shows a severe, bilateral, high-frequency sensorineural loss. The left click AP(N 1 ) shows a prolonged latency of 1.92 ms, a low amplitude of 8.8 μv. The width of the complex wave was 2.25 ms, an abnormally broad wave. The detection threshold for a 4-kHz tone burst AP was 90 dbnhl, nearly equal to the 85-dB audiometric threshold at 4 khz. The detection threshold of the click AP was 60 dbnhl. The amplitude of SP was 0.7 μv, and the SP/AP ratio was also low, 8%. The detection threshold of CM was almost identical to the audiometric threshold. These findings indicate hair cell damage, primarily in the high-frequency region. Discussion Various theories have been proposed to explain the mechanism of the abnormally broad wave. They include: (1) a relative increase of SP due to the decrease of AP amplitude [Portmann and Aran, 1972], and (2) insufficient synchrony of firing of nerve fibers [Eggermont et al., 1980]. The exact cause, however, still remains unknown. Relative to criteria of abnormality of the width of the complex wave, Gibson and Beagley [1976] suggested that 4 ms or more was abnormal, but without further justification. On the basis of results in our normal-hearing subjects we suggest that a waveform in excess of 1.5 ms is abnormally broad. There was a tendency for the width of AP(N 1 ) to widen as the amplitude of AP(N 1 )was substantially lowered. These cases were excluded. The distinction between AP(N 1 ) and SP can be made on the basis that AP(N 1 ) shows adaptation when the stimulus interval is shortened. However, separate measurement of each width Electrocochleography 9

17 is difficult. Hence, we have studied the total AP/ SP complex wave. There may be cases of an abnormally broad AP(N 1 ) but in our series this did not occur. In the dissociated response type, we noted an abrupt or gradually sloping audiometric contour in many cases of inner ear disorder (e.g. case 5). In these cases, the click AP detection threshold was better than both the 4-kHz audiometric threshold level and the 4-kHz tone burst AP detection threshold. In the CP angle tumor group, many cases showed a substantial difference in CM detection threshold between 4 and 1 khz (4?1 khz), and better AP detection threshold for click stimulation than for a 4-kHz tone burst. The fact that the click, a wide-band signal as compared to a 4-kHz tone burst with better frequency specificity [Eggermont and Odenthal, 1974], results in a better AP detection threshold is due to the additional responses in the lower-frequency region (approximately khz) where hearing sensitivity is relatively normal. The dissociated type is often seen when hair cells are damaged severely in the high-frequency region but are undamaged in the low-frequency region (approximately khz). The addition of responses in the low-frequency region, where hearing is normal, seems to cause the abnormally broad wave. In Ménière s disease, prolongation of latency was observed in the advanced disease stage. The 13 cases showing an abnormally broad wave were so-called Ménière s disease type III wherein the 4-kHz CM threshold was very high and the AP(N 1 ) latency, if any, was not remarkable, while the 4-kHz CM detection threshold was satisfactory. An abnormally broad wave was not observed in these cases. In cochlear disorders other than endolymphatic hydrops, prolongation of AP(N 1 ) latency, if any, was slight and without an abnormally broad wave, so long as the 4-kHz CM responses could be detected down to approximately 60 dbnhl, but marked prolongation of click AP(N 1 ) latency and an abnormally broad wave were observed as the damage became more profound. The relationship between the 4-kHz CM detection threshold and the click AP(N 1 ) latency at 90 dbnhl in 29 cases of CP angle tumor, excluding the dissociated type, is shown in figure 7. As the 4-kHz CM detection threshold increased, the click AP(N 1 ) latency was prolonged (r>0.633). The relationship between the 4-kHz CM detection threshold and the width of the AP/ SP complex wave at 90 dbnhl is also shown in figure 7. No broad wave was observed while the 4-kHz CM detection threshold was 40 dbnhl or less, but the complex wave increased in width as the detection threshold increased (r>0.49). In other words, in the AP/ SP mixed type, even among CP tumor cases, there was profound hair cell damage in the highfrequency region as in case 1. On the other hand, in cases of more typical retrocochlear deafness (e.g. case 3) wherein CM and AP responses were satisfactory and the function from the hair cells to the spiral ganglion was likely to be preserved, an abnormally broad wave was not observed. Kumagami/Nakata/Hirano/Tsukazaki 10

18 Fig. 7. Relations among CM detection threshold, AP latency and AP-SP width in 29 cases of CP angle tumor (excluding dissociated type). As the 4-kHz CM detection threshold exceeds 40 dbnhl there is an associated prolongation of the AP latency. No abnormally broad wave is seen. However, an increase of the width is observed with an increase in the CM detection threshold. Among the cases of so-called endolymphatic hydrops, the SP showed a high amplitude and the width of the complex wave was slightly increased so as to show no broad wave in Ménière s disease and William et al. s [1950] endolymphatic hydrops without vertigo. As for Ménière s disease, type III, with a mixed type AP/ SP, a dominant SP was observed in many cases but there was no increase of SP amplitude. Dominant SP was also frequent in cases of other inner ear disorders and in CP angle tumor, but there was not absolute increase of SP, in spite of relatively dominant SP, because of low AP(N 1 ) amplitude. All cases of mixed type AP/ SP, whether inner ear disorder or CP angle tumor, showed markedly prolonged latency and low AP(N 1 ) amplitude. The major causes of an abnormally broad wave are the prolonged latency and low amplitude of AP(N 1 ) even though there is a relative increase of SP. The latency of AP(N 1 ) seemed to be prolonged due to the profound inner ear hair cell damage in the high-frequency region. It has been reported by several investigators that an abnormally broad wave is frequently observed in retrocochlear deafness. However, the cases summarized above show that the broad wave is not specific to retrocochlear hearing loss. It is also observed in loss due to cochlear disorder. The most important factor contributing to an abnormally broad wave is profound hair cell damage in the high-frequency region. Electrocochleography 11

19 Table 4. Distribution of sex and age as a function of status Total M:F M:F M:F M:F M:F M:F (M:F) Improved 0:0 0:8 1:2 2:0 1:2 1:0 17 (5:12) Fluctuated 0:0 1:0 0:0 0:2 2:1 2:0 8 (5:3) Unchanged 1:0 0:0 3:1 0:3 5:1 1:1 16 (10:6) Unknown 2:0 2:1 0:2 1:1 1:0 0:2 12 (6:6) Total 3:0 3:9 4:5 3:6 9:4 4:3 53 (26:27) M>Male; F>female. ECoG Study of Acute Low-Frequency Sensorineural Hearing Loss Recently, many investigators have reported cases of low-frequency sensorineural hearing loss (LFSHL) such as endolymphatic hydrops without vertigo, as described by Williams et al. [1950], and low-frequency sudden loss, or familial LFSHL, as reported by Konigsmark et al. [1971]. Patients may show several clinical courses such as a rapid recovery, a long-term fluctuant LFSHL, development of Ménière s disease [Abe and Tuiki, 1992], or no fluctuation and recovery after the first attack. In this section we will describe the ECoG findings in acute LFSHL, excluding Ménière s disease, and evaluate its prognostic value. Method From 1984 to 1993, 53 cases of LFSHL, ranging in age from 22 to 65 years (26 males and 27 females), were examined by pure-tone audiometry and transtympanic ECoG. They satisfied the following criteria: (1) an average hearing level poorer than 30 db in the low-frequency region (0.25 and 0.5 khz) and better than 20 db in the high-frequency region (2, 4 and 8 khz); (2) a report of sudden loss; (3) no complaint of vertigo or dizziness, and (4) no apparent cause. Prognosis was evaluated according to whether there was improvement, fluctuation or no change in the pure-tone audiogram. As shown in table 4, the prevalence of LFSHL shows no gender difference, but is more frequent in females in the age decade (9 cases; 17%) and in the age decade for males (9 cases; 17.0%). Females, especially in their 20s (8 cases; 47.1%), show better prognosis (12 improved cases; 70.6%) than males (5 cases; 29.4%), whereas males show fluctuation (5 cases; 62.5%) or no change (10 cases; 62.5%). We could not follow the course in 12 cases (unknown cases). Kumagami/Nakata/Hirano/Tsukazaki 12

20 Table 5. Summary of status in each type of lesion Type Male Female Total Endolymphatic hydrops Improved Fluctuating Unchanged Unknown Hair cell damage Fluctuating Unchanged Unknown Neural damage Improved Fluctuating Unchanged Total On the basis of pure-tone audiometry and ECoG, we divided LFSHL patients into three groups: (1) endolymphatic hydrops; (2) hair cell damage, and (3) retrocochlear neural lesion. Thirty-three cases (62.3%) showed a lower CM threshold than pure-tone audiometry thresholds (PTAT), almost the same AP threshold as PTAT and a high amplitude on CM, a negative summating potential ( SP) and an AP indicating endolymphatic hydrops as seen in Ménière s disease [Kumagami et al., 1982]. Seventeen cases (32.1%) revealed approximately the same deteriorated threshold on CM and AP as TPTA, indicating hair cell damage [Kumagami, 1984]. Three cases (5.7%) showed an approximately normal CM response and low AP anplitude indicating retrocochlear neural lesion [Kumagami, 1984]. The relationship between category of lesion and prognosis is shown in table 5. Sixteen (94.1%) out of the improved 17 cases showed endolymphatic hydrops, which was also seen in 3 fluctuating and 9 unchanged cases. No improved cases were observed in hair cell damage, which was present in 4 fluctuating and 6 unchanged cases. In the neural damage patients, there was 1 case of each type. In table 6, the mean values and standard deviations (SD) of the ECoG data for each prognosis in endolymphatic hydrops are compared with normal values. The improved cases showed a significantly prolonged AP latency ( ms) and deteriorated CM detection threshold ( dbnhl at 0.5 khz). The fluctuating cases revealed an even more prolonged AP latency ( ms), low AP amplitude ( μv), high SP/AP ratio Electrocochleography 13

21 Table 6. Means and standard deviations of ECoG data in endolymphatic hydrops Normal Improved Unchanged Fluctuating AP latency, ms AP amplitude, μv SP amlitude, μv SP/AP khz CM threshold, dbnhl khz CM ammplitude, μv p=0.10. ( %) and deteriorated CM detection threshold ( dbnhl). The unchanged cases showed not only results similar to the fluctuating cases but also a much lower CM amplitude ( μv at 0.5 khz). The mean input-output values of AP amplitude show a recruitment-like curve with the L-part and H-part [Kumagami and Osawa 1984] in the improved cases and a significantly low amplitude in the poor-prognosis cases (fig. 8a). The mean input-output values of SP amplitude indicate no significant differences among the prognostic groups, but those in the improved category show slightly higher amplitudes at 80 and 90 db than those in the other two categories (fig. 8b). Illustrative Cases Case 1: Endolymphatic hydrops with improvement (fig. 9). A 22-year-old female complained of fullness in the right ear. Her pure-tone audiogram on the 2nd day after the onset showed a mean loss of 37.5 db in the low frequencies accompanied by a slight loss in the high frequenies (fig. 9a). An ECoG on this day demonstrated a normal AP latency, favorable AP and SP amplitude (112.4 and 25.2 μv at 90 dbnhl, respectively), normal SP/AP ratio (22.4%), normal CM detection threshold, and satisfactory CM amplitude (90 μv at 90 dbnhl of 0.5 khz) (fig. 9b). She recovered completely on the 3rd day (fig. 9c). Case 2: Endolymphatic hydrops without change (fig. 10). A 48-year-old female had complained of tinnitus in the right ear for 7 months. Her pure-tone audiogram showed a mean of 45 db in the middle and low frequencies (fig. 10a). ECoG demonstrated a normal AP latency, favorable AP and SP amplitude (39.5 and 24.1 μv at 90 dbnhl, respectively), high SP/AP ratio (61%), and satisfactory CM amplitude (56 and 110 μv at 90 dbnhl of 0.5 and 1 khz, respectively), but revealed approximately the same CM detection threshold at PTAT in the range of the middle and low frequencies (fig. 10b). No improvement or fluctuation of LFSHL was observed until 2 years post onset. Kumagami/Nakata/Hirano/Tsukazaki 14

22 Fig. 8. Relationships between stimulus intensity (input) and amplitudes of the AP and SP (outputs) in the three prognostic groups. a Mean input-output functions for AP amplitude. Note recruitment-positive curves with the L-part and H-part in the improved cases. b Mean input-output values of SP amplitude. There were no significant differences among prognostic groups, but those in the improved cases show slightly higher amplitude at 80 or 90 dbnhl. Case 3: Endolymphatic hydrops with fluctuation (fig. 11). A 56-year-old male was first examined on the 10th day after the onset of tinnitus and hearing loss in the right ear. The pure-tone audiogram showed a mean loss of 60 db in the range of the middle and low frequencies with 4,000-Hz dip (fig. 11a). The ECoG findings on the same day were as follows: AP showed a prolonged latency (1.20 ms) and slightly decreased amplitude (45 μv at 90 dbnhl). SP manifested a normal SP amplitude (18.8 μv) and a high SP/AP ratio (41.8%). The CM response was satisfactory with a lower threshold (40 dbnhl at 0.5 or 1 khz) than the audiometric threshold and sufficient amplitude (almost 68 μv at 90 dbnhl of 0.5 or 1 khz) (fig. 11b). Despite these hydropic findings, the hearing loss showed no improvement but fluctuated and became worse with vertigo after 8 years (fig. 11c). Case 4: Unchanged after hair cell damage (fig. 12). A 42-year-old female was first examined on the 10th day after the onset of tinnitus and fullness in the left ear. She showed a mean loss of 50 db in the low-frequency of the pure-tone audiogram (fig. 12a). ECoG findings on the same were as follows: AP indicated a normal latency (1.02 ms) and favorable amplitude (55.2 μv at 90 dbnhl), a small SP amplitude (9 μv). The SP/AP ratio was 16%. CM revealed the same detection threshold as the audiometric threshold and a low amplitude (about 24 μv at 90 dbnhl of 0.5 or 1 khz) (fig 12b). Neither recovery nor fluctuation was observed over a 1-year period. Electrocochleography 15

23 Fig. 9. Audiometric and ECoG findings in a 22-year-old female with endolymphatic hydrops on the 2nd day after onset. a Pure-tone audiogram. b ECoG findings on this day. c Complete recovery of the pure-tone audiogram on the 3rd day. Discussion It is generally supposed that the prognosis in acute LFSHL is favorable. In our clinical study, however, only 17 (41.5%) out of 41 cases of acute LFSHL showed an excellent (improved) prognosis and 24 (58.5%) showed a poor (fluctuated or unchanged) prognosis. These results, which might be due to an immediate recovery in many cases of LFSHL before ECoG examination, show that we should not automatically assume that the prognosis in LFSHL is necessarily going to be excellent. Consequently, it is extremely important to attempt to estimate the prognosis of LFSHL in the individual patient, particularly at the initial stage of the disease. Apparently, cases involving hair cell damage reflect the poorest prognosis (e.g. case 4). Kumagami/Nakata/Hirano/Tsukazaki 16

24 Fig. 10. Audiometric and ECoG findings in a 48-year-old female with endolymphatic hydrops in the 7th month after onset. No improvement was observed until 2 years after onset. a Pure-tone audiogram. b ECoG findings. Approximately 90% of improved cases showed evidence of endolymphatic hydrops. However, hydropic lesions were also present in fluctuating or unchanged cases. Comparison of the ECoG findings for each prognosis in endolymphatic hydrops with those of normal hearing cases suggests the following: In improved cases there may be hydropic lesion without hair cell damage as shown in type I Ménière s disease [Kumagami et al., 1982]. On the other hand, patients with a poor prognosis might be thought to have a hydropic lesion with moderate hair cell damage as shown in type II-III Ménière s disease [Kumagami and Miyazaki, 1983]. In neural damage, we are unable to relate any particular ECoG findings to prognosis because of the small number of cases. In summary, the prognosis in patients with LFSHL may be estimated at the initial stage of the onset by ECoG, as revealed by lower CM threshold Electrocochleography 17

25 Fig. 11. Audiometric and ECoG findings in a 56-year-old male with endolymphatic hydrops. a Pure-tone audiogram on the 10th day after onset. b ECoG findings on this day. c Pure-tone audiogram 8 years later. than audiometric threshold, satisfactory CM and SP amplitude, recruitmentlike AP response with a slightly prolonged latency, and nearly normal SP/ AP ratio. The cause of LFSHL may be either a blood flow disturbance, viral infection, or endolymphatic hydrops [Tonndorf, 1976]. In our ECoG study, 62.3% of LFSHL patients showed endolymphatic hydrops, which may also damage hair cells. The fact that almost all of the improved cases showed a prompt recovery within 1 week is consistent with the view that endolymphatic hydrops may develop due to the rapid production of endolymph at the stria vascularis, and promptly resolve due to the reabsorption at the endolymphatic sac. With respect to possible hormonal influence on LFSHL, it is interesting to note that 50% of the improved cases were seen in females in the age decade Kumagami/Nakata/Hirano/Tsukazaki 18

26 Fig. 12. Audiometric and ECoG findings in a 42-year-old female with hair cell damage. a Pure-tone audiogram on the 10th day after onset. No improvement was observed throughout the next year. b ECoG findings on the 10th day after onset years and 34% of the cases of poor prognosis were in males in the age decade of years. Andrews et al. [1992] reported that the symptoms of endolymphatic hydrops (Ménière s disease) might be exacerbated in females during the premenstrual period. Conclusion To conclude: (1) An abnormally broad AP/SP complex wave is not specific to retrocochlear disorders. It was observed in both inner ear deafness and retrocochlear deafness. (2) An abnormally broad wave is not observed in cases of CP angle tumor that show a typical pattern of retrocochlear deafness. (3) The dissociated type appears to show an abnormally broad wave since responses in the normal low-frequency region contribute to the response even though hair Electrocochleography 19

27 cell damage was profound in the high-frequency region. (4) The most important factor contributing to an abnormally broad wave is profound hair cell damage in the high-frequency region. (5) Finally, the prognosis in patients with acute low-frequency sensorineural hearing loss may be estimated at the initial stage by ECoG. References Abe T, Tuiki T: Progressing cases from low-tone sudden deafness to Ménière s disease. Otolaryngology (Jpn) 1992;95: Andrews JC, Gregory AA, Vincente H: The exacerbation of symptoms in Ménière s disease during the premenstrual period. Arch Otolaryngol Head Neck Surg 1992;118: Eggermont JJ, Don M, Brackmann DE: Electrocochleography and auditory brainstem electric responses in patients with pontine angle tumors. Ann Otol Rhinol Laryngol Suppl 1980;75:1 19. Eggermont JJ, Odenthal DW: Methods in electrocochleography. Acta Otolaryngol 1974;316: Gibson WPR, Beagley HA: Electrocochleography in the diagnosis of acoustic neurinoma. J Laryngol Otol 1976;90: Konigsmark BW, Mengel M, Berlin CT: Familial low-frequency hearing loss. Laryngoscope 1971;81: Kumagami H: Sensorineural deafness and electrocochleography. Otol Fukuoka (Jpn) 1984;30: Kumagami H, Miyazaki M: Chronological changes of electrocochleogram in experimental endolymphatic hydrops. ORL 1983;45: Kumagami H, Nishida H, Baba H: Electrocochleographic study of Ménière s disease. Arch Otolaryngol 1982;108: Kumagami H, Osawa H: Electrocochleographic studies of recruitment phenomenon. Auris Nasus Larynx (Tokyo) 1984;11: Portmann M, Aran JM: Relations entre (Pattern) électrocochléographique et pathologie rétro-labyrinthique. Acta Otolargyngol 1972;73: Tonndorf J: Endolymphatic hydrops: Mechanical causes of hearing loss. Arch Otorhinolaryngol 1976; 211: Williams HL, Horton BT, Day LA: Endolymphatic hydrops without vertigo. Arch Otolaryngol 1950;51: H. Kumagami, Department of Otolaryngology, School of Medicine, Nagasaki University, 7-1 Sakamoto 1-Chome, Nagasaki 852 (Japan) Kumagami/Nakata/Hirano/Tsukazaki 20

28 Alford BR, Jerger J, Jenkins HA (eds): Electrophysiologic Evaluation in Otolaryngology. Adv Otorhinolaryngol. Basel, Karger, 1997, vol 53, pp Auditory Brainstem Response: Recent Developments in Recording and Analysis James W. Hall III, Katheryn A. Rupp Division of Hearing and Speech Sciences and Department of Otolaryngology, School of Medicine, Vanderbilt University, Nashville, Tenn., USA Since the auditory brainstem response (ABR) was first described by Jewett and Williston [1] a quarter of a century ago, its clinical utility has been widely recognized. In many clinics, ABR measurement has become a routine part of a battery of tests for evaluating peripheral auditory sensitivity, as well as the neural integrity of the auditory CNS. ABR measurement is useful with varied populations, including individuals unable to respond reliably during behavioral audiometry, those with nonorganic hearing loss, patients posing a masking dilemma due to severe bilateral conductive hearing loss, individuals suspect for Ménière s syndrome, and patients undergoing evaluation to rule out retrocochlear pathology [2]. During the first two decades following Jewett and Williston s description of the ABR, clinical procedures and guidelines for recording valid and reliable ABRs were developed. With the recent advances in computer technology impacting commercially available equipment, current ABR measurement strategies are focused on the development of new techniques to (1) decrease the time in which it takes to record the response, (2) enhance the quality of the response, and (3) increase the objectivity of the test, through improved signalto-noise ratio (SNR) averaging methods. The purpose of this chapter is to introduce the clinician to recent major developments in ABR stimulation and analysis techniques, to review their clinical utility, and provide the clinician with guidelines for implementing these strategies into their routine ABR test protocol.

29 Minimizing Test Time While the ABR is an invaluable clinical tool for objectively assessing the status of the peripheral and brainstem auditory pathways, one restriction to using this measure extensively in daily clinical practice is the time required for reliably recording and confidently interpreting responses from most patients. Because the ABR is a small amplitude response embedded in a background of larger amplitude EEG activity (noise), averaging techniques must be used to tease out the response from the ongoing background noise. In particularly nervous or tense individuals, electromyogenic (EMG), or muscle, potentials can obscure the response as well. Thus, in daily clinical practice, obtaining an ABR usually requires averaging anywhere from several hundred to several thousand stimulus sweeps. A sweep in this sense refers to a stimulus-response pair. For example, as with any transient response, the ABR is elicited by a single stimulus presentation and the response, along with the corresponding noise, is recorded before the next stimulus is presented. As responses to sequential stimuli are averaged together, the random activity (noise) eventually approaches an average amplitude of zero, allowing the ABR (the signal) to emerge from the noise. The transient nature of the response, as just described, also adds to the ABR test time. Because only one response is recorded at a time, and because a single response occurs over a time period of approximately ms, the maximum rate at which the stimulus can be presented without the responses overlapping is around /s. However, stimulus rates higher than about 20/s have been shown to affect the latency and amplitude of the ABR [1, 3]. Thus, in clinical measurement, slower stimulus rates are typically used. The slower the rate, however, the longer ABR recording will take. It seems, then, that in order to minimize the time it takes to record the ABR, either the SNR must be improved or a method must be implemented so that the rate of stimulus presentation can be increased. Maximum Length Sequences and Chained Stimuli In 1982, a method for decreasing ABR test time through increased repetition rate was proposed by Eysholdt and Schreiner [4]. The authors described a stimulus presentation paradigm called maximum length sequences (MLS), whereby a binary sequence of pulses, occurring at pseudorandom time intervals, is presented to the ear and the application of appropriate computations allows the ABR to be extracted from the resulting responses [4]. At this point, you may be asking yourself, What does all that mean?. For the more advanced Hall/Rupp 22

30 Fig. 1. An example of an MLS stimulus of length 7. Upward pointing lines indicate click events, while downward pointing lines are no-click events in the series. The resulting waveforms corresponding to each event are shown in the bottom tracing (see text). [Adapted from 7.] scientist and mathematician, several mathematical models and theories behind the use of MLS are presented elsewhere [4 6]. A basic description and explanation of the MLS procedure will be attempted here. The Stimulus An example of an MLS stimulus is depicted in figure 1. Basically, an MSL is a type of stimulus that is made up of a series of binary events. Binary meaning that each event in the series has only one of two possible values (i.e., click or no-click). The series is a specified length (L) equal to 2 n Ö1, where n is an integer, often referred to as the order of the sequence [6, 7]. For example, an MLS of order 3 would yield a series length of 2 3 Ö1>7 events. The number of events in the sequence that trigger a stimulus pulse, or click, is determined by the equation (L+1)/2. In our example, (7+1)/2>4. Thus, our series would consist of 4 clicks and the other 3 events would be no-clicks, or silences. The events are placed in a pseudorandom order with a fixed interval between them. An important point to remember with MLS is that the series, as shown in figure 1, constitutes only one stimulus of the MLS technique. In practice, many stimuli (series) are presented in sequence, with no break between subsequent stimuli. MLS Response Analysis For analysis purposes, a cross-correlation of the responses obtained from each stimulus is performed such that activity that is common to the tracings will be added and activity that is not will be subtracted. The result is a disentangling of the overlapping waveforms [6]. As a simplified example, the averaging technique used to analyze the MLS-ABR using an MLS of length 7 is shown in figure 2. This figure, as well as figure 3, is based on an MLS Auditory Brainstem Response 23

31 Fig. 2. An MLS-ABR analysis. From the two MLS stimuli (top tracing), 7 subaverages are recorded which correspond to the 7 events (steps) in the MLS stimulus. Each subaverage, after the first, is shifted so that the response to that particular step occurs first and the previous waveforms wrap around to the end of the tracing. [Adapted from 7.] Fig. 3. Continuation of the MLS-ABR analysis. The 7 subaverages from figure 2 are shown here, aligned. The traces to be added are outlined in bold and are seen as vertexpositive waves. The traces not beginning with a response to a click are subtracted (shown here as inverted). Addition of the traces results in a recording of the bottom tracing (total). Because every interval, after the first, contains 2 positive and 2 negative waveforms which cancel each other out, only the response in the first interval is enhanced. [Adapted from 7.] Hall/Rupp 24

32 analysis example depicted by Marsh [7]. Two consecutive MLS stimuli series are shown at the top of the figure and 7 sub-averages of the response, corresponding to the 7 events in the stimulus, are depicted beneath. Tracing 1 is the response to the whole MLS series, beginning with the first event (a click) in the MLS stimulus. The next tracing is the response to the series beginning with the second event in the MLS stimulus, another click. The third and subsequent tracings are identical to the first two, but the traces always begin with the response to the event in the series corresponding to the sweep number. Thus, each waveform, although identical to the first, is shifted by one interval more than the tracing immediately before it. Further, the tracings show a circular shift, such that the part of the waveform that was once at the beginning of the sweep has wrapped around and is now at the end of the sweep. Now that we have one original tracing and 6 shifted versions of the original, the 7 waveforms are either added to or subtracted from each other. All the tracings beginning with a response to a click [1 3, 6] are added. If the tracing does not begin with a response to a click, then it is subtracted. This portion of the analysis is easily understood if the responses are aligned, as in figure 3. The traces to be added are outlined in bold and are seen as upward-going positive waveforms. The traces that will be subtracted are inverted. We can see that the waveforms in the first interval all correlate, therefore, they are added together and the response is enhanced. In all of the other intervals, two positive (those beginning with a click response) and two inverted traces (those beginning with a no-click response) cancel each other out. Thus, the resulting waveform is the total, shown in the bottom trace. From this example, we can see that, in the same time period required to record one response (waveform) with conventional ABR, we have collected and averaged 4 waveforms with the MLS-ABR technique. Although this is a simple example of an MLS of length 7, the same rules apply to MLSs of longer lengths as well [7]. Clinical Utility of Rapid Stimulation Because the number of clicks that can be presented within a particular time period using MLS is significantly higher than conventional ABR rates, MLS shows promise as a clinical tool for recording ABR, particularly in situations where time is limited (i.e., newborn and pediatric assessment). In fact, Thornton and Slaven [8] demonstrated that the ABR could be obtained with MLS using maximum stimulus rates of up to 1,000 clicks/s! However, as in conventional ABR averaging techniques, higher stimulus rates with MLS increase wave V latency, and considerably reduce waveform morphology and amplitude [4, 6 8]. Presumably, this would mean that the SNR is compromised with MLS, requiring more averaging. This, indeed, has been confirmed [6 8]. When higher stimulus rates are used, adaptation occurs in the auditory system Auditory Brainstem Response 25

33 A 4 and response amplitudes are decreased. In fact, Thornton and Slaven [8] observed greater than 90% adaptation, as measured by wave V amplitude, when stimulus rates were increased from 9.1 to 1,000 clicks/s. The results of several studies, however, suggest that the most efficient MLS paradigms, ones in which the SNR is not significantly affected, include maximum stimulus rates of between 70 and 500 clicks/s [4, 8]. Further, Thornton and Slaven [8] reported that a maximum rate of 200/s requires less time to achieve a SNR comparable to conventional ABR recorded at a stimulus rate of 10/s. The advantages of using this MLS rate may be more prevalent when compared to higher conventional ABR stimulus rates, such as 20 or 30/s. Figure 4 shows a comparison of a conventionally recorded ABR intensity series using 21.1 clicks/s and two MLS-ABR intensity series using click rates of and 1,000/s. While the time window of the conventional ABR recording is 15 ms, versus the 24 ms time window of the MLS recordings, the sensitivity scale of all recordings are the same. The decrease in ABR Hall/Rupp 26

34 B C Fig. 4. Comparison of a conventional ABR intensity series and two MLS intensity series for the left ear of an adult female with no known otologic or audiologic pathology: A conventional ABR intensity series using a stimulus rate of 21.1 clicks/s and a time window of 15 ms; B MLS-ABR intensity series using a click rate of 500.1/s in a 24-ms time window; C MLS-ABR intensity series using a click rate of 1,000/s in a 24-ms time window. Each recording was made with a fixed sensitivity of 0.16 μv/ division. Auditory Brainstem Response 27

35 amplitude with increasing stimulus rate is easily observed from this figure. In fact, at a stimulus rate of 1,000 clicks/s, ABR wave V is identified at an intensity 10 db greater than the other, lower, click rates. This illustrates well the findings of Thornton and Slaven [8]. Thus, an MLS stimulus rate of 500 clicks/s or less is recommended. While the increase in wave V latency, and the subsequent decrease in ABR waveform morphology, that occurs with MLS would seem to preclude its use in neurodiagnostic testing, the MLS technique may be useful in conducting rate studies with patients suspected of having retrocochlear pathology. Stressing the auditory system with high rate MLS-ABR and comparing the resulting waveform with ABR results recorded at slower rates may increase the sensitivity of ABR in neurodiagnosis [9]. In addition, because wave V may be identified at very high stimulus rates used in MLS recording, the MLS technique may be particularly advantageous for determining ABR threshold in difficult-totest populations, where time is often limited [6 8, 10 12]. Maximum length sequence-intensity functions, like that shown in figure 4, have been reported by several groups using click and tonal stimuli [6, 12]. Lasky et al. [12] reported that MLS-ABR thresholds for adults and newborns, using click stimuli, were similar, yet slightly elevated, when compared to their conventional ABR threshold counterparts. The authors noted that the small ISI used in the MLS recordings (1.1 ms) may have compromised the identifiability of wave V at lower intensity levels due to the poorer SNR. Wider intervals between successive clicks may enable identification of wave V at levels corresponding to conventional ABR threshold intensities. Indeed, Hamill et al. [10, 11] used a stimulus paradigm similar to MLS to study intensity functions in adults. This group used a chained-stimulus technique, which includes a series of clicks separated by equal intervals (versus the pseudorandom intervals of MLS) of 12 ms. No silent (no-click) events are used in this paradigm. Each successive click in the series differs in intensity from the previous one by 10 or 20 db, and the responses to each stimulus are stored in separate buffers for each intensity; A buffers for odd numbered sweeps and B buffers for even numbered sweeps. The responses stored in buffer A may then be statistically compared to the responses in buffer B for objective analysis of response presence or absence. Figure 5 contains an example of a chained-stimulus used in ABR threshold estimation. In their studies with normally hearing and hearing-impaired adults, Hamill et al. [10, 11] reported that thresholds using the chained-stimuli were essentially equivalent to thresholds obtained using conventional ABR. In addition, the authors noted that responses obtained with the chained-stimulus technique were collected in a minimal amount of time; approximately 8 min per ear. Thus, the advantages of using this technique for rapid threshold estimation are clear. Hall/Rupp 28

36 Fig. 5. Example of a chained-stimuli paradigm used to record threshold ABR responses. Up to 20 buffers are used to store waveforms for each event in the series. A buffers are used to store odd-numbered sweeps, while B buffers contain even-numbered sweeps. [From Intelligent Hearing Systems, 1995, pers. commun., reprinted by permission.] While threshold estimation using click stimuli is a useful and popular technique currently used in the audiology clinic, this measure primarily reflects hearing sensitivity in the 2,000- to 4,000-Hz region. Thus, hearing loss at lower or higher frequencies may go undetected. In many clinics, a commonly used adjunct to the click threshold ABR is the use of short duration tonal stimuli to obtain frequency-specific information. This can also become time-consuming, unless chained-stimuli of MLS is used. Using a minimum ISI of 13 ms, Picton et al. [6] recorded frequencyspecific MLS-ABR using 500- and 2,000-Hz tonepips. The authors were able to obtain MLS-ABR for the 2,000-Hz tonepips at levels 10 db above behavioral threshold. The 500-Hz MLS-ABR thresholds were recorded at levels 25 db above behavioral threshold [6]. These findings are consistent with conventional tone-burst ABR reports [13]. Thus, because the same information can be obtained by using the faster rate MLS with tone-burst stimuli versus conventional ABR, the advantage of the MLS technique is obvious. Namely, the time required to obtain frequencyspecific information is significantly reduced. Even faster rates may be applied to higher frequency stimuli [6]. It should be noted, however, that the longer duration required to produce lower frequency tonepips (10 ms for 500 Hz of cycles, recommended by Davis et al. [14]) will not allow rapid stimulation rates for low-frequency MLS using an ISI of less than 10 ms. If time is the main factor in obtaining frequency-specific ABR thresholds, then use of click stimuli in combination with a high-pass masking noise may be used. This technique, the derived response, has been described for conventional ABR use Auditory Brainstem Response 29

37 Fig. 6. Example of a TOPSTIM stimulus series. Each successive pulse in the sequence is a different frequency, but of equal intensity. [From 16, by permission.] [15] and may be the most efficient means by which frequency-specific ABR can be obtained using MLS [6]. A similar technique using tone-burst stimuli in a chained-stimuli paradigm was described by Hoke et al. [16]. This group recorded threshold ABRs to tone-burst stimuli in conjunction with a gliding high-pass masker at levels down to within 20 db of behavioral thresholds. They referred to this technique as TOPSTIM (tone-pulse series stimulation) with GHINOMA (gliding highpass noise masking). While the chained-stimulus described previously consists of a series of equal-frequency stimuli at different intensities, the TOPSTIM technique employs a series of different frequency stimuli at equal intensities [16]. An example of the TOPSTIM stimulus series is shown in figure 6. The possible advantages of the MLS and chained-stimuli techniques are obvious and undisputed. As time is a major factor in auditory assessment of newborns and young children, use of these two techniques may prove to be substantially beneficial in the audiology clinic. Initially, the limited availability of commercial equipment having the ability to record ABR using these techniques precluded their use in the clinic. In fact, many of the studies mentioned in this review were conducted with the use of laboratory, or specially designed, computer equipment. Currently, however, several commercially available clinical systems incorporate software which allow these techniques to be used. These systems are listed in table 1. In addition to monaural MLS and chainedstimuli techniques, several systems also allow simultaneous binaural stimulation using these methods. Stimulation of both ears simultaneously can literally cut evaluation time in half. Simultaneous Binaural Stimulation In 1993, Marsh [17] reported that recording conventional ABRs from both ears simultaneously, without contamination from the opposite ear, is possible if slightly different stimulus rates are used for each ear. Comparing simultaneous binaural stimulation ABRs to monaurally recorded responses Hall/Rupp 30

38 Table 1. A listing of the advanced ABR techniques reviewed in this chapter and the commercially available systems which employ them Technique Commercially available systems Bio-Logic Intelligent Natus Nicolet Systems Hearing Medical Instrument Corp. Systems Inc. Corp. Maximum length Spirit sequences Chained-stimuli Smart Screener Simultaneous binaural Algo-2 Spirit stimulation 40-Hz SSR Traveler Express; SmartEp Spirit; Pathfinder Navigator; Viking; Compass; Explorer C-series 80-Hz AMFR SmartEp Viking Family F sp Spirit Response correlation Traveler Express; Smart Screener; Spirit Navigator; SmartEp Explorer Template matching Algo-1; Algo-2 in adult subjects with normal hearing, the author observed no significant differences in wave V mean amplitudes or latencies. The author did note, however, that when the stimulus intensities to each ear were very different during binaural stimulation (i.e., 80 dbnhl for the right ear and 40 dbnhl for the left ear), wave V latencies were slightly, yet significantly, prolonged. This was the only difference noted in the report, thus the conclusion was made that concurrent testing may be a valuable clinical technique as long as the stimulus intensities between the two ears is not too dissimilar [17]. In fact, this technique is used for infant hearing screening with ABR, and is available on the Algo-2, an FDA-approved, clinical ABR screening device. In much the same way as recording simultaneous binaural conventional ABRs, simultaneous binaural MLS-ABRs may be recorded. That is, MLS- ABRs may be recorded concurrently by applying either two separate MLS stimuli series to each ear, or by using the same MLS stimulus series for both ears, but shifting one ear s stimulus presentation in time relative to the other ear s stimulus presentation. In this way, the cross-correlation rule used to analyze the response is dissimilar for the two ears and will only serve to extract Auditory Brainstem Response 31

39 the response from the ear in which the stimulus generation rule matches. The response from the contralateral ear, then, is seen as random activity and becomes averaged out with the background noise. Using this MLS-ABR technique, Lasky et al. [18] obtained very similar results to those reported by Marsh [17] for binaural stimulation using conventional ABR techniques. Recording monaural and binaural MLS-ABRs from normal hearing adult subjects, Lasky et al. [18] observed no significant differences between the types of recordings for suprathreshold or threshold level stimuli. The only differences noted in their report were those between conventional monaural ABR and both types of MLS-ABR latency intensity and amplitude intensity functions, which would be expected. That is, conventional ABR latency intensity and amplitude intensity functions are steeper than MLS-ABR functions. Thus, using MLS to record monaural or simultaneous binaural ABRs will not yield significantly different results from each other, but will differ from conventional ABR recordings in the expected ways mentioned previously. Further, simultaneous binaural stimulation with MLS will significantly reduce test time, which will be appealing to any clinician. Limitations of MLS and Chained-Stimuli These techniques, while having advantages, do not come without their disadvantages as well. Picton et al. [6] noted several disadvantages of the MLS technique which may also be true for the chained-stimuli technique, including (1) the large memory requirement for response cross-correlation over a large number of sequences, especially for multiple channel recordings, (2) that more stimuli may need to be averaged in the presence of even a few artifacts. That is, any briefly occurring artifact can cause an entire stimulus sequence to be discarded. Thus, more averaging may be needed to obtain an adequate amount of sweeps. The amount of artifacts is especially detrimental for longer length stimuli, and (3) responses obtained with these techniques contain more noise than responses obtained with conventional ABR. Nevertheless, once the limitations of these methods are realized, the clinician may be able to successfully overcome them. In fact, the clinician is encouraged to keep in mind two points when using MLS. First, when attempting to record an ABR with MLS, the high stimulus rate will be perceived by the patient as being much louder than the intensity dial reading would suggest. Thus, lower intensities (=90 dbnhl) should be used to eliminate any discomfort to the patient. Second, because wave V is shifted out during testing with MLS, latency comparisons to conventional ABR norms will be ineffective. Each clinic should establish its own normative data, as well as its own measurement parameters. This will be especially important for threshold estimation with MLS versus chained-stimuli, as MLS data will not fit into existing latency intensity functions. Hall/Rupp 32

40 Steady-State Evoked Responses Another method proposed for rapid and objective assessment of hearing using auditory evoked responses includes recording steady-state evoked response, or just steady-state responses (SSR). As opposed to the conventional ABR, which is a transient response, SSR are elicited by stimuli occurring in rapid succession so that the recorded responses overlap in time with a periodicity characteristic of the rate at which the stimuli are presented. SSRs actually include components that do not fall within the anatomic or temporal constraints of the conventional ABR. These responses are different than MLS- ABR or chained-stimuli responses because they represent neural discharge which is phase-locked, versus time-locked to the stimulus. That is, the responses are analyzed according to the number of repeated cycles occurring in a particular time window (their frequency), rather than the latency of particular peaks in the waveform occurring in that time window. Also, they do not require the responses to be disentangled before analysis. The 40-Hz SSR Probably the most widely recognized SSR is the 40-Hz response, first introduced by Galambos et al. [19]. The 40-Hz response is elicited by a toneburst or click stimulus occurring every 25 ms (40/s), and is comprised of a series of peaks which are observed in the time domain every 25 ms. This corresponds to 40 Hz in the frequency domain. Thus, in a 100-ms analysis time window, about 4 cycles of the response can be observed. Clinical Utility: Several features of the 40-Hz response would seemingly make it an excellent evoked response for measurement of auditory sensitivity in difficult-to-test populations. The amplitude of the response is large (usually 1.0 μv or more) so that it is easily identified without much averaging, and it can be identified at stimulus levels close to auditory threshold. In addition, the use of tone-burst stimuli allows the tester to acquire frequency specific information in a timely fashion. Although this evoked response has many attractive features, several groups have discovered some major limitations of the response which preclude its usefulness with several populations for whom this measurement would seem ideal. Limitations: While the 40-Hz response is robust in awake adults, its amplitude decreases significantly in sleeping subjects [19, 20]. Furthermore, it is difficult to record the 40-Hz response in newborns and young children [21 23]. Thus, the clinical utility of this measure in the populations for which it would be most useful (individuals unable to respond during behavioral audiometry) is severely limited. Auditory Brainstem Response 33

41 The 80-Hz SSR The auditory SSR can be recorded using higher stimulus rates, with the focus on tonal stimuli in order to obtain frequency-specific data [24 26]. The use of sinusoidally amplitude-modulated (SAM) tones to elicit the SSR provides more frequency-specific information than conventional ABR toneburst stimuli due to their narrower power spectrum. From figure 7, it is clear that the SAM tone contains considerably less energy at frequencies below the center tone frequency than the conventional tonal stimulus using Blackman windowing. In addition, the response to the SAM tone is observed to follow the frequency of modulation. Thus, the response was named the amplitudemodulation following response (AMFR) [27]. The Stimulus: A SAM tone is produced by mixing two sine waves, each generated separately. One of the inputs is called the carrier frequency, or tone, and is set at the audiometric frequency the tester wishes to evaluate. The other input is the modulation frequency (MF), which is usually set at a low frequency (=200 Hz). When the two inputs are mixed, the amplitude of the carrier tone will fluctuate at the rate of the MF (i.e., an MF of 50 Hz will cause the amplitude of a 1,000-Hz carrier tone to fluctuate 50 times/s). The response elicited by the SAM tone stimulus reflects synchronous firing of auditory neurons phase-locked to the modulation frequency [27]. Presence or absence of the 80-Hz AMFR is automatically and objectively determined by phase spectral analysis. This analysis measure employs FFT analysis to determine the frequency of the response, and the power of the response (the signal versus the noise) is statistically determined by calculating the component synchrony measure (CSM), indicating the amount of phase variance in the Fourier component [28]. Clinical Utility: In a systematic study to find the optimal MF for recording the response in young children, Aoyagi et al. [26] found that MFs of Hz, with a modulation depth of 95%, elicited a response close to auditory threshold in young children during sleep. Furthermore, using a SAM tone stimulus, threshold estimation was more accurate than threshold estimation by ABR using toneburst stimuli [28]. In fact, Aoyagi et al. [29] were able to measure 80-Hz AMFR thresholds for 1,000-Hz SAM tones at levels 10 db lower than conventional ABR thresholds. Thresholds for adults using this same stimulus, however, were considerably higher than conventional ABR threshold measures. Although the reasons for this finding were not clearly stated, the authors recommended restricting the use of 80-Hz AMFR testing to newborns and children up to their middle teenage years. The authors suggested that lower modulation frequencies, such as 40 Hz or less, were more appropriate for estimating threshold levels of adults. Further investigation of the clinical feasibility and value of the 80-Hz AMFR technique in pediatric and adult patient populations is warranted. Hall/Rupp 34

42 A B C D Fig. 7. Comparison of a conventional ABR tone-burst and a SAM tone both centered at 500 Hz. A and B illustrate the spectral content of the two stimuli. Note that the SAM tone spectrum contains 3 closely spaced energy peaks. The peak in the middle corresponds to the carrier tone (the frequency of interest) and the 2 side peaks are comprised of the carrier plus modulation (MF>80 Hz) tones. In C and D the tonal stimuli have been measured through an insert earphone (ER-3A). It is easy to see that the SAM tone contains less energy below the center frequency than the conventional ABR 500-Hz tone-burst. At higher modulation frequencies (?80 Hz), the 2 side peaks separate from the carrier tone peak, reducing the frequency specificity of the stimulus. Auditory Brainstem Response 35

43 Limitations: While the AMFR may be clinically useful for estimating thresholds of newborns and young children, the development of commercially available equipment and software designed to create the SAM tone stimuli has been slow. Thus, the AMFR is not widely used. Development of software to interface with clinical ABR hardware is currently underway and should be available for use in the very near future, according to Intelligent Hearing Systems engineers. Enhancing Response Quality and Increasing Test Objectivity through Improved Signal-to-Noise Ratio Calculations Once ABR recording is underway, continuous visual evaluation of the waveforms is required in order to determine the presence or absence of a response. While ABR recording is objective, in contrast to behavioral measures of hearing, response identification and analysis typically requires clinical judgement. Confident response interpretation by the clinician is dependent on the stability of the response (signal) and the amount of random activity (noise) in the tracings. With poorer SNR, the clinician usually needs to average more sweeps to visually detect the response. Increased signal averaging will reduce the background noise, permitting ABR identification, but it will also lengthen the time required to record the response. In short, the determination of ABR presence or absence is highly dependent on the SNR. Recently developed techniques may facilitate objective evaluation of response quality and adequacy of the SNR. Plus/Minus Signal-to-Noise Measurement Technique One objective way to determine the amount of noise that is present in the ABR recording involves averaging the odd numbered stimuli and the even numbered stimuli separately, so that two waveforms are generated. One waveform is then subtracted from the other. This is commonly referred to as the plus/minus ( ) technique. The subtraction of the waveforms will effectively cancel any activity that is stable in the two recordings (the response), while relatively random activity (noise) will not be completely cancelled. Thus, the resulting waveform is a representation of the noise present in the recording. A SNR is then calculated by dividing the variance of the response by the variance of the reference [30]. Clinical Utility: Current computer technology used in clinical ABR systems allows the clinician to easily obtain a measure of the SNR using the method. Software of this type usually employs two separate buffers into which the odd and even numbered stimuli are separated. Therefore, the clinician can Hall/Rupp 36

44 view the two waves separately, while obtaining a measure of the SNR. These two waveforms can also be overlayed to better verify the presence of a response and its replicability. This would also reduce test time considerably because the response and its replication are collected simultaneously. Also, by using stimuli of alternating polarity, responses to rarefaction stimuli and condensation stimuli may be stored separately into their respective buffers and individually analyzed [31]. There is, therefore, no need for separate recordings of the response for each stimulus polarity to determine which polarity will yield the optimal ABR waveform. The method also increases test objectivity because the clinician determines response presence or absence based on a statistical criterion of the SNR compared to the F distribution. That is, determination of response presence is made once the SNR value exceeds the set criteria. F sp Technique In 1984, Elberling and Don [32] showed the variance of the background noise in an ABR recording could be more reliably estimated by measuring the variance of a single point in the recording over several hundred sweeps. This technique is known as F sp, where F refers to the distribution with which the variance estimates will be compared (the F distribution), and sp corresponds to the single point in the samples that will be measured in order to give us this variance estimate. With an estimate of the variance in the background noise, the amount of averaging needed to detect the ABR can be systematically determined. The detailed mathematical computations and derivation of the formulas used in this technique are presented elsewhere [32] and will not be described here. The basic underlying assumptions of the technique, however, will be explained. The F sp equation used to determine the quality of the response is as follows: VAR (S) F sp > VAR (SP) where VAR (S) is the variance in the evoked response and VAR (SP) is the estimate of the variance in the background noise in the recording. The basis for this equation is the assumption that any single point in the recording contributing to the true ABR neural response will remain at a constant latency and amplitude across many sweeps. Any single point contributing to the background noise, however, will vary from sweep to sweep, as noise is composed of random activity. The measures of variance, the F sp value calculated from the equation, is then compared to the F distribution. With the F table, a statistical criterion is established for the minimum number of averages needed Auditory Brainstem Response 37

45 Fig. 8. Illustration of the amount of averaging (in sweeps) required to reach critical F sp values in quiet and noisy recording conditions as a function of intensity level. It is apparent that as stimulus intensity is increased, less averaging is required to meet the F sp criterion, even in a noisy recording condition. For very low intensity levels, F sp may not reach criterion level, especially in noisy recording conditions. By averaging more responses, however, the quality of the recording (F sp ) is increased. to detect a response within a specific confidence interval of the F distribution (i.e., the 95 or 99% confidence interval), based on the calculated variance estimate, the F sp. Figure 8 illustrates an example of the F sp technique. F sp value is calculated as a function of number of sweeps averaged and stimulus intensity level. From this figure, it is clear that for higher stimulus intensities, less averaging is needed to meet the F sp criterion for response detection (500 sweeps Hall/Rupp 38

46 at 20 dbsl). For lower intensities, however, the smaller response requires more averaging to meet the criteria [33]. The amount of averaging required to reach agivenf sp is, of course, indirectly related to the SNR. Clinical Utility: In instances where a clear and reliable response is obtained, continued averaging is unnecessary. With the F sp measure, clinicians record and replicate a response according to the F sp value measured. That is, instead of always replicating with a constant number of sweeps, averaging is terminated once the same predetermined F sp value is achieved for each record. Applying this technique in quiet recording situations reduces test time substantially. However, probably the most useful feature of F sp is observed in recording situations which are either noisy or where, for other reasons, the visual identification of a response is obscured. At stimulus intensity levels close to threshold, the amplitude of the ABR is reduced considerably. Wave V, often the only detectable component in the response, may be so small in comparison to the background noise that continued averaging will not contribute importantly to visual detection. Or, fluctuations in the noise may be incorrectly interpreted as a response. The statistical calculations of F sp can eliminate the questions of response presence or absence within a specified interval of confidence. Sininger [33] reports that, using a 95% confidence interval with F sp, threshold ABR to click stimuli can be obtained within 10 db of behavioral pure tone averages. In addition, she suggests that evaluation of the number of averages needed to meet F sp criteria may be useful in determining step size decriment during threshold estimation. For example, if F sp criterion is achieved with a relatively small number of averages (i.e. 1,000), then the stimulus is decreased by 20 db. If, on the other hand, F sp criterion is reached only after averaging many sweeps, then the intensity of the stimulus should be decreased by only 10 db [33]. The fact that this method can be applied during data collection (on-line) allows the audiologist to determine threshold in a more efficient and timely manner. Furthermore, F sp effectively increases the objectivity of the test by calculating the variance in the recording, thus allowing the examiner to compare the F sp value to a statistical criterion. Limitations: While F sp may be considered a powerful tool for objective assessment of ABR responses in the time domain [34], most clinical ABR devices do not routinely offer F sp software for response averaging. One system with F sp capabilities is mentioned in table 1. For those ABR systems which do not allow objective response detection through F sp calculations, there are other techniques for objective response analysis. Finally, there are limited guidelines on which F sp criterion, or criteria, are appropriate for response identification, or confirmation, in diverse patient populations under often varying measurement and subject conditions. Auditory Brainstem Response 39

47 Fig. 9. Template used in objective detection of ABR response presence or absence. Nine points in the template are used for comparison with the recorded data points. The data points are heavily weighted toward the latency values of data corresponding to wave V and the large negativity following it. [From 35, by permission.] Template Correlational Analysis Some evoked response systems employ a correlational technique for the objective determination of response presence or absence. This technique is similar to human observation and evaluation of response presence or absence, in that each response is compared to an already determined template of what the response should look like. While the degree of reliability among human observers using this technique is highly dependent on the experience and psychophysical criteria of each examiner, these variables can be reduced by programming the evoked response system to identify the ABR according to the likelihood of obtaining a set of data points sufficiently similar to known data point values. In other words, calculation of the probability that a recording is an actual response, based on the ABR template of traces from many normal subjects, is programmed into the evoked response system. An example of this template analysis is shown in figure 9. Two ABR screening devices employ this method of response analysis, using an algorithm to compare the recorded data to nine selected data points in the ABR template (table 1). The algorithm used in this method of response analysis uses a binomial sampling approach, where sampled data are statistically related to one of two conditions: a response-plus-noise condition or a noise-only condition. From this analysis, a likelihood ratio (the likelihood that the recorded data constitutes an actual response) is calculated [35]. Clinical Utility: Use of a template to objectively determine the presence or absence of a response reportedly decreases test time dramatically, especially in hearing screening with ABR, while maintaining a high level of sensitivity and Hall/Rupp 40

48 specificity [36]. In most cases a single tracing can be recorded and compared to the template. The time savings of this technique, then, are apparent. This technique is currently used in ABR screening with newborns [37]. Another advantage to using this technique for screening purposes is that, because of its objectivity, the clinician is not required to interpret the response or manipulate the equipment. That is, volunteers or technicians with minimal knowledge of ABR concepts can easily record the response. Limitations: While a template correlation technique may be useful in ABR screening of newborns, where peak latencies for a given stimulus intensity are known, this technique is limited in searching for ABR threshold, where wave V peak latency is unpredictable and shifts depending on stimulus intensity, patient age, patient auditory status, and other factors. In routine clinical practice, the number of variables that must be taken into account may preclude the use of a template correlation technique with all patients. Response-Replication Correlation A technique similar to template correlation is the objective analysis of the agreement, or the relationship, between the response and its replication. Ordinarily, the examiner performs this type of assessment visually after replicating the initial recording and overlaying the traces. The examiner then judges whether the responses are alike enough to constitute a response. A more objective measure, however, involves a computerized correlation calculation between the two traces. A correlation coefficient is calculated for the traces, and response presence or absence is determined on the basis of specific criteria. A correlation coefficient of 1.0 indicates a perfect relationship between the responses, while a correlation of 0 indicates that the measured activity in the traces are not related and, thus, does not constitute a response. The criterion for a positive identification of a response is set at a relatively high level of correlation (i.e., r>0.80). While various methods are used by the different manufacturers of ABR systems to calculate the correlation between two waveforms, the basic process is the same. For instance, some software correlates two waveforms based on the descriptive statistics of all the data points in each trace. The differences between the two responses with regard to mean amplitude of the data points included, as well as the variance, are entered into the equation for calculating the correlation between the recorded waveforms [38]. Figure 10 is an example of an ABR printout including the statistical analysis of the recorded waveforms. This recording was made with a quiet, adult individual with normal hearing, at an intensity of 90 dbnhl. The SNR of these traces is very low, contributing to the high correlation between the responses (r>0.94). Auditory Brainstem Response 41

49 Fig. 10. Example of an ABR response replication correlation technique. Responses were recorded on a quiet, adult subject with normal hearing, at 90 dbnhl. Descriptive statistics are calculated for the data points of the 2 waveforms, and a correlation coefficient is calculated based on the statistical differences (see text). [From Naze C, Miller E: Statistical calculation of response replications used in the Nicolet Spirit ABR system; pers. commun., 1995.] Another method for calculating response correlation involves the same underlying principle as that just described, but the time window of data points is broken down into several intervals corresponding to a particular latency region of the ABR. Separate correlations for each latency interval are calculated and the total correlation coefficient is based on an algorithm incorporating the values obtained for each interval. Limitations: With correlational techniques, it is very important to set the appropriate criterion level for determination of response presence versus absence. In order to reach statistical significance for a particular criterion, the Hall/Rupp 42

50 number of observations in the samples collected must be sufficiently high. The common assumption that each data point in the tracing constitutes an independent sample is not altogether correct. In fact, neighboring data points are rarely independent of each other [34] and should not be counted as independent samples. As Dobie [34] clearly points out, error in statistical analysis may arise because the standard deviations of each data point in the recording may not be the same. Because the physiological background noise in ABR recordings is usually made up of generally low frequencies in a relatively narrow band width, the variance in each data point will not be the same over the entire ABR waveform. More variance may be seen in the data points corresponding to the low-frequency components of the response. Thus, we should not assume that there is homogeneity of variance in the statistical measure. In order to reach significance, then, the correlation coefficient must be high. In clinical practice, however, high correlations are difficult to obtain with certain patients who may be nervous or restless, leading to increasing amounts of noise in the response. Noise variations from one trace to the next may effectively lower the correlation coefficient between the two waveforms. In addition, high correlation coefficients are more difficult to obtain when the neural response amplitude is small. Such is the case during threshold estimation with ABR. As stimulus intensity approaches threshold, the amplitude of the response decreases substantially. Therefore, the response-replication technique may falter in the relatively adverse clinical conditions when it is most needed to objectively confirm response presence. Summary and Conclusions During the past 25 years since the discovery of the ABR, clinicians world-wide have exploited the clinical utility of this evoked response with many different populations. The 1970s and 1980s saw the development of ABR protocols for increasing the reliability and validity of the response in various clinical situations. Now, in the last decade of the century, advanced technology and the development of increasingly sophisticated software allows more flexibility in these measurements. Thus, ABR testing continues to evolve at a rapid pace. The main focus for ABR in the 1990s has been on developing techniques to improve the quality of the response, decrease the time in which it takes to record the response, and minimize human error through objective response analysis. Some of the major recent developments were reviewed in this chapter. The intent of this review is to provide the researcher and the clinician with Auditory Brainstem Response 43

51 an understanding of the underlying principles of the techniques which will be, and are already, available to them on their ABR equipment. Many of these techniques are promising for use with newborns, children, and difficult-to-test populations where time is a limiting factor in the amount of information that can be obtained. We encourage any and all clinicians to experiment with these techniques to determine how each technique might contribute to their particular clinic protocols. As with any new technique, there will be a learning curve associated with understanding the underlying principles, mastering the technical requirements, and realizing the most valuable clinical applications of these methods. Once the procedures become familiar to clinicians and applied in varied clinical settings, it is likely that the neurodiagnostic and audiologic value of ABR will be profoundly enhanced. References 1 Jewett D, Williston J: Auditory-evoked far fields averaged from the scalp of humans. Brain 1971; 94: Hall JW III: Handbook of Auditory Evoked Responses. Needham, Allyn & Bacon, Don M, Allen A, Starr A: Effect of click rate on the latency of auditory brainstem responses in humans. Ann Otol Rhinol Laryngol 1977;86: Eysholdt U, Schreiner C: Maximum length sequences A fast method for measuring brain-stemevoked responses. Audiology 1982;21: Li H, Chan F, Poon P, Hwang J, Chan W: Maximum length sequence applied to the measurement of brainstem auditory evoked responses. J Biomed Eng 1988;10: Picton T, Champagne S, Kellett A: Human auditory evoked potentials recorded using maximum length sequences. Electroencephalogr Clin Neurophysiol 1992;84: Marsh R: Signal to noise constraints on maximum length sequence auditory brainstem responses. Ear Hear 1992;13: Thornton ARD, Slaven A: Auditory brainstem responses recorded at fast stimulation rate using maximum length sequences. Br J Audiol 1993;27: Pratt H, Ben-David Y, Peled R, Podoshin L, Scharf B: Auditory brain stem evoked potentials: Clinical promise of increasing stimulus rate. Electroencephalogr Clin Neurophysiol 1981;51: Hamill T, Hussung R, Sammeth C: Rapid threshold estimation using the chained-stimuli technique for auditory brain stem response measurement. Ear Hear 1991;12: Hamill T, Yanez I, Collier C, Lionbarger J: Threshold estimation using the chained-stimuli auditory brain stem response technique. Ear Hear 1992;13: Lasky R, Perlman J, Hecox K: Maximum length sequence auditory evoked brainstem responses in human newborns and adults. J Am Acad Audiol 1992;3: Gorga M, Kaminski J, Beauchaine K, Jestedt W: Auditory brainstem responses to tone bursts in normally hearing subjects. J Speech Hear Res 1988;31: Davis H, Hirsh S, Popelka G, Formby C: Frequency selectivity and thresholds of brief stimuli suitable for electric response audiometry. Audiology 1984;23: Don M, Eggermont J, Brackman D: Reconstruction of the audiogram using brainstem responses and high-pass noise masking. Ann Otol Rhinol Laryngol 1979(suppl 57): Hoke M, Pantev C, Ansa L, Lutkenhoner B, Herrmann E: A timesaving BERA technique for frequency-specific assessment of the auditory threshold through tone-pulse series stimulation (TOP- STIM) with simultaneous gliding high-pass noise masking (GHINOMA). Acta Otolaryngol 1991; (suppl 482): Hall/Rupp 44

52 17 Marsh R: Concurrent right and left ear auditory brain stem response recording. Ear Hear 1993; 14: Lasky R, Shi Y, Hecox K: Binaural maximum length sequence auditory-evoked brain-stem responses in human adults. J Acoust Soc Am 1993;93: Galambos R, Makeig S, Talmachoff P: A 40-Hz auditory potential recorded from the human scalp. Proc Natl Acad Sci USA 1981;78: Linden R, Campbell K, Hamel G, Picton T: Human auditory steady-state potentials during sleep. Ear Hear 1985;6: Suzuki T, Kobayashi K: An evaluation of 40-Hz event-related potentials in young children. Audiology 1984;23: Stapells D, Galambos R, Costello J, Makeig S: Inconsistency of auditory middle latency and steadystate responses in infants. Electroencephalogr Clin Neurophysiol 1988;71: Maurizi M, Almadori G, Paludetti G, Ottaviani F, Rosignoli M, Luciano R: 40-Hz steady-state response in newborns and in children. Audiology 1990;29: Rees A: Human auditory amplitude modulation rate sensitivity determined by recording steadystate evoked potentials. J Physiol 1982;326: Rickards F, Clark G: Steady-state evoked potentials to amplitude-modulated tones; in Nodar R, Barber C (eds): Evoked Potentials. II. Boston, Butterworth, 1984, pp Aoyagi M, Kiren T, Kim Y, Suzuki Y, Fuse T, Koike Y: Frequency specificity of amplitudemodulation following response detected by phase spectral analysis. Audiology 1993;32: Kuwada S, Batra R, Maher V: Scalp potentials of normal and hearing-impaired subjects in response to sinusoidally amplitude-modulated tones. Hear Res 1986;21: Aoyagi M, Kiren T, Furuse H, Fuse T, Suzuki Y, Yokota M, Koike Y: Pure-tone threshold prediction by 80-Hz amplitude-modulation following response. Acta Otolaryngol 1994;(suppl 511): Aoyagi M, Kiren T, Furuse H, Fuse T, Suzuki Y, Yokota M, Koike Y: Effects of aging on amplitudemodulation following response. Acta Otolaryngol 1994;(suppl 511): Wong P, Bickford K: Brain stem auditory evoked potentials: The use of noise estimates. Electroencephalogr Clin Neurophysiol 1980;50: Nicolet Viking IV User s Manual. Madison, Nicolet Instrument Corp., Elberling C, Don M: Quality estimation of averaged auditory brainstem response. Scand Audiol 1984;13: Sininger Y: Auditory brain stem response for objective measures of hearing. Ear Hear 1993;14: Dobie R: Objective response detection. Ear Hear 1993;14: Algo-2 Newborn Hearing Screener User s Manual. San Carlos, Natus Medical Inc., Hall JW III, Kileny P, Ruth R: Clinical trials for the Algo-1 newborn hearing screening device. 10th Biennial Meeting of the International Electric Response Study Group, Charlottesville Kileny P: Algo-1 automated infant hearing screener: Preliminary results. Semin Hear 1987;8: Nicolet Spirit User s Manual. Madison, Nicolet Instrument Corp, James W. Hall III, PhD, Vanderbilt Balance and Hearing Center, st Avenue South, Suite 2600, Nashville, TN (USA) Auditory Brainstem Response 45

53 Alford BR, Jerger J, Jenkins HA (eds): Electrophysiologic Evaluation in Otolaryngology. Adv Otorhinolaryngol. Basel, Karger, 1997, vol 53, pp Hearing as Reflected by Middle and Long Latency Event-Related Potentials 1 Gary P. Jacobson a, Nina Kraus b, Therese J. McGee c a Division of Audiology, Henry Ford Hospital, Detroit, Mich.; b Departments of Communication Sciences and Disorders, Neurobiology and Physiology and Otolaryngology, Northwestern University, Evanston, Ill., and c Department of Communication Sciences and Disorders, Northwestern University, Evanston, Ill., USA One of the few ways of obtaining neural information in humans is with evoked responses. Research in auditory evoked responses has gone through an evolution over the past 30 years. Initially, there was intense interest in the development of long latency responses (i.e. evoked responses with latencies exceeding 50 ms) as a method for objectively assessing auditory system sensitivity. With the advent of more efficient computers, attention was focused on shorter latency responses beginning with the fast responses (now referred to as middle latency responses) and then with the auditory brainstem response. The discovery of the auditory brainstem response brought forth an explosion of investigations that demonstrated the usefulness of this response for assessment of auditory system sensitivity and the transmission capabilities of the pontine auditory pathways. The bulk of these investigations occurred between 1975 and Beginning in the early 1980s and continuing today there has been renewed interest in both the middle and long latency auditory evoked responses and the nonmodality-specific endogenous responses. Interest in these electrical events with longer latencies is rooted in the knowledge that they originate from more rostral structures (midbrain, thalamus, cortex), and thus, provide us with information about auditory processing at a higher level than can be assessed with the auditory brainstem response. That is, these longer 1 Portions of this chapter were modified from references 34, 137, 244 and 245.

54 latency responses represent not only transmission of the auditory signal as modified by the central nervous system, but also reception, processing and integration of these auditory signals. Short latency evoked responses (e.g. electrocochleogram and auditory brainstem response) provide information only about the transmission characteristics of the auditory pathway (e.g. synchronization and speed of transmission). The longer latency responses provide us with information about the reception and interpretation of these auditory signals that occurs at the level of the cortex (i.e. we hear with the auditory cortex). The purpose of this brief chapter will be to review what is known, and conversely, what is not known about middle and long latency responses. Much of the research regarding evoked response origins has involved the use of magnetoencephalographic instrumentation. The evoked activity recorded with this instrumentation is called an evoked field. Thus, the more generic term evoked response has been chosen and will be used except when specific points are being made. This chapter is organized into two main headings representing descriptions of exogenous and endogenous evoked responses. Within a major heading, evoked responses will be described in the approximate temporal order in which they occur. Additionally, attempts will be made to describe, in summary form, what is known about the physiological origins of each response, how they are elicited, what processes they represent, maturational issues and examples of how they have been used (if at all) for clinical purposes. It is hoped that what cannot be discussed in this chapter can be obtained by the reader through a reading of the references listed at the end of this chapter. Exogenous and Endogenous Evoked Responses Evoked responses can be grouped broadly into two categories exogenous and endogenous responses. Exogenous evoked responses are modality specific (e.g. a light flash elicits a visual evoked response, a click elicits an auditory evoked response) and the characteristics of the evoked response (e.g. latency and amplitude) are dependent upon the physical characteristics of the evoking stimulus (e.g. stimulus frequency, intensity, rate of presentation). In contrast, endogenous responses are evoked brain events that are not modality specific. That is, the same endogenous response can be elicited following stimulation of any sensory modality (or combinations of modalities) and the characteristics of these responses are dependent not so much on the physical characteristics of the evoking stimuli but on the psychological conditions within which the listener is placed. These responses are sometimes referred to as cognitive evoked responses. Middle and Long Latency ERPs 47

55 Examples of purely exogenous responses include the electrocochleogram and the auditory brainstem response. Examples of purely endogenous responses include the negative difference wave (Nd) and the P300. Some evoked responses may be predominately exogenous but may be affected by the psychological state of the subject (e.g. though N1 is an exogenous response it gains amplitude during focused attention). Exogenous (Auditory) Evoked Responses Middle Latency Auditory Evoked Responses The middle latency response (MLR) appears as a series of waves occurring from approximately 15 ms and extending to approximately 50 ms after stimulus onset (using optimal stimulating and recording techniques). These components have a visual appearance of a 40-Hz sine wave (e.g. the peaks are separated by about 25 ms) and are typically labeled Na, Pa, Nb, Pb (also referred to as P50 or P1 of the late cortical auditory evoked response) and TP41 (fig. 1). Na, Pa, Nb and Pb are observed in recordings from the anterior midline; TP41 is typically recorded over the temporal lobe. Origins The MLR is a neurogenic response which sometimes is contaminated by myogenic activity [1 5]. 2 The Na component probably has mesencephalic origins. Evidence supporting this contention may be found in the work of Hashimoto et al. [7] who showed a near-field response with equivalent latency recorded from the region of the inferior colliculus of humans undergoing thalamotomies for intractable pain. Also, McGee et al. [8] have reported that injection of lidocaine into the inferior colliculus affects all surface-recorded MLR components. Additionally, Kileny et al. [9] have reported that temporal lobe lesions affecting Pa do not affect Na, although this finding is at odds with the report of Jacobson et al. [10] who observed significant changes in Na following anterior temporal lobe resections in patients with intractable epilepsy. All evidence suggests that the Pa component is generated, at least in part, in the auditory cortex. This assertion is supported by comparisons of far-field 2 There is a large family of sonomotor responses including the postauricular muscle reflex (PAM), auropalpebral reflex, the frontalis m. reflex (all of the above involve the auditory division of VIII N for the afferent limb and the VII N for the efferent limb), the temporalis and acoustic jaw reflexes (afferent limb VIII N, efferent limb V N), and the inion potential (afferent limb vestibular division of VIII N, efferent limb VII N). It was at one time felt that these responses could be used in conjunction with the auditory brainstem response to assist in the detection of demyelinating disorders [6]. Jacobson/Kraus/McGee 48

56 Fig. 1. Four-channel (coronal chain) middle latency response (MLR) from a normal subject. Electrode derivations are: channel 1>Cz-A2; channel 2>Fz-A2; channel 3>left midtemporal/parietal-a2; channel 4>right midtemporal/parietal-a2. The stimulus was presented to the right ear. Note that the MLR is largest at Fz. Also, note that the TP41 response is present at the midtemporal electrode sites. The stimulus was an unfiltered click presented to the right ear at 75 db nhl (rate>8.44/s). The EEG was filtered 10 3,000 Hz. The analysis period was 75 ms (amplitude calibration>0.5 (μv/div). and near-field recordings [11 13] which have demonstrated a polarity reversal of Pa across the Sylvian fissure [13 16], and the results of dipole source analysis of scalp-recorded electrical activity [17]. Additionally, pathophysiological correlational studies suggest that Pa is most affected by disorders of the temporal lobes [10, 18 24]. It is significant to note that there exists compelling evidence suggesting that a subset of Pa generators are located in, or potentiated by, subcortical sources. For example, a number of investigators have reported that Pa is affected by sleep or sleep stage [25, 26]. Additionally, Parving et al. [27], Rosati et al. [28] and Woods et al. [29] have reported patients who have sustained bilateral temporal lobe infarctions and have remained physiologically capable of generating a Pa component. Kraus et al. [30] have described in detail a Middle and Long Latency ERPs 49

57 dissociation between temporal lobe and midline recorded correlates of the Pa component in guinea pigs. The injection of local anesthetics (e.g. lidocaine) into auditory cortex did not affect the midline-recorded Pa component, nor did electrolytic lesioning of the temporal lobes. Systemic anesthesia (e.g. Innovar) affected the temporal recordings of Pa but did not affect the midline-recorded Pa. Increasing stimulation rates decreased the amplitude of the temporal lobe components and did not affect the midline-recorded response. The investigators also studied the ontogeny of the MLR in the gerbil. The midline-recorded MLR showed an earlier maturation than the temporal lobe components. Based on several lines of evidence, the authors hypothesized that the scalprecorded Pa component in humans is composed of two functionally distinct generator systems: one located in the temporal lobes bilaterally and another that is a deep midline generator system that possibly resides within the polymodal thalamus. Finally, results of recent magnetoencephalographic (MEG) investigations have suggested that the generator system of the Pa component is tonotopically organized but opposite to the tonotopic organization of N1 (high-frequency responses represented more superficially and low frequencies represented deep to the scalp [31]. The TP41 represents an evoked response recordable only over the temporal lobes. As the name suggests, this response has a mean latency of approximately 41 ms and unlike the Pa component the generator of TP41 has a long refractory cycle (i.e. it can be recorded optimally only using interstimulus intervals of?1 s). Dipole source measurements obtained from scalp voltage [23] and magnetic field measurements [32] have placed the equivalent current dipole (ECD i.e. the estimated location, orientation and strength of the center of gravity of current sources underlying TP41) for the TP41 in the temporal lobe. Clinical Data The primary usefulness of the MLR has been in the area of the assessment of auditory sensitivity. Because the generators of Pa are not as dependent as are the generators of the ABR on sharp neuronal synchronization, the MLR can be recorded in patients with absent ABR (due to severe hearing loss, or, neurological disease) [33]. The detectability of the MLR is poorer in children than in adults, and this appears to be a result of the age dependence of MLR on the state of awareness. That is, it has been reported that in sleeping children Pa can be detected consistently in alpha sleep, stage 1 and REM sleep but disappears in stage 4 sleep [26], yet adults show only a small MLR amplitude reduction with sleep [34]. This finding has been interpreted as being consistent with a multigenerator hypothesis for the MLR with generators differing in sleep dependence and in maturational time course. Jacobson/Kraus/McGee 50

58 The usefulness of the MLR for the evaluation of auditory sensitivity may be found in the observation that since the response is not critically dependent (as is the ABR) on neuronal synchronization [35], it is possible to elicit the MLR with low-frequency stimuli [36, 37]. This means that the auditory brainstem response and MLR may serve complementary functions. For example, the rapid onset stimulus (e.g. click stimulus) required to elicit the ABR carries a large amount of high-frequency energy. Therefore, ABR wave V threshold provides information only about auditory sensitivity for high frequencies (e.g. 2,000 4,000 Hz). However, the MLR can be recorded with low-frequency stimuli, and therefore MLR threshold searches may provide an estimate of auditory sensitivity at the low-frequency end of the auditory spectrum (e.g. 500 Hz). The electrically generated MLR, the EMLR (e.g. evoked with a stimulating electrode placed at the promontory) may provide prognosticating information about the numbers of surviving neural elements for patients undergoing cochlear implantation [20, 38, 39]. Also the EMLR may serve as an objective measure of threshold and comfort level settings postoperatively [20]. Although, as noted earlier, a number of studies have been reported illustrating that the MLR, and specifically component Pa, may be absent in the presence of ipsilateral temporal lobe disease, this response still has not found its way into widespread clinical practice in the neuroaudiologic evaluation of these patients. It is probable that interest in the MLR will increase as the interest in auditory electrophysiology extends beyond transmission characteristics toward an understanding of the cortical processing of the neural code. Steady-State (40 Hz) Response Origins In the transient stimulation paradigm, the generator of a particular response recovers fully (or at least substantially) prior to the presentation of the next stimulus (in fact, for evoked responses beyond the ABR we rarely permit generators to go through a full refractory cycle). In the steady-state paradigm, stimuli are delivered faster than some generators can respond optimally. For a multiply generated response, the faster rate may even favor more rateresistant generators. Steady-state stimulation techniques have been utilized by many to study the functional properties of the visual and auditory sensory systems. The use of steady-state stimulation in MEG investigations of auditory cortical function [40] coincides in time with the first report of the 40-Hz response event-related potential [41]. The auditory 40-Hz steady-state response (SSR) has been hypothesized as being a rate-modulated ABR and MLR (i.e. the 40-Hz Middle and Long Latency ERPs 51

59 Fig. 2. Steady-state response (SSR) (40 Hz) recorded from a normal subject. Note that there are two cycles of 40-Hz activity recorded in this 50-ms analysis period (25 ms/cycle) and that the amplitude of the SSR is larger (amplitude calibration 0.5 (μv/div) than the MLR from the same individual (see fig. 1). The signal again was an unfiltered click presented to the right ear at a rate of 40 Hz. Also, note that the ABR can be observed clearly for each cycle of the SSR. The electrode derivations and filter bandpass were same as that described in figure 1. SSR is believed to represent a coalescence of ABR and MLR components; fig. 2). However, unlike the MLR, the 40-Hz SSR has been shown to be relatively unaffected in patients with temporal lobe disease and in coma [42, 43]. For these reasons it has been hypothesized that the SSR derives its origins from slightly different generators than the Pa component. These sources include subcortical polysensory centers in the thalamus [41, 44]. MEG evidence has shown that the ECD 3 source location of the SSR overlaps the ECD location of Pa [45]. 3 The term equivalent current dipole (ECD) describes the location (Cartesian coordinates X, Y and Z measured in cm or mm), orientation (measured in degrees) and strength (usually measured in units of current) of the neural tissue responsible for a spontaneous or evoked electrical response. Although several, local, coactivated sources may contribute to a given electrical event, the ECD location describes the center of gravity of these responses. Jacobson/Kraus/McGee 52

60 Since the SSR is larger than the Pa component it is more attractive for use as an auditory electrophysiological indicator of peripheral hearing sensitivity. Specifically, it has been reported that the SSR achieves half its maximum amplitude within 15 db of behavioral auditory threshold [41]. Also, the SSR is largest following stimulation of a low-frequency tone pip [41, 46, 47] in contrast to the ABR which is dependent upon the sharp neuronal synchronization accompanying the onset of a transient stimulus (with poor frequency-resolving capabilities). Finally, since the response appears as a 40- Hz sine wave, the data may be analyzed online in the frequency domain (through fast Fourier transformation) instead of in the conventional time domain [48]. Spydell et al. [42] have reported that subtle phase abnormalities were observed for the SSR recorded from patients with midbrain disease. Long Latency Auditory Evoked Responses (Predominately Exogenous) P50 The long latency auditory evoked response consists of a number of positive and negative polarity deflections beginning with a component that occurs at approximately 50 ms to maximal stimulation (fig. 3). P50 is also referred to as the P1 component and is followed by N1, P2, N2 and P3 (see next sections for a discussion of N1 and P2). This component also represents, to some, the last component of the middle latency response (Pb). P50 has not received a great deal of attention until recently, due in part to the difficulty in recording this response coupled with the confusion over where it belongs in the continuum of auditory evoked potentials (e.g. middle latency or long latency response). Origins The P50 response is best recorded using slow stimulation rates (e.g. 1/s) [49]. P50 is recorded optimally at the central-frontal midline (Cz, Fz). It is known that P50 probably is generated within the ascending reticular activating system [50]. This assertion is based upon the rate/recovery characteristics of the response (described above) and results of studies demonstrating that P50 disappears during slow wave sleep and reappears during REM sleep in animals (i.e. cat) and humans [50]. Clinical Data The clinical application of P50 has been specific to the field of psychiatry. It has been demonstrated that when a pair of clicks separated by an interval of 500 ms are presented to the ear of a normal subject, the P50 response Middle and Long Latency ERPs 53

61 Fig. 3. P50 (P1) response recorded from the Cz electrode in a normal subject. Tracings represent four independent trials. The stimulus was a 60-dB nhl, 1,000-Hz tone burst of 125 ms duration and having a 15-ms rise/fall time. The stimulus was presented to the right ear. The repetition rate was 1 Hz. The filter bandpass was Hz. Also shown in this figure (but not labeled) following P50 (P1) are AEP components N1 and P2. elicited to the second click ( test stimulus) will have an amplitude 20% or less than that elicited by the first click ( conditioning stimulus). This normal suppression has not been observed in patients with schizophrenia (diagnosed by DSM-III criteria) and has been attributed to defective sensory gating (as a function of impaired catecholamine metabolism) on the part of schizophrenic patients [51 55]. It should be noted that there has been great variability in the degree of suppression in schizophrenic patients from report to report [56]. Technical issues may explain this variability [57]. It has been hypothesized that the P50 response is generated in the thalamus by a cholinergic component of the ascending reticular activating system [58]. This hypothesis has been supported by the results of animal studies demonstrating that wave A in cats (i.e. the cat equivalent of P50 in human), disappears Jacobson/Kraus/McGee 54

62 at high rates of auditory stimulation, is present following bilateral removal of cortex, basal ganglia and limbic system, and, is absent following destruction of cholinergic cells in the pedunculopontine nucleus or injections of a muscarinic receptor blocker such as scopolamine [59 62]. This hypothesis has been supported in human investigations showing that P50 was absent, or, of low amplitude in patients with probable Alzheimer s disease (a disease affecting the cholinergic system) [58]. Gamma Band Response Recently, investigators using MEG recording techniques have described high-frequency wavelets (fig. 4a, b) that are superimposed upon the auditory middle latency and long latency responses [63 65]. The oscillations have a spectral peak frequency between 30 and 40 Hz and have been termed gamma band responses (GBR) [63]. Unlike the 40-Hz SSR [41], the auditory evoked gamma band response (aegbr) is best elicited by transient tone burst stimulation with long interstimulus intervals (ISI) (?2 s). Origins The precise functional significance of the GBR is unclear but several parallel lines of evidence suggest that this electrical event may serve to bind together cortical areas that serve a common purpose. Each group of functional connections is termed a single neural assembly. These connections may be local (e.g. adjacent cortical columns) or distributed (e.g. within the temporal lobe, or, throughout the brain). It is believed that these neural assemblies are called into play to help fuse or bind together separate characteristics of auditory signals (e.g. frequency spectrum, intensity, duration, velocity of frequency and intensity change, character of sound) into a single unitary percept (e.g. the sound associated with a dog bark ) [63, 66, 67]. The creation and preservation of these neural assemblies probably is influenced by the repeated experience on the part of the listener to the same aggregate auditory event. That is, functional connections are made through the repeated exposure of the listener to the same auditory event and the recognition on the part of the listener of the significance of this event. Evoked oscillations in the gamma band of this type have been recorded from stimulation of visual and olfactory sensory systems in animals (e.g. vision [68 75]; olfaction [76 78]). To date, investigations of the characteristics of the human aegbr have shown that the auditory evoked gamma bend field (aegbf) is present in approximately 33% of normal subjects [C. Pantev, pers. commun., 1994] due in large part to its small magnitude and associated poor signal-to-noise ratio. Additionally, the source location of generators underlying the aegbf are spatially separate from those underlying Pa, the steady-state 40-Hz response, Middle and Long Latency ERPs 55

63 a b 4 Jacobson/Kraus/McGee 56

64 and N1 in the supratemporal auditory complex [45, 63]. Also, unlike N1 that appears as a stationary field, the aegbr appears as a moving dipole, arcing 1 cm or greater in an anterior-posterior trajectory over the time period from 20 to 130 ms [63]. The aegbr decreases in magnitude as a function of decreased interstimulus interval but to a lesser extent than N1 [45]. The generator system responsible for the aegbr is not tonotopically organized as are the generators of both Pa and N1 [79]. Finally, the GBR may be modulated by attention, and therefore it may not be entirely exogenous [80]. MEG recordings have demonstrated that the generator source (or sources) of the MLR and SSR appears stationary when activated, whereas the generator source of the GBR moves in a posterior arcing trajectory over a period of ms [63]. The apparent movement of this ECD may represent the sequential activation of adjacent cortical columns, or possibly, the activation of two fixed dipoles, offset slightly in time, and located at the two ends of the observed arc (see Moran et al. [81] for a discussion of this phenomenon specific to N1). The net effect of these observations is that the MLR and SSR differ from the GBR in several important ways. N1 The negative and positive going waves following P50 have peak latencies of approximately 100 and 175 ms, respectively, and are referred to as N1 and P2 (fig. 5). When submitted to spectral analysis, these latter waveforms show most of their energy to be concentrated in the frequency range below 20 Hz [82]. The N1 response was the first of the long latency responses to be described in the scientific literature [83]. The conventional stimulating paradigm for eliciting these responses entails the use of a tone burst with relatively slow onset (e.g ms rise/fall). Additionally, an ISI of 500 1,000 ms is used commonly to record N1 and P2 despite the knowledge that the response amplitude can be improved markedly by extending the ISI up to 8 16 s [84 86]. The N1 occurs at the onset of an appropriate auditory stimulus and also at the offset of the stimulus (although the offset response is less than one-half the amplitude of the onset response). Fig. 4. a Shown are 3 channels of AEP obtained from Cz, T3 and T4 electrode sites. The stimulus was a 500-ms duration, 1,000-Hz tone burst having a 15-ms rise/fall time. The stimulus repetition rate was 0.5 Hz. The signals were presented to the right ear only. The EEG was filtered between 1 and 100 Hz. b Same data as depicted in figure 4a but bandpass filtered (12 db/octave, zero phase shift, Butterworth filter) between 24 and 48 Hz. Note the residual high-frequency wavelets representing the gamma band response. Also note that the latency of the GBR recorded at T3 (contralateral temporal electrode) is shorter by ms than that recorded at T4 (ipsilateral temporal electrode). Middle and Long Latency ERPs 57

65 Fig. 5. Shown are AEP components N1 and P2 recorded from the Cz electrode site from a normal subject. The stimulus was a 125-ms, 60-dB nhl 1,000-Hz tone burst with a 15-ms rise/fall time. The stimulus was presented to the right ear. The stimulus repetition rate in this example varied randomly between 2.5 and 3.5 Hz. Origins There are at least three potentially simultaneously active generator systems in the cerebral cortex that produce electrical responses during the interval when N1 occurs. These include: component 1, which consists of a voltage field that is generated in the supratemporal plane and recorded maximal in the frontocentral scalp [15], component 2, a biphasic waveform positive in polarity at 100 ms and negative in polarity at 150 ms. It is generated on the superior temporal gyrus and maximal at the midtemporal electrodes [87], and component 3 which is recorded at the scalp surface as a vertex-negative wave with a latency of 100 ms. Although the source location of component 3 is unknown, Näätänen and Picton [88] suggest that it may be generated in the frontal motor and premotor cortex and may be under the influence of the reticular formation and ventrolateral (VL) nucleus of the thalamus. The VL nucleus projects to the precentral gyrus, superior, middle and inferior frontal gyri and the supplemental motor area (SMA) on the mesial surface of the frontal lobe. These areas receive input from the auditory association cortex. Jacobson/Kraus/McGee 58

66 MEG investigations have demonstrated that the ECD location of at least one component of N1 is 2 4 cm below the scalp surface. This ECD is perpendicular to the Sylvian fissure. Studies combining high-resolution MRI and MEG have localized N1m to the primary auditory cortex and primary association areas [89 91]. A number of functional characteristics of the N1 generator system have been described with evoked potential and MEG techniques and these include: (a) Tonotopicity: at least one component of the N1 generator system appears to be tonotopically organized. Specifically, MEG recordings have demonstrated that the ECD location for N1 in response to a high-frequency tone is more anterior than that to a low-frequency tone [92, 93]. Evidence of tonotopic organization as demonstrated through N1 latency changes has been reported recently in evoked potential recordings [94]. (b) Amplitopicity: MEG investigations of N1 have shown that the ECD for N1 becomes progressively more superficial as the stimulus intensity is increased [82, 95]. (c) Binaural interaction: both MEG and evoked potential recordings have shown that the contralaterally recorded N1 following binaural stimulation is smaller than that recorded following monaural stimulation [96 98]. Additionally, MEG studies have demonstrated a hemispheric dominance for N1. Specifically, the N1 ECD is approximately 1.4 cm more posterior over the left hemisphere than the right hemisphere for right-handed individuals (the opposite is true for left-handed individuals). Additionally, both MEG and evoked potential studies have demonstrated that N1 recorded over the contralateral scalp (with reference to the ear stimulated) is of larger amplitude and occurs on average 5 10 ms earlier than N1m recorded over the ipsilateral scalp [94, 96, ]. These differences reflect the superiority of crossed auditory pathways. Finally, it is known that the generator system of N1 requires up to 8 16 s to cycle through its absolute refractory period [86]. Clinical Data Cerebrovascular Disease. Long latency auditory evoked responses have been recorded from patients who have sustained ischemic strokes [102, 103]. Leinonen and Joutsiniemi [102] studied 4 patients with temporal lobe infarctions. Abnormalities were found in all 4 cases. N1 abnormalities included absent responses and responses that were accentuated in amplitude. It had been shown previously that absent responses were caused by damage involving primary auditory cortex and posterior association areas [29]. The patient with accentuated responses had lesions involving the anterior and middle supratemporal cortex, insula, claustrum and white matter containing connections between auditory cortex and frontal lobe and limbic structures. It was Middle and Long Latency ERPs 59

67 thought by the authors that the accentuated responses represented a loss of inhibitory control from the frontal lobe. Mäkelä et al. [103] studied 8 patients who had ischemic brain lesions. In 2 cases the patients had temporoparietal lesions and the N1m was absent when recordings were made over the affected hemisphere. One patient had a frontotemporal lesion that was superficial to the auditory cortex. This patient demonstrated a small N1m. Patients with lesions affecting the frontal lobe or small infarctions in the area of the supratemporal plane demonstrated N1. The authors have suggested that the structural extent of lesions on CT scan may not be representative of the functional extent of the lesion. Schizophrenia. N1 has been shown to be delayed in latency and lower in amplitude for schizophrenic patients [ ]. Reite et al. [106] reported the MEG characteristics of N1m in a sample of 6 male subjects. All patients had schizophrenia of paranoid type that was chronic in nature. The authors reported less asymmetry than normally observed in the ECD for N1 in the schizophrenic patients. These findings suggested possible structural and functional differences in the temporal lobes of this sample of schizophrenic patients. Tinnitus. Differences in the amplitude and latency of N1 have been reported in patients with tinnitus. Specifically, Hoke et al. [107] and Pantev et al. [108] reported that the auditory evoked cortical field (AEF) N1m component was larger, and P2m was smaller and occurred later in subjects with unilateral tinnitus compared with normal subjects. These group amplitude differences resulted in a P2m/N1m amplitude ratio that was smaller for the subjects with tinnitus. The researchers presented a scatterplot of P2m/N1m amplitude ratios showing that a cut-off ratio of 0.5 effectively separated patients with and without tinnitus (patients without tinnitus showed amplitude ratios exceeding 0.5). Additionally, the investigators reported that N1 latency was longer for patients with tinnitus. The abnormalities involving N1m and P2m amplitude were explained as having occurred because the afferent activity that accompanied tinnitus was being processed by the generator of P2m. This made the generator less able to respond to transient tonal stimulation. The generators of N1 and P2 are coactive, resulting in a reduction in both N1 and P2 amplitudes (due to phase cancellation). Therefore, the reduction in amplitude of P2 resulted in a large N1 response. Contradictory results were reported in two similar studies conducted by Jacobson et al. [109] and Colding-Jorgenson et al. [110]. Jacobson et al. [109] and Colding-Jorgenson et al. [110] saw no evidence suggesting that the N1m amplitude was larger, the P2m latency later, or, the P2m/N1m amplitude ratios smaller, when the two samples are compared. In fact, it was the rare normal subject that demonstrated P2m [111]. Jacobson/Kraus/McGee 60

68 Cochlear Implantation. It has been reported that the recording of N1 might be useful in the assessment of patients with cochlear implants [ ]. These investigators used the N1 response to validate that the auditory cortex could be stimulated by a cochlear implant. Additionally, it has been suggested that the strength of the dipole moment in MEG recordings following stimulation of a cochlear implant could be used to estimate the numbers of surviving VIII N fibers peripherally (and thus aid in the determination of candidacy for cochlear implantation). Unfortunately, the findings contained in these reports differ. The latency of N1m varies by report; it may be normal, early or delayed in patients with cochlear implants. However, there are several findings in common between reports: N1m appears to have a dipolar pattern, and the depth and direction of the ECD for N1m are consistent with that seen in normal hearing subjects. P2 Origins Although N1m has been studied in detail, comparatively little is known about P2m (fig. 5). P2 appears to have major generators within the auditory cortex [15, 100, 115]. The ECD location for the magnetically recorded P2 differs from N1 although the direction has differed from report to report. Pantev et al. [82] have reported that the location of P2m is on average 8 mm anterior and 4 mm medial to N1m. These findings are in general agreement with those of Hari et al. [32] who reported that the ECD location for P2m was anterior to N1m (by almost 20 mm in 1 subject). The anatomical separation between N1m and P2m sources suggests that the functional significance of P2m may differ from N1m. In our experience, we have found the goodnessof-fit of P2m to a single ECD is generally poor (r=0.90). When present and when the signal-to-noise ratio is optimal, the magnetic field pattern for P2m often appears quadrapolar. The poor fit of P2m to a single ECD model suggests that it may be generated by multiple coactive sources and better modeled as dual or multiple sources. Clinical Data There have been few investigations showing P2 abnormalities specifically. It has been reported that children with Down s syndrome showed longer N1 latencies and higher amplitude P2 [116]. Jirsa and Clontz [117] noted longer P2 latencies in children 8 11 years old with auditory processing disorders. Middle and Long Latency ERPs 61

69 Mismatch Negativity When an auditory stimulus is presented rapidly (e.g. 3/s) in a train, a series of low-amplitude N1 responses may be recorded. When a stimulus that is physically deviant from those in the train is presented, a second negativity is generated that lasts another 100 ms or more. The second response is called the mismatch negativity (MMN) [118] and it is derived by subtracting the evoked response tracing obtained to the common stimuli from the evoked response obtained to the physically deviant stimuli (fig. 6). The MMN is predominately exogenous; however, more recent information has suggested that attention may potentiate the response [119]. The MMN reflects the central processing of very fine differences in acoustic stimuli. It can be elicited by differences between stimuli at threshold levels (e.g. differences of as little as 8 Hz or 5 db) [ ]. The MMN has been obtained in response to frequency, intensity, duration, spatial and phonemic changes [ ]. It is believed that the rapid presentation of the common stimulus creates a neural representation of this stimulus in echoic memory that lasts 4 10 s and then decays [ ]. The neural representation may represent component 1 of the N1 response (see preceding section). The presentation of the deviant stimulus results in the detection of a mismatch between the common and deviant stimuli. The mismatch that occurs at a preconscious level is the trigger for the MMN. Thus, it appears that the MMN reflects a neuronal representation of the discrimination of numerous auditory stimulus attributes. If this response reflects the ability to discriminate between acoustic stimuli, then it may not only be of research interest but may have clinical value because speech perception, by its very nature, depends on a neuronal response to stimulus change. It has been demonstrated that the MMN is a robust phenomenon not only in adults [see 121 for a review] but also in children [127, 130, 138]. Additionally, the MMN can be elicited with speech stimuli [139, 140] that are at psychophysical threshold [120, 123, 127, 131]. More importantly, the MMN has been obtained during sleep in infants [141] and adults [142], and during sleep and barbiturate anesthesia in animal models [143, 144]. This would suggest that the MMN may become a potential clinical tool for the objective evaluation of patients for whom communication is difficult or compromised, or for whom auditory discrimination is in question (at-risk infants, children with language or learning disorders, cochlear implant users, adults with aphasia or dementia) [121, 145, 146]. However, it is significant to note that sleep stage (and the associated changes in background EEG activity) may affect significantly the recordability of the MMN. Specifically, an MMN-like response has been recorded during sleep in infants [141] and sleep has been shown to systematically affect this response in an animal model [143, 147]. In Jacobson/Kraus/McGee 62

70 Fig. 6. Mismatch negativity (MMN) recorded from a normal subject. The top tracing is the evoked potential recorded in response to the oddball stimulus (75 ms duration, 15 ms rise/fall time, 500 Hz stimulus). The tracing that lays beneath the oddball tracing is the evoked response recorded to the standard stimulus (125 ms duration, 15-ms rise/fall time, 500 Hz stimulus). The stimuli were delivered to the right ear at a rate of 3 Hz and at an intensity level of 60 db nhl ( standard probability of occurrence>80%, oddball probability of occurrence>20%). Stimulus duration was the dimension that determined whether the stimulus was same or different. The bottom tracing was derived by subtracting the evoked response to the frequent or standard stimulus from the evoked response obtained in response to the different or oddball stimulus. This derived tracing represents the MMN. EEG was bandpassed from 1 to 100 Hz. this regard, it has been demonstrated that cortical evoked potentials appear to be more consistently recorded in infants during REM sleep [148, 149]. Since infants have a high percentage of REM sleep [150], they are particularly likely to spend a significant amount of time in sleep stages favorable for ERP recording. Controlling for sleep stage during the recording of the MMN may improve the detectability of the response during sleep in infants [151, 152]. Middle and Long Latency ERPs 63

71 Origins The auditory cortex appears to be a major generating source for the MMN [88, 125, 128, ], with contributions from auditory thalamus and hippocampus [143, 144, 156]. Dipole analysis has demonstrated two distinct and partially overlapping sources for MMN, corresponding to the subcomponents which differentially respond to the size of the stimulus deviation [24]. Recently it has been demonstrated in MEG studies that the generator system for the MMN is organized tonotopically [157]. That is, the neurophysiological response of the brain to the detection of differences in tonal frequency may be mapped out spatially in a tonotopic manner. Overall, neuroanatomic sources differ depending on the acoustic change that is used to elicit the response [137, 144]. Clinical Data The wide variability observed in the performance of patients with cochlear implants may be reflective of differences in the central auditory processing abilities of implant users. MMNs to synthetic speech sounds have been elicited in cochlear implant users and can be similar to those obtained in normal hearing individuals [146]. Preliminary data suggest that good and poor implant users have distinctive MMNs. Deficient auditory perception has been associated with certain auditorybased learning problems [ ]. The MMN, which reflects auditory sensory processing, by inference, may be linked to auditory comprehension problems in school-age children [137, 145]. The characteristics of the MMN suggest its potential clinical use with patients for whom communication is difficult or compromised and for whom auditory discrimination and memory are in question (e.g., at-risk infants, children with language or learning disorders, cochlear implant users, adults with dementia or aphasia). Since it does not require conscious attention to the stimuli, the MMN may provide an objective measure of the discrimination of stimulus differences. Consequently, it may permit an objective analysis of sensory processing and discrimination, and auditory learning [137]. Thus, it is through the use of the MMN that investigators [103] have been able to probe tonal and speech processing abilities of patients with neurological disease. In this regard, the MMN has been employed to investigate auditory processing abilities in patients with temporal lobe infractions and aphasia. These patients have been reported to demonstrate MMN for pure tones but not speech stimuli [162], or to pitch and vowels but not to consonantal changes [123]. These findings suggest that the coding of differences for complex stimuli is not only different than that for simple tones, but that the ability to encode change is reflected in the MMN. Jacobson/Kraus/McGee 64

72 Long Latency Responses (Endogenous) Processing Negativity (Pn, Nd ) Selective attention describes the ability of a person to attend to one channel of information or to a class of information in one channel to the exclusion of other types of information routed to the same or different channels. Auditory selective attention can be indexed through the measurement of an endogenous event-related potential called the processing negativity, or negative difference wave (Nd) [121]. This response is elicited in a double-oddball paradigm where subjects are instructed to attend to one ear only and respond when an occasional (probability 10%) target stimulus is presented in a field of frequent stimuli (probability 40%) to that ear. The other ear is presented with frequent (probability 40%) and infrequent stimuli (probability 10%) as well (total probability of all stimuli>100%). At no point are the stimuli presented to both ears simultaneously. The Nd has an onset latency as early as 50 ms [163]. It appears as a negative polarity bias in the late cortical auditory evoked response waveform recorded in response to the frequent stimuli presented to the attended ear when this waveform is compared with the evoked response to the frequent stimuli presented to the ignored ear. The Nd is derived by subtracting the ignore-frequent waveform from the attend-frequent waveform (fig. 7). The onset latency and peak magnitude of the Nd wave may serve as an index of the time course and strength of a person s ability to selectively attend to one channel (e.g. stimuli presented to the target ear) and ignore others. Origins When originally observed, it was felt that the enhancement of N1 amplitude during selective auditory attention represented a simple potentiation of the N1 generator. 4 However, it was demonstrated that the enhanced N1 negativity could be dissociated from the N1 peak by varying the stimulating paradigm (e.g. rate of stimulus presentation) [165]. Thus, it was demonstrated that the Nd wave represented a true independent phenomenon. Most recently it has been demonstrated using neuromagnetic field recording techniques that the location of the ECD sources underlying the N1 and Nd waves, though located in the temporal lobe, are spatially distinct [166]. It is noteworthy that the Nd wave, and thus, the onset of selective auditory attention precedes the onset of N1 and may continue for hundreds of milliseconds after N1. 4 The view that accentuation of N1 with focused attention is caused by a potentiation of one or more generators of underlying N1 has support [121, 164]. Middle and Long Latency ERPs 65

73 Fig. 7. Negative difference wave (Nd) recorded from a normal subject. The stimulus paradigm is described in the text. The dashed tracing represents the evoked potential recorded in response to frequent stimuli routed to the ignored channel (ear). The solid tracing represents the evoked potential recorded in response to frequent stimuli routed to the attended channel (ear). The negative-going separation between these two tracings is referred to as the processing negativity. The subtraction of the ignored tracing from the attended tracing yields the Nd wave. Stimuli were 500 Hz (attended) and 1,000 Hz (ignored) tone bursts, that were 125 ms in duration with 15-ms rise/fall times. They were presented at 60 db nhl at a rate that varied randomly between 2.5 and 3.5 Hz. The EEG was bandpass filtered between 1 and 100 Hz. The process by which Nd is generated is complex and not completely understood. It is possible, or likely, that the process of selective auditory attention, which is initiated at prefrontal sites, affects auditory processing at a subcortical level, possibly at the level of the nucleus reticularis thalami, a nucleus which, as has been demonstrated in cats, affects afferent activity bound for the cortex [167]. The Nd wave (or processing negativity Pn) is an electrophysiological index of selective attention ability. It is felt that the physical characteristics of each frequent stimulus (as represented by the source location of N1) are stored automatically in echoic memory. Jacobson/Kraus/McGee 66

74 This auditory image resides in echoic memory for 4 s and probably no longer than 10 s [ ] and the speed of this decay may be faster as we age [168]. When a target stimulus (i.e. infrequent stimulus in the attended channel (ear)) is presented, the conflict between the echoic memory and the target results in the generation at a preconscious level of the MMN (see previous section). The conscious overt comparison of each stimulus with its predecessor in the attended channel is believed to represent the source of the Nd wave [121]. Näätänen [121] has offered hypotheses regarding the origins of activity underlying the Nd. It is his belief that the early electrical activity (with modality-specific scalp topography) represents the rehearsal of the incoming stimulus with the attentional trace of previously attended auditory stimuli. The term attentional trace refers to the neural image, or, neural memory of each auditory stimulus. Each different auditory stimulus is associated with an attentional trace. When the incoming stimulus is common or frequent the attentional trace (which lasts but a few seconds in sensory memory) is strong. In the example of the typical Nd paradigm the target stimulus is presented infrequently. Therefore, when the target stimulus is presented the listener must first compare it to the strongest attentional trace which represents the sensory memory of the frequent stimulus. Once the initial spatial comparison is made (e.g. spatial in the sense that the auditory cortex is tonotopically organized) and found to mismatch, further processing takes place to determine whether the stimulus represents the target. The smaller the physical differences between the attentional trace and the incoming stimulus, the longer the processing is required to determine whether they are same or different. The recognition of the stimulus as the target results in the initiation of rehearsal activities [121] that serve to strengthen the attentional trace of the target stimulus. Clinical Data Studies evaluating the clinical usefulness of the Nd have been few. Recently, it has been demonstrated that the amplitude of Nd is significantly smaller in schizophrenic children compared with normal children [169]. The results were interpreted by the authors as evidence that schizophrenic children have impaired abilities to allocate attentional resources for the discriminative processing of visual stimuli (span of apprehension SPAN task). Most recently, Jacobson et al. [170] have evaluated selective auditory attention abilities in normal subjects and subjects with bothersome tinnitus. Subjects with bothersome tinnitus were found to demonstrate Nd amplitudes that were larger in the ms time period (early Nd wave) compared with normal subjects. These findings were interpreted by the authors as supporting the contention that attention to the tinnitus occurring over a long duration increased the strength of selective auditory attention abilities of the tinnitus subjects. Middle and Long Latency ERPs 67

75 Fig. 8. P300 recorded from a normal subject. The stimulus paradigm is described in the text. Shown are two trials recorded from the Pz electrode. The top tracings are the evoked potentials recorded in response to the standard tone bursts. The middle tracings are the evoked potentials recorded in response to the oddball tone bursts. The bottom tracing represents the result of subtracting the standard tracing from the oddball tracing (removing N1 and leaving P300). The discrimination task was quite difficult which explains the long peak latency of P300 (450 ms). Standard stimuli were 125-ms duration, 1,000-Hz tone bursts (15-ms rise/fall) presented at a rate of Hz and at an intensity of 60 db nhl. The oddball stimulus was a 75-ms duration, 1,000-Hz tone burst presented at the same intensity and rate. EEG was acquired with a bandpass of Hz. P300 (P3) The P300 response was described originally by Sutton et al. [171]. The P300 response requires attention to, and discrimination of, stimulus differences. It is elicited in an oddball paradigm, in which an unexpected stimulus occurs in a series of expected stimuli (fig. 8). The conventional recording paradigm is to have subjects count the number of times a rare stimulus occurs in a train Jacobson/Kraus/McGee 68

76 of frequent stimuli [172, 173]. The P300 can be elicited through stimulation of any sensory modality (or combination of sensory modalities). P300 is a large response achieving amplitudes of μv under ideal recording conditions, and under these circumstances, requires averaging of only presentations of target stimuli [174]. Most commonly, the auditory P300 is elicited by tones, but other acoustic stimuli including speech can be used [ ]. Using speech stimuli, Kurtzberg et al. [148, 149, 178] have elicited a P300-like response which they call the cortical discriminative response (CDR). P300 can be further divided into waves P3a and P3b. P3a occurs in response to large stimulus differences whether or not the subject is attending to the stimulus sequence, while P3b occurs only when the subject is actively discriminating between stimuli [177, ]. In general, P300 is best recorded from central-parietal (e.g. Pz) scalp regions [181]. A considerable body of research has amassed concerned with paradigms which elicit a P300 in normal subjects. These efforts have focused on a delineation of the cognitive processes reflected in the components and subcomponents comprising P300 Processes of attention, auditory discrimination, memory and semantic expectancy appear to be invoked in the generation of P300 [182]. It has been suggested that P300 may be a neural correlate of sequential information processing, short-term memory, and/or decision-making [ ]. Origins Results of investigations using intracranial recording techniques in humans have suggested that the generation of P300 involves multiple subcortical sites [187]. The limbic system, and particularly the hippocampus, have been postulated as generators both on the basis of surface electromagnetic recordings [188] and intracranial recordings [ ]. Large P300-like potentials showing steep voltage gradients and polarity reversals across electrode locations have been recorded from the limbic system. Thalamic contributions to P300 have been proposed based upon intracranial recording in humans [187]. Pathways involving the mesencephalic reticular formation, medial thalamus and prefrontal cortex are thought to contribute to the P300 based on the role of these structures in the regulation of selective attention [167, 192]. Topographic mapping, intracranial recordings and neuromagnetic field data have indicated that the frontal cortex [172, 193], centroparietal cortex [15, ] and the auditory cortex [198] contribute to the auditory P300. Clinical Data Kurtzberg et al. [148, 149] have studied speech evoked CAEPs and CDRs in high-risk infants who were at risk for language dysfunction. Twenty-one Middle and Long Latency ERPs 69

77 percent showed abnormal CAEPs, and all of these had absent CDRs. Of 55 infants with normal CAEPs, 15 had absent CDRs. CAEP to speech sounds of at-risk babies were significantly less mature than those of normal newborns. At 3 months of age, both groups of babies had similar AEPs. The authors reported that behavioral tests of language function performed later showed that the early CAEPS and CDRs were predictive of language function. They concluded that CAEPs and CDRs to speech sounds accurately reflected the infants capacity for processing stimuli important for development of speech and language [178]. For children, low-amplitude P300 has been linked to hyperactivity, schizophrenia, autism and reading disability with few changes in P300 latency [191, 199]. P300 abnormalities have also been linked to attentional disorders in hyperactive children [200], auditory processing disorders [117], Down s syndrome [201], and psychiatric disorders [202]. Finley et al. [203] used P300 to differentiate functional from organic cognitive disorders in children. In adults, P300 has been studied in patients with Parkinson s disease [204], chronic renal failure [205], chronic alcoholism [206], senile dementia [ ], cerebrovascular lesions, head trauma, brain tumors [ ], schizophrenia [ ], and aphasia [215]. Amplitude reductions and prolonged latencies have been observed in patients with Alzheimer s disease [208, ]. Tests of memory function derived from P300 latency measures have been applied to conditions where deficiencies of recognition and storage have been implicated [207, 208, 219]. Unlike other AEPs, P300 shows little asymmetry in patients with asymmetric hemispheric lesions. In patients with temporal lobe lesions, Musiek et al. [212] noted no significant effects of site of brain lesion either with ear of stimulation or location of the recording electrode. Similarly, no differences in amplitude for affected versus nonaffected hemisphere were seen in groups of patients with head trauma or brain tumors [220]. Johnson and Fedio [221] did show laterality effects in patients with unilateral temporal lobectomy using C4 and C3 electrode sites. P300 is not adversely affected by hearing loss, as long as the subject can perceive the stimulus, thus peripheral hearing loss should not impede the use of this measure [212]. In this regard, there have been recently two reports documenting the usefulness of the P300 for probing auditory processing capabilities in cochlear implant recipients [222, 223]. Both groups of investigators were able to record P300 components in both adults [222] and children [223]. These investigators have suggested that the presence of P300 may be predictive of how successful a patient will be with a cochlear implant. It is important to note, however, that P300 shows a great deal of intersubject variability in latency and amplitude. Picton and Hillyard [182] observed Jacobson/Kraus/McGee 70

78 that the P300 may correlate more with the degree of global cognitive dysfunction than with any specific diagnosis, since the response is abnormal with a wide range of disorders affecting cognition. It is important to realize that the generation of P300 probably is associated with the point in time a listener recognizes that a significant event has occurred (e.g. the recognition that a target stimulus has been presented). This means that the state of the listener as modified by the effects of medications, motivation, fatigue will have an effect on the latency and, in turn, the amplitude of P300. These limitations affect greatly the clinical usefulness of not only P300 but all endogenous responses. N400 (Semantic Incongruity Response) The N400 appears to reflect semantic processing of language. Like the P300, N400 is not modality specific (i.e. it can be elicited by auditory, visual and sign language stimuli) [ ]. Since eliciting N400 requires the subject to access language, N400 could be developed as a valuable part of an auditory processing battery. As with other long latency evoked responses, N400 should not be considered a single phenomenon, but rather the admixture of evoked electrical events underlying several psychological processes. The N400 eliciting task involves the perception of semantic incongruity. For example, the sentence I take coffee with cream and dog would elicit an N400. A semantically appropriate sentence, I take coffee with cream and sugar, would not elicit an N400. The latter sentence elicits a slow positive response [ ]. The more complex or unexpected the stimulus, the larger the N400 response. Other semantic tasks can elicit an N400: Reading isolated words that are semantically incongruous with a preceding phrase [229], discrepant word contexts [181, 230, 231], and naming pictures [232]. Words will elicit a larger N400 than pictures [233]. N400 was not elicited by words that were physically deviant on a visual task such as words in larger type [228, 234]. Kutas et al. [226] observed visual N400 in congenitally deaf adults to sign language stimuli and argue on that basis, that the response represents conceptual processing of the word s meaning rather than phonological processing of the acoustic aspects of the stimulus. That the N400 indexes a linguistic process was further demonstrated by Besson and Macar [235] who failed to find N400 to deviations involving nonlinguistic expectancies such as geometric patterns of increasing or decreasing size, scale notes of increasing or decreasing frequency and well-known melodies. However, Rugg [139, 140] found that rhyming and nonrhyming words are differentiated by a negative component following the nonrhyming words in the same way that related and unrelated word pairs are differentiated by the Middle and Long Latency ERPs 71

79 N400. Possibly this weakens the hypothesis that N400 is tied to semantic processes. Also possible is that the N400 response to semantic expectancy and the response to rhyming are nonidentical. Stuss et al. [236] speculate that two distinct processes are involved, one associated with detection of a stimulus and a second associated with the evaluation of complex or anomalous stimuli. Stuss et al. [237] describe an N400 for both semantic (naming) and nonsemantic (mental rotation) tasks, but the tasks elicited different scalp distributions suggesting that N400 differs for different tasks. Some processes may be common to both semantic and nonsemantic processing, while other processes are specific to the semantic interpretation. They describe a biphasic negative wave. The Nx wave of this complex may represent the initial registration of the stimulus, while the Ny component may occur due to further processing, perhaps involving access to long-term memory. Origins Little is known of the physiological origins of N400. Since this wave underlies several psychological processes, it is to be expected that the N400 represents the interactions of distributed sources in the brain. It has been reported that N400 is larger over the right than the left hemisphere [ ]. Picton and Hillyard [182] speculate that this may be related to clinical evidence that patients with right hemispheric damage have difficulty understanding the contextual framework of narratives, in appreciating humor, and in interpreting metaphors. In studies of the scalp topography of speech-elicited potentials, semantic processing elicited a posterior extension in later components, indicating that a more extensive portion of language cortex is engaged in semantic classification than in verbal identification [241]. Blood flow and metabolism studies have indicated that the frontal cortex is activated during semantic processing and that this area may also contribute to a speech-elicited negativity at N380. Clinical Data N400 may prove useful in the evaluation and the processing of language. Using visual stimuli it has been reported that normal readers have larger amplitude visual N400s than disabled readers [242, 243]. Conclusions The preceding discussion represents a brief overview of middle latency responses and a number of long latency responses. This has not been an Jacobson/Kraus/McGee 72

80 exhaustive review. That is, a number of interesting evoked responses have been omitted. These responses include the exogenous sustained response (sustained potential and sustained field) and the contingent negative variation (CNV). In most cases the evoked responses that have been discussed represent the activation of a unique set of neural structures that is associated with processes of audition. Among the many issues that have yet to be resolved is the question of how, if at all, each of these evoked responses are functionally linked. We know from the behavior of N1 that it must in some way represent an early step in the analysis of the auditory signal. The MMN represents the preconscious response to change in the physical characteristics of a sequence of stimuli. The P300 represents the conscious recognition of the significance of the difference as represented by the MMN. The Nd wave represents the ability of auditory cortical centers to open the gate for the desired signal channel and to close the gate on an unwanted signal channel. This selective attention function occurs in parallel with, and can begin some 50 ms prior to, the peak of N1. The gamma band response may represent the linking together of local and distributed (multiple distant) brain sources to achieve a unitary perception of the auditory event. How can what we know about these evoked responses help us in the future to evaluate the auditory system? These evoked electrical events represent some of the neurophysiological processes that are necessary to break apart, or decode, the signal that is encoded at the cochlea. That is, these evoked responses may provide us with a window on not how sound is transmitted through the brain pathways, but instead, how this neural code is recovered and converted into understandable auditory perceptions. It would seem that the characteristics of these evoked responses are key in the assessment of hearing for speech. For example, speech signals vary in both frequency and intensity over time. It is not happenstance that the N1 dipole location varies as a function of both frequency and intensity. Also, it would be difficult or impossible to process speech in a background of noise if the listener had impaired selective attention abilities (e.g. Nd). Additionally, if the brain is incapable of acknowledging changes in the physical characteristics of sound (e.g. MMN), it would seem that it would be impossible to consciously recognize (e.g. P300) these differences. (Is it possible for P300 to be present if the MMN is absent?) These questions are being investigated presently and it is hoped that the answers will bring us closer to an understanding of the behavior we call hearing. Middle and Long Latency ERPs 73

81 Acknowledgments This work was supported by NIH grants RO1 DC01510, RO1 DC00264 (Drs. Kraus and McGee) and by a grant from the American Tinnitus Association (Dr. Jacobson). References 1 Geisler CD, Frishkopf LS, Rosenblith WA: Extracranial responses to acoustic clicks in man. Science 1958;1289: Bickford RG, Jacobson JL, Cody DTR: The nature of averaged evoked potentials recorded from the human scalp. Electroencephalogr Clin Neurophysiol 1963;15: Mast TE: Short latency human evoked responses to clicks. J Appl Physiol 1965;20: Harker LA, Hosick E, Voots RJ, Mendel MI: Influence of succinocholine on middle component auditory evoked potentials. Arch Otolaryngol 1977;103: Kileny PR, Dodson D, Gelfand E: Middle latency auditory evoked reponses during open-heart surgery with hypothermia. Electroencephalogr Clin Neurophysiol 1983;55: Robinson K, Rudge P: Abnormalities of the auditory evoked potentials in patients with multiple sclerosis. Brain 1977;100: Hashimoto I, Ishiyama Y, Yoshimoto T, Nemoto S: Brainstem auditory evoked potentials recorded directly from the human thalamus. Brain 1981;104: McGee T, Kraus N, Comperatore C, Nicol T: Subcortical and cortical components of the MLR generating system. Brain Res 1991;54: Kileny P, Paccioretti D, Wilson AF: Effects of cortical lesions on middle-latency auditory evoked responses. Electroencephalogr Clin Neurophysiol 1987;66: Jacobson GP, Privitera M, Neils JM, Yeh H-S: The effects of anterior temporal lobectomy on the middle latency auditory evoked potential. Electroencephalogr Clin Neurophysiol 1990;75: Chatrian GE, Petersen MC, Lazarte JA: Responses to clicks from the human brain: Some depth electrographic observations. Electroencephalogr Clin Neurophysiol 1960;12: Ruhm H, Walker E, Flanigan H: Acoustically-evoked potentials in man: Mediation of early components. Laryngoscope 1967;77: Lee YS, Lueders H, Dinner DS, Lesser RP, Hahn J, Klem G: Recording of auditory evoked potentials in man using chronic subdural electrodes. Brain 1984;107: Celesia GC, Broughton RJ, Rasmussen T, Branch C: Auditory evoked responses from the exposed human cortex. Electroencephalogr Clin Neurophysiol 1968;24: Vaughan HG Jr, Ritter W: The sources of auditory evoked responses recorded from the human scalp. Electroencephalogr Clin Neurophysiol 1970;28: Wood CC, Wolpaw JR: Scalp distribution of human auditory evoked potentials. II. Evidence for overlapping sources and involvement of auditory cortex. Electroencephalogr Clin Neurophysiol 1982;54: Scherg M, Hari R, Hämäläinen M: Frequency-specific sources of the auditory N19-P30-P50 response detected by a multiple source analysis of evoked magnetic fields and potentials; in Williamson SJ, Hoke M, Stroink G, Kotani M (eds): Advances in Biomagnetism. New York, Plenum, 1989, pp Jacobson GP, Newman CW, Privitera M, Grayson AS: Differences in superficial and deep source contributions to middle latency auditory evoked potential Pa component in normal subjects and patients with neurological disease. J Am Acad Audiol 1991;2: Kraus N, Özdamar Ö, Hier D, Stein L: Auditory middle latency responses in patients with cortical lesions. Electroencephalogr Clin Neurophysiol 1982;54: Kileny PR, Kemink JL: Electrically evoked middle-latency auditory potentials in cochlear implant candidates. Arch Otolaryngol 1987;113: Jacobson/Kraus/McGee 74

82 21 Özdamar Ö, Kraus N: Auditory middle latency responses in humans. Audiology 1983;22: Pool KD, Finitzo T, Hong CT, Rogers J, Pickett RB: Infarction of the superior temporal gyrus: A description of auditory evoked potential latency and amplitude topology. Ear Hear 1989;10: Scherg M, Von Cramon D: Evoked dipole source potentials of the human auditory cortex. Electroencephalogr Clin Neurophysiol 1986;65: Scherg M, Vajsar J, Picton T: A source analysis of the late human auditory evoked potentials. J Cogn Neurosci 1989;1: Osterhammel PA, Shallop JK, Terkildsen K: The effect of sleep on the auditory brainstem response and the middle latency response. Scand Audiol 1985;14: Kraus N, McGee T, Comperatore C: MLRs in children are consistently present during wakefulness, stage 1, and REM sleep. Ear Hear 1989;10: Parving A, Salomon G, Elberling C, Larsen B, Lassen NA: Middle components of the auditory evoked response in bilateral temporal lobe lesions. Scand Audiol 1980;9: Rosati G, Bastiani PD, Paolino E, Prosser A, Arslan E, Artioli, M: Clinical and audiological findings in a case of auditory agnosia. J Neurol 1982;227: Woods DL, Clayworth CC, Knight RT, Simpson GV, Naeser MA: Generators of middle- and longlatency auditory evoked potentials: Implications from studies of patients with bitemporal lesions. Electroencephalogr Clin Neurophysiol 1987;68: Kraus N, Smith DI, McGee T: Midline and temporal lobe MLRs in the guinea pig originate from different generator systems: A conceptual framework for new and existing data. Electroencephalogr Clin Neurophysiol 1988;70: Pantev C, Bertrand O, Eulitz C, Verkindt C, Hampson S, Schuierer G, Elbert T: Specific tonotopic organizations of different areas of the human auditory cortex revealed by simultaneous magnetic and electrical recordings. Electroencephalogr Clin Neurophysiol 1995;94: Hari R, Pelizzone M, Mäkelä JP, Hällström J, Leinonen L, Lounasmaa OV: Neuromagnetic responses of the human auditory cortex to on- and offsets of noise bursts. Audiology 1987;26: Kavanagh KT, Gould H, McCormick G, Franks R: Comparison of the identifiability of the low intensity ABR and MLR in the mentally handicapped patient. Ear Hear 1989;10: Kraus N, McGee T: Electrophysiology of the human auditory system; in Popper AN, Fay RR (eds): The Mammalian Auditory Pathway: Neurophysiology. New York, Springer, 1992, vol 2, pp Vivion MC, Hirsch JE, Frye-Osier H, Goldstein R: Effects of stimulus rise-fall time and equivalent duration on middle components of AER. Scand Audiol 1980;9: Kavanagh KT, Harker LA, Tyler RS: Auditory brainstem and middle latency responses. I. Effects of response filtering and waveform identification. II. Threshold responses to a 500-Hz tone pip. Acta Otolaryngol 1984;108: Kraus N, Özdamar Ö, Stein L, Reed N: Absent auditory brainstem response: Peripheral hearing loss or brainstem dysfunction? Laryngoscope 1984;94: Gardi JN: Human brain stem and middle latency responses to electrical stimulation: A preliminary observation; in Schindler R, Merzenich M (eds): Cochlear Implants. New York, Raven Press, 1985, pp Miyamoto RT: Electrically evoked potential in cochlear implant subjects. Laryngoscope 1986;96: Romani G-L, Williamson S, Kaufman L, Brenner D: Characterization of human auditory cortex by neuromagnetic method. Exp Brain Res 1982;47: Galambos R, Makeig S, Talmachoff PJ: A 40 Hz auditory potential recorded from the human scalp. Proc Natl Acad Sci USA 1981;78: Spydell JD, Pattee G, Goldie WD: The 40 Hz event-related potential: Normal values and effects of lesions. Electroencephalogr Clin Neurophysiol 1985;62: Firsching R, Luther J, Eidelberg E, Brown WE, Story JL, Boop FA: 40-Hz middle latency auditory evoked response in comatose patients. Electroencephalogr Clin Neurophysiol 1987;67: Galambos R: Tactile and auditory stimuli repeated at high rates (30 50 s) produce similar event related potentials. Ann NY Acad Sci 1982;388: Middle and Long Latency ERPs 75

83 45 Pantev C, Elbert T, Makeig S, Hampson S, Eulitz C, Hoke M: Relationship of transient and steadystate auditory evoked fields. Electroencephalogr Clin Neurophysiol 1993;88: Stapells DR, Linden D, Suffield JB, Hamel G, Picton TW: Human auditory steady state potentials. Ear Hear 1984;5: Rodriguez R, Picton T, Linden D, Hamel G, Laframboise G: Human auditory steady state responses: Effects of intensity and frequency. Ear Hear 1986;7: Stapells DR, Makeig S, Galambos R: Auditory steady-state responses: Threshold prediction using phase coherence. Electroencephalogr Clin Neurophysiol 1987;67: Erwin RJ, Buchwald JS: Midlatency auditory evoked responses: Differential recovery cycle characteristics. Electroencephalogr Clin Neurophysiol 1986;64: Erwin R, Buchwald JS: Midlatency auditory evoked responses: Differential effects of sleep in the human. Electroencephalogr Clin Neurophysiol 1986;65: Adler LE, Waldo MC, Freedman R: Neurophysiologic studies of sensory gating in schizophrenia: Comparison of auditory and visual responses. Biol Psychiatry 1985;20: Nagamoto HT, Adler LE, Waldo MC, Freedman R: Sensory gating in schizophrenics and normal controls: Effects of changing stimulation interval. Biol Psychiatry 1989;25: Boutros NN, Overall J, Zouridakis G: Test-retest reliability of the P50 mid-latency auditory evoked response. Psychiatry Res 1991;39: Waldo M, Gerhardt G, Baker N, Drebing C, Adler L, Freedman R: Auditory sensory gating and catecholamine metabolism in schizophrenic and normal subjects. Psychiatry Res 1992;44: Cardenas VA, Gerson J, Fein G: The reliability of P50 suppression as measured by the conditioning/ testing ratio is vastly improved by dipole modeling. Biol Psychiatry 1993;33: Kathman N, Engel RR: Sensory gating in normals and schizophrenics: A failure to find strong P50 suppression in normals. Biol Psychiatry 1990;27: Smith DA, Boutros NN, Schwarzkopf SB: Reliability of P50 auditory event-related potential indices of sensory gating. Psychophysiology 1994;31: Buchwald JS, Erwin RJ, Read S, Van Lancker D, Cummings JL: Midlatency auditory evoked responses: Differential abnormality of P1 in Alzheimer s disease. Electroencephalogr Clin Neurophysiol 1989;74: Buchwald JS, Hinman C, Norman RJ, Huang CM, Brown KA: Middle- and long-latency auditory evoked responses recorded from the vertex of normal and chronically lesioned cats. Brain Res 1981; 205: Hinman CL, Buchwald JS: Depth evoked potential and single unit correlates of vertex midlatency auditory evoked responses. Brain Res 1983;264: Dickerson L, Buchwald J, Chen BM: Midlatency auditory evoked responses in the cat: Effects of scopalomine, a postsynaptic antagonist of muscarinic cholinergic neurotransmission. Neurosci Abstr 1986;12: Harrison J, Buchwald J, Song S, Woolf N, Butcher L: Pontine reticular formation lesions in the cat: Effects of P1 potential and behavior. Neurosci Abstr 1988;14: Pantev C, Makeig S, Hoke M, Galambos R, Gallen C, Hampson S: Human auditory evoked gamma band magnetic fields. Proc Natl Acad Sci USA 1991;88: Pantev C, Elbert T, Makeig S, Hampson S, Eulitz C, Hoke M: Relationship of transient and steadystate auditory evoked fields. Electroencephalogr Clin Neurophysiol 1993;88: Pantev C: Evoked and induced gamma-band activity of the human cortex. Brain Topogr 1995;76: Singer W: Neuronal representations, assemblies, and temporal coherence. Prog Brain Res 1993;95: Singer W: Synchronization of cortical activity and its putative role in information processing and learning. Annu Rev Physiol 1993;55: Engel A, Konig P, Kreiter A, Singer W: Interhemispheric synchronization of oscillatory neuronal responses in cat visual cortex. Science 1991;252: Engel A, Konig P, Singer W: Direct physiological evidence for scene segmentation by temporal coding. Proc Natl Acad Sci USA 1991;88: Jacobson/Kraus/McGee 76

84 70 Engel A, Kreiter A, Konig P, Singer W: Synchronization of oscillatory neuronal responses between striate and extrastriate visual cortical areas of the cat. Proc Natl Acad Sci USA 1991;88: Engel AK, König P, Kreiter AK, Schillen TB, Singer W: Temporal coding in the visual cortex: New vistas on integration in the nervous sytem. Trends Neurosci 1992;15: Gray CM, Singer W: Stimulus-specific neuronal oscillations in orientation columns of cat visual cortex. Proc Natl Acad Sci USA 1989;86: Gray C, Konig P, Engel A, Singer W: Oscillatory responses in cat visual cortex exhibit intercolumnar synchronization which reflects global stimulus properties. Nature 1989;338: Jagadeesh B, Gray CM, Ferster D: Visually evoked oscillations of membrane potential in cells of cat visual cortex. Science 1992;257: Konig P, Engel A, Singer W: Relation between oscillatory activity and long-range synchronization in cat visual cortex. Proc Natl Acad Sci USA 1995;92: Adrian ED: Olfactory reactions in the brain of the hedgehog. J Physiol 1942;100: Freeman WJ: Mass Action in the Nervous System. New York, Academic Press, Freeman WJ: Nonlinear dynamics of paleocortex manifested in the olfactory EEG. Biol Cybern 1979;35: Bertrand O, Pantev C: Stimulus frequency dependence of the transient oscillatory auditory evoked responses (40 Hz) studied by electric and magnetic recordings in human; in Pantev C, Elbert T (eds): Oscillatory Event Related Brain Dynamics. New York, Plenum, 1994, pp Tiitinen H, Sinkkonen J, Reinikainen K, Alho K, Lavikainen J, Näätänen R: Selective attention enhances the auditory 40 Hz transient response in humans. Nature 1993;364: Moran JE, Tepley N, Jacobson GP, Barkley G: Evidence for multiple generators in evoked responses using finite difference field mapping: Auditory evoked fields. Brain Topogr 1993;5: Pantev C, Hoke M, Lütkenhöner B, Lehnertz K: Neuromagnetic evidence of functional organization of the auditory cortex in humans. Acta Otolaryngol 1991;491: Davis PA: Effects of acoustic stimuli on the waking human brain. J Neurophysiol 1939;2: Nelson DA, Lassman FM: Effects of intersignal interval on the human auditory evoked response. J Acoust Soc Am 1968;44: Rothman HH, Davis H, Hay IS: Slow evoked cortical potentials and temporal features of stimulation. Electroencephalogr Clin Neurophysiol 1970;29: Hari R, Kaila K, Katila T, Tuomisto T, Varpula T: Interstimulus interval dependence of the auditory vertex response and its magnetic counterpart: Implications for their neural generation. Electroencephalogr Clin Neurophysiol 1982;54: Wolpaw JR, Penry JK: A temporal component of the auditory evoked response. Electroencephalogr Clin Neurophysiol 1975;39: Näätänen R, Picton T: The N1 wave of the human electric and magnetic response to sound. Psychophysiology 1987;24: Yamamoto T, Williamson SJ, Kaufman L, Nicholson C, Llinas R: Magnetic localization of neuronal activity in the human brain. Proc Natl Acad Sci USA 1988;85: Pantev C, Hoke M, Lehnertz K, Lütkenhöner B, Fahrendorf G, Stöber U: Identification of sources of brain neuronal activity with high spatiotemporal resolution through combination of neuromagnetic source localization and magnetic resonance imaging. Electroencephalogr Clin Neurophysiol 1990; 75: Papanicolaou AC, Baumann S, Rogers RL, Caydjari C, Amparo EG, Eisenberg HM: Localization of auditory response sources using magnetoencephalography and magnetic resonance imaging. Arch Neurol 1990;47: Elberling C, Bak C, Kofoed B, Lebech J, Saermark K: Auditory magnetic fields. Source location and tonotopic organization in the right hemisphere of the human brain. Scand Audiol 1982;11: Pantev C, Hoke M, Lehnertz K, Lütkenhöner B, Anogianakis G, Wittkowski W: Tonotopic organization of the human auditory cortex revealed by transient auditory evoked magnetic fields. Electroencephalogr Clin Neurophysiol 1988;69: Jacobson GP, Lombardi DM, Gibbens ND, Ahmad BK, Newman CW: The effects of stimulus frequency and recording site on the amplitude and latency of multichannel cortical auditory evoked potential component N1. Ear Hear 1992;13: Middle and Long Latency ERPs 77

85 95 Pantev C, Hoke M, Lehnertz K, Lütkenhöner B: Neuromagnetic evidence of an amplitopic organization of the auditory cortex. Electroencephalogr Clin Neurophysiol 1989;72: Pantev C, Lütkenhöner B, Hoke M, Lehnertz K: Comparison between simultaneously recorded auditory-evoked magnetic fields and potentials elicited by ipsilateral, contralateral and binaural tone burst stimulation. Audiology 1986;25: Hari R: The neuromagnetic method in the study of the human auditory cortex; in Grandori F, Hoke M, Romani GL (eds): Auditory Evoked Magnetic Fields and Electric Potentials. Adv Audiol. Basel, Karger, 1990, vol 6, pp Tiihonen J, Hari R, Kaukoranta E, Kajola M: Interaural interaction in the human auditory cortex. Audiology 1989;28: Elberling C, Bak C, Kofoed B, Lebech J, Saermark K: Auditory magnetic fields from the human cortex. Influence of stimulus intensity. Scand Audiol 1981;10: Elberling C, Bak C, Kofoed B, Lebech J, Saermark K: Auditory magnetic fields from the human cerebral cortex: Location and strength of an equivalent current dipole. Acta Neurol Scand 1982; 65: Joutsiniemi S-L: Comparison between electric evoked potentials, source dipole components and magnetic fields elicited by noise/square-wave stimuli. Acta Neurol Scand 1988;78: Leinonen L, Joutsiniemi S-L: Auditory evoked potentials and magnetic fields in patients with lesions of the auditory cortex. Acta Neurol Scand 1989;79: Mäkelä JP, Hari R, Valanne L, Ahonen A: Auditory evoked magnetic fields after ischemic brain lesions. Ann Neurol 1991;30: Connolly JF, Manchanda R, Gruzelier JH, Hirsch SR: Pathway and hemispheric differences in the event related potential to monaural stimulation: A comparison of schizophrenic patients with normal controls. Biol Psychiatry 1985;20: Sandman CA, Gerner R, O Halloran JP, Isenhart R: Event related potentials and item recognition in depressed, schizophrenic, and alcoholic patients. Int J Psychopathol 1987;5: Reite M, Teale P, Goldstein L, Whalen J, Linnville S: Late auditory magnetic sources may differ in the left hemisphere of schizophrenic patients. Arch Gen Psychiatry 1989;46: Hoke M, Feldmann H, Pantev C, Lütkenhöner B, Lehnertz K: Objective evidence of tinnitus in auditory evoked magnetic fields. Hear Res 1989;37: Pantev C, Hoke M, Lütkenhöner B, Lehnertz K, Kumpf W: Tinnitus remission objectified by neuromagnetic measurements. Hear Res 1989;40: Jacobson GP, Ahmad BK, Moran J, Newman CW, Tepley N, Wharton J: Auditory evoked cortical magnetic field (M100/M200) measurements in tinnitus and normal groups. Hear Res 1991;56: Colding-Jorgenson E, Lauritzen M, Johnsen NJ, Mikkelsen KB, Saermark K: On the evidence of auditory evoked magnetic fields as an objective measure of tinnitus. Electroencephalogr Clin Neurophysiol 1992;83: Jacobson GP, Ahmad BK, Moran J, Newman CW, Wharton J, Tepley N: Occurrence of auditory evoked field N1m and P2m components in a sample of normal subjects. Ear Hear 1992;13: Pelizzone M, Hari R, Mäkelä JP, Kaukoranta E, Montandon P: Activation of the auditory cortex by cochlear stimulation in a deaf patient. Neurosci Lett 1986;68: Hoke M, Pantev C, Lütkenhöner B, Lehnertz K, Sürth W: Magnetic fields from the auditory cortex of a deaf human individual occurring spontaneously or evoked by stimulation through a cochlear prosthesis. Audiology 1989;28: Hari R, Pelizzone M, Mäkelä JP, Huttunen J: Neuromagnetic responses from a deaf subject to stimuli presented through a multichannel cochlear prosthesis. Ear Hear 1988;9: Hari R, Aittoniemi K, Järvinen M-L, Katila T, Varpula T: Auditory evoked transient and sustained magnetic fields of the human brain: Localization of neural generators. Exp Brain Res 1980;40: Squires NK, Galbraith GC, Aine CJ: Event-related potential assessment of sensory and cognitive deficits in the mentally retarded; in Lehmann D, Callaway E (eds): Human Evoked Potentials: Applications and Problems. New York, Plenum Press, 1979, pp Jirsa R, Clontz K: Long latency auditory event-related potentials from children with auditory processing disorders. Ear Hear 1990;11: Jacobson/Kraus/McGee 78

86 118 Näätänen R, Gaillard AWK, Mäntysalo S: Early selective attention effect on evoked potential reinterpreted. Acta Psychol 1978;42: Näätänen T, Paavilainen P, Tiitinen H, Jiang D, Alho A: Attention and mismatch negativity. Psychophysiology 1993;30: Kraus N, McGee T, Micco A, Sharma A, Carrell T, Nicol T: Mismatch negativity in school-age children to speech stimuli that are just perceptibly different. Electroencephalogr Clin Neurophysiol 1993;88: Näätänen R: Attention and Brain Function. Hillsdale/NJ, Erlbaum Assoc, Sams M, Hämäläinen M, Antervo A, Kaukaraunta E, Reinikainen K, Hari R: Cerebral neuromagnetic responses evoked by short auditory stimuli. Electroencephalogr Clin Neurophysiol 1985;61: Sharma A, Kraus N, McGee T, Carrell T, Nicol T: Acoustic vs phonetic representation of speech stimuli as reflected by the mismatch negativity event-related potential. Electroencephalogr Clin Neurophysiol 1993;88: Aaltonen O, Niemi P, Nyrke T, Tuhkanenen M: Event-related brain potentials and the perception of a phonetic continuum. Biol Psychol 1987;24: Kaukoranta E, Sams M, Hari R, Hämäläinen M, Näätänen R: Reactions of human auditory cortex to changes in tone duration: Indirect evidence for duration-specific neurons. Hear Res 1989;41: Näätänen R: The role of attention in auditory information processing as revealed by event-related brain potentials and other brain measures of cognitive function. Behav Brain Sci 1990;13: Näätänen R, Paavilainen P, Alho K, Reinikainen K, Sams M: The mismatch negativity to intensity changes in an auditory stimulus sequence. Electroencephalogr Clin Neurophysiol 1987;(suppl 40): Näätänen R, Paavilainen P, Reinikainen K: Do event-related potentials reveal the mechanism of auditory sensory memory in the human brain? Neurosci Lett 1989;98: Novak G, Ritter W, Vaughan H, Wiznitzer M: Differentiation of negative event-related potentials in an auditory discrimination task. Electroencephalogr Clin Neurophysiol 1990;75: Paavilainen P, Karlsson M, Reinikainen K, Näätänen R: Mismatch negativity to changes in the spatial location of an auditory stimulus. Electroencephalogr Clin Neurophysiol 1989;73: Sams M, Paavilainen P, Alho K, Näätänen R: Auditory frequency discrimination and event-related potentials. Electroencephalogr Clin Neurophysiol 1985;62: Ritter W, Simson R, Vaughan HG Jr, Friedman DA: A brain event related to the making of a sensory discrimination. Science 1979;203: Snyder E, Hillyard S: Long-latency evoked potentials to irrelevant, deviant stimuli. Behav Biol 1976; 16: Mäntysalo S, Näätänen R: Duration of a neuronal trace of an auditory stimulus as indicated by event-related potentials. Biol Psychol 1987;24: Böttcher-Gandor C, Ullsperger P: Mismatch negativity in event-related potentials to auditory stimuli as a function of varying interstimulus interval. Psychophysiology 1992;29: Imada T, Hari R, Loveless N, McEvoy L, Sams M: Determinants of the auditory mismatch response. Electroencephalogr Clin Neurophysiol 1993;87: Kraus N, McGee T, Sharma A, Carrell T: Neurophysiologic bases of speech discrimination. Ear Hear 1995;16: Csépe V: On the origin of the mismatch negativity. Ear Hear 1995;16: Rugg MD: Event-related potentials and the phonological processing of words and non-words. Neuropsychologia 1984;22: Rugg MD: Event-related potentials in phonological matching tasks. Brain Lang 1984;23: Alho K, Sainio K, Sajaniemi N, Reinikainen K, Näätänen R: Event-related brain potential of human newborns to pitch change of an acoustic stimulus. Electroencephalogr Clin Neurophysiol 1990;77: Nielsen-Bohlman L, Knight RT, Woods DL, Woodward K: Differential auditory processing continues during sleep. Electroenceph Clin Neurophysiol 1991;79: Middle and Long Latency ERPs 79

87 143 Csépe V, Karmos G, Molnár M: Evoked potential correlates of stimulus deviance during wakefulness and sleep in cat Animal model of mismatch negativity. Electroencephalogr Clin Neurophysiol 1987;66: Kraus N, McGee T, Carrell T, King C, Littman T, Nicol T: Discrimination of speech-like signals in auditory thalamus and cortex. J Acoust Soc Am 1994;96: Korpilahti P, Lang H: The auditory ERP components and mismatch negativity in dysphasic children. Electroencephalogr Clin Neurophysiol 1994;91: Kraus N, Micco A, Koch D, McGee T, Carrell T, Wiet R, Weingarten C, Sharma A: The mismatch negativity cortical evoked potential elicited by speech in cochlear-implant users. Hear Res 1993;65: Csépe V, Karmos G, Molnár M: Evoked potential correlates of sensory mismatch process during sleep in cats; in Koella WP, Obal F, Schulz H, Visser P (eds): Sleep 86. Stuttgart, Thieme, 1988, pp Kurtzberg D, Hilpert P, Kreuzer J, Vaughan HG: Differential maturation of cortical auditory evoked potentials to speech sounds in normal full term and very low-birthweight infants. Dev Med Child Neurol 1984;26: Kurtzberg D, Vaughan HG, Courchesne E, Friedman D, Harter MR, Putnam LE: Developmental aspects of event-related potentials. Ann NY Acad Sci 1984;425: Roffwarg H, Muzio J, Dement W: Ontogenetic development of the human sleep-dream cycle. Science 1966;152: Kraus N, McGee T: Clinical implications of primary and non-primary components of the MLR generating system. Ear Hear 1993;14: McGee T, Kraus N, Killion M, Rosenberg R, King C: Improving the reliability of the auditory middle latency response. Ear Hear 1993;14: Sams M, Kaukoranta E, Hari R, Hämäläinen M, Näätänen R: Cortical activity elicited by changes in auditory stimuli: Different sources for the magnetic N100m and mismatch responses. Psychophysiology 1991;28: Giard MH, Perrin F, Pernier J, Bouchet P: Brain generators implicated in processing of auditory stimulus deviance: A topographic study. Psychophysiology 1990;27: Javitt D, Schroeder C, Steinschneider M, Arezzo J, Vaughan H: Demonstration of mismatch negativity in monkey. Electroencephalogr Clin Neurophysiol 1992;83: Kraus N, McGee T, Littman T, Nicol T, King C: Encoding of acoustic change involves non-primary auditory thalamus. J Neurophysiol 1994;72: Tiitinen H, Alho K, Huotilainen M, Ilmoniemi RJ, Simola J, Näätänen R: Tonotopic auditory cortex and the magnetoencephalographic equivalent of the mismatch negativity. Psychophysiology 1993;30: Elliott L, Hammer M: Longitudinal changes in auditory discrimination in normal children and children with language-learning problems. J Speech Hear Dis 1988;53: Elliott L, Hammer M, Scholl M: Fine-grained auditory discrimination in normal children and children with language-learning problems. J Speech Hear Res 1989;32: Tallal P, Stark R, Kallman C, Mellitis D: Developmental dysphasia: The relation between acoustic processing deficits and verbal processing. Neuropsychologia 1980;18: Tallal P, Stark R, Mellitis F: The relationship between auditory temporal analysis and receptive language development: Evidence from studies of developmental language disorder. Neuropsychologia 1985;23: Aaltonen O, Tuomainen J, Laine M, Niemi P: Cortical differences in tonal versus vowel processing as revealed by an ERP component called mismatch negativity. Brain Lang 1993;44: Woods DL: The physiological basis of selective attention: Implications of event-related potential studies; in Rohrbaugh JW, Parasuraman R, Johnson R (eds): Event-Related Brain Potentials. New York, Oxford Press, 1990, pp Hillyard SA, Hink RF, Schwent VL, Picton TW: Electrical signs of selective attention in the human brain. Science 1973;182: Näätänen R, Michie PT: Early selective attention effects of the evoked potential. A critical review and reinterpretation. Biol Psychol 1979;8: Jacobson/Kraus/McGee 80

88 166 Arthur DL, Lewis PS, Medvick PA, Flynn ER: A neuromagnetic study of selective attention. Electroencephalogr Clin Neurophysiol 1991;78: Yingling CD, Skinner JE: Gating of thalamic input to cerebral cortex by nucleus reticularis thalami; in Desmedt JE (ed): Attention, Voluntary Contraction and Event-Related Cerebral Potentials. Prog Clin Neurophysiol. Basel, Karger, 1977, vol 1, pp Pekkonen E, Jousmäki V, Partanen J, Karhu J: Mismatch negativity area and age-related auditory memory. Electroencephalogr Clin Neurophysiol 1993;87: Strandburg RJ, Marsh JT, Brown WS, Asarnow RF, Guthrie D, Higa J: Reduced attention-related negativepotentialsinschizophrenicchildren. ElectroencephalogrClinNeurophysiol1991;79: Jacobson GP, Calder JC, Newman CW, Peterson EL, Wharton JA, Ahmad BK: Electrophysiological indices of selective auditory attention in subjects with and without tinnitus. Hear Res 1996;97: Sutton S, Braren M, Zubin J, John ER: Evoked-potential correlates of stimulus uncertainty. Science 1965;150: Courchesne E: Neurophysiological correlates of cognitive development: Changes in long-latency event-related potentials from childhood to adulthood. Electroencephalogr Clin Neurophysiol 1978; 45: Kurtzberg D, Vaughan HG, Kreuzer JA: Task-related cortical potentials in children. Prog Clin Neurophysiol 1979;6: Polich J, Starr A: Middle, late and long latency auditory evoked potentials; in Moore E (ed): Bases of Auditory Brainstem Evoked Responses. New York, Grune & Stratton, 1983, pp Klinke R, Fruhstorfer H, Finkenzellar P: Evoked responses as a function of external and stored information. Electroencephalogr Clin Neurophysiol 1968;25: Picton TW, Hillyard SH, Krausz HI, Galambos R: Human auditory evoked potentials. I. Evaluation of components. Electroencephalogr Clin Neurophysiol 1974;36: Squires NK, Squires KC, Hillyard SA: Two varieties of long-latency positive waves evoked by unpredictable auditory stimuli in man. Electroencephalogr Clin Neurophysiol 1975;38: Kurtzberg D, Stapells DR, Wallace IF: Event-related potential assessment of auditory system integrity: Implications for language development; in Vietze P, Vaughan HG (eds): Early Identification of Infants with Developmental Disabilities. Philadelphia, Grune & Stratton, 1988, pp Roth W: Auditory evoked responses to unpredictable stimuli. Psychophysiology 1973;10: Polich J: Frequency, intensity and duration as determinants of P300 from auditory stimuli. J Clin Neurophysiol 1989;6: Polich J: Semantic categorization and event-related potentials. Brain Lang 1985;26: Picton TW, Hillyard SA: Endogenous event-related potentials; in Picton TW (ed): Human Event- Related Potentials. Amsterdam, Elsevier Science, Donchin E: Surprise! Surprise? Psychophysiology 1981;18: Ford JM, Mohs RC, Pfefferbaum A, Kopell BS: On the utility of P3 latency and RT for studying cognitive processes; in Kornhuber HH, Deecke L (eds): Motivation, Motor and Sensory Processes of the Brain. Prog Brain Res. Amsterdam, Elsevier, 1980, vol 54, pp Squires KC, Wickens C, Squires NK, Donchin E: The effect of stimulus sequence on the waveform of the cortical event-related potential. Science 1976;193: Squires NK, Donchin E, Squires KC, Grossberg S: Bisensory stimulation: Inferring decision-related processes from the P300 component. J Exp Psychol [Hum Percept] 1977;2: Wood CC, Allison T, Goff WR, Williamson PD, Spencer DB: On the neural origin of P300 in man; in Kornhuber HH, Deecke L (eds): Motivation, Motor and Sensory Processes of the Brain. Prog Brain Res. Amsterdam, Elsevier, 1980, vol 54, pp Okada YC, Kaufman L, Williamson SJ: The hippocampal formation as a source of the slow endogenous potentials. Electroencephalogr Clin Neurophysiol 1983;55: Halgren E, Squires NK, Wilson CL, Rohrbaugh JR, Babb TL, Crandall PH: Endogenous potentials generated in the human hippocampal formation and amygdala by infrequent events. Science 1980; 210: McCarthy G, Wood CC, Alison T, Goff WR, Williamson PD, Spencer DD: Intracranial recordings of event-related potentials in humans engaged in cognitive tasks. Soc Neurosci Abstr 1982;8:976. Middle and Long Latency ERPs 81

89 191 Squires NK, Halgren E, Wilson C, Crandall P: Human endogenous limbic potentials: Cross-modality and depth/surface comparisons in epileptic subjects; in Gaillard AWK, Ritter W (eds): Tutorials in ERP Research: Endogenous Components. Amsterdam, North-Holland, 1983, pp Yingling CD, Hosobuchi Y: A subcortical correlate of P300 in man. Electroencephalogr Clin Neurophysiol 1984;59: Desmedt JE, Debecker J: Wave form and neural mechanism of the decision P350 elicited without pre-stimulus CNV or readiness potential in random sequences of near threshold auditory clicks and finger stimuli. Electroencephalogr Clin Neurophysiol 1979;47: Simson R, Vaughan HG Jr, Ritter W: The scalp topography of potentials in auditory and visual go/no go tasks. Electroencephalogr Clin Neurophysiol 1977;43: Simson R, Vaughan HG Jr, Ritter W: The scalp topography of potentials in auditory and visual discrimination tasks. Electroencephalogr Clin Neurophysiol 1977;42: Goff ER, Allison T, Vaughan HG Jr: The functional neuroanatomy of event-related potentials; in Calaway E, Tueting P, Koslow SH (eds): Event-Related Potentials in Man. New York, Academic Press, 1978, pp Pritchard WS: Psychophysiology of P300. Psychol Bull 1981;89: Richer F, Johnson RA, Beatty J: Sources of late components of the brain magnetic response. Soc Neurosci Abstr 1983;9: Ciesielki K, Courchesne E, Elmasian R: Effects of focused selective attention tasks on eventrelated potentials in autistic and normal individuals. Electroencephalogr Clin Neurophysiol 1990; 75: Loiselle DL, Stamm JA, Maitinsky S, Whipple SC: Evoked potential and behavioral signs of attentive dysfunctions in hyperactive boys. Psychophysiology 1980;17: Lincoln A, Courchesne E, Kilman B, Galambos R: Neuropsychological correlates of information processing by children with Down s syndrome. Am J Ment Defic 1985;89: Diner D, Holcomb P, Dykman R: P-300 in a major depressive disorder. Psychiatry Res 1985;15: Finley WW, Faux SF, Hutcheson J, Amstutz L: Long-latency event-related potentials in the evaluation of cognitive function in children. Neurology 1985;35: Hansch EC, Syndulko K, Cohen SM, Goldberg ZI, Potvin AR, Tourtellotte WW: Cognition in Parkinson disease: An event-related potential perspective. Ann Neurol 1982;11: Cohen SN, Syndulko K, Rever B, Kraut J, Coburn J, Tourtellotte WW: Visual evoked potentials and long latency event-related potentials in chronic renal failure. Neurology 1983;33: Pfefferbaum A, Horvath T, Rothe W, Kopell B: Event related potential changes in chronic alcoholics. Electroencephalogr Clin Neurophysiol 1979;47: Goodin DS, Squires KC, Henderson BH, Starr A: Age-related variations in evoked potentials to auditory stimuli in normal human subjects. Electroencephalogr Clin Neurophysiol 1978;44: Goodin DS, Squires K, Starr A: Long latency event-related components of the auditory evoked potential in dementia. Brain 1978;101: Pfefferbaum A, Ford J, Roth W, Kopell B: Age-related changes in auditory event-related potentials. Electroencephalogr Clin Neurophysiol 1980;49: Ebner A, Haas J, Lucking C, Schily M, Wallesch C, Zimmerman P: Event-related brain potentials (P300) and neuropsychological deficit in patients with focal brain lesions. Neurosci Lett 1986;64: Michalewski H, Rosenberg C, Starr A: Event related potentials in dementia; in Cracco R, Bodis- Wollner I (eds): Evoked Potentials. New York, Liss, 1986, pp Musiek FE, Baran JA, Pinheiro ML: P300 results in patients with lesions of the auditory areas of the cerebrum. J Am Acad Audiol 1992;3: Baribeau-Braun J, Picton TW, Gosselin J-Y: Schizophrenia: A neurophysiological evaluation of abnormal information processing. Science 1983;219: Roth WT, Horvath TB, Pfefferbaum A, Kopell BS: Event-related potentials. Electroencephalogr Clin Neurophysiol 1980;8: Selinger M, Prescott T: Auditory event-related potentials probes and behavioral measures of aphasia. Brain Lang 1989;36: Jacobson/Kraus/McGee 82

90 216 Brown WS, Marsh JT, Larue A: Event-related potentials in psychiatry: Differentiating depression and dementia in the elderly. Bull LA Neurol Soc 1982;47: Syndulko K, Hansch MA, Cohen SN, Pearce JW, Goldberg Z, Montan B, Tourtellotte WW, Potvin AR: Long-latency event-related potentials in normal aging and dementia; in Courjon J, Mauguiere F, Revol M (eds): Clinical Applications of Evoked Potentials in Neurology. New York, Raven Press, 1982, pp Chayasirisobhon S, Brinkman S, Gerganoff S, Gershon S, Pomara N, Green V: Event-related potential in Alzheimer disease. Clin Electroencephalogr 1985;16: Ford JM, Roth WT, Mohs RC, Hopkins WF, Kopell BS: Event-related potentials recorded from young and old adults during a memory retrieval task. Electroencephalogr Clin Neurophysiol 1979; 47: Olbrich HM, Nau HE, Lodemann E, Zerbin D: Evoked potential assessment of mental function during recovery from severe head injury. Surg Neurol 1986;26: Johnson R, Fedio P: Task related changes in P-300 scalp distribution in temporal lobectomy patients; in Johnson R, Rohrbaugh J, Parasuraman R (eds): Current Trends in Evoked Potential Research. Electroencephalogr Clin Neurophysiol 1987;(suppl 40): Kileny P: Use of electrophysiologic measures in the management of children with cochlear implants: Brainstem, middle latency and cognitive (P300) responses. Am J Otol 1991;12: Micco AG, Kraus N, Koch DB, McGee TJ, Carrell TD, Sharma A, Nicol T, Wiet RJ: Speech evoked cognitive P300 potentials in cochlear implant recipients. Am J Otol 1995;16: Herning RI, Jones RT, Hunt JS: Speech event related potentials reflect linguistic content and processing level. Brain Lang 1987;30: McCallum WC, Farmer SF, Pocock PK: The effects of physical and semantic incongruities on auditory event-related potentials. Electroencephalogr Clin Neurophysiol 1984;59: Kutas M, Neville HJ, Holcomb P: A preliminary comparison of the N400 response to semantic anomalies during reading, listening and signing. Electroencephalogr Clin Neurophysiol 1987;(suppl 39): Kutas M, Hillyard SA: Reading senseless sentences: Brain potentials reflect semantic incongruity. Science 1980;207: Kutas M, Hillyard SA: Event-related brain potentials to semantically inappropriate and surprisingly large words. Biol Psychol 1980;11: Neville HJ, Kutas M, Chesney G, Schmidt AL: Event-related brain potentials during initial encoding and recognition memory of congruous and incongruous words. J Mem Lang 1986;25: Harbin TJ, Marsh GR, Harvey MT: Differences in the late components of the event-related potential due to age and to semantic and non-semantic tasks. Electroencephalogr Clin Neurophysiol 1984; 59: Bentin S, McCarthy G, Wood CC: Event-related potentials, lexical decision and semantic priming. Electroencephalogr Clin Neurophysiol 1985;60: Stuss DT, Leech EE, Sarazin FF, Picton TW: Event-related potentials during naming. Ann NY Acad Sci 1984;425: Noldy-Cullum N, Stelmack R: Recognition memory for pictures and words: The effect of incidental and intentional learning on N400. Electroencephalogr Clin Neurophysiol 1987;(suppl 40): Kutas M, Hillyard SA: Event-related brain potentials elicited by novel stimuli during sentence processing. Ann NY Acad Sci 1984;425: Besson M, Macar F: An event-related potential analysis of incongruity in music and other nonlingual contexts. Psychophysiology 1987;24: Stuss DT, Picton TW, Cerri AM: Electrophysiological manifestations of typicality judgment. Brain Lang 1988;33: Stuss DT, Sarazin FF, Leech EE, Picton TW: Event-related potentials during naming and mental rotation. Electroencephalogr Clin Neurophysiol 1983;56: Kutas M, Hillyard SA: The lateral distribution of event-related potentials during natural sentence processing. Neuropsychologia 1982;20: Kutas M, Van Petten C, Besson M: Event-related potential asymmetries during the reading of sentences. Electroencephalogr Clin Neurophysiol 1988;69: Middle and Long Latency ERPs 83

91 240 Fischler I, Bloom PA, Childers DG, Roucos SE, Perry NW Jr: Brain potentials related to stages of sentence verification. Psychophysiology 1983;20: Lovrich D, Novick B, Vaughan HG Jr: Topographic analysis of auditory event-related potentials associated with acoustic and semantic processing. Electroencephalogr Clin Neurophysiol 1988;71: Kutas M, Van Petten C: Event-related potential studies of language; in Ackles PK, Jennings JR, Coles MGH (eds): Adv Psychophysiol. Greenwich Conn, JAI Press, 1987, vol 3, pp Stelmach RM, Saxe BJ, Noldy-Cullum N, Campbell KB, Armitage R: Recognition memory for words and event-related potentials: A comparison of normal and disabled readers. J Clin Exp Neuropsychol 1988;10: Kraus N, McGee T: Auditory event-related potentials; in Katz J (ed): Handbook of Clinical Audiology. Baltimore, Williams & Wilkins, 1994, pp Jacobson GP: Magnetoencephalographic studies of auditory system function. J Clin Neurophysiol 1994;11: Gary P. Jacobson, PhD, Director, Division of Audiology, Henry Ford Hospital, 2700 West Grand Blvd, Detroit, MI (USA) Jacobson/Kraus/McGee 84

92 Alford BR, Jerger J, Jenkins HA (eds): Electrophysiologic Evaluation in Otolaryngology. Adv Otorhinolaryngol. Basel, Karger, 1997, vol 53, pp Objective Measurements and the Audiological Management of Cochlear Implant Patients Jon K. Shallop Research and Clinical Services, Denver Ear Institute, Englewood, Colo., USA Various behavioral and electrophysiological procedures have been utilized to evaluate cochlear implant candidates and to optimize speech recognition performance for patients with cochlear implant patients. These procedures include electrical promontory testing (PROM), verification of device and electrode integrity using real-time electrode voltages (EV) and averaged electrode voltages (AEV), whole nerve action potentials (EAP), electrically elicited stapedius reflexes (ESR), electrical auditory brainstem (EABR), middle latency (EMLR) responses and various electrically elicited cortical responses. This chapter presents an overview of these objective measures and how they are applied to the management of cochlear implant patients. These measurements can be especially helpful for young children. The AEV, ESR and EABR procedures can assist with device programming. The cortical responses, including color topographic brainmapping, provide insight into how stimulation from a cochlear implant may be processed by the brain. As additional patients receive cochlear implants and as additional devices are developed, the need will continue for objective measurement techniques for these patients, especially young children who may not be able to provide adequate behavioral responses. This chapter reviews various objective measurement techniques which are utilized with cochlear implant patients, before, during or after their surgery.

93 Electrical Promontory Testing Electrical PROM testing was one of the first procedures used in the selection of prospective patients for cochlear implantation. It is not an objective technique in the strictest sense since it requires behavioral cooperation and responses from the patient. However, this procedure has been utilized for a number of years and has resulted in the development of various objective procedures which do not require behavioral responses. The PROM test has been recommended for patients who do not have any known audiometric responses or in other situations where the potential benefit from a cochlear implant is questioned during preoperative evaluations. Instrumentation The most common technique for electrical PROM testing is to place a transtympanic needle electrode on the promontory. A second reference disk electrode is placed on the forehead. Charge-balanced biphasic electrical square waves are then presented via these electrodes. The current range necessary to produce auditory nerve stimulation with a promontory needle electrode is typically in the range of 10 to 1 ma. These charged-balanced stimuli are used to conduct several tests to evaluate the viability of neural elements of the auditory nerve. Promontory stimulation instruments are available for the various cochlear implant systems in use throughout the world. Procedures The measures which are most likely to be used during promontory testing include the following: (1) electrical stimulation threshold; (2) electrical stimulation comfort level; (3) frequency discrimination; (4) temporal discrimination, and (5) neural adaptation. Electrical stimulation threshold is determined by carefully increasing the output current until the patient can consistently detect the signal. Pulsed signals are usually easier for the patients to detect, especially if they have any tinnitus. Control presentations without a signal and having the patient count signal presentations can help the clinician to verify responses during promontory testing. Comfort level is established by providing the patient with a clear explanation of a loudness scale such as: 0> signal is not detected ; 1> first hearing or sensation, very soft (threshold); 2> soft ; 3> medium ; 4> loud & comfortable and 5> too loud. This is a simple loudness scale that can be used with a graphic presentation of the scale which enables the patient to track the relative loudness of presented signals with their finger. It is important to make sure that the patient s responses and perception are clearly understood by the clinicians. It is possible for patients to perceive nonauditory sensations, Shallop 86

94 Fig. 1. Mean PROM stimulation thresholds from a group of 550 adult deaf patients and adult patient (LN) illustrate the increasing current required to establish threshold as the frequency of the pulsatile stimuli are increased from 50 to 1,600 Hz. The normative data for this illustration are used with the permission of Battmer [1994]. such as pain perception down into the neck. Such nonauditory responses must be carefully evaluated. In some instances, it may be necessary to have the promontory electrode moved closer to the round window to eliminate these nonauditory sensations. Figure 1 shows some typical responses which may be expected with the Cochlear Corporation Promontory Stimulator. The mean thresholds 1SD are illustrated for the octave pulse rates between 50 and 1,600 Hz for preoperative testing on 550 adult cochlear implant candidates seen for evaluation at the Cochlear Implant Clinic of the Medizinische Hochschule in Hannover, Germany [Battmer, 1994]. The individual results for a 35- year-old male (LN) with a profound sensorineural hearing loss are shown in comparison to the Hannover normative data. Note how the threshold levels increase as the frequency increases. As mentioned above, occasionally patients will report nonauditory sensations during promontory testing. These sensations may include mild pain from the tympanic plexus on the promontory. In this case, the stimulating electrode should be moved closer to the round window which may reduce these sensations. Additional nonauditory responses have been observed in patients with congenital deafness and long-term acquired deafness. These responses may include sensations of dizziness and/or tingling sensations, typically in the arms, chest or head. Such sensations are probably false interpretations by the brain since the person lacks adequate auditory memory to associate with the electrical stimulation of the auditory nerve. When these responses occur, it can be difficult to distinguish valid responses for false-positive responses. Clinicians must be careful and certain about reporting no response. They must make certain that the electrodes have continuity and that there is in fact The Audiological Management of Cochlear Implant Patients 87

95 a signal being presented from the instrument output. An oscilloscope can be used to monitor the output of the promontory stimulator. If these technical points are assured, then the absence of a response may be factual across the range of current and frequencies available with the instrumentation used during testing. The absence of a promontory response is generally considered to be a definite contraindication for cochlear implantation. When doubt exists regarding behavioral promontory testing or when the patient is too young to use the procedure, then additional objective procedures may be required. These points will be described later in this chapter. In general it has been observed that low PROM thresholds and wide dynamic ranges correlate with speech recognition in adult cochlear implant patients [Fritze and Eisenwort, 1988; Kileny et al., 1991]. Frequency discrimination task results can assure the clinician that the patient is perceiving true auditory sensations from the electrical signals. Paired comparison presentations or alternative forced-choice paradigms of different frequencies at comfort level should be given to the patient with adequate randomization. If the patient is capable of distinguishing between paired presentations and effectively ranks 3 or 4 frequencies (e.g Hz), this should be considered as a favorable finding for implantation. Temporal discrimination tasks might include the measurement of gap detection between paired signal bursts and burst duration difference limens. The gap detection procedure is conducted with the presentation of control and gap signals. The total signal duration is constant for the control no gap and the measured gap conditions. Gap detection and burst duration discrimination tasks are hypothesized to relate to the number of surviving neural elements of the auditory nerve and potential benefits from a cochlear implant, but this correlation has not been firmly established [Hochmair-Desoyer and Klasek, 1987; Skinner, 1989]. For a good summary of temporal processing in persons with cochlear implants, see Shannon [1990]. Adaptation testing of electrical stimulation should be considered for all patients with suspected retrocochlear pathology, which could negatively affect the ultimate successful use of a cochlear implant. This test is conducted in the same manner as an auditory tone decay test, which is familiar to audiologists. The electrical stimulation should be presented at comfort level for one or more frequencies for 1 min. The patient should be able to continue to hear the signal without significant adaptation. If adaptation is noted, careful consideration regarding etiology should be considered before the final decision regarding implantation. If adaptation is ignored by the clinicians, the patient may be expected to experience adaptation of speech signals with their cochlear implant. Shallop 88

96 Promontory Electrode Impedances Promontory electrode impedances may need to be measured preoperatively, intraoperatively or postoperatively. A constant low level measurement current at a specific frequency (e.g. 30, 100 Hz) is applied to the active electrode which is referenced to a ground electrode. From the voltage applied to maintain the constant current, the impedance is measured using Ohm s law, E>I R (voltage equals current times resistance). The current to check electrode impedances must be kept very low (=5μA) in order to not produce auditory sensations. Instrumentation The clinician needs to be certain that the equipment used to measure electrode impedances produces safe levels of current which are used for the measurements. For example, a commercial promontory unit can produce very low current levels (e.g. 1 μa) that cannot be detected when the promontory needle electrode impedance is tested. However, other impedance meters or evoked potential systems used for checking surface electrode impedances may produce current levels which are easily detected and may in fact be uncomfortable or painful to the patient during transtympanic promontory testing. The impedance measurement circuit of an evoked potential system is typically designed for surface electrodes and may produce constant current which exceeds 10 μa. Such levels may produce detectable to uncomfortable sensations for some patients. Thus there is an advantage of using a promontory device as described above since the clinician can set the exact measurement current very low (1 μa) during the impedance check. Procedures The measurement of electrode impedance is a useful test to verify the function of specific electrodes in a cochlear implant. This procedure is possible in a hardwired device such as the Inneraid (Cochlear Corp.) and in a transcutaneous system such as the Clarion (Advanced Bionics) and Med-El devices. The Inneraid device uses a small impedance meter which can be used to safely check electrode impedances while the patient is awake or asleep. The Clarion and Med-El systems use reverse telemetry to receive measurements back from the internal device including all paired combinations of electrode impedances. This type of telemetry measurement is very useful and it is likely to be used in most cochlear implant devices developed in the future. For this procedure, the patient can be asleep or cooperatively awake. The Audiological Management of Cochlear Implant Patients 89

97 Electrode Voltages Electrode voltages are measured from surface electrodes placed on the head to optimize the measured voltages resulting from activation of the cochlear implant. Typically the recording electrodes are placed on the ipsilateral mastoid (reference the implanted ear) and on the forehead. A ground electrode can be placed on the opposite mastoid. Instrumentation Surface disk recording electrodes are taped to the mastoid of each ear and a ground electrode is placed on the forehead. These electrodes are connected to an isolation biological amplifier with a gain of about 10,000. The output signal from the amplifier is then connected to an oscilloscope (battery-powered for electrical isolation and safety). It is helpful to use an external trigger signal to synchronize signal presentation from the cochlear implant with the oscilloscope. The cochlear implant is then activated with an appropriate test signal and the device output or stimulation artifact can be measured on the oscilloscope. In this manner, any cochlear implant device can be checked as it is activated. Procedures The cochlear implant should be activated with a low-level signal which can then be gradually increased. From normative studies, the characteristics of the expected waveforms can be anticipated. The advantage of this procedure is that it is simple and requires minimal equipment to obtain the response waveforms. The disadvantages of this technique include the difficulty to measure the low-level signals from apical bipolar electrodes and testing children who are not fully cooperative, since movement (muscle potentials) can make it difficult to measure the responses. Averaged Electrode Voltages Averaged electrode voltages (AEVs) employ signal averaging to improve the recordings of stimulation artifact and has been referred to as averaged surface potentials or averaged electrode voltages. This enables the measurement of responses to as low as 10 μv [Heller et al., 1991; Shallop 1993a, b; Shallop et al., 1993; Almqvist et al., 1993; Mens et al., 1993, 1994a, b; Mahoney and Rotz Proctor, 1994; Peterson et al., 1995]. Shallop 90

98 Fig. 2. A schematic diagram illustrates the equipment used to record averaged electrode voltages. Surface electrodes are the input to a clinical evoked potential system which averages the voltages generated by the biphasic stimulation of specific electrodes of the Nucleus Mini- 22 cochlear implant. The implant is activated by the clinical Diagnostic Programming System (DPS) and appropriate software (DPS version 6.90) installed on an MS-DOS compatible computer. The output of the computer is from an interface card (IF3 or IF4) to a speech processor (wearable speech processor, WSP III or mini-speech processor, MSP or Spectra 22). The signal from the speech processor is conducted to a transmitting coil which transfers the signal to the internal receiver stimulator. Instrumentation Recording electrodes are taped in place at each mastoid tip; active positive on the implant side and a negative reference at the vertex (Cz) or on the forehead at FPz. A ground electrode is placed on the opposite mastoid. The mastoid to vertex placement of the electrodes assures that a large response will be obtained during activation of the implant. Intraoperative recordings during cochlear implant surgery utilize subdermal needle electrodes, taking care to avoid contamination of the surgical field by placing the positive electrode in front of the tragus. The surface recording electrodes serve as the input to a clinical evoked potential system as shown in figure 2. This figure shows the electrode montage as ipsilateral mastoid to the opposite mastoid. Analysis parameters should be selected to minimize distortion and this includes the placement of the active electrodes at the mastoid and vertex if possible, rather than mastoid to mastoid. The evoked potential system should be configured to be triggered externally by the control signal from the implant-programming system. Typical evoked potential system settings include: preamplifier sensitivity of 1 mv, The Audiological Management of Cochlear Implant Patients 91

99 Fig. 3. The biphasic negative phase leading ouput current of the Nucleus cochlear implant is shown along with the typical AEV patterns which are typically observed. The upper trace is the negative leading charged-balanced output. The middle trace is a surfacerecorded AEV, also negative leading. The lower trace shows the phase inversion which is sometimes observed on middle and apical electrodes. bandpass filtering of 1 10,000 Hz, analysis time of 10 ms and external averager trigger. The number of averages necessary will be dependent on the state of the patient. Procedures When patients are quiet or asleep, 25 averages will usually be adequate, which takes about 1 s/electrode. However, when the patient is awake and movement artifacts are likely, more averaged samples will need to be obtained. For the Nucleus cochlear implant, electrodes can be activated using the standard computer interface system for this device; a PC computer with the Cochlear Corp. MSP interface card (IF4), dual processor interface (DPI) and a mini-speech processor (MSP) or a Spectra 22 speech processor. The output of the speech processor is connected to the patient s headset (HS6) or a test headset (HS7). Stimulation parameters of the Diagnostic Programming Software (DPS) should be stimulation mode BP+1, pulse width 200 μs/phase, current level 126, pulse rate 250 Hz, stimulation on time of 1,000 ms and stimulation off time of 1 ms. This combination of stimulation parameters will result in a continuous pulse train at 250 Hz at a current of approximately 300 μa peak. In a few instances, this current may be above the patient s behavioral comfort level. In this instance, measurements can be obtained at comfort level for these electrodes. The output from the implant is a negative leading charge-balanced biphasic waveform. Shallop 92

100 Fig. 4. AEV responses from the 20 active electrodes of an adult Nucleus cochlear implant patient (DW) are illustrated. Stimulation was at a current of 300 μa at the rate of 250 pulses/s. Stimulation mode was BP+1. Note the variations in the AEV amplitudes for each of DW s electrodes. The amplitudes of these responses ranged from about 20 to 75 μv. Phase reversals and 2 null points (electrodes 9 and 17) are described in the text. Case Examples Figure 3 demonstrates the waveforms of the stimulation current, the expected normal AEV and an inverted AEV. Inverted waveforms are quite typical from the mid to apical electrodes of the Nucleus device when the stimulation mode is BP+1. The averaged waveforms typically show a slight distortion resulting from the capacitive effects of the stimulating electrodes. Each electrode can be tested in sequence, e.g. from base (electrode 1) to apex (electrode 20). This sequence is preferred since the largest responses will be obtained from the basal electrodes in bipolar modes. Total testing time will be typically 5 10 min. With an automated acquisition program on the evoked potential system, the testing time can be reduced. AEVs measured in CG The Audiological Management of Cochlear Implant Patients 93

101 Fig. 5. The mean and 1SD of the peak-to-peak amplitude of the averaged electrode voltages (AEV) are plotted for each electrode for 30 adult normative subjects. All responses were obtained with a stimulation current of 300 μa peak (pulse width>200 μs, current programming level>126) at a pulse rate of 250 Hz. Response amplitudes were measurable from about 1 μv on apical electrodes to the maximum values we observed on some basal electrodes of 700 μv. The response amplitude variability was the greatest in the basal region of the cochlea [Shallop, 1993a]. often demonstrate distorted waveforms due to the difference in phase 1 vs. phase 2 volume conduction of the electrode voltages. The stimulation rate of 250 Hz results in two measurable waveforms within the 10-ms analysis time since the interstimulus interval is 4 ms. Figure 4 shows the AEV responses for the 20 active electrodes in mode BP+1 for an adult cochlear implant patient (DW), who has a full insertion of all active and stiffening rings of the Nucleus Mini-22 cochlear implant. This patient lost his hearing as the result of cochlear otosclerosis and head trauma. The AEV waveforms for this patient illustrate normal and abnormal morphology. Electrodes 1 8 show a series of negative leading (noninverted) responses that vary in amplitude from base to apex. Typically the AEV amplitudes in BP+1 decrease consistently from base to apex since the current flows between paired electrodes which are successively deeper into the cochlea. The volume-conducted electrode voltages from each stimulated pair of electrodes must then flow out of the cochlea, presumably via the round window, to the surface recording electrodes. In the case of DW, the AEVs are phase inverted from electrode 10 to 16. The AEVs for electrodes return to negative leading waveforms. Note the voltage nulls of the AEVs for electrodes 9 and 17 where the phase reversals occur. This unusual AEV series for patient DW most likely results from the etiology (otosclerosis) of his deafness as pointed out by Mens et al. [1994b]. Shallop 94

102 Fig. 6. Stimulogram AEVs are shown for a fixed mode of stimulation using the most basal electrode (E1) as the indifferent electrode for all other electrodes. Stimulation current was fixed at about 35 μa. Note that the AEVs increase in amplitude from basal to apical cochlear stimulation sites in contrast to the BP+1 AEVs summarized in figure 5. These AEVs were obtained from an adult cochlear implant patient (Nucleus 22 channel) who had a complete insertion of all active electrodes. Stimulation parameters were: rate>700 Hz, amplitude of current level>20 (35 μa), pulse width>200 μs/phase. Acquisition was for 400 averages with the preamplifier filtering set at 1 10,000 Hz. Special thanks to the authors for the preparation and use of this figure [Almqvist et al., 1993]. The summarized BP+1 AEVs for 30 adult Nucleus cochlear implant patients are shown in figure 5. The mean 1 SD deviation of the peak-topeak amplitude of the AEVs are plotted for each electrode. Response amplitudes were measurable from about 5 10 μv peak on apical electrodes to the maximum values we observed on some basal electrodes of 700 μv peak. Note that response variability is greatest in the basal region. The small amplitude apical responses obtained in the BP+1 mode can be enhanced by another AEV technique as described by several authors [Mens et al., 1993; Almqvist et al., 1993; Heller et al., 1993]. In this technique, each active electrode is paired with a single or a series of fixed electrodes, e.g. electrode 1. The procedure can also be repeated with the next fixed electrode, e.g. electrode 2, etc. This technique causes the current to flow toward the fixed indifferent electrode (e.g. electrode 1) from each of the other electrodes (2 22). An example of the AEVs using the technique of Almqvist et al. [1993] is illustrated in figure 6. They The Audiological Management of Cochlear Implant Patients 95

103 Fig. 7. AEVs are shown for an Inneraid cochlear implant user. The AEVs demonstrate the results from a defective cable for the speech processor to the connecting plug. The AEVs were obtained by pairing each electrode (1 6) to an extracochlear electrode (8). In this monopolar configuration, stimulation current was set at 65 μa, pulse width at 400 μs/ phase and rate at 250 Hz. The AEV for electrode 1 (trace M1) had an amplitude of 1.13 mv and the AEV amplitude for electrode 5 (trace M5) was 1.56 mv. Note the abnormal AEV morphology for electrode 6 (trace M6) and reduced amplitude. refer to this technique as a Stimulogram since it represents the sequential stimulation of electrodes 1 22, always paired with electrode 1 as the indifferent. Thus electrode 1 is tested in CG since it is connected to all electrodes as CGs when the default-indifferent electrode is specified as electrode 1 for the active electrode 1. Thus by using a low level of current (35 μa in this example), welldefined AEVs can be obtained quickly from each electrode. Obviously the fixed indifferent electrode must be functional for this procedure to be effective. Mens et al. [1993] pair all electrode combinations which makes electrode problems very apparent in their three-dimensional graphic presentation showing the amplitude and leading phase of each response waveform. Examples of AEVs recorded from an Inneraid cochlear implant are shown in figure 7. These AEVs from an adult patient (KE) were recorded from the most apical electrode (1) to the remaining intracochlear electrodes 2 6. Each electrode was paired in a monopolar configuration to extracochlear electrode 8. KE had reported poor sound quality as a recent complaint but she had not experienced this problem previously. Her electrodes were activated with a6-μa pulse train at 250 Hz. Amplitudes of her AEVs were large ranging from 1.13 mv (electrode 1) to 1.56 mv (electrode 5). Note that the AEV for Shallop 96

104 electrode 6 has abnormal morphology and low amplitude (0.35 mv). This fault was traced to an intermittent cable from the speech processor. Additional Acquistion Parameters There are some additional acquistion parameters which should be highlighted at this point since they can have the effect of distorting AEVs. Effects of Amplifier Gain. It is important to use the proper level of preamplifier gain when assessing AEVs. We typically set the preamplifier gain at a sensitivity of 1,000 μv (gain>2,400). This gain is usually adequate to measure AEVs?100 and =1,000 μv. If the AEVs exceed 1,000 μv, then we suggest that the amplifier sensitivity must be reduced to avoid peak clipping. If the AEVs are =100 μv, the amplifier sensitivity should be increased to better resolve the waveforms. Amplifier Bandwidth Effects. AEVs can be easily distorted by using a restricted preamplifier bandwith (e.g ,000 Hz). The use of a wide amplifier bandwidth will reduce distortion of the waveforms. For our normative and clinical studies, we have consistently used 1 10,000 Hz as our recording bandwidth. We have also measured the effects of systematically changing the amplifier bandwidth for adult cochlear implant patients with complete insertion of all active electrodes and stiffening rings. These results demonstrated that high-frequency cutoffs of =3,000 Hz and low-frequency cutoffs?30 Hz will distort AEVs. These distortions include asymmetric biphasic AEVs and reduced peak-to-peak amplitudes. We recommend that a wide bandwidth should always be used without the use of a notch filter. Postmeasurement digital filters or smoothing can be used to selectively eliminate some interference signals but usually this is not necessary in most situations. We occasionally encounter high-frequency interference when recording AEVs intraoperatively which can be filtered out posthoc. Recording Electrode Montages. The largest AEV amplitudes will be obtained using an ipsilateral to Cz recording montage. When the inverting electrode (Ö) is moved from Cz to FPz there will be about a 10% reduction in the AEV amplitudes. An additional 10% amplitude reduction will result from moving the inverting electrode to the contralateral mastoid. Effects of Radiofrequency (RF) Interference. When the measured AEVs are very small (=10 μv p-p), or when recording electrodes and leads are close to the headset cable of the transmitting cable of a cochlear implant, artifact signals from the RF transmission carrier to the implant receiver-stimulator can interfere with the recorded waveforms as shown in figure 8. The RF signal used to transmit data instructions can be blocked by an RF-blocking filter between the surface recording electrodes and the evoked potential system The Audiological Management of Cochlear Implant Patients 97

105 Fig. 8. The transmission of the RF signals of a cochlear implant can result in a variety of unusual AEV waveform morphologies. Trace A shows a normal, biphasic AEV waveform. Traces B and C show RF distorts which may occur when RF filtering is not used or when the recording electrode leads are in close proximity to the headset cord. preamplifier or by an RF filter built into the headbox or preamplifier. Rectification of the RF signals can result in a variety of unusual AEV waveform morphologies as shown in figure 8. Trace A illustrates a normal AEV. Placement of the recording electrodes too close to the transmitter coil produced trace B. An increase in the stimulation current level on a more apical electrode produced trace C. Since the RF signal level effects can be influenced by the relative positions of the headset cord and the recording electrode leads, it is essential that the input of the evoked potential system have RF filtering to exclude the RF transmission picked up by the recording electrode leads. Without filtering, this RF interference will often distort and/or obliterate the AEVs. Effects of CG Mode. Since some clinicians may prefer to program young children in CG mode, AEVs could also be measured in CG mode. However, it must be stressed that this mode can distort AEVs. A CG stimulation mode in any cochlear implant system will cause significant distortion AEV waveforms. Whereas in bipolar modes, the current path is more restricted between the active and indifferent electrodes. It is always recommended to use wide bipolar modes of stimulation with a basal electrode as the indifferent electrode when assessing AEVs. If CG is used, the results must be compared to results from a bipolar mode. Summary of AEV Testing. Although various stimulation modes can be used to measure AEVs from a multichannel cochlear implant, the use of a basal or extracochlear electrode is recommended as the indifferent electrode. When this monopolar technique is used, AEV amplitudes will increase proportionally to the width of the stimulation mode. The AEV amplitudes from the Shallop 98

106 apical electrodes are significantly larger in these modes at a stimulation current of 65 μa in comparison to the AEV values of the apical electrodes obtained in BP+1 at a current of 300 μa. Thus we now prefer to use the widening bipolar modes for the measurement of AEVs rather than BP+1 [Shallop, 1993a; Shipp et al., 1993; Mahoney and Rotz Proctor, 1994] or CG as recommended by Kileny et al. [1995]. AEVs provide valuable information regarding specific electrode functioning as well as the operation of the internal receiver and stimulator device. A clinical evoked potential system enhances results through the averaging of electrode voltages. AEVs can be measured easily from children and adults intraoperatively or as a postoperative test whenever device or electrode failure is suspected. The Electrical Stapedius Reflex Another objective procedure which can be used to help confirm behavioral response levels is the ESR. The stapedius reflex to sound has been used in clinical audiology to predict hearing levels, slope of hearing loss and hearing-aid settings. Its use with cochlear implant patients can be useful as long as the reflex is intact. Several authors have noted that this response may be absent in as many as 25% of cochlear implant patients [Jerger et al., 1988; Battmer et al., 1990; Hodges, 1996]. The primary use of the ESR with cochlear implants to date, has been to predict comfort level settings for the speech processor [Jerger et al., 1986; Battmer et al., 1990; Spivak and Chute, 1994]. Instrumentation The ESR can be elicited with a promontory needle electrode or through electrodes of a cochlear implant. Electrical stimuli are presented from a promontory stimulator for the promontory needle technique or from the computeractivated speech processor of an implant system. The signal is typically a burst of 250 1,000 ms at a specific pulse rate (e.g. 200 pulses/s) within the burst. An appropriate duty cycle (e.g. 50%) provides adequate time for the ESR to recover and makes identification of the response easier. An electroacoustic impedance bridge is connected to the patient in the same manner as used for acoustic reflex measurements. The contralateral ear is typically used in preference to the ipsilateral ear. The instrumentation should include an output recording device (e.g. strip chart or computer) which enables the clinician to easily observe the responses. Computer averaging of the responses can also be utilized. The Audiological Management of Cochlear Implant Patients 99

107 Fig. 9. The correlation (r>0.85) between ESR threshold and programming electrical comfort level is evident in this figure. These measures were obtained from adult (n>17) Nucleus cochlear implant users. The ESR was determined by three different methods (see text for additional explanation). Procedures The time needed is minimal from a cooperative or sedated patient. If patients are to be tested with this technique intraoperatively, the patient must not be paralyzed with muscle relaxants which would inhibit the reflex arc of the stapedius muscle. The ESR shows amplitude growth and at amplitude saturation, the ESR has been suggested to be indicative of behavioral comfort levels. However, as with any electrophysiological technique, an absent response must be interpreted with caution. Jerger et al. [1986] reported a technique to elicit and average the ESR from a multichannel cochlear implant patient. They obtained the ESR from several electrodes and demonstrated its amplitude growth. They suggested that an initial dynamic for speech processor current range for a specific electrode may be predicted based on ESR measures on that same electrode. The saturation level of the ESR correlated well with this patient s preferred loudness level. Hodges [1996] reported the results of her investigation of 6 cochlear implant patients and correlated their ESR threshold with comfort level in programming units of their Nucleus implant. She measured the ESR on at least three electrodes per patient, using the same type of stimuli for both measures including stimulation mode, pulse rate and pulse width. Her results demonstrated that the current level needed to elicit the ESR was strongly correlated (r>0.91) with the comfort level settings of their speech processor program. The results of our own experience is summarized in figure 9. Our results were obtained using three methods of determining the patient s comfort level: adjustments by an audiologist (A), self-adjustments with the computer keyboard by the patient (S) and self-adjustments using a continuous turning Shallop 100

108 knob control by the patient (K). All three methods had a strong correlation (r>0.85) with the contralateral ESR [Shallop and Ash, 1995]. In another ESR study, Battmer et al. [1990] investigated the amplitude growth function of the ESR in 25 patients with the Nucleus 22 channel cochlear implant. They varied the stimulation mode from BP+1 to BP+3. The amplitude growth function shifted as the mode of stimulation was widened from 1.5 to 2.3 and 3.1 mm (BP+1, BP+2 and BP+3, respectively) and tended to saturate near the comfort level in programming units in the same stimulation mode. Their findings are in agreement with typical behavioral findings with the Nucleus device, i.e. as the stimulation mode widens, threshold and comfort levels generally decrease. They also reported that they were able to elicit the ESR in 76% of their patients studied. The absence of the ESR in some patients may be the result of inadequate current levels and/or the number of surviving nerve fibers of the VIIIth nerve. Middle ear pathology in the recording probe ear must be considered whenever the ESR is absent. Intraoperatively, the ESR may be influenced by anesthetic agents [Gnadeberg et al., 1994]. Electrically Evoked, Whole Nerve Action Potentials Electrically evoked, whole nerve action potentials (EAP) is a technique which has been developed primarily through the efforts of the cochlear implant program at the University of Iowa [Abbas and Brown, 1991]. It is difficult to record this response because the artifact from stimulation can easily overlap the short latency of the EAP which typically has a latency of =0.5 ms. The latency of the EAP (or wave I of the electrically evoked ABR (EABR) is shorter than the acoustically evoked ABR because the transmission and transduction properties of the middle ear and the inner ear have been bypassed. Instrumentation This technique requires customized equipment in order to present biphasic current pulses using a forward masking paradigm [Abbas and Brown, 1991]. The Abbas and Brown EAP procedure is an adaptation of the procedure developed in animal research by Charlet de Sauvage et al. [1983] which eliminates stimulus artifact using a subtraction technique. Through the use of this technique a residual response of the EAP elicited by the biphasic current probe provides a measure of response from the electrically stimulated auditory nerve. The Audiological Management of Cochlear Implant Patients 101

109 Fig. 10. An example of an EABR response for adult SG is shown for an apical electrode (E20) which was stimulated in a BP+1 mode using biphasic electrical pulses through a Nucleus cochlear implant at the rate of 17/s. Current level was the patient s comfort level for this slow rate stimulation. The patient was awake and relaxed during these recordings. A blanking amplifier was used to reduce stimulus artifact for these ipsilateral EABR tracings. Procedures Extracochlear stimulation is achieved by placing a ball electrode in the niche of the round window. Intracochlear stimulation is accomplished through the hardwired Inneraid cochlear implant electrode. In both instances, the subtraction technique enables the measurement of the EAP amplitudes in response to varied current levels and interpulse intervals. Biphasic current pulses are presented and the EAP is recorded from the same extracochlear ball electrode or from a separate electrode pair of the intracochlear Inneraid device. The resulting EAP is the compound action potential (N1 response) of the auditory nerve. To date, this technique has not been reported as a procedure with other cochlear implant devices. However, Heller et al. [1996] recently reported a technique of neural response telemetry for an experimental cochlear implant. This technique would allow the recording of intracochlear potentials using back telemetry circuits built into a cochlear implant receiver stimulator. Shallop 102

110 Electrical Auditory Brainstem Response (EABR) Electrical auditory brainstem response (EABR) has been used by several investigators as a method to aid in device programming and to correlate with future benefits as measured by speech recognition scores. An example of an EABR tracing is shown in figure 10. This congenitally blind patient (SG) was 34 years old at the time of implantation of the Nucleus device. These EABR tracings were recorded ipsilaterally, i.e. on the same side as the patient s cochlear implant device. These tracings were recorded at the patient s comfort level for click stimuli presented at 10/s. It is unusual to record wave I in an EABR due to its short latency and interference from stimulation artifact. We have been able to record these responses by using a custom-built stimulus blanking amplifier (Cochlear Corp.). Instrumentation Recording electrodes are taped in place at each mastoid tip; active negative on the implant side and a negative on the forehead at FPz. A ground electrode is placed on the opposite mastoid. The mastoid placement of the negative (active, noninverting) electrode assures that a large wave I response may be obtained during activation of the implant. This placement also means that the stimulus artifact will be prominent unless it is cancelled electronically or blocked by temporal electronic switching. Intraoperative recordings during cochlear implant surgery utilize subdermal needle electrodes, taking care to avoid contamination of the surgical field by placing the negative electrode in front of the tragus. The recording electrodes serve as the input to a clinical evoked potential system (Nicolet Compact 4 or Nicolet Viking II), essentially the same instrumentation as shown in figure 2. When a blocking amplifier is used, it is placed in between the recording electrodes and the preamplifier. Analysis parameters of the evoked potential system should be configured to be triggered externally by the control signal from the implant programming system. Typical evoked potential system settings include: preamplifier sensitivity of 100 μv, bandpass filtering of 100 3,000 Hz, analysis time of 10 ms and external averager trigger. The number of averages necessary will be dependent on the state of the patient. When patients are asleep, responses may be adequate. If patients are awake, 2,000 3,000 responses may need to be averaged. Procedures For the Nucleus cochlear implant, electrodes can be activated using the standard computer interface system for this device; a PC computer with the Cochlear Corp. interface card (IF4), dual processor interface (DPI) and a The Audiological Management of Cochlear Implant Patients 103

111 mini-speech processor (MSP) or Spectra 22 speech processor. The output of the speech processor is connected to the patient s headset (HS6) or a test headset (HS7). Stimulation parameters of the Diagnostic Programming Software (DPS version 6.90) might be stimulation mode BP+1, pulse width 200 μs/phase, current level as indicated, pulse rate Hz, stimulation on time of 1,000 ms and stimulation off time of 1 ms. This combination of stimulation parameters will result in a continuous biphasic pulse train of electrical stimuli. It is important to make sure that the test signals are not too loud in awake patients. In this instance, measurements can be obtained at the psychophysical comfort level for the specific electrode pairs which are activated. The detection level of the EABR will typically correlate directly with the behavioral threshold measures for the same stimuli. The EABR thresholds will be higher than the speech processor thresholds [Shallop, 1993b] as a result of the known temporal integration functions for electrical stimulation. Hodges [1996] found a good correlation between EABR thresholds and programming thresholds. She also observed a correlation between electrical stapedius muscle thresholds and programming comfort levels on specific electrodes. She advocated a combined use of both electrophysiological methods to aid in the programming of difficult cases. Similar procedures and findings should be obtainable with various cochlea implant devices. Electrical Middle Latency Responses Electrical middle latency responses (EMLR) is another evoked potential which has been used with cochlear implant patients. This response has been recorded preoperatively using a promontory needle electrode or round window ball electrode, and intraoperatively or postoperatively from various cochlear implant devices. Instrumentation The instrumentation for the EMLR is essentially the same as for the EABR. However, there are a few equipment acquisition parameters which must be changed. Typical evoked potential system settings include: preamplifier sensitivity of 250 μv, bandpass filtering of Hz, analysis time of 80 ms and external averager trigger. The number of averages necessary will also be dependent on the state of the patient. When patients are asleep, responses may be adequate; however sleep stage will affect the amplitude of the EMLR quite dramatically. There are also known age-dependent maturational effects on the morphology and detectability of the middle latency responses. If patients are awake, more responses will need to be averaged. Shallop 104

112 Fig. 11. An example of an EMLR response for adult EM is shown. Stimulation was biphasic electrical pulses through a Nucleus cochlear implant at a rate of 9/s. The current level was equal to the patient s comfort level for the same stimuli. The patient was awake and relaxed during these recordings. The two tracings show good replication on successive trials of 1,000 sweeps. Note the EABR waveforms at the beginning of the tracings, waves III and V are evident. Procedures Surface disk or subdermal needle electrodes are typically placed at Cz (positive), ipsilateral mastoid (negative) and an appropriate ground electrode. Stimulation of specific electrodes is identical to the EABR procedures. However, the stimulation rate must be slow enough to present a single stimulation for each analysis period, e.g. 9/s when the analysis period is 80 ms. An example of an EMLR intensity series is shown in figure 11. These responses were recorded from an awake, relaxed adult using a Nucleus 22 channel cochlear implant. The stimulation was with biphasic click pulsatile stimuli. It is possible to also use longer stimulation bursts for EMLR procedures. Electrical Late Latency Responses Electrical late latency responses (ELLR) are the final group of evoked potentials to be discussed in this chapter. The cortical evoked potentials have had limited application with cochlear implant patients. However, in the past few years, there has been a renewed interest in studying these potentials with The Audiological Management of Cochlear Implant Patients 105

113 this patient population. This is especially true for the event related cortical potentials, the mismatch negativity (MMN) and the P300 responses. Instrumentation The instrumentation for cortical evoked potential studies includes an evoked potential system that is capable of having parameter settings to optimize the acquisition of these responses. In contrast to the settings for EABR and EMLR studies, ELLR techniques require longer analysis times and different preamplifier settings. The analysis time period for ELLRs should be adjustable in the range of 500 2,000 ms. The preamplifier gain can be reduced since the response amplitude of the ELLRs is times larger than the EABR. Filter settings need to be adjusted for the lower EEG spectral energy in the range of 1 40 Hz. Multichannel preamplifiers and processing are required for topographic brainmapping, usually channels depending on the equipment specifications. Procedures ELLR techniques are typically done only on awake patients. There can be some exceptions. Cortically evoked potentials are known to be dramatically affected by sleep stages. Stages 3 and 4 can especially interfere with and reduce cortical responses due to the large amplitude low-frequency EEG energy =10 Hz. Stimuli of ELLRs with cochlear implant patients can be generated directly from the interface system used to control and program the speech processor or stimuli can be presented soundfield. A simple technique for recording cortical event related potentials will be described to further illustrate the procedures for ELLRs. Event Related Potentials (ERPs) ERPS are a class of evoked potentials which are the result of unique stimulus paradigms, most commonly the odd-ball paradigm. The events of this paradigm are two different stimuli presented in a randomized sequence. One of the stimuli is presented as the frequent signal and the second stimulus, less frequently, as the rare stimulus. The evoked responses to the two contrasting stimuli are averaged in separate memories of an evoked potential system. If the stimuli are processed differently by the brain, the responses will be distinctly different. Some examples of these differences include the P300 response and the MMN response. A method to obtain ERPs for individuals using the Nucleus 22 channel cochlear implant will now be described. This method utilizes a simple twoelectrode program MAP in which specific electrodes will be stimulated at a precise current level. The odd-ball paradigm ERP requires a frequent stimulus Shallop 106

114 Table 1. Sample threshold (T) and comfort level (C) current levels are listed for 6 selected electrodes for a patient using the Nucleus 22 channel cochlear implant Electrodes E1 E5 E9 E13 E17 E21 T C The stimulation mode in this instance is bipolar. Each comfort level should be carefully assessed and balanced for loudness against the adjacent electrode(s). Sweeping all of the electrodes in both pitch directions at comfort level will assure the best possible agreement of equal loudness for the selected electrodes. The threshold level is then arbitrarily set to equal the current level of the comfort level. These values are then used to make a two-electrode map which is then activated by the output tones from an evoked potential system. This method assures discrete stimulation of specific electrodes for the oddball paradigms used to measure ERPs such as P300 and the MMN responses. and a rare stimulus which are presented in a specified ratio, e.g. 80% frequent and 20% rare. Tones presented soundfield from the evoked potential system can be used as the frequent/rare stimuli using the individual s regular program MAP. However, the activation of specific electrodes at the desired current level may be inaccurate and erratic as the speech processor codes the input tones. Our method utilizes a simple two-electrode MAP which will activate electrodes in response to puretone stimuli. The desired electrodes for stimulation are selected in the preferred stimulation mode using current level rather than stimulus level. If stimulus level is used, this introduces the additional variable of pulse width changes. The number of electrodes to be used may be as few as two and as many as all of the active electrodes. Each selected electrode is tested in psychophysics using the standard software (DPS version 6.90 or higher). We carefully assess and balance comfort level for each electrode. We then set the threshold (T) level at one current level below the comfort level (C). Table 1 illustrates sample T/C values that can be used for a sample ERP MAP for the Nucleus cochlear implant. It is apparent that activation of the selected electrodes in table 1 from any microphone or external input will be at comfort level since the dynamic range is zero for each electrode. The electrodes to be used as the frequent and rare stimuli are then selected by the experimenter, e.g. E1 as frequent and E21 The Audiological Management of Cochlear Implant Patients 107

115 Table 2. A sample MAP (bipolar mode) for ERPs was created using Cochlear Corp. DPS software version 6.90 using the T and C values listed in table 1 Active Reference T C Frequency electrode electrode boundaries E21 E ,400 E1 E ,401 4,000 The frequency boundaries have been adjusted to optimize the stimulation of the desired electrode in response to an acoustic microphone input to the speech processor (MSP or Spectra 22). In the create map (F5) section of the software, the frequency boundaries can be adjusted and in this case the F2 cutoff frequency was adjusted to 1,400 Hz to create this map. The coding strategy selected should be F0F2 which will then activate only one electrode for each tonal signal. In this example, a 500-Hz tone will activate apical electrode 21 and a 2,000-Hz tone will activate basal electrode 1. as rare. A MAP is then created in the desired mode, in this case bipolar as shown in table 2. The coding strategy typically used is F0F2 in order to assure that a single puretone signal will cause stimulation on a specific electrode at a known current level, comfort level in this example. In the example MAP, a 1,000-Hz tone will activate E20, and 3,000 Hz will activate E1. The parameters of the evoked potential system are then set for the desired frequent and rare acoustic stimuli; e.g. 1,000 Hz frequent and 3,000 Hz rare. An example of P300 and MNN responses are shown in figure 12. These responses were obtained from a 35-year-old male cochlear implant patient (SG) who is congenitally blind due to maternal rubella. SG is also congenitally hearing impaired and became profoundly deaf in his left ear 4 years prior to his cochlear implant surgery in May These ERP responses were obtained using the NeuroScience, Inc. Brain Imager. The averaged responses were also analyzed as color topographic images (not shown). The 32 surface electrodes were applied using an electrode cap (Electrocap) and input to the preamplifier and averaged. The acoustic (puretone bursts) output of the earphones from the evoked potential system (Neuroscience Brain Imager) was coupled to a small external input microphone for the speech processor. The external microphone was placed between the earphones and taping them together. The speech processor sensitivity control was set to 1 Shallop 108

116 Fig. 12. An example of an ELLR from cochlear implant patient SG is shown in to a series of odd-ball stimulations of apical electrode 20 as the frequent signal and mid-electrode 12 as the infrequent signal. These responses were obtained while SG was awake and alert. Stimulation was at SG s comfort level for a 50-ms signal having a pulse rate of 250 pps. Responses were obtained at 28 electrode sites with 4 being displayed (Pz, PO1, PO2 and OZ2). The frequent response waveform (F) shows a clear N1-P2 complex. The infrequent response (R) shows a strong P300 response at about 350 ms. The shaded area at about 200 ms is a MMN response. in order to produce consistent stimulation of the frequent and rare electrodes in the ERP MAP. We have observed that setting the sensitivity to typical use settings of a conventional MAP (sensitivity>3.5) produces spurious signals which are reported as two tones for each single stimulus. It is likely that the tone input can overdrive the input of the MSP. Thus by setting the sensitivity to the low value of 1 for the 80-dB earphone signals, cochlear implant patients The Audiological Management of Cochlear Implant Patients 109

117 report distinct signals equivalent to stimulation of these same electrodes in the psychophysics section of the DPS software. This method provides precise control for electrode stimulation of the Nucleus cochlear implant. Conclusion Cochlear implants have advanced considerably over the past 20 years. Levels of speech recognition without lipreading have improved so that typical adult cochlear implant users achieve sentence recognition scores of 70 80% and word recognition scores of 35 45%. Selected users may perform better than these scores, but at present, these are the values we use when counselling patients who are considering a multichannel cochlear implant. We do not know the full potential of children, but we should expect similar levels of speech recognition when parental and educational support are good. This chapter has discussed various objective procedures which can be used to assist in the management of cochlear implant patients. These methods are used in conjunction with good medical and audiological management of these patients. References Abbas PJ, Brown C: Assessment of the status of the auditory nerve; in Cooper H (ed): Cochlear Implants: A Practical Guide, chap 8. San Diego, Singular Press, 1991, pp Almqvist B, Harris S, Jonsson KE: The stimulogram; in Hochnair-Desoyer IJ, Hochmair ES (eds): Advances in Cochlear Implants. Wien, Manz, 1993, pp Battmer R-D: Electrical promontory thresholds and comfort levels for 550 patients at the Cochlear Implant Clinic of the Medizinische Hochschule in Hannover, Germany. Pers commun, July Battmer R-D, Laszig R, Lehnhardt E: Electrically elicited stapedius reflex in cochlear implant patients. Ear Hear 1990;11: Charlet de Sauvage R, Cazals Y, Erre JP, Aran JM: Acoustically derived auditory nerve action potential evoked by electrical stimulation: An estimation of the waveform of single unit contribution. J Acoust Soc Amer 1983;73: Fritze W, Eisenwort B: Zur Vorhersagbarkert des Ergebnisses nach Cochlearimplantation. HNO 1988; 36: Gnadeberg D, Battmer RD, Lüllwitz E, Laszig R, Dybus U, Lenarz Th: Der Einfluss der Narkose auf den intraoperativ elektrisch ausgelösten Stapediusreflex. Laryngorhinootologie 1994;73: Heller JW, Dillier N, Abbas PJ: Neural response telemetry. 3rd Eur Symp on Pediatric Cochlear Implantation, Hannover June Heller JW, Shallop JK, Abbas PJ: Cochlear implant assessment by averaged electrode voltages; in Hochnair- Desoyer IJ, Hochmair ES (eds): Advances in Cochlear Implants. Wien, Manz, 1993, pp Heller JW, Sinopoli T, Fowler-Brehm N, Shallop JK: The characterization of averaged electrode voltages from the Nucleus cochlear implant. IEEE Trans, Nov Hochmair-Desoyer IJ, Klasek O: Comparison of stimulation via transtympanic promontory electrodes, implanted electrodes and salt electrodes in the ear canal. Proc Int Cochlear Implant Symposium, Düren Hodges AV: Electrical middle ear muscle reflex: Use in cochlear implant programming. Proc 6th Symp on Cochlear Implants in Children, Univ. of Miami, 1996, p 61. Shallop 110

118 Jerger JF, Jenkins H, Fifer R, Mecklenburg D: Stapedius reflex to electrical stimulation in a patient with a cochlear implant. Ann Otol Rhinol Laryngol 1986;95: Jerger JF, Oliver TA, Chmiel RA: Prediction of dynamic range from stapedius reflex in cochlear implant patients. Ear Hear 1988;15: Kileny PR, Meiteles LZ, Zwolan TA, Tilian SA: Cochlear implant device failure: Diagnosis and management. Am J Otol 1995;16: Kileny PR, Zimmerman-Phillips S, Kemink JL, Schmaltz SP: The effects of preoperative electrical stimulability and historical factors on performance with multichannel cochlear implant. Ann Otol Rhinol Laryngol 1991;100: Mahoney MJ, Rotz Proctor LA: The use of averaged electrode voltages to assess the function of Nucleus internal cochlear implant devices in children. Ear Hear 1994;15: Mens HM, Oostendorp T, van den Broek P: Electrode-by-electrode mapping of cochlear implant generated surface potentials: (Partial) device failures; in Fraysse B, Deguine O (eds): Cochlear Implants: New Perspectives. Adv Otorhinolaryngol. Basel, Karger, 1993, vol 48, pp Mens HM, Oostendorp T, van den Broek P: Identifying electrode failures with cochlear implant generated surface potentials. Ear Hear 1994a;15: Mens HM, Oostendorp T, van den Broek P: Cochlear implant generated surface potentials: Current spread and side effects. Ear Hear 1994b;15: Peterson AM, Brey RH, Facer GW: Averaged electrode voltages used to identify nonfunctioning electrodes in cochlear implants: Case study. J Am Acad Audiol 1995;6: Shallop JK: Objective electrophysiological measures from cochlear implant patients; in Hochnair-Desoyer IJ, Hochmair ES (eds): Advances in Cochlear Implants. Wien, Manz, 1993a, pp Shallop JK: Objective electrophysiological measures from cochlear implant patients. Ear Hear 1993b;14: Shallop JK, Ash KR: Relationships among comfort levels determined by cochlear implant patient s selfprogramming, audiologist s programming and electrical stapedius reflex thresholds. Ann Otol Rhinol Laryngol 1995;104(suppl 166): Shallop JK, Kelsall DC, Turnacliff KA: Multichannel cochlear implant in children with labyrinthitis; in Hochnair-Desoyer IJ, Hochmair ES (eds): Advances in Cochlear Implants. Wien, Manz, 1993, pp Shannon RV: A model of temporal integration and forward masking for electrical stimulation of the auditory nerve; in Miller JM, Spelman FA (eds): Cochlear Implants: Models of the Stimulated Ear. New York, Springer, 1990, pp Shipp DB, Murad C, Nedzelski JM: Test-retest reliability of averaged electrode voltage measurements with the Nucleus 22-channel cochlear implant; in Hochnair-Desoyer IJ, Hochmair ES (eds): Advances in Cochlear Implants. Wien, Manz, 1993, pp Skinner MA: Relation between pre-operative electrical stimulation and post-operative speech recognition performance with a cochlear implant. Annual Conference of the New Zealand Audiological Society, Hamilton Spivak LG, Chute PM: The relationship between electrical acoustic reflex thresholds and behavioral comfort levels in children and adult cochlear implant patients. Ear Hear 1994;15: Jon K. Shallop, PhD, Director of Research and Clinical Services, Denver Ear Institute, 799 East Hampden Ave 520, Englewood, CO (USA) The Audiological Management of Cochlear Implant Patients 111

119 Alford BR, Jerger J, Jenkins HA (eds): Electrophysiologic Evaluation in Otolaryngology. Adv Otorhinolaryngol. Basel, Karger, 1997, vol 53, pp Electrocochleography Hidehaku Kumagami, Takashige Nakata, Yasuhiro Hirano, Naoki Tsukazaki Department of Otolaryngology, School of Medicine, Nagasaki University, Nagasaki, Japan In clinical electrocochleography (ECoG), particularly the transtympanic electrode technique using needle electrodes, we record the cochlear microphonic (CM), the summating potential (SP) and the compound cochlear nerve action potential (APN 1 ). This chapter considers how certain aspects of the ECoG, particularly the pathophysiology of a widened AP-SP complex (abnormally broad wave), interact with audiometric parameters. We present separate sections on (1) ECoG study of the AP-SP complex, and (2) the diagnostic significance of ECoG in patients with acute low-frequency sensorineural hearing loss. There have been many reports that a widened AP-SP complex is observed in retrolabyrinthine deafness but the cause has been controversial. In this report we have attempted to evaluate the broad ECoG wave in patients with cerebellopontine (CP) angle tumor and with inner ear disorders. Methods for Recording and Categorizing the ECoG Response For the measurement of AP, we have used a click produced by 1 cycle of a 4-kHz sinusoid. For the measurement of CM, we have used short tone bursts (3 ms duration at 8 and 4 khz, 4 ms duration at 2 khz, 6 ms duration at 1 and 0.5 khz). At all frequencies the rise-decay time was 1 ms. All signals are delivered by a shielded loudspeaker located 50 cm lateral to the tested ear. The AP-SP complex wave was recorded in response to click stimulation at 90 dbnhl. We defined a broad AP-SP complex as a waveform in which the width between the rising portion of the negative wave and the baseline crossing was 1.50 ms or more. Abnormal waves were further subdivided into an AP-SP mixed type, which is usually observed, and a dissociated type which shows a two-peak waveform (fig. 1).

120 Fig. 1. Width of the AP-SP complex wave and classification of the abnormally broad wave. The latter was defined as an AP-SP complex wave width of 1.50 ms or more, and was divided into an AP-SP mixed type and a dissociated type. Subjects We report results on a total of 109 individuals: 18 normal controls, 35 patients with CP angle tumors, and 56 patients with presumed cochlear disorders. Patients were divided into three major groups: (1) hair cell damage (H type); (2) retrocochlear damage (R type), and (3) mixed (M type). The mixed type was further subdivided into M-H type (more H than R) and M-R type (more R than H). The H type represents cases in which the AP and CM detection thresholds are almost identical to the pure-tone audiometric level. The R type represents cases in which the CM detection threshold is close to normal, and inner ear hair cells are fairly well preserved. The M type represents cases of probable damage to both inner ear hair cells and retrolabyrinthine pathways. Results Normal Control Group Average ECoG findings at 90 dbnhl in 18 normal hearing subjects were as follows: The click AP(N 1 ) latency was ms, the output potential was approximately 80 μv. For the negative SP the output potential was SP 15 μv ( SP/AP ratio 19%). The width of AP-SP complex wave was ms. The mean CM output potentials at 0.5, 1 and 4 khz were 66, 83 and 85 μv, respectively. The detection thresholds of the CM at 0.5 and 4 khz were approximately 20 and 40 dbnhl, respectively. The threshold at 1 khz was detectable up to the same level as the pure-tone audiometric threshold. A SP/AP ratio of 30% or more defined a dominant negative summating potential [Kumagami et al., 1982]. Kumagami/Nakata/Hirano/Tsukazaki 2

121 Table 1. Relationship between the ECoG classification and the abnormally broad wave in 35 CP angle tumor cases AP-SP width AP-SP width Total 1.50 ms 1.50 ms (broad wave) Hair cell damage (H) type WWWWWXX WWWWX 12 Mixed (M) type 19 M-H type WWWW WWXX 8 M-R type WWWWWWXp 11 Retrocochlear damage (R) type X WWX 4 Total W>Acoustic neurinoma; X>meningioma; >cerebellar astrocytoma; >medulloblastoma; p>prepontine pseudocyst. Table 2. Relationship between the ECoG classification and each type of loss in broad waves in CP angle tumor cases AP-SP mixed type Dissociated type Total Hair cell damage (H) type WWWX WWX 7 Mixed (M) type 7 M-H type WWW W 4 M-R type 3 Retrocochlear damage (R) type X 1 Total W>Acoustic neurinoma; X>meningioma; >cerebellar astrocytoma; >medulloblastoma. Results in Patients with Cerebellopontine Angle Tumor (n>35) The relationship between the ECoG classification and the abnormally broad wave is summarized in table 1. There were 12 H type cases, 19 M type cases (8 M-H and 11 M-R type cases) and 4 R type cases. An abnormally broad wave was observed in 15 cases (42.9%). Of these 15 cases, 7 were H type cases, 7 were M type cases (4 M-H and 3 M-R cases) and 1 was an R type case. R types were relatively infrequent. Most cases showed hair cell damage. The relationship between the ECoG classification and the type of abnormally broad wave is shown in table 2. Nine cases were of the AP/ SP mixed type and 6 cases were of the dissociated type. Electrocochleography 3

122 Table 3. Mean values of the detection thresholds of AP(N 1 ) and CM, output amplitudes of AP(N 1 ) and the width of the AP-SP complex wave at the stimulus intensity of 90 dbnl No. SP AP(N 1 ) Width CM det.thres. 1 Hearing level 2 μv ms latency ampl. det.thres. 0.5 khz 1 khz 4 khz 0.5 khz 1 khz 4 khz ms μv dbnhl (dbnhl) (db) (db) (db) 1 Normal hearing (n>18) CP angle tumors (n>35) Broad wave AP-SP mixed type (1) (4) (5) (5) Dissociated type Not broad wave (5) (5) (5) 3 Cochlear disorders (n>56) Broad wave AP-SP mixed type (1) Dissociated type (2) Flat moderate SHL Low tone losses Ménière s disease Low tone (Williams) No response at 90 dbnhl. 2 Beyond equipment limits. 3 Excludes endolymphatic hydrops. 4 Williams endolymphatic hydrops without vertigo. The mean values of the various parameters by each type are shown in table 3. Many of the CP angle tumor cases showed good agreement between the AP(N 1 ) detection thresholds, the CM response, and the pure-tone audiometric threshold. Five of these cases, though profoundly deafened, showed satisfactory AP(N 1 ) and CM responses. In the SP/AP mixed type, the detection thresholds for both the CM at 4 khz and for click AP(N 1 ) were high. Click AP(N 1 ) showed prolongation of latency and small amplitude. In the dissociated type, the CM detection threshold was high at 4 khz but satisfactory as in the normal group at 1 khz. The detection threshold of the click AP and its latency were close to normal. Illustrative Cases In the following section we discuss ECoG findings in various illustrative patients. Case 1: 69-year-old male, right acoustic schwannoma, abnormally broad wave, AP/ SP mixed type (fig. 2). The pure-tone audiogram for the right ear showed a profound Kumagami/Nakata/Hirano/Tsukazaki 4

123 Fig. 2. Audiogram, ECoG waveform, and input-output curves in a 69-year-old male with right acoustic schwannoma (AP-SP mixed type). sensorineural loss. The click AP(N 1 ) latency was prolonged to 2.00 ms and its amplitude was only 4 μv. The width of the AP/ SP complex wave was 2.00 ms (an abnormally broad wave). The detection threshold of the click-evoked AP(N 1 ) was 60 dbnhl. One- and 4-kHz tone burst AP(N 1 ) thresholds were 60 and 90 dbnhl, respectively. The SP amplitude was low. The CM amplitude was low and was particularly remarkable at 4 khz. The CM detection threshold was somewhat better than the pure-tone audiometric level. These ECoG findings indicated profound inner ear hair cell damage mostly in the high-frequency area (H type). Case 2: 51-year-old female, right acoustic schwannoma, broad wave, dissociated type (fig. 3). The pure-tone audiogram for the right ear showed a severe high-frequency sensorineural loss. The click AP(N 1 ) latency was prolonged to 1.56 ms and its output amplitude was only 6.8 μv. The width of the complex wave was 2.50 ms showing an abnormally broad wave of the dissociated type. The 4-kHz pure-tone audiometric threshold and the AP detection threshold were almost identical, 70 dbnhl. The threshold for click stimulation was even better, 50 dbnhl. The SP amplitude was only 5.9 μv but the SP was dominant with reference to the SP/AP ratio. (What was the ratio?) The CM detection threshold was almost identical to the pure-tone audiometric level. These findings indicated profound hair cell damage (H type) in the high-frequency region. Case 3: 40-year-old female, right acoustic schwannoma, normal AP/SP complex, retrocochlear damage type (fig. 4). In this case, the pure-tone audiogram showed total loss of hearing in the right ear. The click AP(N 1 ) latency was 1.22 ms with minimal prolongation but a high amplitude of 107 μv. The width of the complex wave was 1.20 ms, almost within the normal range. The detection threshold for click AP(N 1 ) was 10 dbnhl, and 1- and 4- khz tone burst AP(N 1 ) thresholds were 20 and 10 dbnhl, respectively, well within the normal range. The SP amplitude and the SP/AP ratio were also within the normal range. CM responses at 4 khz were generally satisfactory although the amplitude at 90 dbnhl was somewhat low (23 μv) and the detection threshold was 50 dbnhl showing a slight increase. In view of the above ECoG findings, this case reflected typical retrocochlear damage type (R type). Electrocochleography 5

124 Fig. 3. Audiogram, ECoG waveform, and input-output curves in a 51-year-old female with right acoustic schwannoma (dissociated type). Deafness due to Cochlear Disorder (n>56) Of the 56 patients in this group there were 49 cases showing an abnormally broad wave, 38 cases were of the AP/ SP mixed type and 11 cases were of the dissociated type. In the AP/ SP mixed type, the mean hearing levels at 0.5, 1 and 4 khz were 57, 55 and 73 db, respectively. The mean detection threshold for click AP(N 1 ) were 57 dbnhl 55, 51 and 74 dbnhl, respectively, excluding 1 case of no response. Thus, profound hair cell damage was noted in the highfrequency area. The click AP(N 1 ) latency was ms, showing a marked prolongation. The amplitude was only 14 μv. To investigte the relationship between the abnormally broad wave and inner ear hair cell damage in the high-frequency region, we reviewed results in various types of hearing disorder. In 16 cases of flat, moderate sensorineural loss (2 cases of sudden loss, 1 case of acute trauma, 2 cases of familial loss, and 11 cases of sensorineural loss of unknown etiology), the mean detection threshold of the CM at 0.5 and 1 khz was approximately 50 dbnhl, almost identical to results in the AP/ SP mixed group. At 4 khz, it was 60 dbnhl, Kumagami/Nakata/Hirano/Tsukazaki 6

125 Fig. 4. Audiogram, ECoG waveform, and input-output curves in a 40-year-old female with right acoustic schwannoma. significantly better than the former group (p=0.0001). The click AP(N 1 ) latency was ms with little prolongation, and the width of the complex wave was ms with no increase. In 19 cases of low-frequency sensorineural loss with almost normal responses in the high-frequency region (12 cases of familial loss, 7 cases of sensorineural loss of unknown etiology, excluding cases of endolymphatic hydrops), there was no prolongation of the click AP(N 1 ) latency and no increase of the width of the complex wave at the stimulus level of 90 dbnhl. In 10 cases of Ménière s disease, the SP was 24.1 μv, a high value. The width of the complex wave was slightly increased but was not abnormally broad. Electrocochleography 7

126 Fig. 5. Audiogram, ECoG waveform, and input-output curves in a 48-year-old female with left Ménière s disease (AP-SP mixed type). In 11 cases of low-frequency sensorineural loss, the so-called endolymphatic hydrops without vertigo, the click AP(N 1 ) latency was 1.14 ms without notable prolongation, and the SP showed a high amplitude of 24.1 μv. The width of the complex wave was slightly increased to 1.23 ms but an abnormally broad wave was not observed in any case. Among 11 cases with a dissociated-response type, the slope of the sensorineural loss was either abrupt or gradual in as many as 8 cases. The click AP(N 1 ) showed a prolonged latency and a low amplitude. In comparison with the 4-kHz pure-tone audiometric level and the mean detection threshold of the AP, the 4-kHz threshold level was 69 db and the 4-kHz tone burst was 62 dbnhl, nearly identical to results in the former group. The threshold for click stimulation was 40 dbnhl. Illustrative Cases Case 4: 48-year-old female, left Ménière s disease, type III [Kumagami et al., 1982], abnormally broad wave, AP/ SP mixed type (fig. 5). The pure-tone audiogram shows a severe sensorineural loss with a somewhat gradual sloping audiometric contour. The click AP(N 1 ) shows a marked prolongation of latency (1.88 ms) and a low amplitude of 16.4 μv. The width of the AP/ SP complex wave was 2.40 ms, a broad wave. The detection threshold was 60 dbnhl for the click AP(N 1 ), and 60 and 80 dbnhl, respectively, for the AP(N 1 )at1 and 4 khz. The amplitude of SP was 8.8 μv, well within the normal range. The SP/AP ratio was 54%, indicating a dominant SP. The CM showed a low amplitude at 4 khz, but was normal in the medium-low frequency region. The detection thresholds of the CM at 0.5, 1 and 4 khz were 40, 60 and 90 dbnhl, respectively, somewhat better than the pure-tone threshold levels in the medium-low frequency region, but profound inner ear hair cell damage was indicated in the high-frequency region. Kumagami/Nakata/Hirano/Tsukazaki 8

127 Fig. 6. Audiogram, ECoG waveform, and input-output curves in a 12-year-old male with familial hearing loss (dissociated type). Case 5: 12-year-old male, familial loss, abnormally broad wave, dissociated type (fig. 6). The pure-tone audiogram shows a severe, bilateral, high-frequency sensorineural loss. The left click AP(N 1 ) shows a prolonged latency of 1.92 ms, a low amplitude of 8.8 μv. The width of the complex wave was 2.25 ms, an abnormally broad wave. The detection threshold for a 4-kHz tone burst AP was 90 dbnhl, nearly equal to the 85-dB audiometric threshold at 4 khz. The detection threshold of the click AP was 60 dbnhl. The amplitude of SP was 0.7 μv, and the SP/AP ratio was also low, 8%. The detection threshold of CM was almost identical to the audiometric threshold. These findings indicate hair cell damage, primarily in the high-frequency region. Discussion Various theories have been proposed to explain the mechanism of the abnormally broad wave. They include: (1) a relative increase of SP due to the decrease of AP amplitude [Portmann and Aran, 1972], and (2) insufficient synchrony of firing of nerve fibers [Eggermont et al., 1980]. The exact cause, however, still remains unknown. Relative to criteria of abnormality of the width of the complex wave, Gibson and Beagley [1976] suggested that 4 ms or more was abnormal, but without further justification. On the basis of results in our normal-hearing subjects we suggest that a waveform in excess of 1.5 ms is abnormally broad. There was a tendency for the width of AP(N 1 ) to widen as the amplitude of AP(N 1 )was substantially lowered. These cases were excluded. The distinction between AP(N 1 ) and SP can be made on the basis that AP(N 1 ) shows adaptation when the stimulus interval is shortened. However, separate measurement of each width Electrocochleography 9

128 is difficult. Hence, we have studied the total AP/ SP complex wave. There may be cases of an abnormally broad AP(N 1 ) but in our series this did not occur. In the dissociated response type, we noted an abrupt or gradually sloping audiometric contour in many cases of inner ear disorder (e.g. case 5). In these cases, the click AP detection threshold was better than both the 4-kHz audiometric threshold level and the 4-kHz tone burst AP detection threshold. In the CP angle tumor group, many cases showed a substantial difference in CM detection threshold between 4 and 1 khz (4?1 khz), and better AP detection threshold for click stimulation than for a 4-kHz tone burst. The fact that the click, a wide-band signal as compared to a 4-kHz tone burst with better frequency specificity [Eggermont and Odenthal, 1974], results in a better AP detection threshold is due to the additional responses in the lower-frequency region (approximately khz) where hearing sensitivity is relatively normal. The dissociated type is often seen when hair cells are damaged severely in the high-frequency region but are undamaged in the low-frequency region (approximately khz). The addition of responses in the low-frequency region, where hearing is normal, seems to cause the abnormally broad wave. In Ménière s disease, prolongation of latency was observed in the advanced disease stage. The 13 cases showing an abnormally broad wave were so-called Ménière s disease type III wherein the 4-kHz CM threshold was very high and the AP(N 1 ) latency, if any, was not remarkable, while the 4-kHz CM detection threshold was satisfactory. An abnormally broad wave was not observed in these cases. In cochlear disorders other than endolymphatic hydrops, prolongation of AP(N 1 ) latency, if any, was slight and without an abnormally broad wave, so long as the 4-kHz CM responses could be detected down to approximately 60 dbnhl, but marked prolongation of click AP(N 1 ) latency and an abnormally broad wave were observed as the damage became more profound. The relationship between the 4-kHz CM detection threshold and the click AP(N 1 ) latency at 90 dbnhl in 29 cases of CP angle tumor, excluding the dissociated type, is shown in figure 7. As the 4-kHz CM detection threshold increased, the click AP(N 1 ) latency was prolonged (r>0.633). The relationship between the 4-kHz CM detection threshold and the width of the AP/ SP complex wave at 90 dbnhl is also shown in figure 7. No broad wave was observed while the 4-kHz CM detection threshold was 40 dbnhl or less, but the complex wave increased in width as the detection threshold increased (r>0.49). In other words, in the AP/ SP mixed type, even among CP tumor cases, there was profound hair cell damage in the highfrequency region as in case 1. On the other hand, in cases of more typical retrocochlear deafness (e.g. case 3) wherein CM and AP responses were satisfactory and the function from the hair cells to the spiral ganglion was likely to be preserved, an abnormally broad wave was not observed. Kumagami/Nakata/Hirano/Tsukazaki 10

129 Fig. 7. Relations among CM detection threshold, AP latency and AP-SP width in 29 cases of CP angle tumor (excluding dissociated type). As the 4-kHz CM detection threshold exceeds 40 dbnhl there is an associated prolongation of the AP latency. No abnormally broad wave is seen. However, an increase of the width is observed with an increase in the CM detection threshold. Among the cases of so-called endolymphatic hydrops, the SP showed a high amplitude and the width of the complex wave was slightly increased so as to show no broad wave in Ménière s disease and William et al. s [1950] endolymphatic hydrops without vertigo. As for Ménière s disease, type III, with a mixed type AP/ SP, a dominant SP was observed in many cases but there was no increase of SP amplitude. Dominant SP was also frequent in cases of other inner ear disorders and in CP angle tumor, but there was not absolute increase of SP, in spite of relatively dominant SP, because of low AP(N 1 ) amplitude. All cases of mixed type AP/ SP, whether inner ear disorder or CP angle tumor, showed markedly prolonged latency and low AP(N 1 ) amplitude. The major causes of an abnormally broad wave are the prolonged latency and low amplitude of AP(N 1 ) even though there is a relative increase of SP. The latency of AP(N 1 ) seemed to be prolonged due to the profound inner ear hair cell damage in the high-frequency region. It has been reported by several investigators that an abnormally broad wave is frequently observed in retrocochlear deafness. However, the cases summarized above show that the broad wave is not specific to retrocochlear hearing loss. It is also observed in loss due to cochlear disorder. The most important factor contributing to an abnormally broad wave is profound hair cell damage in the high-frequency region. Electrocochleography 11

130 Table 4. Distribution of sex and age as a function of status Total M:F M:F M:F M:F M:F M:F (M:F) Improved 0:0 0:8 1:2 2:0 1:2 1:0 17 (5:12) Fluctuated 0:0 1:0 0:0 0:2 2:1 2:0 8 (5:3) Unchanged 1:0 0:0 3:1 0:3 5:1 1:1 16 (10:6) Unknown 2:0 2:1 0:2 1:1 1:0 0:2 12 (6:6) Total 3:0 3:9 4:5 3:6 9:4 4:3 53 (26:27) M>Male; F>female. ECoG Study of Acute Low-Frequency Sensorineural Hearing Loss Recently, many investigators have reported cases of low-frequency sensorineural hearing loss (LFSHL) such as endolymphatic hydrops without vertigo, as described by Williams et al. [1950], and low-frequency sudden loss, or familial LFSHL, as reported by Konigsmark et al. [1971]. Patients may show several clinical courses such as a rapid recovery, a long-term fluctuant LFSHL, development of Ménière s disease [Abe and Tuiki, 1992], or no fluctuation and recovery after the first attack. In this section we will describe the ECoG findings in acute LFSHL, excluding Ménière s disease, and evaluate its prognostic value. Method From 1984 to 1993, 53 cases of LFSHL, ranging in age from 22 to 65 years (26 males and 27 females), were examined by pure-tone audiometry and transtympanic ECoG. They satisfied the following criteria: (1) an average hearing level poorer than 30 db in the low-frequency region (0.25 and 0.5 khz) and better than 20 db in the high-frequency region (2, 4 and 8 khz); (2) a report of sudden loss; (3) no complaint of vertigo or dizziness, and (4) no apparent cause. Prognosis was evaluated according to whether there was improvement, fluctuation or no change in the pure-tone audiogram. As shown in table 4, the prevalence of LFSHL shows no gender difference, but is more frequent in females in the age decade (9 cases; 17%) and in the age decade for males (9 cases; 17.0%). Females, especially in their 20s (8 cases; 47.1%), show better prognosis (12 improved cases; 70.6%) than males (5 cases; 29.4%), whereas males show fluctuation (5 cases; 62.5%) or no change (10 cases; 62.5%). We could not follow the course in 12 cases (unknown cases). Kumagami/Nakata/Hirano/Tsukazaki 12

131 Table 5. Summary of status in each type of lesion Type Male Female Total Endolymphatic hydrops Improved Fluctuating Unchanged Unknown Hair cell damage Fluctuating Unchanged Unknown Neural damage Improved Fluctuating Unchanged Total On the basis of pure-tone audiometry and ECoG, we divided LFSHL patients into three groups: (1) endolymphatic hydrops; (2) hair cell damage, and (3) retrocochlear neural lesion. Thirty-three cases (62.3%) showed a lower CM threshold than pure-tone audiometry thresholds (PTAT), almost the same AP threshold as PTAT and a high amplitude on CM, a negative summating potential ( SP) and an AP indicating endolymphatic hydrops as seen in Ménière s disease [Kumagami et al., 1982]. Seventeen cases (32.1%) revealed approximately the same deteriorated threshold on CM and AP as TPTA, indicating hair cell damage [Kumagami, 1984]. Three cases (5.7%) showed an approximately normal CM response and low AP anplitude indicating retrocochlear neural lesion [Kumagami, 1984]. The relationship between category of lesion and prognosis is shown in table 5. Sixteen (94.1%) out of the improved 17 cases showed endolymphatic hydrops, which was also seen in 3 fluctuating and 9 unchanged cases. No improved cases were observed in hair cell damage, which was present in 4 fluctuating and 6 unchanged cases. In the neural damage patients, there was 1 case of each type. In table 6, the mean values and standard deviations (SD) of the ECoG data for each prognosis in endolymphatic hydrops are compared with normal values. The improved cases showed a significantly prolonged AP latency ( ms) and deteriorated CM detection threshold ( dbnhl at 0.5 khz). The fluctuating cases revealed an even more prolonged AP latency ( ms), low AP amplitude ( μv), high SP/AP ratio Electrocochleography 13

132 Table 6. Means and standard deviations of ECoG data in endolymphatic hydrops Normal Improved Unchanged Fluctuating AP latency, ms AP amplitude, μv SP amlitude, μv SP/AP khz CM threshold, dbnhl khz CM ammplitude, μv p=0.10. ( %) and deteriorated CM detection threshold ( dbnhl). The unchanged cases showed not only results similar to the fluctuating cases but also a much lower CM amplitude ( μv at 0.5 khz). The mean input-output values of AP amplitude show a recruitment-like curve with the L-part and H-part [Kumagami and Osawa 1984] in the improved cases and a significantly low amplitude in the poor-prognosis cases (fig. 8a). The mean input-output values of SP amplitude indicate no significant differences among the prognostic groups, but those in the improved category show slightly higher amplitudes at 80 and 90 db than those in the other two categories (fig. 8b). Illustrative Cases Case 1: Endolymphatic hydrops with improvement (fig. 9). A 22-year-old female complained of fullness in the right ear. Her pure-tone audiogram on the 2nd day after the onset showed a mean loss of 37.5 db in the low frequencies accompanied by a slight loss in the high frequenies (fig. 9a). An ECoG on this day demonstrated a normal AP latency, favorable AP and SP amplitude (112.4 and 25.2 μv at 90 dbnhl, respectively), normal SP/AP ratio (22.4%), normal CM detection threshold, and satisfactory CM amplitude (90 μv at 90 dbnhl of 0.5 khz) (fig. 9b). She recovered completely on the 3rd day (fig. 9c). Case 2: Endolymphatic hydrops without change (fig. 10). A 48-year-old female had complained of tinnitus in the right ear for 7 months. Her pure-tone audiogram showed a mean of 45 db in the middle and low frequencies (fig. 10a). ECoG demonstrated a normal AP latency, favorable AP and SP amplitude (39.5 and 24.1 μv at 90 dbnhl, respectively), high SP/AP ratio (61%), and satisfactory CM amplitude (56 and 110 μv at 90 dbnhl of 0.5 and 1 khz, respectively), but revealed approximately the same CM detection threshold at PTAT in the range of the middle and low frequencies (fig. 10b). No improvement or fluctuation of LFSHL was observed until 2 years post onset. Kumagami/Nakata/Hirano/Tsukazaki 14

133 Fig. 8. Relationships between stimulus intensity (input) and amplitudes of the AP and SP (outputs) in the three prognostic groups. a Mean input-output functions for AP amplitude. Note recruitment-positive curves with the L-part and H-part in the improved cases. b Mean input-output values of SP amplitude. There were no significant differences among prognostic groups, but those in the improved cases show slightly higher amplitude at 80 or 90 dbnhl. Case 3: Endolymphatic hydrops with fluctuation (fig. 11). A 56-year-old male was first examined on the 10th day after the onset of tinnitus and hearing loss in the right ear. The pure-tone audiogram showed a mean loss of 60 db in the range of the middle and low frequencies with 4,000-Hz dip (fig. 11a). The ECoG findings on the same day were as follows: AP showed a prolonged latency (1.20 ms) and slightly decreased amplitude (45 μv at 90 dbnhl). SP manifested a normal SP amplitude (18.8 μv) and a high SP/AP ratio (41.8%). The CM response was satisfactory with a lower threshold (40 dbnhl at 0.5 or 1 khz) than the audiometric threshold and sufficient amplitude (almost 68 μv at 90 dbnhl of 0.5 or 1 khz) (fig. 11b). Despite these hydropic findings, the hearing loss showed no improvement but fluctuated and became worse with vertigo after 8 years (fig. 11c). Case 4: Unchanged after hair cell damage (fig. 12). A 42-year-old female was first examined on the 10th day after the onset of tinnitus and fullness in the left ear. She showed a mean loss of 50 db in the low-frequency of the pure-tone audiogram (fig. 12a). ECoG findings on the same were as follows: AP indicated a normal latency (1.02 ms) and favorable amplitude (55.2 μv at 90 dbnhl), a small SP amplitude (9 μv). The SP/AP ratio was 16%. CM revealed the same detection threshold as the audiometric threshold and a low amplitude (about 24 μv at 90 dbnhl of 0.5 or 1 khz) (fig 12b). Neither recovery nor fluctuation was observed over a 1-year period. Electrocochleography 15

134 Fig. 9. Audiometric and ECoG findings in a 22-year-old female with endolymphatic hydrops on the 2nd day after onset. a Pure-tone audiogram. b ECoG findings on this day. c Complete recovery of the pure-tone audiogram on the 3rd day. Discussion It is generally supposed that the prognosis in acute LFSHL is favorable. In our clinical study, however, only 17 (41.5%) out of 41 cases of acute LFSHL showed an excellent (improved) prognosis and 24 (58.5%) showed a poor (fluctuated or unchanged) prognosis. These results, which might be due to an immediate recovery in many cases of LFSHL before ECoG examination, show that we should not automatically assume that the prognosis in LFSHL is necessarily going to be excellent. Consequently, it is extremely important to attempt to estimate the prognosis of LFSHL in the individual patient, particularly at the initial stage of the disease. Apparently, cases involving hair cell damage reflect the poorest prognosis (e.g. case 4). Kumagami/Nakata/Hirano/Tsukazaki 16

135 Fig. 10. Audiometric and ECoG findings in a 48-year-old female with endolymphatic hydrops in the 7th month after onset. No improvement was observed until 2 years after onset. a Pure-tone audiogram. b ECoG findings. Approximately 90% of improved cases showed evidence of endolymphatic hydrops. However, hydropic lesions were also present in fluctuating or unchanged cases. Comparison of the ECoG findings for each prognosis in endolymphatic hydrops with those of normal hearing cases suggests the following: In improved cases there may be hydropic lesion without hair cell damage as shown in type I Ménière s disease [Kumagami et al., 1982]. On the other hand, patients with a poor prognosis might be thought to have a hydropic lesion with moderate hair cell damage as shown in type II-III Ménière s disease [Kumagami and Miyazaki, 1983]. In neural damage, we are unable to relate any particular ECoG findings to prognosis because of the small number of cases. In summary, the prognosis in patients with LFSHL may be estimated at the initial stage of the onset by ECoG, as revealed by lower CM threshold Electrocochleography 17

136 Fig. 11. Audiometric and ECoG findings in a 56-year-old male with endolymphatic hydrops. a Pure-tone audiogram on the 10th day after onset. b ECoG findings on this day. c Pure-tone audiogram 8 years later. than audiometric threshold, satisfactory CM and SP amplitude, recruitmentlike AP response with a slightly prolonged latency, and nearly normal SP/ AP ratio. The cause of LFSHL may be either a blood flow disturbance, viral infection, or endolymphatic hydrops [Tonndorf, 1976]. In our ECoG study, 62.3% of LFSHL patients showed endolymphatic hydrops, which may also damage hair cells. The fact that almost all of the improved cases showed a prompt recovery within 1 week is consistent with the view that endolymphatic hydrops may develop due to the rapid production of endolymph at the stria vascularis, and promptly resolve due to the reabsorption at the endolymphatic sac. With respect to possible hormonal influence on LFSHL, it is interesting to note that 50% of the improved cases were seen in females in the age decade Kumagami/Nakata/Hirano/Tsukazaki 18

137 Fig. 12. Audiometric and ECoG findings in a 42-year-old female with hair cell damage. a Pure-tone audiogram on the 10th day after onset. No improvement was observed throughout the next year. b ECoG findings on the 10th day after onset years and 34% of the cases of poor prognosis were in males in the age decade of years. Andrews et al. [1992] reported that the symptoms of endolymphatic hydrops (Ménière s disease) might be exacerbated in females during the premenstrual period. Conclusion To conclude: (1) An abnormally broad AP/SP complex wave is not specific to retrocochlear disorders. It was observed in both inner ear deafness and retrocochlear deafness. (2) An abnormally broad wave is not observed in cases of CP angle tumor that show a typical pattern of retrocochlear deafness. (3) The dissociated type appears to show an abnormally broad wave since responses in the normal low-frequency region contribute to the response even though hair Electrocochleography 19

138 cell damage was profound in the high-frequency region. (4) The most important factor contributing to an abnormally broad wave is profound hair cell damage in the high-frequency region. (5) Finally, the prognosis in patients with acute low-frequency sensorineural hearing loss may be estimated at the initial stage by ECoG. References Abe T, Tuiki T: Progressing cases from low-tone sudden deafness to Ménière s disease. Otolaryngology (Jpn) 1992;95: Andrews JC, Gregory AA, Vincente H: The exacerbation of symptoms in Ménière s disease during the premenstrual period. Arch Otolaryngol Head Neck Surg 1992;118: Eggermont JJ, Don M, Brackmann DE: Electrocochleography and auditory brainstem electric responses in patients with pontine angle tumors. Ann Otol Rhinol Laryngol Suppl 1980;75:1 19. Eggermont JJ, Odenthal DW: Methods in electrocochleography. Acta Otolaryngol 1974;316: Gibson WPR, Beagley HA: Electrocochleography in the diagnosis of acoustic neurinoma. J Laryngol Otol 1976;90: Konigsmark BW, Mengel M, Berlin CT: Familial low-frequency hearing loss. Laryngoscope 1971;81: Kumagami H: Sensorineural deafness and electrocochleography. Otol Fukuoka (Jpn) 1984;30: Kumagami H, Miyazaki M: Chronological changes of electrocochleogram in experimental endolymphatic hydrops. ORL 1983;45: Kumagami H, Nishida H, Baba H: Electrocochleographic study of Ménière s disease. Arch Otolaryngol 1982;108: Kumagami H, Osawa H: Electrocochleographic studies of recruitment phenomenon. Auris Nasus Larynx (Tokyo) 1984;11: Portmann M, Aran JM: Relations entre (Pattern) électrocochléographique et pathologie rétro-labyrinthique. Acta Otolargyngol 1972;73: Tonndorf J: Endolymphatic hydrops: Mechanical causes of hearing loss. Arch Otorhinolaryngol 1976; 211: Williams HL, Horton BT, Day LA: Endolymphatic hydrops without vertigo. Arch Otolaryngol 1950;51: H. Kumagami, Department of Otolaryngology, School of Medicine, Nagasaki University, 7-1 Sakamoto 1-Chome, Nagasaki 852 (Japan) Kumagami/Nakata/Hirano/Tsukazaki 20

139 Alford BR, Jerger J, Jenkins HA (eds): Electrophysiologic Evaluation in Otolaryngology. Adv Otorhinolaryngol. Basel, Karger, 1997, vol 53, pp Auditory Brainstem Response: Recent Developments in Recording and Analysis James W. Hall III, Katheryn A. Rupp Division of Hearing and Speech Sciences and Department of Otolaryngology, School of Medicine, Vanderbilt University, Nashville, Tenn., USA Since the auditory brainstem response (ABR) was first described by Jewett and Williston [1] a quarter of a century ago, its clinical utility has been widely recognized. In many clinics, ABR measurement has become a routine part of a battery of tests for evaluating peripheral auditory sensitivity, as well as the neural integrity of the auditory CNS. ABR measurement is useful with varied populations, including individuals unable to respond reliably during behavioral audiometry, those with nonorganic hearing loss, patients posing a masking dilemma due to severe bilateral conductive hearing loss, individuals suspect for Ménière s syndrome, and patients undergoing evaluation to rule out retrocochlear pathology [2]. During the first two decades following Jewett and Williston s description of the ABR, clinical procedures and guidelines for recording valid and reliable ABRs were developed. With the recent advances in computer technology impacting commercially available equipment, current ABR measurement strategies are focused on the development of new techniques to (1) decrease the time in which it takes to record the response, (2) enhance the quality of the response, and (3) increase the objectivity of the test, through improved signalto-noise ratio (SNR) averaging methods. The purpose of this chapter is to introduce the clinician to recent major developments in ABR stimulation and analysis techniques, to review their clinical utility, and provide the clinician with guidelines for implementing these strategies into their routine ABR test protocol.

140 Minimizing Test Time While the ABR is an invaluable clinical tool for objectively assessing the status of the peripheral and brainstem auditory pathways, one restriction to using this measure extensively in daily clinical practice is the time required for reliably recording and confidently interpreting responses from most patients. Because the ABR is a small amplitude response embedded in a background of larger amplitude EEG activity (noise), averaging techniques must be used to tease out the response from the ongoing background noise. In particularly nervous or tense individuals, electromyogenic (EMG), or muscle, potentials can obscure the response as well. Thus, in daily clinical practice, obtaining an ABR usually requires averaging anywhere from several hundred to several thousand stimulus sweeps. A sweep in this sense refers to a stimulus-response pair. For example, as with any transient response, the ABR is elicited by a single stimulus presentation and the response, along with the corresponding noise, is recorded before the next stimulus is presented. As responses to sequential stimuli are averaged together, the random activity (noise) eventually approaches an average amplitude of zero, allowing the ABR (the signal) to emerge from the noise. The transient nature of the response, as just described, also adds to the ABR test time. Because only one response is recorded at a time, and because a single response occurs over a time period of approximately ms, the maximum rate at which the stimulus can be presented without the responses overlapping is around /s. However, stimulus rates higher than about 20/s have been shown to affect the latency and amplitude of the ABR [1, 3]. Thus, in clinical measurement, slower stimulus rates are typically used. The slower the rate, however, the longer ABR recording will take. It seems, then, that in order to minimize the time it takes to record the ABR, either the SNR must be improved or a method must be implemented so that the rate of stimulus presentation can be increased. Maximum Length Sequences and Chained Stimuli In 1982, a method for decreasing ABR test time through increased repetition rate was proposed by Eysholdt and Schreiner [4]. The authors described a stimulus presentation paradigm called maximum length sequences (MLS), whereby a binary sequence of pulses, occurring at pseudorandom time intervals, is presented to the ear and the application of appropriate computations allows the ABR to be extracted from the resulting responses [4]. At this point, you may be asking yourself, What does all that mean?. For the more advanced Hall/Rupp 22

141 Fig. 1. An example of an MLS stimulus of length 7. Upward pointing lines indicate click events, while downward pointing lines are no-click events in the series. The resulting waveforms corresponding to each event are shown in the bottom tracing (see text). [Adapted from 7.] scientist and mathematician, several mathematical models and theories behind the use of MLS are presented elsewhere [4 6]. A basic description and explanation of the MLS procedure will be attempted here. The Stimulus An example of an MLS stimulus is depicted in figure 1. Basically, an MSL is a type of stimulus that is made up of a series of binary events. Binary meaning that each event in the series has only one of two possible values (i.e., click or no-click). The series is a specified length (L) equal to 2 n Ö1, where n is an integer, often referred to as the order of the sequence [6, 7]. For example, an MLS of order 3 would yield a series length of 2 3 Ö1>7 events. The number of events in the sequence that trigger a stimulus pulse, or click, is determined by the equation (L+1)/2. In our example, (7+1)/2>4. Thus, our series would consist of 4 clicks and the other 3 events would be no-clicks, or silences. The events are placed in a pseudorandom order with a fixed interval between them. An important point to remember with MLS is that the series, as shown in figure 1, constitutes only one stimulus of the MLS technique. In practice, many stimuli (series) are presented in sequence, with no break between subsequent stimuli. MLS Response Analysis For analysis purposes, a cross-correlation of the responses obtained from each stimulus is performed such that activity that is common to the tracings will be added and activity that is not will be subtracted. The result is a disentangling of the overlapping waveforms [6]. As a simplified example, the averaging technique used to analyze the MLS-ABR using an MLS of length 7 is shown in figure 2. This figure, as well as figure 3, is based on an MLS Auditory Brainstem Response 23

142 Fig. 2. An MLS-ABR analysis. From the two MLS stimuli (top tracing), 7 subaverages are recorded which correspond to the 7 events (steps) in the MLS stimulus. Each subaverage, after the first, is shifted so that the response to that particular step occurs first and the previous waveforms wrap around to the end of the tracing. [Adapted from 7.] Fig. 3. Continuation of the MLS-ABR analysis. The 7 subaverages from figure 2 are shown here, aligned. The traces to be added are outlined in bold and are seen as vertexpositive waves. The traces not beginning with a response to a click are subtracted (shown here as inverted). Addition of the traces results in a recording of the bottom tracing (total). Because every interval, after the first, contains 2 positive and 2 negative waveforms which cancel each other out, only the response in the first interval is enhanced. [Adapted from 7.] Hall/Rupp 24

143 analysis example depicted by Marsh [7]. Two consecutive MLS stimuli series are shown at the top of the figure and 7 sub-averages of the response, corresponding to the 7 events in the stimulus, are depicted beneath. Tracing 1 is the response to the whole MLS series, beginning with the first event (a click) in the MLS stimulus. The next tracing is the response to the series beginning with the second event in the MLS stimulus, another click. The third and subsequent tracings are identical to the first two, but the traces always begin with the response to the event in the series corresponding to the sweep number. Thus, each waveform, although identical to the first, is shifted by one interval more than the tracing immediately before it. Further, the tracings show a circular shift, such that the part of the waveform that was once at the beginning of the sweep has wrapped around and is now at the end of the sweep. Now that we have one original tracing and 6 shifted versions of the original, the 7 waveforms are either added to or subtracted from each other. All the tracings beginning with a response to a click [1 3, 6] are added. If the tracing does not begin with a response to a click, then it is subtracted. This portion of the analysis is easily understood if the responses are aligned, as in figure 3. The traces to be added are outlined in bold and are seen as upward-going positive waveforms. The traces that will be subtracted are inverted. We can see that the waveforms in the first interval all correlate, therefore, they are added together and the response is enhanced. In all of the other intervals, two positive (those beginning with a click response) and two inverted traces (those beginning with a no-click response) cancel each other out. Thus, the resulting waveform is the total, shown in the bottom trace. From this example, we can see that, in the same time period required to record one response (waveform) with conventional ABR, we have collected and averaged 4 waveforms with the MLS-ABR technique. Although this is a simple example of an MLS of length 7, the same rules apply to MLSs of longer lengths as well [7]. Clinical Utility of Rapid Stimulation Because the number of clicks that can be presented within a particular time period using MLS is significantly higher than conventional ABR rates, MLS shows promise as a clinical tool for recording ABR, particularly in situations where time is limited (i.e., newborn and pediatric assessment). In fact, Thornton and Slaven [8] demonstrated that the ABR could be obtained with MLS using maximum stimulus rates of up to 1,000 clicks/s! However, as in conventional ABR averaging techniques, higher stimulus rates with MLS increase wave V latency, and considerably reduce waveform morphology and amplitude [4, 6 8]. Presumably, this would mean that the SNR is compromised with MLS, requiring more averaging. This, indeed, has been confirmed [6 8]. When higher stimulus rates are used, adaptation occurs in the auditory system Auditory Brainstem Response 25

144 A 4 and response amplitudes are decreased. In fact, Thornton and Slaven [8] observed greater than 90% adaptation, as measured by wave V amplitude, when stimulus rates were increased from 9.1 to 1,000 clicks/s. The results of several studies, however, suggest that the most efficient MLS paradigms, ones in which the SNR is not significantly affected, include maximum stimulus rates of between 70 and 500 clicks/s [4, 8]. Further, Thornton and Slaven [8] reported that a maximum rate of 200/s requires less time to achieve a SNR comparable to conventional ABR recorded at a stimulus rate of 10/s. The advantages of using this MLS rate may be more prevalent when compared to higher conventional ABR stimulus rates, such as 20 or 30/s. Figure 4 shows a comparison of a conventionally recorded ABR intensity series using 21.1 clicks/s and two MLS-ABR intensity series using click rates of and 1,000/s. While the time window of the conventional ABR recording is 15 ms, versus the 24 ms time window of the MLS recordings, the sensitivity scale of all recordings are the same. The decrease in ABR Hall/Rupp 26

145 B C Fig. 4. Comparison of a conventional ABR intensity series and two MLS intensity series for the left ear of an adult female with no known otologic or audiologic pathology: A conventional ABR intensity series using a stimulus rate of 21.1 clicks/s and a time window of 15 ms; B MLS-ABR intensity series using a click rate of 500.1/s in a 24-ms time window; C MLS-ABR intensity series using a click rate of 1,000/s in a 24-ms time window. Each recording was made with a fixed sensitivity of 0.16 μv/ division. Auditory Brainstem Response 27

146 amplitude with increasing stimulus rate is easily observed from this figure. In fact, at a stimulus rate of 1,000 clicks/s, ABR wave V is identified at an intensity 10 db greater than the other, lower, click rates. This illustrates well the findings of Thornton and Slaven [8]. Thus, an MLS stimulus rate of 500 clicks/s or less is recommended. While the increase in wave V latency, and the subsequent decrease in ABR waveform morphology, that occurs with MLS would seem to preclude its use in neurodiagnostic testing, the MLS technique may be useful in conducting rate studies with patients suspected of having retrocochlear pathology. Stressing the auditory system with high rate MLS-ABR and comparing the resulting waveform with ABR results recorded at slower rates may increase the sensitivity of ABR in neurodiagnosis [9]. In addition, because wave V may be identified at very high stimulus rates used in MLS recording, the MLS technique may be particularly advantageous for determining ABR threshold in difficult-totest populations, where time is often limited [6 8, 10 12]. Maximum length sequence-intensity functions, like that shown in figure 4, have been reported by several groups using click and tonal stimuli [6, 12]. Lasky et al. [12] reported that MLS-ABR thresholds for adults and newborns, using click stimuli, were similar, yet slightly elevated, when compared to their conventional ABR threshold counterparts. The authors noted that the small ISI used in the MLS recordings (1.1 ms) may have compromised the identifiability of wave V at lower intensity levels due to the poorer SNR. Wider intervals between successive clicks may enable identification of wave V at levels corresponding to conventional ABR threshold intensities. Indeed, Hamill et al. [10, 11] used a stimulus paradigm similar to MLS to study intensity functions in adults. This group used a chained-stimulus technique, which includes a series of clicks separated by equal intervals (versus the pseudorandom intervals of MLS) of 12 ms. No silent (no-click) events are used in this paradigm. Each successive click in the series differs in intensity from the previous one by 10 or 20 db, and the responses to each stimulus are stored in separate buffers for each intensity; A buffers for odd numbered sweeps and B buffers for even numbered sweeps. The responses stored in buffer A may then be statistically compared to the responses in buffer B for objective analysis of response presence or absence. Figure 5 contains an example of a chained-stimulus used in ABR threshold estimation. In their studies with normally hearing and hearing-impaired adults, Hamill et al. [10, 11] reported that thresholds using the chained-stimuli were essentially equivalent to thresholds obtained using conventional ABR. In addition, the authors noted that responses obtained with the chained-stimulus technique were collected in a minimal amount of time; approximately 8 min per ear. Thus, the advantages of using this technique for rapid threshold estimation are clear. Hall/Rupp 28

147 Fig. 5. Example of a chained-stimuli paradigm used to record threshold ABR responses. Up to 20 buffers are used to store waveforms for each event in the series. A buffers are used to store odd-numbered sweeps, while B buffers contain even-numbered sweeps. [From Intelligent Hearing Systems, 1995, pers. commun., reprinted by permission.] While threshold estimation using click stimuli is a useful and popular technique currently used in the audiology clinic, this measure primarily reflects hearing sensitivity in the 2,000- to 4,000-Hz region. Thus, hearing loss at lower or higher frequencies may go undetected. In many clinics, a commonly used adjunct to the click threshold ABR is the use of short duration tonal stimuli to obtain frequency-specific information. This can also become time-consuming, unless chained-stimuli of MLS is used. Using a minimum ISI of 13 ms, Picton et al. [6] recorded frequencyspecific MLS-ABR using 500- and 2,000-Hz tonepips. The authors were able to obtain MLS-ABR for the 2,000-Hz tonepips at levels 10 db above behavioral threshold. The 500-Hz MLS-ABR thresholds were recorded at levels 25 db above behavioral threshold [6]. These findings are consistent with conventional tone-burst ABR reports [13]. Thus, because the same information can be obtained by using the faster rate MLS with tone-burst stimuli versus conventional ABR, the advantage of the MLS technique is obvious. Namely, the time required to obtain frequencyspecific information is significantly reduced. Even faster rates may be applied to higher frequency stimuli [6]. It should be noted, however, that the longer duration required to produce lower frequency tonepips (10 ms for 500 Hz of cycles, recommended by Davis et al. [14]) will not allow rapid stimulation rates for low-frequency MLS using an ISI of less than 10 ms. If time is the main factor in obtaining frequency-specific ABR thresholds, then use of click stimuli in combination with a high-pass masking noise may be used. This technique, the derived response, has been described for conventional ABR use Auditory Brainstem Response 29

148 Fig. 6. Example of a TOPSTIM stimulus series. Each successive pulse in the sequence is a different frequency, but of equal intensity. [From 16, by permission.] [15] and may be the most efficient means by which frequency-specific ABR can be obtained using MLS [6]. A similar technique using tone-burst stimuli in a chained-stimuli paradigm was described by Hoke et al. [16]. This group recorded threshold ABRs to tone-burst stimuli in conjunction with a gliding high-pass masker at levels down to within 20 db of behavioral thresholds. They referred to this technique as TOPSTIM (tone-pulse series stimulation) with GHINOMA (gliding highpass noise masking). While the chained-stimulus described previously consists of a series of equal-frequency stimuli at different intensities, the TOPSTIM technique employs a series of different frequency stimuli at equal intensities [16]. An example of the TOPSTIM stimulus series is shown in figure 6. The possible advantages of the MLS and chained-stimuli techniques are obvious and undisputed. As time is a major factor in auditory assessment of newborns and young children, use of these two techniques may prove to be substantially beneficial in the audiology clinic. Initially, the limited availability of commercial equipment having the ability to record ABR using these techniques precluded their use in the clinic. In fact, many of the studies mentioned in this review were conducted with the use of laboratory, or specially designed, computer equipment. Currently, however, several commercially available clinical systems incorporate software which allow these techniques to be used. These systems are listed in table 1. In addition to monaural MLS and chainedstimuli techniques, several systems also allow simultaneous binaural stimulation using these methods. Stimulation of both ears simultaneously can literally cut evaluation time in half. Simultaneous Binaural Stimulation In 1993, Marsh [17] reported that recording conventional ABRs from both ears simultaneously, without contamination from the opposite ear, is possible if slightly different stimulus rates are used for each ear. Comparing simultaneous binaural stimulation ABRs to monaurally recorded responses Hall/Rupp 30

149 Table 1. A listing of the advanced ABR techniques reviewed in this chapter and the commercially available systems which employ them Technique Commercially available systems Bio-Logic Intelligent Natus Nicolet Systems Hearing Medical Instrument Corp. Systems Inc. Corp. Maximum length Spirit sequences Chained-stimuli Smart Screener Simultaneous binaural Algo-2 Spirit stimulation 40-Hz SSR Traveler Express; SmartEp Spirit; Pathfinder Navigator; Viking; Compass; Explorer C-series 80-Hz AMFR SmartEp Viking Family F sp Spirit Response correlation Traveler Express; Smart Screener; Spirit Navigator; SmartEp Explorer Template matching Algo-1; Algo-2 in adult subjects with normal hearing, the author observed no significant differences in wave V mean amplitudes or latencies. The author did note, however, that when the stimulus intensities to each ear were very different during binaural stimulation (i.e., 80 dbnhl for the right ear and 40 dbnhl for the left ear), wave V latencies were slightly, yet significantly, prolonged. This was the only difference noted in the report, thus the conclusion was made that concurrent testing may be a valuable clinical technique as long as the stimulus intensities between the two ears is not too dissimilar [17]. In fact, this technique is used for infant hearing screening with ABR, and is available on the Algo-2, an FDA-approved, clinical ABR screening device. In much the same way as recording simultaneous binaural conventional ABRs, simultaneous binaural MLS-ABRs may be recorded. That is, MLS- ABRs may be recorded concurrently by applying either two separate MLS stimuli series to each ear, or by using the same MLS stimulus series for both ears, but shifting one ear s stimulus presentation in time relative to the other ear s stimulus presentation. In this way, the cross-correlation rule used to analyze the response is dissimilar for the two ears and will only serve to extract Auditory Brainstem Response 31

150 the response from the ear in which the stimulus generation rule matches. The response from the contralateral ear, then, is seen as random activity and becomes averaged out with the background noise. Using this MLS-ABR technique, Lasky et al. [18] obtained very similar results to those reported by Marsh [17] for binaural stimulation using conventional ABR techniques. Recording monaural and binaural MLS-ABRs from normal hearing adult subjects, Lasky et al. [18] observed no significant differences between the types of recordings for suprathreshold or threshold level stimuli. The only differences noted in their report were those between conventional monaural ABR and both types of MLS-ABR latency intensity and amplitude intensity functions, which would be expected. That is, conventional ABR latency intensity and amplitude intensity functions are steeper than MLS-ABR functions. Thus, using MLS to record monaural or simultaneous binaural ABRs will not yield significantly different results from each other, but will differ from conventional ABR recordings in the expected ways mentioned previously. Further, simultaneous binaural stimulation with MLS will significantly reduce test time, which will be appealing to any clinician. Limitations of MLS and Chained-Stimuli These techniques, while having advantages, do not come without their disadvantages as well. Picton et al. [6] noted several disadvantages of the MLS technique which may also be true for the chained-stimuli technique, including (1) the large memory requirement for response cross-correlation over a large number of sequences, especially for multiple channel recordings, (2) that more stimuli may need to be averaged in the presence of even a few artifacts. That is, any briefly occurring artifact can cause an entire stimulus sequence to be discarded. Thus, more averaging may be needed to obtain an adequate amount of sweeps. The amount of artifacts is especially detrimental for longer length stimuli, and (3) responses obtained with these techniques contain more noise than responses obtained with conventional ABR. Nevertheless, once the limitations of these methods are realized, the clinician may be able to successfully overcome them. In fact, the clinician is encouraged to keep in mind two points when using MLS. First, when attempting to record an ABR with MLS, the high stimulus rate will be perceived by the patient as being much louder than the intensity dial reading would suggest. Thus, lower intensities (=90 dbnhl) should be used to eliminate any discomfort to the patient. Second, because wave V is shifted out during testing with MLS, latency comparisons to conventional ABR norms will be ineffective. Each clinic should establish its own normative data, as well as its own measurement parameters. This will be especially important for threshold estimation with MLS versus chained-stimuli, as MLS data will not fit into existing latency intensity functions. Hall/Rupp 32

151 Steady-State Evoked Responses Another method proposed for rapid and objective assessment of hearing using auditory evoked responses includes recording steady-state evoked response, or just steady-state responses (SSR). As opposed to the conventional ABR, which is a transient response, SSR are elicited by stimuli occurring in rapid succession so that the recorded responses overlap in time with a periodicity characteristic of the rate at which the stimuli are presented. SSRs actually include components that do not fall within the anatomic or temporal constraints of the conventional ABR. These responses are different than MLS- ABR or chained-stimuli responses because they represent neural discharge which is phase-locked, versus time-locked to the stimulus. That is, the responses are analyzed according to the number of repeated cycles occurring in a particular time window (their frequency), rather than the latency of particular peaks in the waveform occurring in that time window. Also, they do not require the responses to be disentangled before analysis. The 40-Hz SSR Probably the most widely recognized SSR is the 40-Hz response, first introduced by Galambos et al. [19]. The 40-Hz response is elicited by a toneburst or click stimulus occurring every 25 ms (40/s), and is comprised of a series of peaks which are observed in the time domain every 25 ms. This corresponds to 40 Hz in the frequency domain. Thus, in a 100-ms analysis time window, about 4 cycles of the response can be observed. Clinical Utility: Several features of the 40-Hz response would seemingly make it an excellent evoked response for measurement of auditory sensitivity in difficult-to-test populations. The amplitude of the response is large (usually 1.0 μv or more) so that it is easily identified without much averaging, and it can be identified at stimulus levels close to auditory threshold. In addition, the use of tone-burst stimuli allows the tester to acquire frequency specific information in a timely fashion. Although this evoked response has many attractive features, several groups have discovered some major limitations of the response which preclude its usefulness with several populations for whom this measurement would seem ideal. Limitations: While the 40-Hz response is robust in awake adults, its amplitude decreases significantly in sleeping subjects [19, 20]. Furthermore, it is difficult to record the 40-Hz response in newborns and young children [21 23]. Thus, the clinical utility of this measure in the populations for which it would be most useful (individuals unable to respond during behavioral audiometry) is severely limited. Auditory Brainstem Response 33

152 The 80-Hz SSR The auditory SSR can be recorded using higher stimulus rates, with the focus on tonal stimuli in order to obtain frequency-specific data [24 26]. The use of sinusoidally amplitude-modulated (SAM) tones to elicit the SSR provides more frequency-specific information than conventional ABR toneburst stimuli due to their narrower power spectrum. From figure 7, it is clear that the SAM tone contains considerably less energy at frequencies below the center tone frequency than the conventional tonal stimulus using Blackman windowing. In addition, the response to the SAM tone is observed to follow the frequency of modulation. Thus, the response was named the amplitudemodulation following response (AMFR) [27]. The Stimulus: A SAM tone is produced by mixing two sine waves, each generated separately. One of the inputs is called the carrier frequency, or tone, and is set at the audiometric frequency the tester wishes to evaluate. The other input is the modulation frequency (MF), which is usually set at a low frequency (=200 Hz). When the two inputs are mixed, the amplitude of the carrier tone will fluctuate at the rate of the MF (i.e., an MF of 50 Hz will cause the amplitude of a 1,000-Hz carrier tone to fluctuate 50 times/s). The response elicited by the SAM tone stimulus reflects synchronous firing of auditory neurons phase-locked to the modulation frequency [27]. Presence or absence of the 80-Hz AMFR is automatically and objectively determined by phase spectral analysis. This analysis measure employs FFT analysis to determine the frequency of the response, and the power of the response (the signal versus the noise) is statistically determined by calculating the component synchrony measure (CSM), indicating the amount of phase variance in the Fourier component [28]. Clinical Utility: In a systematic study to find the optimal MF for recording the response in young children, Aoyagi et al. [26] found that MFs of Hz, with a modulation depth of 95%, elicited a response close to auditory threshold in young children during sleep. Furthermore, using a SAM tone stimulus, threshold estimation was more accurate than threshold estimation by ABR using toneburst stimuli [28]. In fact, Aoyagi et al. [29] were able to measure 80-Hz AMFR thresholds for 1,000-Hz SAM tones at levels 10 db lower than conventional ABR thresholds. Thresholds for adults using this same stimulus, however, were considerably higher than conventional ABR threshold measures. Although the reasons for this finding were not clearly stated, the authors recommended restricting the use of 80-Hz AMFR testing to newborns and children up to their middle teenage years. The authors suggested that lower modulation frequencies, such as 40 Hz or less, were more appropriate for estimating threshold levels of adults. Further investigation of the clinical feasibility and value of the 80-Hz AMFR technique in pediatric and adult patient populations is warranted. Hall/Rupp 34

153 A B C D Fig. 7. Comparison of a conventional ABR tone-burst and a SAM tone both centered at 500 Hz. A and B illustrate the spectral content of the two stimuli. Note that the SAM tone spectrum contains 3 closely spaced energy peaks. The peak in the middle corresponds to the carrier tone (the frequency of interest) and the 2 side peaks are comprised of the carrier plus modulation (MF>80 Hz) tones. In C and D the tonal stimuli have been measured through an insert earphone (ER-3A). It is easy to see that the SAM tone contains less energy below the center frequency than the conventional ABR 500-Hz tone-burst. At higher modulation frequencies (?80 Hz), the 2 side peaks separate from the carrier tone peak, reducing the frequency specificity of the stimulus. Auditory Brainstem Response 35

154 Limitations: While the AMFR may be clinically useful for estimating thresholds of newborns and young children, the development of commercially available equipment and software designed to create the SAM tone stimuli has been slow. Thus, the AMFR is not widely used. Development of software to interface with clinical ABR hardware is currently underway and should be available for use in the very near future, according to Intelligent Hearing Systems engineers. Enhancing Response Quality and Increasing Test Objectivity through Improved Signal-to-Noise Ratio Calculations Once ABR recording is underway, continuous visual evaluation of the waveforms is required in order to determine the presence or absence of a response. While ABR recording is objective, in contrast to behavioral measures of hearing, response identification and analysis typically requires clinical judgement. Confident response interpretation by the clinician is dependent on the stability of the response (signal) and the amount of random activity (noise) in the tracings. With poorer SNR, the clinician usually needs to average more sweeps to visually detect the response. Increased signal averaging will reduce the background noise, permitting ABR identification, but it will also lengthen the time required to record the response. In short, the determination of ABR presence or absence is highly dependent on the SNR. Recently developed techniques may facilitate objective evaluation of response quality and adequacy of the SNR. Plus/Minus Signal-to-Noise Measurement Technique One objective way to determine the amount of noise that is present in the ABR recording involves averaging the odd numbered stimuli and the even numbered stimuli separately, so that two waveforms are generated. One waveform is then subtracted from the other. This is commonly referred to as the plus/minus ( ) technique. The subtraction of the waveforms will effectively cancel any activity that is stable in the two recordings (the response), while relatively random activity (noise) will not be completely cancelled. Thus, the resulting waveform is a representation of the noise present in the recording. A SNR is then calculated by dividing the variance of the response by the variance of the reference [30]. Clinical Utility: Current computer technology used in clinical ABR systems allows the clinician to easily obtain a measure of the SNR using the method. Software of this type usually employs two separate buffers into which the odd and even numbered stimuli are separated. Therefore, the clinician can Hall/Rupp 36

155 view the two waves separately, while obtaining a measure of the SNR. These two waveforms can also be overlayed to better verify the presence of a response and its replicability. This would also reduce test time considerably because the response and its replication are collected simultaneously. Also, by using stimuli of alternating polarity, responses to rarefaction stimuli and condensation stimuli may be stored separately into their respective buffers and individually analyzed [31]. There is, therefore, no need for separate recordings of the response for each stimulus polarity to determine which polarity will yield the optimal ABR waveform. The method also increases test objectivity because the clinician determines response presence or absence based on a statistical criterion of the SNR compared to the F distribution. That is, determination of response presence is made once the SNR value exceeds the set criteria. F sp Technique In 1984, Elberling and Don [32] showed the variance of the background noise in an ABR recording could be more reliably estimated by measuring the variance of a single point in the recording over several hundred sweeps. This technique is known as F sp, where F refers to the distribution with which the variance estimates will be compared (the F distribution), and sp corresponds to the single point in the samples that will be measured in order to give us this variance estimate. With an estimate of the variance in the background noise, the amount of averaging needed to detect the ABR can be systematically determined. The detailed mathematical computations and derivation of the formulas used in this technique are presented elsewhere [32] and will not be described here. The basic underlying assumptions of the technique, however, will be explained. The F sp equation used to determine the quality of the response is as follows: VAR (S) F sp > VAR (SP) where VAR (S) is the variance in the evoked response and VAR (SP) is the estimate of the variance in the background noise in the recording. The basis for this equation is the assumption that any single point in the recording contributing to the true ABR neural response will remain at a constant latency and amplitude across many sweeps. Any single point contributing to the background noise, however, will vary from sweep to sweep, as noise is composed of random activity. The measures of variance, the F sp value calculated from the equation, is then compared to the F distribution. With the F table, a statistical criterion is established for the minimum number of averages needed Auditory Brainstem Response 37

156 Fig. 8. Illustration of the amount of averaging (in sweeps) required to reach critical F sp values in quiet and noisy recording conditions as a function of intensity level. It is apparent that as stimulus intensity is increased, less averaging is required to meet the F sp criterion, even in a noisy recording condition. For very low intensity levels, F sp may not reach criterion level, especially in noisy recording conditions. By averaging more responses, however, the quality of the recording (F sp ) is increased. to detect a response within a specific confidence interval of the F distribution (i.e., the 95 or 99% confidence interval), based on the calculated variance estimate, the F sp. Figure 8 illustrates an example of the F sp technique. F sp value is calculated as a function of number of sweeps averaged and stimulus intensity level. From this figure, it is clear that for higher stimulus intensities, less averaging is needed to meet the F sp criterion for response detection (500 sweeps Hall/Rupp 38

157 at 20 dbsl). For lower intensities, however, the smaller response requires more averaging to meet the criteria [33]. The amount of averaging required to reach agivenf sp is, of course, indirectly related to the SNR. Clinical Utility: In instances where a clear and reliable response is obtained, continued averaging is unnecessary. With the F sp measure, clinicians record and replicate a response according to the F sp value measured. That is, instead of always replicating with a constant number of sweeps, averaging is terminated once the same predetermined F sp value is achieved for each record. Applying this technique in quiet recording situations reduces test time substantially. However, probably the most useful feature of F sp is observed in recording situations which are either noisy or where, for other reasons, the visual identification of a response is obscured. At stimulus intensity levels close to threshold, the amplitude of the ABR is reduced considerably. Wave V, often the only detectable component in the response, may be so small in comparison to the background noise that continued averaging will not contribute importantly to visual detection. Or, fluctuations in the noise may be incorrectly interpreted as a response. The statistical calculations of F sp can eliminate the questions of response presence or absence within a specified interval of confidence. Sininger [33] reports that, using a 95% confidence interval with F sp, threshold ABR to click stimuli can be obtained within 10 db of behavioral pure tone averages. In addition, she suggests that evaluation of the number of averages needed to meet F sp criteria may be useful in determining step size decriment during threshold estimation. For example, if F sp criterion is achieved with a relatively small number of averages (i.e. 1,000), then the stimulus is decreased by 20 db. If, on the other hand, F sp criterion is reached only after averaging many sweeps, then the intensity of the stimulus should be decreased by only 10 db [33]. The fact that this method can be applied during data collection (on-line) allows the audiologist to determine threshold in a more efficient and timely manner. Furthermore, F sp effectively increases the objectivity of the test by calculating the variance in the recording, thus allowing the examiner to compare the F sp value to a statistical criterion. Limitations: While F sp may be considered a powerful tool for objective assessment of ABR responses in the time domain [34], most clinical ABR devices do not routinely offer F sp software for response averaging. One system with F sp capabilities is mentioned in table 1. For those ABR systems which do not allow objective response detection through F sp calculations, there are other techniques for objective response analysis. Finally, there are limited guidelines on which F sp criterion, or criteria, are appropriate for response identification, or confirmation, in diverse patient populations under often varying measurement and subject conditions. Auditory Brainstem Response 39

158 Fig. 9. Template used in objective detection of ABR response presence or absence. Nine points in the template are used for comparison with the recorded data points. The data points are heavily weighted toward the latency values of data corresponding to wave V and the large negativity following it. [From 35, by permission.] Template Correlational Analysis Some evoked response systems employ a correlational technique for the objective determination of response presence or absence. This technique is similar to human observation and evaluation of response presence or absence, in that each response is compared to an already determined template of what the response should look like. While the degree of reliability among human observers using this technique is highly dependent on the experience and psychophysical criteria of each examiner, these variables can be reduced by programming the evoked response system to identify the ABR according to the likelihood of obtaining a set of data points sufficiently similar to known data point values. In other words, calculation of the probability that a recording is an actual response, based on the ABR template of traces from many normal subjects, is programmed into the evoked response system. An example of this template analysis is shown in figure 9. Two ABR screening devices employ this method of response analysis, using an algorithm to compare the recorded data to nine selected data points in the ABR template (table 1). The algorithm used in this method of response analysis uses a binomial sampling approach, where sampled data are statistically related to one of two conditions: a response-plus-noise condition or a noise-only condition. From this analysis, a likelihood ratio (the likelihood that the recorded data constitutes an actual response) is calculated [35]. Clinical Utility: Use of a template to objectively determine the presence or absence of a response reportedly decreases test time dramatically, especially in hearing screening with ABR, while maintaining a high level of sensitivity and Hall/Rupp 40

159 specificity [36]. In most cases a single tracing can be recorded and compared to the template. The time savings of this technique, then, are apparent. This technique is currently used in ABR screening with newborns [37]. Another advantage to using this technique for screening purposes is that, because of its objectivity, the clinician is not required to interpret the response or manipulate the equipment. That is, volunteers or technicians with minimal knowledge of ABR concepts can easily record the response. Limitations: While a template correlation technique may be useful in ABR screening of newborns, where peak latencies for a given stimulus intensity are known, this technique is limited in searching for ABR threshold, where wave V peak latency is unpredictable and shifts depending on stimulus intensity, patient age, patient auditory status, and other factors. In routine clinical practice, the number of variables that must be taken into account may preclude the use of a template correlation technique with all patients. Response-Replication Correlation A technique similar to template correlation is the objective analysis of the agreement, or the relationship, between the response and its replication. Ordinarily, the examiner performs this type of assessment visually after replicating the initial recording and overlaying the traces. The examiner then judges whether the responses are alike enough to constitute a response. A more objective measure, however, involves a computerized correlation calculation between the two traces. A correlation coefficient is calculated for the traces, and response presence or absence is determined on the basis of specific criteria. A correlation coefficient of 1.0 indicates a perfect relationship between the responses, while a correlation of 0 indicates that the measured activity in the traces are not related and, thus, does not constitute a response. The criterion for a positive identification of a response is set at a relatively high level of correlation (i.e., r>0.80). While various methods are used by the different manufacturers of ABR systems to calculate the correlation between two waveforms, the basic process is the same. For instance, some software correlates two waveforms based on the descriptive statistics of all the data points in each trace. The differences between the two responses with regard to mean amplitude of the data points included, as well as the variance, are entered into the equation for calculating the correlation between the recorded waveforms [38]. Figure 10 is an example of an ABR printout including the statistical analysis of the recorded waveforms. This recording was made with a quiet, adult individual with normal hearing, at an intensity of 90 dbnhl. The SNR of these traces is very low, contributing to the high correlation between the responses (r>0.94). Auditory Brainstem Response 41

160 Fig. 10. Example of an ABR response replication correlation technique. Responses were recorded on a quiet, adult subject with normal hearing, at 90 dbnhl. Descriptive statistics are calculated for the data points of the 2 waveforms, and a correlation coefficient is calculated based on the statistical differences (see text). [From Naze C, Miller E: Statistical calculation of response replications used in the Nicolet Spirit ABR system; pers. commun., 1995.] Another method for calculating response correlation involves the same underlying principle as that just described, but the time window of data points is broken down into several intervals corresponding to a particular latency region of the ABR. Separate correlations for each latency interval are calculated and the total correlation coefficient is based on an algorithm incorporating the values obtained for each interval. Limitations: With correlational techniques, it is very important to set the appropriate criterion level for determination of response presence versus absence. In order to reach statistical significance for a particular criterion, the Hall/Rupp 42

161 number of observations in the samples collected must be sufficiently high. The common assumption that each data point in the tracing constitutes an independent sample is not altogether correct. In fact, neighboring data points are rarely independent of each other [34] and should not be counted as independent samples. As Dobie [34] clearly points out, error in statistical analysis may arise because the standard deviations of each data point in the recording may not be the same. Because the physiological background noise in ABR recordings is usually made up of generally low frequencies in a relatively narrow band width, the variance in each data point will not be the same over the entire ABR waveform. More variance may be seen in the data points corresponding to the low-frequency components of the response. Thus, we should not assume that there is homogeneity of variance in the statistical measure. In order to reach significance, then, the correlation coefficient must be high. In clinical practice, however, high correlations are difficult to obtain with certain patients who may be nervous or restless, leading to increasing amounts of noise in the response. Noise variations from one trace to the next may effectively lower the correlation coefficient between the two waveforms. In addition, high correlation coefficients are more difficult to obtain when the neural response amplitude is small. Such is the case during threshold estimation with ABR. As stimulus intensity approaches threshold, the amplitude of the response decreases substantially. Therefore, the response-replication technique may falter in the relatively adverse clinical conditions when it is most needed to objectively confirm response presence. Summary and Conclusions During the past 25 years since the discovery of the ABR, clinicians world-wide have exploited the clinical utility of this evoked response with many different populations. The 1970s and 1980s saw the development of ABR protocols for increasing the reliability and validity of the response in various clinical situations. Now, in the last decade of the century, advanced technology and the development of increasingly sophisticated software allows more flexibility in these measurements. Thus, ABR testing continues to evolve at a rapid pace. The main focus for ABR in the 1990s has been on developing techniques to improve the quality of the response, decrease the time in which it takes to record the response, and minimize human error through objective response analysis. Some of the major recent developments were reviewed in this chapter. The intent of this review is to provide the researcher and the clinician with Auditory Brainstem Response 43

162 an understanding of the underlying principles of the techniques which will be, and are already, available to them on their ABR equipment. Many of these techniques are promising for use with newborns, children, and difficult-to-test populations where time is a limiting factor in the amount of information that can be obtained. We encourage any and all clinicians to experiment with these techniques to determine how each technique might contribute to their particular clinic protocols. As with any new technique, there will be a learning curve associated with understanding the underlying principles, mastering the technical requirements, and realizing the most valuable clinical applications of these methods. Once the procedures become familiar to clinicians and applied in varied clinical settings, it is likely that the neurodiagnostic and audiologic value of ABR will be profoundly enhanced. References 1 Jewett D, Williston J: Auditory-evoked far fields averaged from the scalp of humans. Brain 1971; 94: Hall JW III: Handbook of Auditory Evoked Responses. Needham, Allyn & Bacon, Don M, Allen A, Starr A: Effect of click rate on the latency of auditory brainstem responses in humans. Ann Otol Rhinol Laryngol 1977;86: Eysholdt U, Schreiner C: Maximum length sequences A fast method for measuring brain-stemevoked responses. Audiology 1982;21: Li H, Chan F, Poon P, Hwang J, Chan W: Maximum length sequence applied to the measurement of brainstem auditory evoked responses. J Biomed Eng 1988;10: Picton T, Champagne S, Kellett A: Human auditory evoked potentials recorded using maximum length sequences. Electroencephalogr Clin Neurophysiol 1992;84: Marsh R: Signal to noise constraints on maximum length sequence auditory brainstem responses. Ear Hear 1992;13: Thornton ARD, Slaven A: Auditory brainstem responses recorded at fast stimulation rate using maximum length sequences. Br J Audiol 1993;27: Pratt H, Ben-David Y, Peled R, Podoshin L, Scharf B: Auditory brain stem evoked potentials: Clinical promise of increasing stimulus rate. Electroencephalogr Clin Neurophysiol 1981;51: Hamill T, Hussung R, Sammeth C: Rapid threshold estimation using the chained-stimuli technique for auditory brain stem response measurement. Ear Hear 1991;12: Hamill T, Yanez I, Collier C, Lionbarger J: Threshold estimation using the chained-stimuli auditory brain stem response technique. Ear Hear 1992;13: Lasky R, Perlman J, Hecox K: Maximum length sequence auditory evoked brainstem responses in human newborns and adults. J Am Acad Audiol 1992;3: Gorga M, Kaminski J, Beauchaine K, Jestedt W: Auditory brainstem responses to tone bursts in normally hearing subjects. J Speech Hear Res 1988;31: Davis H, Hirsh S, Popelka G, Formby C: Frequency selectivity and thresholds of brief stimuli suitable for electric response audiometry. Audiology 1984;23: Don M, Eggermont J, Brackman D: Reconstruction of the audiogram using brainstem responses and high-pass noise masking. Ann Otol Rhinol Laryngol 1979(suppl 57): Hoke M, Pantev C, Ansa L, Lutkenhoner B, Herrmann E: A timesaving BERA technique for frequency-specific assessment of the auditory threshold through tone-pulse series stimulation (TOP- STIM) with simultaneous gliding high-pass noise masking (GHINOMA). Acta Otolaryngol 1991; (suppl 482): Hall/Rupp 44

163 17 Marsh R: Concurrent right and left ear auditory brain stem response recording. Ear Hear 1993; 14: Lasky R, Shi Y, Hecox K: Binaural maximum length sequence auditory-evoked brain-stem responses in human adults. J Acoust Soc Am 1993;93: Galambos R, Makeig S, Talmachoff P: A 40-Hz auditory potential recorded from the human scalp. Proc Natl Acad Sci USA 1981;78: Linden R, Campbell K, Hamel G, Picton T: Human auditory steady-state potentials during sleep. Ear Hear 1985;6: Suzuki T, Kobayashi K: An evaluation of 40-Hz event-related potentials in young children. Audiology 1984;23: Stapells D, Galambos R, Costello J, Makeig S: Inconsistency of auditory middle latency and steadystate responses in infants. Electroencephalogr Clin Neurophysiol 1988;71: Maurizi M, Almadori G, Paludetti G, Ottaviani F, Rosignoli M, Luciano R: 40-Hz steady-state response in newborns and in children. Audiology 1990;29: Rees A: Human auditory amplitude modulation rate sensitivity determined by recording steadystate evoked potentials. J Physiol 1982;326: Rickards F, Clark G: Steady-state evoked potentials to amplitude-modulated tones; in Nodar R, Barber C (eds): Evoked Potentials. II. Boston, Butterworth, 1984, pp Aoyagi M, Kiren T, Kim Y, Suzuki Y, Fuse T, Koike Y: Frequency specificity of amplitudemodulation following response detected by phase spectral analysis. Audiology 1993;32: Kuwada S, Batra R, Maher V: Scalp potentials of normal and hearing-impaired subjects in response to sinusoidally amplitude-modulated tones. Hear Res 1986;21: Aoyagi M, Kiren T, Furuse H, Fuse T, Suzuki Y, Yokota M, Koike Y: Pure-tone threshold prediction by 80-Hz amplitude-modulation following response. Acta Otolaryngol 1994;(suppl 511): Aoyagi M, Kiren T, Furuse H, Fuse T, Suzuki Y, Yokota M, Koike Y: Effects of aging on amplitudemodulation following response. Acta Otolaryngol 1994;(suppl 511): Wong P, Bickford K: Brain stem auditory evoked potentials: The use of noise estimates. Electroencephalogr Clin Neurophysiol 1980;50: Nicolet Viking IV User s Manual. Madison, Nicolet Instrument Corp., Elberling C, Don M: Quality estimation of averaged auditory brainstem response. Scand Audiol 1984;13: Sininger Y: Auditory brain stem response for objective measures of hearing. Ear Hear 1993;14: Dobie R: Objective response detection. Ear Hear 1993;14: Algo-2 Newborn Hearing Screener User s Manual. San Carlos, Natus Medical Inc., Hall JW III, Kileny P, Ruth R: Clinical trials for the Algo-1 newborn hearing screening device. 10th Biennial Meeting of the International Electric Response Study Group, Charlottesville Kileny P: Algo-1 automated infant hearing screener: Preliminary results. Semin Hear 1987;8: Nicolet Spirit User s Manual. Madison, Nicolet Instrument Corp, James W. Hall III, PhD, Vanderbilt Balance and Hearing Center, st Avenue South, Suite 2600, Nashville, TN (USA) Auditory Brainstem Response 45

164 Alford BR, Jerger J, Jenkins HA (eds): Electrophysiologic Evaluation in Otolaryngology. Adv Otorhinolaryngol. Basel, Karger, 1997, vol 53, pp Hearing as Reflected by Middle and Long Latency Event-Related Potentials 1 Gary P. Jacobson a, Nina Kraus b, Therese J. McGee c a Division of Audiology, Henry Ford Hospital, Detroit, Mich.; b Departments of Communication Sciences and Disorders, Neurobiology and Physiology and Otolaryngology, Northwestern University, Evanston, Ill., and c Department of Communication Sciences and Disorders, Northwestern University, Evanston, Ill., USA One of the few ways of obtaining neural information in humans is with evoked responses. Research in auditory evoked responses has gone through an evolution over the past 30 years. Initially, there was intense interest in the development of long latency responses (i.e. evoked responses with latencies exceeding 50 ms) as a method for objectively assessing auditory system sensitivity. With the advent of more efficient computers, attention was focused on shorter latency responses beginning with the fast responses (now referred to as middle latency responses) and then with the auditory brainstem response. The discovery of the auditory brainstem response brought forth an explosion of investigations that demonstrated the usefulness of this response for assessment of auditory system sensitivity and the transmission capabilities of the pontine auditory pathways. The bulk of these investigations occurred between 1975 and Beginning in the early 1980s and continuing today there has been renewed interest in both the middle and long latency auditory evoked responses and the nonmodality-specific endogenous responses. Interest in these electrical events with longer latencies is rooted in the knowledge that they originate from more rostral structures (midbrain, thalamus, cortex), and thus, provide us with information about auditory processing at a higher level than can be assessed with the auditory brainstem response. That is, these longer 1 Portions of this chapter were modified from references 34, 137, 244 and 245.

165 latency responses represent not only transmission of the auditory signal as modified by the central nervous system, but also reception, processing and integration of these auditory signals. Short latency evoked responses (e.g. electrocochleogram and auditory brainstem response) provide information only about the transmission characteristics of the auditory pathway (e.g. synchronization and speed of transmission). The longer latency responses provide us with information about the reception and interpretation of these auditory signals that occurs at the level of the cortex (i.e. we hear with the auditory cortex). The purpose of this brief chapter will be to review what is known, and conversely, what is not known about middle and long latency responses. Much of the research regarding evoked response origins has involved the use of magnetoencephalographic instrumentation. The evoked activity recorded with this instrumentation is called an evoked field. Thus, the more generic term evoked response has been chosen and will be used except when specific points are being made. This chapter is organized into two main headings representing descriptions of exogenous and endogenous evoked responses. Within a major heading, evoked responses will be described in the approximate temporal order in which they occur. Additionally, attempts will be made to describe, in summary form, what is known about the physiological origins of each response, how they are elicited, what processes they represent, maturational issues and examples of how they have been used (if at all) for clinical purposes. It is hoped that what cannot be discussed in this chapter can be obtained by the reader through a reading of the references listed at the end of this chapter. Exogenous and Endogenous Evoked Responses Evoked responses can be grouped broadly into two categories exogenous and endogenous responses. Exogenous evoked responses are modality specific (e.g. a light flash elicits a visual evoked response, a click elicits an auditory evoked response) and the characteristics of the evoked response (e.g. latency and amplitude) are dependent upon the physical characteristics of the evoking stimulus (e.g. stimulus frequency, intensity, rate of presentation). In contrast, endogenous responses are evoked brain events that are not modality specific. That is, the same endogenous response can be elicited following stimulation of any sensory modality (or combinations of modalities) and the characteristics of these responses are dependent not so much on the physical characteristics of the evoking stimuli but on the psychological conditions within which the listener is placed. These responses are sometimes referred to as cognitive evoked responses. Middle and Long Latency ERPs 47

166 Examples of purely exogenous responses include the electrocochleogram and the auditory brainstem response. Examples of purely endogenous responses include the negative difference wave (Nd) and the P300. Some evoked responses may be predominately exogenous but may be affected by the psychological state of the subject (e.g. though N1 is an exogenous response it gains amplitude during focused attention). Exogenous (Auditory) Evoked Responses Middle Latency Auditory Evoked Responses The middle latency response (MLR) appears as a series of waves occurring from approximately 15 ms and extending to approximately 50 ms after stimulus onset (using optimal stimulating and recording techniques). These components have a visual appearance of a 40-Hz sine wave (e.g. the peaks are separated by about 25 ms) and are typically labeled Na, Pa, Nb, Pb (also referred to as P50 or P1 of the late cortical auditory evoked response) and TP41 (fig. 1). Na, Pa, Nb and Pb are observed in recordings from the anterior midline; TP41 is typically recorded over the temporal lobe. Origins The MLR is a neurogenic response which sometimes is contaminated by myogenic activity [1 5]. 2 The Na component probably has mesencephalic origins. Evidence supporting this contention may be found in the work of Hashimoto et al. [7] who showed a near-field response with equivalent latency recorded from the region of the inferior colliculus of humans undergoing thalamotomies for intractable pain. Also, McGee et al. [8] have reported that injection of lidocaine into the inferior colliculus affects all surface-recorded MLR components. Additionally, Kileny et al. [9] have reported that temporal lobe lesions affecting Pa do not affect Na, although this finding is at odds with the report of Jacobson et al. [10] who observed significant changes in Na following anterior temporal lobe resections in patients with intractable epilepsy. All evidence suggests that the Pa component is generated, at least in part, in the auditory cortex. This assertion is supported by comparisons of far-field 2 There is a large family of sonomotor responses including the postauricular muscle reflex (PAM), auropalpebral reflex, the frontalis m. reflex (all of the above involve the auditory division of VIII N for the afferent limb and the VII N for the efferent limb), the temporalis and acoustic jaw reflexes (afferent limb VIII N, efferent limb V N), and the inion potential (afferent limb vestibular division of VIII N, efferent limb VII N). It was at one time felt that these responses could be used in conjunction with the auditory brainstem response to assist in the detection of demyelinating disorders [6]. Jacobson/Kraus/McGee 48

167 Fig. 1. Four-channel (coronal chain) middle latency response (MLR) from a normal subject. Electrode derivations are: channel 1>Cz-A2; channel 2>Fz-A2; channel 3>left midtemporal/parietal-a2; channel 4>right midtemporal/parietal-a2. The stimulus was presented to the right ear. Note that the MLR is largest at Fz. Also, note that the TP41 response is present at the midtemporal electrode sites. The stimulus was an unfiltered click presented to the right ear at 75 db nhl (rate>8.44/s). The EEG was filtered 10 3,000 Hz. The analysis period was 75 ms (amplitude calibration>0.5 (μv/div). and near-field recordings [11 13] which have demonstrated a polarity reversal of Pa across the Sylvian fissure [13 16], and the results of dipole source analysis of scalp-recorded electrical activity [17]. Additionally, pathophysiological correlational studies suggest that Pa is most affected by disorders of the temporal lobes [10, 18 24]. It is significant to note that there exists compelling evidence suggesting that a subset of Pa generators are located in, or potentiated by, subcortical sources. For example, a number of investigators have reported that Pa is affected by sleep or sleep stage [25, 26]. Additionally, Parving et al. [27], Rosati et al. [28] and Woods et al. [29] have reported patients who have sustained bilateral temporal lobe infarctions and have remained physiologically capable of generating a Pa component. Kraus et al. [30] have described in detail a Middle and Long Latency ERPs 49

168 dissociation between temporal lobe and midline recorded correlates of the Pa component in guinea pigs. The injection of local anesthetics (e.g. lidocaine) into auditory cortex did not affect the midline-recorded Pa component, nor did electrolytic lesioning of the temporal lobes. Systemic anesthesia (e.g. Innovar) affected the temporal recordings of Pa but did not affect the midline-recorded Pa. Increasing stimulation rates decreased the amplitude of the temporal lobe components and did not affect the midline-recorded response. The investigators also studied the ontogeny of the MLR in the gerbil. The midline-recorded MLR showed an earlier maturation than the temporal lobe components. Based on several lines of evidence, the authors hypothesized that the scalprecorded Pa component in humans is composed of two functionally distinct generator systems: one located in the temporal lobes bilaterally and another that is a deep midline generator system that possibly resides within the polymodal thalamus. Finally, results of recent magnetoencephalographic (MEG) investigations have suggested that the generator system of the Pa component is tonotopically organized but opposite to the tonotopic organization of N1 (high-frequency responses represented more superficially and low frequencies represented deep to the scalp [31]. The TP41 represents an evoked response recordable only over the temporal lobes. As the name suggests, this response has a mean latency of approximately 41 ms and unlike the Pa component the generator of TP41 has a long refractory cycle (i.e. it can be recorded optimally only using interstimulus intervals of?1 s). Dipole source measurements obtained from scalp voltage [23] and magnetic field measurements [32] have placed the equivalent current dipole (ECD i.e. the estimated location, orientation and strength of the center of gravity of current sources underlying TP41) for the TP41 in the temporal lobe. Clinical Data The primary usefulness of the MLR has been in the area of the assessment of auditory sensitivity. Because the generators of Pa are not as dependent as are the generators of the ABR on sharp neuronal synchronization, the MLR can be recorded in patients with absent ABR (due to severe hearing loss, or, neurological disease) [33]. The detectability of the MLR is poorer in children than in adults, and this appears to be a result of the age dependence of MLR on the state of awareness. That is, it has been reported that in sleeping children Pa can be detected consistently in alpha sleep, stage 1 and REM sleep but disappears in stage 4 sleep [26], yet adults show only a small MLR amplitude reduction with sleep [34]. This finding has been interpreted as being consistent with a multigenerator hypothesis for the MLR with generators differing in sleep dependence and in maturational time course. Jacobson/Kraus/McGee 50

169 The usefulness of the MLR for the evaluation of auditory sensitivity may be found in the observation that since the response is not critically dependent (as is the ABR) on neuronal synchronization [35], it is possible to elicit the MLR with low-frequency stimuli [36, 37]. This means that the auditory brainstem response and MLR may serve complementary functions. For example, the rapid onset stimulus (e.g. click stimulus) required to elicit the ABR carries a large amount of high-frequency energy. Therefore, ABR wave V threshold provides information only about auditory sensitivity for high frequencies (e.g. 2,000 4,000 Hz). However, the MLR can be recorded with low-frequency stimuli, and therefore MLR threshold searches may provide an estimate of auditory sensitivity at the low-frequency end of the auditory spectrum (e.g. 500 Hz). The electrically generated MLR, the EMLR (e.g. evoked with a stimulating electrode placed at the promontory) may provide prognosticating information about the numbers of surviving neural elements for patients undergoing cochlear implantation [20, 38, 39]. Also the EMLR may serve as an objective measure of threshold and comfort level settings postoperatively [20]. Although, as noted earlier, a number of studies have been reported illustrating that the MLR, and specifically component Pa, may be absent in the presence of ipsilateral temporal lobe disease, this response still has not found its way into widespread clinical practice in the neuroaudiologic evaluation of these patients. It is probable that interest in the MLR will increase as the interest in auditory electrophysiology extends beyond transmission characteristics toward an understanding of the cortical processing of the neural code. Steady-State (40 Hz) Response Origins In the transient stimulation paradigm, the generator of a particular response recovers fully (or at least substantially) prior to the presentation of the next stimulus (in fact, for evoked responses beyond the ABR we rarely permit generators to go through a full refractory cycle). In the steady-state paradigm, stimuli are delivered faster than some generators can respond optimally. For a multiply generated response, the faster rate may even favor more rateresistant generators. Steady-state stimulation techniques have been utilized by many to study the functional properties of the visual and auditory sensory systems. The use of steady-state stimulation in MEG investigations of auditory cortical function [40] coincides in time with the first report of the 40-Hz response event-related potential [41]. The auditory 40-Hz steady-state response (SSR) has been hypothesized as being a rate-modulated ABR and MLR (i.e. the 40-Hz Middle and Long Latency ERPs 51

170 Fig. 2. Steady-state response (SSR) (40 Hz) recorded from a normal subject. Note that there are two cycles of 40-Hz activity recorded in this 50-ms analysis period (25 ms/cycle) and that the amplitude of the SSR is larger (amplitude calibration 0.5 (μv/div) than the MLR from the same individual (see fig. 1). The signal again was an unfiltered click presented to the right ear at a rate of 40 Hz. Also, note that the ABR can be observed clearly for each cycle of the SSR. The electrode derivations and filter bandpass were same as that described in figure 1. SSR is believed to represent a coalescence of ABR and MLR components; fig. 2). However, unlike the MLR, the 40-Hz SSR has been shown to be relatively unaffected in patients with temporal lobe disease and in coma [42, 43]. For these reasons it has been hypothesized that the SSR derives its origins from slightly different generators than the Pa component. These sources include subcortical polysensory centers in the thalamus [41, 44]. MEG evidence has shown that the ECD 3 source location of the SSR overlaps the ECD location of Pa [45]. 3 The term equivalent current dipole (ECD) describes the location (Cartesian coordinates X, Y and Z measured in cm or mm), orientation (measured in degrees) and strength (usually measured in units of current) of the neural tissue responsible for a spontaneous or evoked electrical response. Although several, local, coactivated sources may contribute to a given electrical event, the ECD location describes the center of gravity of these responses. Jacobson/Kraus/McGee 52

171 Since the SSR is larger than the Pa component it is more attractive for use as an auditory electrophysiological indicator of peripheral hearing sensitivity. Specifically, it has been reported that the SSR achieves half its maximum amplitude within 15 db of behavioral auditory threshold [41]. Also, the SSR is largest following stimulation of a low-frequency tone pip [41, 46, 47] in contrast to the ABR which is dependent upon the sharp neuronal synchronization accompanying the onset of a transient stimulus (with poor frequency-resolving capabilities). Finally, since the response appears as a 40- Hz sine wave, the data may be analyzed online in the frequency domain (through fast Fourier transformation) instead of in the conventional time domain [48]. Spydell et al. [42] have reported that subtle phase abnormalities were observed for the SSR recorded from patients with midbrain disease. Long Latency Auditory Evoked Responses (Predominately Exogenous) P50 The long latency auditory evoked response consists of a number of positive and negative polarity deflections beginning with a component that occurs at approximately 50 ms to maximal stimulation (fig. 3). P50 is also referred to as the P1 component and is followed by N1, P2, N2 and P3 (see next sections for a discussion of N1 and P2). This component also represents, to some, the last component of the middle latency response (Pb). P50 has not received a great deal of attention until recently, due in part to the difficulty in recording this response coupled with the confusion over where it belongs in the continuum of auditory evoked potentials (e.g. middle latency or long latency response). Origins The P50 response is best recorded using slow stimulation rates (e.g. 1/s) [49]. P50 is recorded optimally at the central-frontal midline (Cz, Fz). It is known that P50 probably is generated within the ascending reticular activating system [50]. This assertion is based upon the rate/recovery characteristics of the response (described above) and results of studies demonstrating that P50 disappears during slow wave sleep and reappears during REM sleep in animals (i.e. cat) and humans [50]. Clinical Data The clinical application of P50 has been specific to the field of psychiatry. It has been demonstrated that when a pair of clicks separated by an interval of 500 ms are presented to the ear of a normal subject, the P50 response Middle and Long Latency ERPs 53

172 Fig. 3. P50 (P1) response recorded from the Cz electrode in a normal subject. Tracings represent four independent trials. The stimulus was a 60-dB nhl, 1,000-Hz tone burst of 125 ms duration and having a 15-ms rise/fall time. The stimulus was presented to the right ear. The repetition rate was 1 Hz. The filter bandpass was Hz. Also shown in this figure (but not labeled) following P50 (P1) are AEP components N1 and P2. elicited to the second click ( test stimulus) will have an amplitude 20% or less than that elicited by the first click ( conditioning stimulus). This normal suppression has not been observed in patients with schizophrenia (diagnosed by DSM-III criteria) and has been attributed to defective sensory gating (as a function of impaired catecholamine metabolism) on the part of schizophrenic patients [51 55]. It should be noted that there has been great variability in the degree of suppression in schizophrenic patients from report to report [56]. Technical issues may explain this variability [57]. It has been hypothesized that the P50 response is generated in the thalamus by a cholinergic component of the ascending reticular activating system [58]. This hypothesis has been supported by the results of animal studies demonstrating that wave A in cats (i.e. the cat equivalent of P50 in human), disappears Jacobson/Kraus/McGee 54

173 at high rates of auditory stimulation, is present following bilateral removal of cortex, basal ganglia and limbic system, and, is absent following destruction of cholinergic cells in the pedunculopontine nucleus or injections of a muscarinic receptor blocker such as scopolamine [59 62]. This hypothesis has been supported in human investigations showing that P50 was absent, or, of low amplitude in patients with probable Alzheimer s disease (a disease affecting the cholinergic system) [58]. Gamma Band Response Recently, investigators using MEG recording techniques have described high-frequency wavelets (fig. 4a, b) that are superimposed upon the auditory middle latency and long latency responses [63 65]. The oscillations have a spectral peak frequency between 30 and 40 Hz and have been termed gamma band responses (GBR) [63]. Unlike the 40-Hz SSR [41], the auditory evoked gamma band response (aegbr) is best elicited by transient tone burst stimulation with long interstimulus intervals (ISI) (?2 s). Origins The precise functional significance of the GBR is unclear but several parallel lines of evidence suggest that this electrical event may serve to bind together cortical areas that serve a common purpose. Each group of functional connections is termed a single neural assembly. These connections may be local (e.g. adjacent cortical columns) or distributed (e.g. within the temporal lobe, or, throughout the brain). It is believed that these neural assemblies are called into play to help fuse or bind together separate characteristics of auditory signals (e.g. frequency spectrum, intensity, duration, velocity of frequency and intensity change, character of sound) into a single unitary percept (e.g. the sound associated with a dog bark ) [63, 66, 67]. The creation and preservation of these neural assemblies probably is influenced by the repeated experience on the part of the listener to the same aggregate auditory event. That is, functional connections are made through the repeated exposure of the listener to the same auditory event and the recognition on the part of the listener of the significance of this event. Evoked oscillations in the gamma band of this type have been recorded from stimulation of visual and olfactory sensory systems in animals (e.g. vision [68 75]; olfaction [76 78]). To date, investigations of the characteristics of the human aegbr have shown that the auditory evoked gamma bend field (aegbf) is present in approximately 33% of normal subjects [C. Pantev, pers. commun., 1994] due in large part to its small magnitude and associated poor signal-to-noise ratio. Additionally, the source location of generators underlying the aegbf are spatially separate from those underlying Pa, the steady-state 40-Hz response, Middle and Long Latency ERPs 55

174 a b 4 Jacobson/Kraus/McGee 56

175 and N1 in the supratemporal auditory complex [45, 63]. Also, unlike N1 that appears as a stationary field, the aegbr appears as a moving dipole, arcing 1 cm or greater in an anterior-posterior trajectory over the time period from 20 to 130 ms [63]. The aegbr decreases in magnitude as a function of decreased interstimulus interval but to a lesser extent than N1 [45]. The generator system responsible for the aegbr is not tonotopically organized as are the generators of both Pa and N1 [79]. Finally, the GBR may be modulated by attention, and therefore it may not be entirely exogenous [80]. MEG recordings have demonstrated that the generator source (or sources) of the MLR and SSR appears stationary when activated, whereas the generator source of the GBR moves in a posterior arcing trajectory over a period of ms [63]. The apparent movement of this ECD may represent the sequential activation of adjacent cortical columns, or possibly, the activation of two fixed dipoles, offset slightly in time, and located at the two ends of the observed arc (see Moran et al. [81] for a discussion of this phenomenon specific to N1). The net effect of these observations is that the MLR and SSR differ from the GBR in several important ways. N1 The negative and positive going waves following P50 have peak latencies of approximately 100 and 175 ms, respectively, and are referred to as N1 and P2 (fig. 5). When submitted to spectral analysis, these latter waveforms show most of their energy to be concentrated in the frequency range below 20 Hz [82]. The N1 response was the first of the long latency responses to be described in the scientific literature [83]. The conventional stimulating paradigm for eliciting these responses entails the use of a tone burst with relatively slow onset (e.g ms rise/fall). Additionally, an ISI of 500 1,000 ms is used commonly to record N1 and P2 despite the knowledge that the response amplitude can be improved markedly by extending the ISI up to 8 16 s [84 86]. The N1 occurs at the onset of an appropriate auditory stimulus and also at the offset of the stimulus (although the offset response is less than one-half the amplitude of the onset response). Fig. 4. a Shown are 3 channels of AEP obtained from Cz, T3 and T4 electrode sites. The stimulus was a 500-ms duration, 1,000-Hz tone burst having a 15-ms rise/fall time. The stimulus repetition rate was 0.5 Hz. The signals were presented to the right ear only. The EEG was filtered between 1 and 100 Hz. b Same data as depicted in figure 4a but bandpass filtered (12 db/octave, zero phase shift, Butterworth filter) between 24 and 48 Hz. Note the residual high-frequency wavelets representing the gamma band response. Also note that the latency of the GBR recorded at T3 (contralateral temporal electrode) is shorter by ms than that recorded at T4 (ipsilateral temporal electrode). Middle and Long Latency ERPs 57

176 Fig. 5. Shown are AEP components N1 and P2 recorded from the Cz electrode site from a normal subject. The stimulus was a 125-ms, 60-dB nhl 1,000-Hz tone burst with a 15-ms rise/fall time. The stimulus was presented to the right ear. The stimulus repetition rate in this example varied randomly between 2.5 and 3.5 Hz. Origins There are at least three potentially simultaneously active generator systems in the cerebral cortex that produce electrical responses during the interval when N1 occurs. These include: component 1, which consists of a voltage field that is generated in the supratemporal plane and recorded maximal in the frontocentral scalp [15], component 2, a biphasic waveform positive in polarity at 100 ms and negative in polarity at 150 ms. It is generated on the superior temporal gyrus and maximal at the midtemporal electrodes [87], and component 3 which is recorded at the scalp surface as a vertex-negative wave with a latency of 100 ms. Although the source location of component 3 is unknown, Näätänen and Picton [88] suggest that it may be generated in the frontal motor and premotor cortex and may be under the influence of the reticular formation and ventrolateral (VL) nucleus of the thalamus. The VL nucleus projects to the precentral gyrus, superior, middle and inferior frontal gyri and the supplemental motor area (SMA) on the mesial surface of the frontal lobe. These areas receive input from the auditory association cortex. Jacobson/Kraus/McGee 58

177 MEG investigations have demonstrated that the ECD location of at least one component of N1 is 2 4 cm below the scalp surface. This ECD is perpendicular to the Sylvian fissure. Studies combining high-resolution MRI and MEG have localized N1m to the primary auditory cortex and primary association areas [89 91]. A number of functional characteristics of the N1 generator system have been described with evoked potential and MEG techniques and these include: (a) Tonotopicity: at least one component of the N1 generator system appears to be tonotopically organized. Specifically, MEG recordings have demonstrated that the ECD location for N1 in response to a high-frequency tone is more anterior than that to a low-frequency tone [92, 93]. Evidence of tonotopic organization as demonstrated through N1 latency changes has been reported recently in evoked potential recordings [94]. (b) Amplitopicity: MEG investigations of N1 have shown that the ECD for N1 becomes progressively more superficial as the stimulus intensity is increased [82, 95]. (c) Binaural interaction: both MEG and evoked potential recordings have shown that the contralaterally recorded N1 following binaural stimulation is smaller than that recorded following monaural stimulation [96 98]. Additionally, MEG studies have demonstrated a hemispheric dominance for N1. Specifically, the N1 ECD is approximately 1.4 cm more posterior over the left hemisphere than the right hemisphere for right-handed individuals (the opposite is true for left-handed individuals). Additionally, both MEG and evoked potential studies have demonstrated that N1 recorded over the contralateral scalp (with reference to the ear stimulated) is of larger amplitude and occurs on average 5 10 ms earlier than N1m recorded over the ipsilateral scalp [94, 96, ]. These differences reflect the superiority of crossed auditory pathways. Finally, it is known that the generator system of N1 requires up to 8 16 s to cycle through its absolute refractory period [86]. Clinical Data Cerebrovascular Disease. Long latency auditory evoked responses have been recorded from patients who have sustained ischemic strokes [102, 103]. Leinonen and Joutsiniemi [102] studied 4 patients with temporal lobe infarctions. Abnormalities were found in all 4 cases. N1 abnormalities included absent responses and responses that were accentuated in amplitude. It had been shown previously that absent responses were caused by damage involving primary auditory cortex and posterior association areas [29]. The patient with accentuated responses had lesions involving the anterior and middle supratemporal cortex, insula, claustrum and white matter containing connections between auditory cortex and frontal lobe and limbic structures. It was Middle and Long Latency ERPs 59

178 thought by the authors that the accentuated responses represented a loss of inhibitory control from the frontal lobe. Mäkelä et al. [103] studied 8 patients who had ischemic brain lesions. In 2 cases the patients had temporoparietal lesions and the N1m was absent when recordings were made over the affected hemisphere. One patient had a frontotemporal lesion that was superficial to the auditory cortex. This patient demonstrated a small N1m. Patients with lesions affecting the frontal lobe or small infarctions in the area of the supratemporal plane demonstrated N1. The authors have suggested that the structural extent of lesions on CT scan may not be representative of the functional extent of the lesion. Schizophrenia. N1 has been shown to be delayed in latency and lower in amplitude for schizophrenic patients [ ]. Reite et al. [106] reported the MEG characteristics of N1m in a sample of 6 male subjects. All patients had schizophrenia of paranoid type that was chronic in nature. The authors reported less asymmetry than normally observed in the ECD for N1 in the schizophrenic patients. These findings suggested possible structural and functional differences in the temporal lobes of this sample of schizophrenic patients. Tinnitus. Differences in the amplitude and latency of N1 have been reported in patients with tinnitus. Specifically, Hoke et al. [107] and Pantev et al. [108] reported that the auditory evoked cortical field (AEF) N1m component was larger, and P2m was smaller and occurred later in subjects with unilateral tinnitus compared with normal subjects. These group amplitude differences resulted in a P2m/N1m amplitude ratio that was smaller for the subjects with tinnitus. The researchers presented a scatterplot of P2m/N1m amplitude ratios showing that a cut-off ratio of 0.5 effectively separated patients with and without tinnitus (patients without tinnitus showed amplitude ratios exceeding 0.5). Additionally, the investigators reported that N1 latency was longer for patients with tinnitus. The abnormalities involving N1m and P2m amplitude were explained as having occurred because the afferent activity that accompanied tinnitus was being processed by the generator of P2m. This made the generator less able to respond to transient tonal stimulation. The generators of N1 and P2 are coactive, resulting in a reduction in both N1 and P2 amplitudes (due to phase cancellation). Therefore, the reduction in amplitude of P2 resulted in a large N1 response. Contradictory results were reported in two similar studies conducted by Jacobson et al. [109] and Colding-Jorgenson et al. [110]. Jacobson et al. [109] and Colding-Jorgenson et al. [110] saw no evidence suggesting that the N1m amplitude was larger, the P2m latency later, or, the P2m/N1m amplitude ratios smaller, when the two samples are compared. In fact, it was the rare normal subject that demonstrated P2m [111]. Jacobson/Kraus/McGee 60

179 Cochlear Implantation. It has been reported that the recording of N1 might be useful in the assessment of patients with cochlear implants [ ]. These investigators used the N1 response to validate that the auditory cortex could be stimulated by a cochlear implant. Additionally, it has been suggested that the strength of the dipole moment in MEG recordings following stimulation of a cochlear implant could be used to estimate the numbers of surviving VIII N fibers peripherally (and thus aid in the determination of candidacy for cochlear implantation). Unfortunately, the findings contained in these reports differ. The latency of N1m varies by report; it may be normal, early or delayed in patients with cochlear implants. However, there are several findings in common between reports: N1m appears to have a dipolar pattern, and the depth and direction of the ECD for N1m are consistent with that seen in normal hearing subjects. P2 Origins Although N1m has been studied in detail, comparatively little is known about P2m (fig. 5). P2 appears to have major generators within the auditory cortex [15, 100, 115]. The ECD location for the magnetically recorded P2 differs from N1 although the direction has differed from report to report. Pantev et al. [82] have reported that the location of P2m is on average 8 mm anterior and 4 mm medial to N1m. These findings are in general agreement with those of Hari et al. [32] who reported that the ECD location for P2m was anterior to N1m (by almost 20 mm in 1 subject). The anatomical separation between N1m and P2m sources suggests that the functional significance of P2m may differ from N1m. In our experience, we have found the goodnessof-fit of P2m to a single ECD is generally poor (r=0.90). When present and when the signal-to-noise ratio is optimal, the magnetic field pattern for P2m often appears quadrapolar. The poor fit of P2m to a single ECD model suggests that it may be generated by multiple coactive sources and better modeled as dual or multiple sources. Clinical Data There have been few investigations showing P2 abnormalities specifically. It has been reported that children with Down s syndrome showed longer N1 latencies and higher amplitude P2 [116]. Jirsa and Clontz [117] noted longer P2 latencies in children 8 11 years old with auditory processing disorders. Middle and Long Latency ERPs 61

180 Mismatch Negativity When an auditory stimulus is presented rapidly (e.g. 3/s) in a train, a series of low-amplitude N1 responses may be recorded. When a stimulus that is physically deviant from those in the train is presented, a second negativity is generated that lasts another 100 ms or more. The second response is called the mismatch negativity (MMN) [118] and it is derived by subtracting the evoked response tracing obtained to the common stimuli from the evoked response obtained to the physically deviant stimuli (fig. 6). The MMN is predominately exogenous; however, more recent information has suggested that attention may potentiate the response [119]. The MMN reflects the central processing of very fine differences in acoustic stimuli. It can be elicited by differences between stimuli at threshold levels (e.g. differences of as little as 8 Hz or 5 db) [ ]. The MMN has been obtained in response to frequency, intensity, duration, spatial and phonemic changes [ ]. It is believed that the rapid presentation of the common stimulus creates a neural representation of this stimulus in echoic memory that lasts 4 10 s and then decays [ ]. The neural representation may represent component 1 of the N1 response (see preceding section). The presentation of the deviant stimulus results in the detection of a mismatch between the common and deviant stimuli. The mismatch that occurs at a preconscious level is the trigger for the MMN. Thus, it appears that the MMN reflects a neuronal representation of the discrimination of numerous auditory stimulus attributes. If this response reflects the ability to discriminate between acoustic stimuli, then it may not only be of research interest but may have clinical value because speech perception, by its very nature, depends on a neuronal response to stimulus change. It has been demonstrated that the MMN is a robust phenomenon not only in adults [see 121 for a review] but also in children [127, 130, 138]. Additionally, the MMN can be elicited with speech stimuli [139, 140] that are at psychophysical threshold [120, 123, 127, 131]. More importantly, the MMN has been obtained during sleep in infants [141] and adults [142], and during sleep and barbiturate anesthesia in animal models [143, 144]. This would suggest that the MMN may become a potential clinical tool for the objective evaluation of patients for whom communication is difficult or compromised, or for whom auditory discrimination is in question (at-risk infants, children with language or learning disorders, cochlear implant users, adults with aphasia or dementia) [121, 145, 146]. However, it is significant to note that sleep stage (and the associated changes in background EEG activity) may affect significantly the recordability of the MMN. Specifically, an MMN-like response has been recorded during sleep in infants [141] and sleep has been shown to systematically affect this response in an animal model [143, 147]. In Jacobson/Kraus/McGee 62

181 Fig. 6. Mismatch negativity (MMN) recorded from a normal subject. The top tracing is the evoked potential recorded in response to the oddball stimulus (75 ms duration, 15 ms rise/fall time, 500 Hz stimulus). The tracing that lays beneath the oddball tracing is the evoked response recorded to the standard stimulus (125 ms duration, 15-ms rise/fall time, 500 Hz stimulus). The stimuli were delivered to the right ear at a rate of 3 Hz and at an intensity level of 60 db nhl ( standard probability of occurrence>80%, oddball probability of occurrence>20%). Stimulus duration was the dimension that determined whether the stimulus was same or different. The bottom tracing was derived by subtracting the evoked response to the frequent or standard stimulus from the evoked response obtained in response to the different or oddball stimulus. This derived tracing represents the MMN. EEG was bandpassed from 1 to 100 Hz. this regard, it has been demonstrated that cortical evoked potentials appear to be more consistently recorded in infants during REM sleep [148, 149]. Since infants have a high percentage of REM sleep [150], they are particularly likely to spend a significant amount of time in sleep stages favorable for ERP recording. Controlling for sleep stage during the recording of the MMN may improve the detectability of the response during sleep in infants [151, 152]. Middle and Long Latency ERPs 63

182 Origins The auditory cortex appears to be a major generating source for the MMN [88, 125, 128, ], with contributions from auditory thalamus and hippocampus [143, 144, 156]. Dipole analysis has demonstrated two distinct and partially overlapping sources for MMN, corresponding to the subcomponents which differentially respond to the size of the stimulus deviation [24]. Recently it has been demonstrated in MEG studies that the generator system for the MMN is organized tonotopically [157]. That is, the neurophysiological response of the brain to the detection of differences in tonal frequency may be mapped out spatially in a tonotopic manner. Overall, neuroanatomic sources differ depending on the acoustic change that is used to elicit the response [137, 144]. Clinical Data The wide variability observed in the performance of patients with cochlear implants may be reflective of differences in the central auditory processing abilities of implant users. MMNs to synthetic speech sounds have been elicited in cochlear implant users and can be similar to those obtained in normal hearing individuals [146]. Preliminary data suggest that good and poor implant users have distinctive MMNs. Deficient auditory perception has been associated with certain auditorybased learning problems [ ]. The MMN, which reflects auditory sensory processing, by inference, may be linked to auditory comprehension problems in school-age children [137, 145]. The characteristics of the MMN suggest its potential clinical use with patients for whom communication is difficult or compromised and for whom auditory discrimination and memory are in question (e.g., at-risk infants, children with language or learning disorders, cochlear implant users, adults with dementia or aphasia). Since it does not require conscious attention to the stimuli, the MMN may provide an objective measure of the discrimination of stimulus differences. Consequently, it may permit an objective analysis of sensory processing and discrimination, and auditory learning [137]. Thus, it is through the use of the MMN that investigators [103] have been able to probe tonal and speech processing abilities of patients with neurological disease. In this regard, the MMN has been employed to investigate auditory processing abilities in patients with temporal lobe infractions and aphasia. These patients have been reported to demonstrate MMN for pure tones but not speech stimuli [162], or to pitch and vowels but not to consonantal changes [123]. These findings suggest that the coding of differences for complex stimuli is not only different than that for simple tones, but that the ability to encode change is reflected in the MMN. Jacobson/Kraus/McGee 64

183 Long Latency Responses (Endogenous) Processing Negativity (Pn, Nd ) Selective attention describes the ability of a person to attend to one channel of information or to a class of information in one channel to the exclusion of other types of information routed to the same or different channels. Auditory selective attention can be indexed through the measurement of an endogenous event-related potential called the processing negativity, or negative difference wave (Nd) [121]. This response is elicited in a double-oddball paradigm where subjects are instructed to attend to one ear only and respond when an occasional (probability 10%) target stimulus is presented in a field of frequent stimuli (probability 40%) to that ear. The other ear is presented with frequent (probability 40%) and infrequent stimuli (probability 10%) as well (total probability of all stimuli>100%). At no point are the stimuli presented to both ears simultaneously. The Nd has an onset latency as early as 50 ms [163]. It appears as a negative polarity bias in the late cortical auditory evoked response waveform recorded in response to the frequent stimuli presented to the attended ear when this waveform is compared with the evoked response to the frequent stimuli presented to the ignored ear. The Nd is derived by subtracting the ignore-frequent waveform from the attend-frequent waveform (fig. 7). The onset latency and peak magnitude of the Nd wave may serve as an index of the time course and strength of a person s ability to selectively attend to one channel (e.g. stimuli presented to the target ear) and ignore others. Origins When originally observed, it was felt that the enhancement of N1 amplitude during selective auditory attention represented a simple potentiation of the N1 generator. 4 However, it was demonstrated that the enhanced N1 negativity could be dissociated from the N1 peak by varying the stimulating paradigm (e.g. rate of stimulus presentation) [165]. Thus, it was demonstrated that the Nd wave represented a true independent phenomenon. Most recently it has been demonstrated using neuromagnetic field recording techniques that the location of the ECD sources underlying the N1 and Nd waves, though located in the temporal lobe, are spatially distinct [166]. It is noteworthy that the Nd wave, and thus, the onset of selective auditory attention precedes the onset of N1 and may continue for hundreds of milliseconds after N1. 4 The view that accentuation of N1 with focused attention is caused by a potentiation of one or more generators of underlying N1 has support [121, 164]. Middle and Long Latency ERPs 65

184 Fig. 7. Negative difference wave (Nd) recorded from a normal subject. The stimulus paradigm is described in the text. The dashed tracing represents the evoked potential recorded in response to frequent stimuli routed to the ignored channel (ear). The solid tracing represents the evoked potential recorded in response to frequent stimuli routed to the attended channel (ear). The negative-going separation between these two tracings is referred to as the processing negativity. The subtraction of the ignored tracing from the attended tracing yields the Nd wave. Stimuli were 500 Hz (attended) and 1,000 Hz (ignored) tone bursts, that were 125 ms in duration with 15-ms rise/fall times. They were presented at 60 db nhl at a rate that varied randomly between 2.5 and 3.5 Hz. The EEG was bandpass filtered between 1 and 100 Hz. The process by which Nd is generated is complex and not completely understood. It is possible, or likely, that the process of selective auditory attention, which is initiated at prefrontal sites, affects auditory processing at a subcortical level, possibly at the level of the nucleus reticularis thalami, a nucleus which, as has been demonstrated in cats, affects afferent activity bound for the cortex [167]. The Nd wave (or processing negativity Pn) is an electrophysiological index of selective attention ability. It is felt that the physical characteristics of each frequent stimulus (as represented by the source location of N1) are stored automatically in echoic memory. Jacobson/Kraus/McGee 66

185 This auditory image resides in echoic memory for 4 s and probably no longer than 10 s [ ] and the speed of this decay may be faster as we age [168]. When a target stimulus (i.e. infrequent stimulus in the attended channel (ear)) is presented, the conflict between the echoic memory and the target results in the generation at a preconscious level of the MMN (see previous section). The conscious overt comparison of each stimulus with its predecessor in the attended channel is believed to represent the source of the Nd wave [121]. Näätänen [121] has offered hypotheses regarding the origins of activity underlying the Nd. It is his belief that the early electrical activity (with modality-specific scalp topography) represents the rehearsal of the incoming stimulus with the attentional trace of previously attended auditory stimuli. The term attentional trace refers to the neural image, or, neural memory of each auditory stimulus. Each different auditory stimulus is associated with an attentional trace. When the incoming stimulus is common or frequent the attentional trace (which lasts but a few seconds in sensory memory) is strong. In the example of the typical Nd paradigm the target stimulus is presented infrequently. Therefore, when the target stimulus is presented the listener must first compare it to the strongest attentional trace which represents the sensory memory of the frequent stimulus. Once the initial spatial comparison is made (e.g. spatial in the sense that the auditory cortex is tonotopically organized) and found to mismatch, further processing takes place to determine whether the stimulus represents the target. The smaller the physical differences between the attentional trace and the incoming stimulus, the longer the processing is required to determine whether they are same or different. The recognition of the stimulus as the target results in the initiation of rehearsal activities [121] that serve to strengthen the attentional trace of the target stimulus. Clinical Data Studies evaluating the clinical usefulness of the Nd have been few. Recently, it has been demonstrated that the amplitude of Nd is significantly smaller in schizophrenic children compared with normal children [169]. The results were interpreted by the authors as evidence that schizophrenic children have impaired abilities to allocate attentional resources for the discriminative processing of visual stimuli (span of apprehension SPAN task). Most recently, Jacobson et al. [170] have evaluated selective auditory attention abilities in normal subjects and subjects with bothersome tinnitus. Subjects with bothersome tinnitus were found to demonstrate Nd amplitudes that were larger in the ms time period (early Nd wave) compared with normal subjects. These findings were interpreted by the authors as supporting the contention that attention to the tinnitus occurring over a long duration increased the strength of selective auditory attention abilities of the tinnitus subjects. Middle and Long Latency ERPs 67

186 Fig. 8. P300 recorded from a normal subject. The stimulus paradigm is described in the text. Shown are two trials recorded from the Pz electrode. The top tracings are the evoked potentials recorded in response to the standard tone bursts. The middle tracings are the evoked potentials recorded in response to the oddball tone bursts. The bottom tracing represents the result of subtracting the standard tracing from the oddball tracing (removing N1 and leaving P300). The discrimination task was quite difficult which explains the long peak latency of P300 (450 ms). Standard stimuli were 125-ms duration, 1,000-Hz tone bursts (15-ms rise/fall) presented at a rate of Hz and at an intensity of 60 db nhl. The oddball stimulus was a 75-ms duration, 1,000-Hz tone burst presented at the same intensity and rate. EEG was acquired with a bandpass of Hz. P300 (P3) The P300 response was described originally by Sutton et al. [171]. The P300 response requires attention to, and discrimination of, stimulus differences. It is elicited in an oddball paradigm, in which an unexpected stimulus occurs in a series of expected stimuli (fig. 8). The conventional recording paradigm is to have subjects count the number of times a rare stimulus occurs in a train Jacobson/Kraus/McGee 68

187 of frequent stimuli [172, 173]. The P300 can be elicited through stimulation of any sensory modality (or combination of sensory modalities). P300 is a large response achieving amplitudes of μv under ideal recording conditions, and under these circumstances, requires averaging of only presentations of target stimuli [174]. Most commonly, the auditory P300 is elicited by tones, but other acoustic stimuli including speech can be used [ ]. Using speech stimuli, Kurtzberg et al. [148, 149, 178] have elicited a P300-like response which they call the cortical discriminative response (CDR). P300 can be further divided into waves P3a and P3b. P3a occurs in response to large stimulus differences whether or not the subject is attending to the stimulus sequence, while P3b occurs only when the subject is actively discriminating between stimuli [177, ]. In general, P300 is best recorded from central-parietal (e.g. Pz) scalp regions [181]. A considerable body of research has amassed concerned with paradigms which elicit a P300 in normal subjects. These efforts have focused on a delineation of the cognitive processes reflected in the components and subcomponents comprising P300 Processes of attention, auditory discrimination, memory and semantic expectancy appear to be invoked in the generation of P300 [182]. It has been suggested that P300 may be a neural correlate of sequential information processing, short-term memory, and/or decision-making [ ]. Origins Results of investigations using intracranial recording techniques in humans have suggested that the generation of P300 involves multiple subcortical sites [187]. The limbic system, and particularly the hippocampus, have been postulated as generators both on the basis of surface electromagnetic recordings [188] and intracranial recordings [ ]. Large P300-like potentials showing steep voltage gradients and polarity reversals across electrode locations have been recorded from the limbic system. Thalamic contributions to P300 have been proposed based upon intracranial recording in humans [187]. Pathways involving the mesencephalic reticular formation, medial thalamus and prefrontal cortex are thought to contribute to the P300 based on the role of these structures in the regulation of selective attention [167, 192]. Topographic mapping, intracranial recordings and neuromagnetic field data have indicated that the frontal cortex [172, 193], centroparietal cortex [15, ] and the auditory cortex [198] contribute to the auditory P300. Clinical Data Kurtzberg et al. [148, 149] have studied speech evoked CAEPs and CDRs in high-risk infants who were at risk for language dysfunction. Twenty-one Middle and Long Latency ERPs 69

188 percent showed abnormal CAEPs, and all of these had absent CDRs. Of 55 infants with normal CAEPs, 15 had absent CDRs. CAEP to speech sounds of at-risk babies were significantly less mature than those of normal newborns. At 3 months of age, both groups of babies had similar AEPs. The authors reported that behavioral tests of language function performed later showed that the early CAEPS and CDRs were predictive of language function. They concluded that CAEPs and CDRs to speech sounds accurately reflected the infants capacity for processing stimuli important for development of speech and language [178]. For children, low-amplitude P300 has been linked to hyperactivity, schizophrenia, autism and reading disability with few changes in P300 latency [191, 199]. P300 abnormalities have also been linked to attentional disorders in hyperactive children [200], auditory processing disorders [117], Down s syndrome [201], and psychiatric disorders [202]. Finley et al. [203] used P300 to differentiate functional from organic cognitive disorders in children. In adults, P300 has been studied in patients with Parkinson s disease [204], chronic renal failure [205], chronic alcoholism [206], senile dementia [ ], cerebrovascular lesions, head trauma, brain tumors [ ], schizophrenia [ ], and aphasia [215]. Amplitude reductions and prolonged latencies have been observed in patients with Alzheimer s disease [208, ]. Tests of memory function derived from P300 latency measures have been applied to conditions where deficiencies of recognition and storage have been implicated [207, 208, 219]. Unlike other AEPs, P300 shows little asymmetry in patients with asymmetric hemispheric lesions. In patients with temporal lobe lesions, Musiek et al. [212] noted no significant effects of site of brain lesion either with ear of stimulation or location of the recording electrode. Similarly, no differences in amplitude for affected versus nonaffected hemisphere were seen in groups of patients with head trauma or brain tumors [220]. Johnson and Fedio [221] did show laterality effects in patients with unilateral temporal lobectomy using C4 and C3 electrode sites. P300 is not adversely affected by hearing loss, as long as the subject can perceive the stimulus, thus peripheral hearing loss should not impede the use of this measure [212]. In this regard, there have been recently two reports documenting the usefulness of the P300 for probing auditory processing capabilities in cochlear implant recipients [222, 223]. Both groups of investigators were able to record P300 components in both adults [222] and children [223]. These investigators have suggested that the presence of P300 may be predictive of how successful a patient will be with a cochlear implant. It is important to note, however, that P300 shows a great deal of intersubject variability in latency and amplitude. Picton and Hillyard [182] observed Jacobson/Kraus/McGee 70

189 that the P300 may correlate more with the degree of global cognitive dysfunction than with any specific diagnosis, since the response is abnormal with a wide range of disorders affecting cognition. It is important to realize that the generation of P300 probably is associated with the point in time a listener recognizes that a significant event has occurred (e.g. the recognition that a target stimulus has been presented). This means that the state of the listener as modified by the effects of medications, motivation, fatigue will have an effect on the latency and, in turn, the amplitude of P300. These limitations affect greatly the clinical usefulness of not only P300 but all endogenous responses. N400 (Semantic Incongruity Response) The N400 appears to reflect semantic processing of language. Like the P300, N400 is not modality specific (i.e. it can be elicited by auditory, visual and sign language stimuli) [ ]. Since eliciting N400 requires the subject to access language, N400 could be developed as a valuable part of an auditory processing battery. As with other long latency evoked responses, N400 should not be considered a single phenomenon, but rather the admixture of evoked electrical events underlying several psychological processes. The N400 eliciting task involves the perception of semantic incongruity. For example, the sentence I take coffee with cream and dog would elicit an N400. A semantically appropriate sentence, I take coffee with cream and sugar, would not elicit an N400. The latter sentence elicits a slow positive response [ ]. The more complex or unexpected the stimulus, the larger the N400 response. Other semantic tasks can elicit an N400: Reading isolated words that are semantically incongruous with a preceding phrase [229], discrepant word contexts [181, 230, 231], and naming pictures [232]. Words will elicit a larger N400 than pictures [233]. N400 was not elicited by words that were physically deviant on a visual task such as words in larger type [228, 234]. Kutas et al. [226] observed visual N400 in congenitally deaf adults to sign language stimuli and argue on that basis, that the response represents conceptual processing of the word s meaning rather than phonological processing of the acoustic aspects of the stimulus. That the N400 indexes a linguistic process was further demonstrated by Besson and Macar [235] who failed to find N400 to deviations involving nonlinguistic expectancies such as geometric patterns of increasing or decreasing size, scale notes of increasing or decreasing frequency and well-known melodies. However, Rugg [139, 140] found that rhyming and nonrhyming words are differentiated by a negative component following the nonrhyming words in the same way that related and unrelated word pairs are differentiated by the Middle and Long Latency ERPs 71

190 N400. Possibly this weakens the hypothesis that N400 is tied to semantic processes. Also possible is that the N400 response to semantic expectancy and the response to rhyming are nonidentical. Stuss et al. [236] speculate that two distinct processes are involved, one associated with detection of a stimulus and a second associated with the evaluation of complex or anomalous stimuli. Stuss et al. [237] describe an N400 for both semantic (naming) and nonsemantic (mental rotation) tasks, but the tasks elicited different scalp distributions suggesting that N400 differs for different tasks. Some processes may be common to both semantic and nonsemantic processing, while other processes are specific to the semantic interpretation. They describe a biphasic negative wave. The Nx wave of this complex may represent the initial registration of the stimulus, while the Ny component may occur due to further processing, perhaps involving access to long-term memory. Origins Little is known of the physiological origins of N400. Since this wave underlies several psychological processes, it is to be expected that the N400 represents the interactions of distributed sources in the brain. It has been reported that N400 is larger over the right than the left hemisphere [ ]. Picton and Hillyard [182] speculate that this may be related to clinical evidence that patients with right hemispheric damage have difficulty understanding the contextual framework of narratives, in appreciating humor, and in interpreting metaphors. In studies of the scalp topography of speech-elicited potentials, semantic processing elicited a posterior extension in later components, indicating that a more extensive portion of language cortex is engaged in semantic classification than in verbal identification [241]. Blood flow and metabolism studies have indicated that the frontal cortex is activated during semantic processing and that this area may also contribute to a speech-elicited negativity at N380. Clinical Data N400 may prove useful in the evaluation and the processing of language. Using visual stimuli it has been reported that normal readers have larger amplitude visual N400s than disabled readers [242, 243]. Conclusions The preceding discussion represents a brief overview of middle latency responses and a number of long latency responses. This has not been an Jacobson/Kraus/McGee 72

191 exhaustive review. That is, a number of interesting evoked responses have been omitted. These responses include the exogenous sustained response (sustained potential and sustained field) and the contingent negative variation (CNV). In most cases the evoked responses that have been discussed represent the activation of a unique set of neural structures that is associated with processes of audition. Among the many issues that have yet to be resolved is the question of how, if at all, each of these evoked responses are functionally linked. We know from the behavior of N1 that it must in some way represent an early step in the analysis of the auditory signal. The MMN represents the preconscious response to change in the physical characteristics of a sequence of stimuli. The P300 represents the conscious recognition of the significance of the difference as represented by the MMN. The Nd wave represents the ability of auditory cortical centers to open the gate for the desired signal channel and to close the gate on an unwanted signal channel. This selective attention function occurs in parallel with, and can begin some 50 ms prior to, the peak of N1. The gamma band response may represent the linking together of local and distributed (multiple distant) brain sources to achieve a unitary perception of the auditory event. How can what we know about these evoked responses help us in the future to evaluate the auditory system? These evoked electrical events represent some of the neurophysiological processes that are necessary to break apart, or decode, the signal that is encoded at the cochlea. That is, these evoked responses may provide us with a window on not how sound is transmitted through the brain pathways, but instead, how this neural code is recovered and converted into understandable auditory perceptions. It would seem that the characteristics of these evoked responses are key in the assessment of hearing for speech. For example, speech signals vary in both frequency and intensity over time. It is not happenstance that the N1 dipole location varies as a function of both frequency and intensity. Also, it would be difficult or impossible to process speech in a background of noise if the listener had impaired selective attention abilities (e.g. Nd). Additionally, if the brain is incapable of acknowledging changes in the physical characteristics of sound (e.g. MMN), it would seem that it would be impossible to consciously recognize (e.g. P300) these differences. (Is it possible for P300 to be present if the MMN is absent?) These questions are being investigated presently and it is hoped that the answers will bring us closer to an understanding of the behavior we call hearing. Middle and Long Latency ERPs 73

192 Acknowledgments This work was supported by NIH grants RO1 DC01510, RO1 DC00264 (Drs. Kraus and McGee) and by a grant from the American Tinnitus Association (Dr. Jacobson). References 1 Geisler CD, Frishkopf LS, Rosenblith WA: Extracranial responses to acoustic clicks in man. Science 1958;1289: Bickford RG, Jacobson JL, Cody DTR: The nature of averaged evoked potentials recorded from the human scalp. Electroencephalogr Clin Neurophysiol 1963;15: Mast TE: Short latency human evoked responses to clicks. J Appl Physiol 1965;20: Harker LA, Hosick E, Voots RJ, Mendel MI: Influence of succinocholine on middle component auditory evoked potentials. Arch Otolaryngol 1977;103: Kileny PR, Dodson D, Gelfand E: Middle latency auditory evoked reponses during open-heart surgery with hypothermia. Electroencephalogr Clin Neurophysiol 1983;55: Robinson K, Rudge P: Abnormalities of the auditory evoked potentials in patients with multiple sclerosis. Brain 1977;100: Hashimoto I, Ishiyama Y, Yoshimoto T, Nemoto S: Brainstem auditory evoked potentials recorded directly from the human thalamus. Brain 1981;104: McGee T, Kraus N, Comperatore C, Nicol T: Subcortical and cortical components of the MLR generating system. Brain Res 1991;54: Kileny P, Paccioretti D, Wilson AF: Effects of cortical lesions on middle-latency auditory evoked responses. Electroencephalogr Clin Neurophysiol 1987;66: Jacobson GP, Privitera M, Neils JM, Yeh H-S: The effects of anterior temporal lobectomy on the middle latency auditory evoked potential. Electroencephalogr Clin Neurophysiol 1990;75: Chatrian GE, Petersen MC, Lazarte JA: Responses to clicks from the human brain: Some depth electrographic observations. Electroencephalogr Clin Neurophysiol 1960;12: Ruhm H, Walker E, Flanigan H: Acoustically-evoked potentials in man: Mediation of early components. Laryngoscope 1967;77: Lee YS, Lueders H, Dinner DS, Lesser RP, Hahn J, Klem G: Recording of auditory evoked potentials in man using chronic subdural electrodes. Brain 1984;107: Celesia GC, Broughton RJ, Rasmussen T, Branch C: Auditory evoked responses from the exposed human cortex. Electroencephalogr Clin Neurophysiol 1968;24: Vaughan HG Jr, Ritter W: The sources of auditory evoked responses recorded from the human scalp. Electroencephalogr Clin Neurophysiol 1970;28: Wood CC, Wolpaw JR: Scalp distribution of human auditory evoked potentials. II. Evidence for overlapping sources and involvement of auditory cortex. Electroencephalogr Clin Neurophysiol 1982;54: Scherg M, Hari R, Hämäläinen M: Frequency-specific sources of the auditory N19-P30-P50 response detected by a multiple source analysis of evoked magnetic fields and potentials; in Williamson SJ, Hoke M, Stroink G, Kotani M (eds): Advances in Biomagnetism. New York, Plenum, 1989, pp Jacobson GP, Newman CW, Privitera M, Grayson AS: Differences in superficial and deep source contributions to middle latency auditory evoked potential Pa component in normal subjects and patients with neurological disease. J Am Acad Audiol 1991;2: Kraus N, Özdamar Ö, Hier D, Stein L: Auditory middle latency responses in patients with cortical lesions. Electroencephalogr Clin Neurophysiol 1982;54: Kileny PR, Kemink JL: Electrically evoked middle-latency auditory potentials in cochlear implant candidates. Arch Otolaryngol 1987;113: Jacobson/Kraus/McGee 74

193 21 Özdamar Ö, Kraus N: Auditory middle latency responses in humans. Audiology 1983;22: Pool KD, Finitzo T, Hong CT, Rogers J, Pickett RB: Infarction of the superior temporal gyrus: A description of auditory evoked potential latency and amplitude topology. Ear Hear 1989;10: Scherg M, Von Cramon D: Evoked dipole source potentials of the human auditory cortex. Electroencephalogr Clin Neurophysiol 1986;65: Scherg M, Vajsar J, Picton T: A source analysis of the late human auditory evoked potentials. J Cogn Neurosci 1989;1: Osterhammel PA, Shallop JK, Terkildsen K: The effect of sleep on the auditory brainstem response and the middle latency response. Scand Audiol 1985;14: Kraus N, McGee T, Comperatore C: MLRs in children are consistently present during wakefulness, stage 1, and REM sleep. Ear Hear 1989;10: Parving A, Salomon G, Elberling C, Larsen B, Lassen NA: Middle components of the auditory evoked response in bilateral temporal lobe lesions. Scand Audiol 1980;9: Rosati G, Bastiani PD, Paolino E, Prosser A, Arslan E, Artioli, M: Clinical and audiological findings in a case of auditory agnosia. J Neurol 1982;227: Woods DL, Clayworth CC, Knight RT, Simpson GV, Naeser MA: Generators of middle- and longlatency auditory evoked potentials: Implications from studies of patients with bitemporal lesions. Electroencephalogr Clin Neurophysiol 1987;68: Kraus N, Smith DI, McGee T: Midline and temporal lobe MLRs in the guinea pig originate from different generator systems: A conceptual framework for new and existing data. Electroencephalogr Clin Neurophysiol 1988;70: Pantev C, Bertrand O, Eulitz C, Verkindt C, Hampson S, Schuierer G, Elbert T: Specific tonotopic organizations of different areas of the human auditory cortex revealed by simultaneous magnetic and electrical recordings. Electroencephalogr Clin Neurophysiol 1995;94: Hari R, Pelizzone M, Mäkelä JP, Hällström J, Leinonen L, Lounasmaa OV: Neuromagnetic responses of the human auditory cortex to on- and offsets of noise bursts. Audiology 1987;26: Kavanagh KT, Gould H, McCormick G, Franks R: Comparison of the identifiability of the low intensity ABR and MLR in the mentally handicapped patient. Ear Hear 1989;10: Kraus N, McGee T: Electrophysiology of the human auditory system; in Popper AN, Fay RR (eds): The Mammalian Auditory Pathway: Neurophysiology. New York, Springer, 1992, vol 2, pp Vivion MC, Hirsch JE, Frye-Osier H, Goldstein R: Effects of stimulus rise-fall time and equivalent duration on middle components of AER. Scand Audiol 1980;9: Kavanagh KT, Harker LA, Tyler RS: Auditory brainstem and middle latency responses. I. Effects of response filtering and waveform identification. II. Threshold responses to a 500-Hz tone pip. Acta Otolaryngol 1984;108: Kraus N, Özdamar Ö, Stein L, Reed N: Absent auditory brainstem response: Peripheral hearing loss or brainstem dysfunction? Laryngoscope 1984;94: Gardi JN: Human brain stem and middle latency responses to electrical stimulation: A preliminary observation; in Schindler R, Merzenich M (eds): Cochlear Implants. New York, Raven Press, 1985, pp Miyamoto RT: Electrically evoked potential in cochlear implant subjects. Laryngoscope 1986;96: Romani G-L, Williamson S, Kaufman L, Brenner D: Characterization of human auditory cortex by neuromagnetic method. Exp Brain Res 1982;47: Galambos R, Makeig S, Talmachoff PJ: A 40 Hz auditory potential recorded from the human scalp. Proc Natl Acad Sci USA 1981;78: Spydell JD, Pattee G, Goldie WD: The 40 Hz event-related potential: Normal values and effects of lesions. Electroencephalogr Clin Neurophysiol 1985;62: Firsching R, Luther J, Eidelberg E, Brown WE, Story JL, Boop FA: 40-Hz middle latency auditory evoked response in comatose patients. Electroencephalogr Clin Neurophysiol 1987;67: Galambos R: Tactile and auditory stimuli repeated at high rates (30 50 s) produce similar event related potentials. Ann NY Acad Sci 1982;388: Middle and Long Latency ERPs 75

194 45 Pantev C, Elbert T, Makeig S, Hampson S, Eulitz C, Hoke M: Relationship of transient and steadystate auditory evoked fields. Electroencephalogr Clin Neurophysiol 1993;88: Stapells DR, Linden D, Suffield JB, Hamel G, Picton TW: Human auditory steady state potentials. Ear Hear 1984;5: Rodriguez R, Picton T, Linden D, Hamel G, Laframboise G: Human auditory steady state responses: Effects of intensity and frequency. Ear Hear 1986;7: Stapells DR, Makeig S, Galambos R: Auditory steady-state responses: Threshold prediction using phase coherence. Electroencephalogr Clin Neurophysiol 1987;67: Erwin RJ, Buchwald JS: Midlatency auditory evoked responses: Differential recovery cycle characteristics. Electroencephalogr Clin Neurophysiol 1986;64: Erwin R, Buchwald JS: Midlatency auditory evoked responses: Differential effects of sleep in the human. Electroencephalogr Clin Neurophysiol 1986;65: Adler LE, Waldo MC, Freedman R: Neurophysiologic studies of sensory gating in schizophrenia: Comparison of auditory and visual responses. Biol Psychiatry 1985;20: Nagamoto HT, Adler LE, Waldo MC, Freedman R: Sensory gating in schizophrenics and normal controls: Effects of changing stimulation interval. Biol Psychiatry 1989;25: Boutros NN, Overall J, Zouridakis G: Test-retest reliability of the P50 mid-latency auditory evoked response. Psychiatry Res 1991;39: Waldo M, Gerhardt G, Baker N, Drebing C, Adler L, Freedman R: Auditory sensory gating and catecholamine metabolism in schizophrenic and normal subjects. Psychiatry Res 1992;44: Cardenas VA, Gerson J, Fein G: The reliability of P50 suppression as measured by the conditioning/ testing ratio is vastly improved by dipole modeling. Biol Psychiatry 1993;33: Kathman N, Engel RR: Sensory gating in normals and schizophrenics: A failure to find strong P50 suppression in normals. Biol Psychiatry 1990;27: Smith DA, Boutros NN, Schwarzkopf SB: Reliability of P50 auditory event-related potential indices of sensory gating. Psychophysiology 1994;31: Buchwald JS, Erwin RJ, Read S, Van Lancker D, Cummings JL: Midlatency auditory evoked responses: Differential abnormality of P1 in Alzheimer s disease. Electroencephalogr Clin Neurophysiol 1989;74: Buchwald JS, Hinman C, Norman RJ, Huang CM, Brown KA: Middle- and long-latency auditory evoked responses recorded from the vertex of normal and chronically lesioned cats. Brain Res 1981; 205: Hinman CL, Buchwald JS: Depth evoked potential and single unit correlates of vertex midlatency auditory evoked responses. Brain Res 1983;264: Dickerson L, Buchwald J, Chen BM: Midlatency auditory evoked responses in the cat: Effects of scopalomine, a postsynaptic antagonist of muscarinic cholinergic neurotransmission. Neurosci Abstr 1986;12: Harrison J, Buchwald J, Song S, Woolf N, Butcher L: Pontine reticular formation lesions in the cat: Effects of P1 potential and behavior. Neurosci Abstr 1988;14: Pantev C, Makeig S, Hoke M, Galambos R, Gallen C, Hampson S: Human auditory evoked gamma band magnetic fields. Proc Natl Acad Sci USA 1991;88: Pantev C, Elbert T, Makeig S, Hampson S, Eulitz C, Hoke M: Relationship of transient and steadystate auditory evoked fields. Electroencephalogr Clin Neurophysiol 1993;88: Pantev C: Evoked and induced gamma-band activity of the human cortex. Brain Topogr 1995;76: Singer W: Neuronal representations, assemblies, and temporal coherence. Prog Brain Res 1993;95: Singer W: Synchronization of cortical activity and its putative role in information processing and learning. Annu Rev Physiol 1993;55: Engel A, Konig P, Kreiter A, Singer W: Interhemispheric synchronization of oscillatory neuronal responses in cat visual cortex. Science 1991;252: Engel A, Konig P, Singer W: Direct physiological evidence for scene segmentation by temporal coding. Proc Natl Acad Sci USA 1991;88: Jacobson/Kraus/McGee 76

195 70 Engel A, Kreiter A, Konig P, Singer W: Synchronization of oscillatory neuronal responses between striate and extrastriate visual cortical areas of the cat. Proc Natl Acad Sci USA 1991;88: Engel AK, König P, Kreiter AK, Schillen TB, Singer W: Temporal coding in the visual cortex: New vistas on integration in the nervous sytem. Trends Neurosci 1992;15: Gray CM, Singer W: Stimulus-specific neuronal oscillations in orientation columns of cat visual cortex. Proc Natl Acad Sci USA 1989;86: Gray C, Konig P, Engel A, Singer W: Oscillatory responses in cat visual cortex exhibit intercolumnar synchronization which reflects global stimulus properties. Nature 1989;338: Jagadeesh B, Gray CM, Ferster D: Visually evoked oscillations of membrane potential in cells of cat visual cortex. Science 1992;257: Konig P, Engel A, Singer W: Relation between oscillatory activity and long-range synchronization in cat visual cortex. Proc Natl Acad Sci USA 1995;92: Adrian ED: Olfactory reactions in the brain of the hedgehog. J Physiol 1942;100: Freeman WJ: Mass Action in the Nervous System. New York, Academic Press, Freeman WJ: Nonlinear dynamics of paleocortex manifested in the olfactory EEG. Biol Cybern 1979;35: Bertrand O, Pantev C: Stimulus frequency dependence of the transient oscillatory auditory evoked responses (40 Hz) studied by electric and magnetic recordings in human; in Pantev C, Elbert T (eds): Oscillatory Event Related Brain Dynamics. New York, Plenum, 1994, pp Tiitinen H, Sinkkonen J, Reinikainen K, Alho K, Lavikainen J, Näätänen R: Selective attention enhances the auditory 40 Hz transient response in humans. Nature 1993;364: Moran JE, Tepley N, Jacobson GP, Barkley G: Evidence for multiple generators in evoked responses using finite difference field mapping: Auditory evoked fields. Brain Topogr 1993;5: Pantev C, Hoke M, Lütkenhöner B, Lehnertz K: Neuromagnetic evidence of functional organization of the auditory cortex in humans. Acta Otolaryngol 1991;491: Davis PA: Effects of acoustic stimuli on the waking human brain. J Neurophysiol 1939;2: Nelson DA, Lassman FM: Effects of intersignal interval on the human auditory evoked response. J Acoust Soc Am 1968;44: Rothman HH, Davis H, Hay IS: Slow evoked cortical potentials and temporal features of stimulation. Electroencephalogr Clin Neurophysiol 1970;29: Hari R, Kaila K, Katila T, Tuomisto T, Varpula T: Interstimulus interval dependence of the auditory vertex response and its magnetic counterpart: Implications for their neural generation. Electroencephalogr Clin Neurophysiol 1982;54: Wolpaw JR, Penry JK: A temporal component of the auditory evoked response. Electroencephalogr Clin Neurophysiol 1975;39: Näätänen R, Picton T: The N1 wave of the human electric and magnetic response to sound. Psychophysiology 1987;24: Yamamoto T, Williamson SJ, Kaufman L, Nicholson C, Llinas R: Magnetic localization of neuronal activity in the human brain. Proc Natl Acad Sci USA 1988;85: Pantev C, Hoke M, Lehnertz K, Lütkenhöner B, Fahrendorf G, Stöber U: Identification of sources of brain neuronal activity with high spatiotemporal resolution through combination of neuromagnetic source localization and magnetic resonance imaging. Electroencephalogr Clin Neurophysiol 1990; 75: Papanicolaou AC, Baumann S, Rogers RL, Caydjari C, Amparo EG, Eisenberg HM: Localization of auditory response sources using magnetoencephalography and magnetic resonance imaging. Arch Neurol 1990;47: Elberling C, Bak C, Kofoed B, Lebech J, Saermark K: Auditory magnetic fields. Source location and tonotopic organization in the right hemisphere of the human brain. Scand Audiol 1982;11: Pantev C, Hoke M, Lehnertz K, Lütkenhöner B, Anogianakis G, Wittkowski W: Tonotopic organization of the human auditory cortex revealed by transient auditory evoked magnetic fields. Electroencephalogr Clin Neurophysiol 1988;69: Jacobson GP, Lombardi DM, Gibbens ND, Ahmad BK, Newman CW: The effects of stimulus frequency and recording site on the amplitude and latency of multichannel cortical auditory evoked potential component N1. Ear Hear 1992;13: Middle and Long Latency ERPs 77

196 95 Pantev C, Hoke M, Lehnertz K, Lütkenhöner B: Neuromagnetic evidence of an amplitopic organization of the auditory cortex. Electroencephalogr Clin Neurophysiol 1989;72: Pantev C, Lütkenhöner B, Hoke M, Lehnertz K: Comparison between simultaneously recorded auditory-evoked magnetic fields and potentials elicited by ipsilateral, contralateral and binaural tone burst stimulation. Audiology 1986;25: Hari R: The neuromagnetic method in the study of the human auditory cortex; in Grandori F, Hoke M, Romani GL (eds): Auditory Evoked Magnetic Fields and Electric Potentials. Adv Audiol. Basel, Karger, 1990, vol 6, pp Tiihonen J, Hari R, Kaukoranta E, Kajola M: Interaural interaction in the human auditory cortex. Audiology 1989;28: Elberling C, Bak C, Kofoed B, Lebech J, Saermark K: Auditory magnetic fields from the human cortex. Influence of stimulus intensity. Scand Audiol 1981;10: Elberling C, Bak C, Kofoed B, Lebech J, Saermark K: Auditory magnetic fields from the human cerebral cortex: Location and strength of an equivalent current dipole. Acta Neurol Scand 1982; 65: Joutsiniemi S-L: Comparison between electric evoked potentials, source dipole components and magnetic fields elicited by noise/square-wave stimuli. Acta Neurol Scand 1988;78: Leinonen L, Joutsiniemi S-L: Auditory evoked potentials and magnetic fields in patients with lesions of the auditory cortex. Acta Neurol Scand 1989;79: Mäkelä JP, Hari R, Valanne L, Ahonen A: Auditory evoked magnetic fields after ischemic brain lesions. Ann Neurol 1991;30: Connolly JF, Manchanda R, Gruzelier JH, Hirsch SR: Pathway and hemispheric differences in the event related potential to monaural stimulation: A comparison of schizophrenic patients with normal controls. Biol Psychiatry 1985;20: Sandman CA, Gerner R, O Halloran JP, Isenhart R: Event related potentials and item recognition in depressed, schizophrenic, and alcoholic patients. Int J Psychopathol 1987;5: Reite M, Teale P, Goldstein L, Whalen J, Linnville S: Late auditory magnetic sources may differ in the left hemisphere of schizophrenic patients. Arch Gen Psychiatry 1989;46: Hoke M, Feldmann H, Pantev C, Lütkenhöner B, Lehnertz K: Objective evidence of tinnitus in auditory evoked magnetic fields. Hear Res 1989;37: Pantev C, Hoke M, Lütkenhöner B, Lehnertz K, Kumpf W: Tinnitus remission objectified by neuromagnetic measurements. Hear Res 1989;40: Jacobson GP, Ahmad BK, Moran J, Newman CW, Tepley N, Wharton J: Auditory evoked cortical magnetic field (M100/M200) measurements in tinnitus and normal groups. Hear Res 1991;56: Colding-Jorgenson E, Lauritzen M, Johnsen NJ, Mikkelsen KB, Saermark K: On the evidence of auditory evoked magnetic fields as an objective measure of tinnitus. Electroencephalogr Clin Neurophysiol 1992;83: Jacobson GP, Ahmad BK, Moran J, Newman CW, Wharton J, Tepley N: Occurrence of auditory evoked field N1m and P2m components in a sample of normal subjects. Ear Hear 1992;13: Pelizzone M, Hari R, Mäkelä JP, Kaukoranta E, Montandon P: Activation of the auditory cortex by cochlear stimulation in a deaf patient. Neurosci Lett 1986;68: Hoke M, Pantev C, Lütkenhöner B, Lehnertz K, Sürth W: Magnetic fields from the auditory cortex of a deaf human individual occurring spontaneously or evoked by stimulation through a cochlear prosthesis. Audiology 1989;28: Hari R, Pelizzone M, Mäkelä JP, Huttunen J: Neuromagnetic responses from a deaf subject to stimuli presented through a multichannel cochlear prosthesis. Ear Hear 1988;9: Hari R, Aittoniemi K, Järvinen M-L, Katila T, Varpula T: Auditory evoked transient and sustained magnetic fields of the human brain: Localization of neural generators. Exp Brain Res 1980;40: Squires NK, Galbraith GC, Aine CJ: Event-related potential assessment of sensory and cognitive deficits in the mentally retarded; in Lehmann D, Callaway E (eds): Human Evoked Potentials: Applications and Problems. New York, Plenum Press, 1979, pp Jirsa R, Clontz K: Long latency auditory event-related potentials from children with auditory processing disorders. Ear Hear 1990;11: Jacobson/Kraus/McGee 78

197 118 Näätänen R, Gaillard AWK, Mäntysalo S: Early selective attention effect on evoked potential reinterpreted. Acta Psychol 1978;42: Näätänen T, Paavilainen P, Tiitinen H, Jiang D, Alho A: Attention and mismatch negativity. Psychophysiology 1993;30: Kraus N, McGee T, Micco A, Sharma A, Carrell T, Nicol T: Mismatch negativity in school-age children to speech stimuli that are just perceptibly different. Electroencephalogr Clin Neurophysiol 1993;88: Näätänen R: Attention and Brain Function. Hillsdale/NJ, Erlbaum Assoc, Sams M, Hämäläinen M, Antervo A, Kaukaraunta E, Reinikainen K, Hari R: Cerebral neuromagnetic responses evoked by short auditory stimuli. Electroencephalogr Clin Neurophysiol 1985;61: Sharma A, Kraus N, McGee T, Carrell T, Nicol T: Acoustic vs phonetic representation of speech stimuli as reflected by the mismatch negativity event-related potential. Electroencephalogr Clin Neurophysiol 1993;88: Aaltonen O, Niemi P, Nyrke T, Tuhkanenen M: Event-related brain potentials and the perception of a phonetic continuum. Biol Psychol 1987;24: Kaukoranta E, Sams M, Hari R, Hämäläinen M, Näätänen R: Reactions of human auditory cortex to changes in tone duration: Indirect evidence for duration-specific neurons. Hear Res 1989;41: Näätänen R: The role of attention in auditory information processing as revealed by event-related brain potentials and other brain measures of cognitive function. Behav Brain Sci 1990;13: Näätänen R, Paavilainen P, Alho K, Reinikainen K, Sams M: The mismatch negativity to intensity changes in an auditory stimulus sequence. Electroencephalogr Clin Neurophysiol 1987;(suppl 40): Näätänen R, Paavilainen P, Reinikainen K: Do event-related potentials reveal the mechanism of auditory sensory memory in the human brain? Neurosci Lett 1989;98: Novak G, Ritter W, Vaughan H, Wiznitzer M: Differentiation of negative event-related potentials in an auditory discrimination task. Electroencephalogr Clin Neurophysiol 1990;75: Paavilainen P, Karlsson M, Reinikainen K, Näätänen R: Mismatch negativity to changes in the spatial location of an auditory stimulus. Electroencephalogr Clin Neurophysiol 1989;73: Sams M, Paavilainen P, Alho K, Näätänen R: Auditory frequency discrimination and event-related potentials. Electroencephalogr Clin Neurophysiol 1985;62: Ritter W, Simson R, Vaughan HG Jr, Friedman DA: A brain event related to the making of a sensory discrimination. Science 1979;203: Snyder E, Hillyard S: Long-latency evoked potentials to irrelevant, deviant stimuli. Behav Biol 1976; 16: Mäntysalo S, Näätänen R: Duration of a neuronal trace of an auditory stimulus as indicated by event-related potentials. Biol Psychol 1987;24: Böttcher-Gandor C, Ullsperger P: Mismatch negativity in event-related potentials to auditory stimuli as a function of varying interstimulus interval. Psychophysiology 1992;29: Imada T, Hari R, Loveless N, McEvoy L, Sams M: Determinants of the auditory mismatch response. Electroencephalogr Clin Neurophysiol 1993;87: Kraus N, McGee T, Sharma A, Carrell T: Neurophysiologic bases of speech discrimination. Ear Hear 1995;16: Csépe V: On the origin of the mismatch negativity. Ear Hear 1995;16: Rugg MD: Event-related potentials and the phonological processing of words and non-words. Neuropsychologia 1984;22: Rugg MD: Event-related potentials in phonological matching tasks. Brain Lang 1984;23: Alho K, Sainio K, Sajaniemi N, Reinikainen K, Näätänen R: Event-related brain potential of human newborns to pitch change of an acoustic stimulus. Electroencephalogr Clin Neurophysiol 1990;77: Nielsen-Bohlman L, Knight RT, Woods DL, Woodward K: Differential auditory processing continues during sleep. Electroenceph Clin Neurophysiol 1991;79: Middle and Long Latency ERPs 79

198 143 Csépe V, Karmos G, Molnár M: Evoked potential correlates of stimulus deviance during wakefulness and sleep in cat Animal model of mismatch negativity. Electroencephalogr Clin Neurophysiol 1987;66: Kraus N, McGee T, Carrell T, King C, Littman T, Nicol T: Discrimination of speech-like signals in auditory thalamus and cortex. J Acoust Soc Am 1994;96: Korpilahti P, Lang H: The auditory ERP components and mismatch negativity in dysphasic children. Electroencephalogr Clin Neurophysiol 1994;91: Kraus N, Micco A, Koch D, McGee T, Carrell T, Wiet R, Weingarten C, Sharma A: The mismatch negativity cortical evoked potential elicited by speech in cochlear-implant users. Hear Res 1993;65: Csépe V, Karmos G, Molnár M: Evoked potential correlates of sensory mismatch process during sleep in cats; in Koella WP, Obal F, Schulz H, Visser P (eds): Sleep 86. Stuttgart, Thieme, 1988, pp Kurtzberg D, Hilpert P, Kreuzer J, Vaughan HG: Differential maturation of cortical auditory evoked potentials to speech sounds in normal full term and very low-birthweight infants. Dev Med Child Neurol 1984;26: Kurtzberg D, Vaughan HG, Courchesne E, Friedman D, Harter MR, Putnam LE: Developmental aspects of event-related potentials. Ann NY Acad Sci 1984;425: Roffwarg H, Muzio J, Dement W: Ontogenetic development of the human sleep-dream cycle. Science 1966;152: Kraus N, McGee T: Clinical implications of primary and non-primary components of the MLR generating system. Ear Hear 1993;14: McGee T, Kraus N, Killion M, Rosenberg R, King C: Improving the reliability of the auditory middle latency response. Ear Hear 1993;14: Sams M, Kaukoranta E, Hari R, Hämäläinen M, Näätänen R: Cortical activity elicited by changes in auditory stimuli: Different sources for the magnetic N100m and mismatch responses. Psychophysiology 1991;28: Giard MH, Perrin F, Pernier J, Bouchet P: Brain generators implicated in processing of auditory stimulus deviance: A topographic study. Psychophysiology 1990;27: Javitt D, Schroeder C, Steinschneider M, Arezzo J, Vaughan H: Demonstration of mismatch negativity in monkey. Electroencephalogr Clin Neurophysiol 1992;83: Kraus N, McGee T, Littman T, Nicol T, King C: Encoding of acoustic change involves non-primary auditory thalamus. J Neurophysiol 1994;72: Tiitinen H, Alho K, Huotilainen M, Ilmoniemi RJ, Simola J, Näätänen R: Tonotopic auditory cortex and the magnetoencephalographic equivalent of the mismatch negativity. Psychophysiology 1993;30: Elliott L, Hammer M: Longitudinal changes in auditory discrimination in normal children and children with language-learning problems. J Speech Hear Dis 1988;53: Elliott L, Hammer M, Scholl M: Fine-grained auditory discrimination in normal children and children with language-learning problems. J Speech Hear Res 1989;32: Tallal P, Stark R, Kallman C, Mellitis D: Developmental dysphasia: The relation between acoustic processing deficits and verbal processing. Neuropsychologia 1980;18: Tallal P, Stark R, Mellitis F: The relationship between auditory temporal analysis and receptive language development: Evidence from studies of developmental language disorder. Neuropsychologia 1985;23: Aaltonen O, Tuomainen J, Laine M, Niemi P: Cortical differences in tonal versus vowel processing as revealed by an ERP component called mismatch negativity. Brain Lang 1993;44: Woods DL: The physiological basis of selective attention: Implications of event-related potential studies; in Rohrbaugh JW, Parasuraman R, Johnson R (eds): Event-Related Brain Potentials. New York, Oxford Press, 1990, pp Hillyard SA, Hink RF, Schwent VL, Picton TW: Electrical signs of selective attention in the human brain. Science 1973;182: Näätänen R, Michie PT: Early selective attention effects of the evoked potential. A critical review and reinterpretation. Biol Psychol 1979;8: Jacobson/Kraus/McGee 80

199 166 Arthur DL, Lewis PS, Medvick PA, Flynn ER: A neuromagnetic study of selective attention. Electroencephalogr Clin Neurophysiol 1991;78: Yingling CD, Skinner JE: Gating of thalamic input to cerebral cortex by nucleus reticularis thalami; in Desmedt JE (ed): Attention, Voluntary Contraction and Event-Related Cerebral Potentials. Prog Clin Neurophysiol. Basel, Karger, 1977, vol 1, pp Pekkonen E, Jousmäki V, Partanen J, Karhu J: Mismatch negativity area and age-related auditory memory. Electroencephalogr Clin Neurophysiol 1993;87: Strandburg RJ, Marsh JT, Brown WS, Asarnow RF, Guthrie D, Higa J: Reduced attention-related negativepotentialsinschizophrenicchildren. ElectroencephalogrClinNeurophysiol1991;79: Jacobson GP, Calder JC, Newman CW, Peterson EL, Wharton JA, Ahmad BK: Electrophysiological indices of selective auditory attention in subjects with and without tinnitus. Hear Res 1996;97: Sutton S, Braren M, Zubin J, John ER: Evoked-potential correlates of stimulus uncertainty. Science 1965;150: Courchesne E: Neurophysiological correlates of cognitive development: Changes in long-latency event-related potentials from childhood to adulthood. Electroencephalogr Clin Neurophysiol 1978; 45: Kurtzberg D, Vaughan HG, Kreuzer JA: Task-related cortical potentials in children. Prog Clin Neurophysiol 1979;6: Polich J, Starr A: Middle, late and long latency auditory evoked potentials; in Moore E (ed): Bases of Auditory Brainstem Evoked Responses. New York, Grune & Stratton, 1983, pp Klinke R, Fruhstorfer H, Finkenzellar P: Evoked responses as a function of external and stored information. Electroencephalogr Clin Neurophysiol 1968;25: Picton TW, Hillyard SH, Krausz HI, Galambos R: Human auditory evoked potentials. I. Evaluation of components. Electroencephalogr Clin Neurophysiol 1974;36: Squires NK, Squires KC, Hillyard SA: Two varieties of long-latency positive waves evoked by unpredictable auditory stimuli in man. Electroencephalogr Clin Neurophysiol 1975;38: Kurtzberg D, Stapells DR, Wallace IF: Event-related potential assessment of auditory system integrity: Implications for language development; in Vietze P, Vaughan HG (eds): Early Identification of Infants with Developmental Disabilities. Philadelphia, Grune & Stratton, 1988, pp Roth W: Auditory evoked responses to unpredictable stimuli. Psychophysiology 1973;10: Polich J: Frequency, intensity and duration as determinants of P300 from auditory stimuli. J Clin Neurophysiol 1989;6: Polich J: Semantic categorization and event-related potentials. Brain Lang 1985;26: Picton TW, Hillyard SA: Endogenous event-related potentials; in Picton TW (ed): Human Event- Related Potentials. Amsterdam, Elsevier Science, Donchin E: Surprise! Surprise? Psychophysiology 1981;18: Ford JM, Mohs RC, Pfefferbaum A, Kopell BS: On the utility of P3 latency and RT for studying cognitive processes; in Kornhuber HH, Deecke L (eds): Motivation, Motor and Sensory Processes of the Brain. Prog Brain Res. Amsterdam, Elsevier, 1980, vol 54, pp Squires KC, Wickens C, Squires NK, Donchin E: The effect of stimulus sequence on the waveform of the cortical event-related potential. Science 1976;193: Squires NK, Donchin E, Squires KC, Grossberg S: Bisensory stimulation: Inferring decision-related processes from the P300 component. J Exp Psychol [Hum Percept] 1977;2: Wood CC, Allison T, Goff WR, Williamson PD, Spencer DB: On the neural origin of P300 in man; in Kornhuber HH, Deecke L (eds): Motivation, Motor and Sensory Processes of the Brain. Prog Brain Res. Amsterdam, Elsevier, 1980, vol 54, pp Okada YC, Kaufman L, Williamson SJ: The hippocampal formation as a source of the slow endogenous potentials. Electroencephalogr Clin Neurophysiol 1983;55: Halgren E, Squires NK, Wilson CL, Rohrbaugh JR, Babb TL, Crandall PH: Endogenous potentials generated in the human hippocampal formation and amygdala by infrequent events. Science 1980; 210: McCarthy G, Wood CC, Alison T, Goff WR, Williamson PD, Spencer DD: Intracranial recordings of event-related potentials in humans engaged in cognitive tasks. Soc Neurosci Abstr 1982;8:976. Middle and Long Latency ERPs 81

200 191 Squires NK, Halgren E, Wilson C, Crandall P: Human endogenous limbic potentials: Cross-modality and depth/surface comparisons in epileptic subjects; in Gaillard AWK, Ritter W (eds): Tutorials in ERP Research: Endogenous Components. Amsterdam, North-Holland, 1983, pp Yingling CD, Hosobuchi Y: A subcortical correlate of P300 in man. Electroencephalogr Clin Neurophysiol 1984;59: Desmedt JE, Debecker J: Wave form and neural mechanism of the decision P350 elicited without pre-stimulus CNV or readiness potential in random sequences of near threshold auditory clicks and finger stimuli. Electroencephalogr Clin Neurophysiol 1979;47: Simson R, Vaughan HG Jr, Ritter W: The scalp topography of potentials in auditory and visual go/no go tasks. Electroencephalogr Clin Neurophysiol 1977;43: Simson R, Vaughan HG Jr, Ritter W: The scalp topography of potentials in auditory and visual discrimination tasks. Electroencephalogr Clin Neurophysiol 1977;42: Goff ER, Allison T, Vaughan HG Jr: The functional neuroanatomy of event-related potentials; in Calaway E, Tueting P, Koslow SH (eds): Event-Related Potentials in Man. New York, Academic Press, 1978, pp Pritchard WS: Psychophysiology of P300. Psychol Bull 1981;89: Richer F, Johnson RA, Beatty J: Sources of late components of the brain magnetic response. Soc Neurosci Abstr 1983;9: Ciesielki K, Courchesne E, Elmasian R: Effects of focused selective attention tasks on eventrelated potentials in autistic and normal individuals. Electroencephalogr Clin Neurophysiol 1990; 75: Loiselle DL, Stamm JA, Maitinsky S, Whipple SC: Evoked potential and behavioral signs of attentive dysfunctions in hyperactive boys. Psychophysiology 1980;17: Lincoln A, Courchesne E, Kilman B, Galambos R: Neuropsychological correlates of information processing by children with Down s syndrome. Am J Ment Defic 1985;89: Diner D, Holcomb P, Dykman R: P-300 in a major depressive disorder. Psychiatry Res 1985;15: Finley WW, Faux SF, Hutcheson J, Amstutz L: Long-latency event-related potentials in the evaluation of cognitive function in children. Neurology 1985;35: Hansch EC, Syndulko K, Cohen SM, Goldberg ZI, Potvin AR, Tourtellotte WW: Cognition in Parkinson disease: An event-related potential perspective. Ann Neurol 1982;11: Cohen SN, Syndulko K, Rever B, Kraut J, Coburn J, Tourtellotte WW: Visual evoked potentials and long latency event-related potentials in chronic renal failure. Neurology 1983;33: Pfefferbaum A, Horvath T, Rothe W, Kopell B: Event related potential changes in chronic alcoholics. Electroencephalogr Clin Neurophysiol 1979;47: Goodin DS, Squires KC, Henderson BH, Starr A: Age-related variations in evoked potentials to auditory stimuli in normal human subjects. Electroencephalogr Clin Neurophysiol 1978;44: Goodin DS, Squires K, Starr A: Long latency event-related components of the auditory evoked potential in dementia. Brain 1978;101: Pfefferbaum A, Ford J, Roth W, Kopell B: Age-related changes in auditory event-related potentials. Electroencephalogr Clin Neurophysiol 1980;49: Ebner A, Haas J, Lucking C, Schily M, Wallesch C, Zimmerman P: Event-related brain potentials (P300) and neuropsychological deficit in patients with focal brain lesions. Neurosci Lett 1986;64: Michalewski H, Rosenberg C, Starr A: Event related potentials in dementia; in Cracco R, Bodis- Wollner I (eds): Evoked Potentials. New York, Liss, 1986, pp Musiek FE, Baran JA, Pinheiro ML: P300 results in patients with lesions of the auditory areas of the cerebrum. J Am Acad Audiol 1992;3: Baribeau-Braun J, Picton TW, Gosselin J-Y: Schizophrenia: A neurophysiological evaluation of abnormal information processing. Science 1983;219: Roth WT, Horvath TB, Pfefferbaum A, Kopell BS: Event-related potentials. Electroencephalogr Clin Neurophysiol 1980;8: Selinger M, Prescott T: Auditory event-related potentials probes and behavioral measures of aphasia. Brain Lang 1989;36: Jacobson/Kraus/McGee 82

201 216 Brown WS, Marsh JT, Larue A: Event-related potentials in psychiatry: Differentiating depression and dementia in the elderly. Bull LA Neurol Soc 1982;47: Syndulko K, Hansch MA, Cohen SN, Pearce JW, Goldberg Z, Montan B, Tourtellotte WW, Potvin AR: Long-latency event-related potentials in normal aging and dementia; in Courjon J, Mauguiere F, Revol M (eds): Clinical Applications of Evoked Potentials in Neurology. New York, Raven Press, 1982, pp Chayasirisobhon S, Brinkman S, Gerganoff S, Gershon S, Pomara N, Green V: Event-related potential in Alzheimer disease. Clin Electroencephalogr 1985;16: Ford JM, Roth WT, Mohs RC, Hopkins WF, Kopell BS: Event-related potentials recorded from young and old adults during a memory retrieval task. Electroencephalogr Clin Neurophysiol 1979; 47: Olbrich HM, Nau HE, Lodemann E, Zerbin D: Evoked potential assessment of mental function during recovery from severe head injury. Surg Neurol 1986;26: Johnson R, Fedio P: Task related changes in P-300 scalp distribution in temporal lobectomy patients; in Johnson R, Rohrbaugh J, Parasuraman R (eds): Current Trends in Evoked Potential Research. Electroencephalogr Clin Neurophysiol 1987;(suppl 40): Kileny P: Use of electrophysiologic measures in the management of children with cochlear implants: Brainstem, middle latency and cognitive (P300) responses. Am J Otol 1991;12: Micco AG, Kraus N, Koch DB, McGee TJ, Carrell TD, Sharma A, Nicol T, Wiet RJ: Speech evoked cognitive P300 potentials in cochlear implant recipients. Am J Otol 1995;16: Herning RI, Jones RT, Hunt JS: Speech event related potentials reflect linguistic content and processing level. Brain Lang 1987;30: McCallum WC, Farmer SF, Pocock PK: The effects of physical and semantic incongruities on auditory event-related potentials. Electroencephalogr Clin Neurophysiol 1984;59: Kutas M, Neville HJ, Holcomb P: A preliminary comparison of the N400 response to semantic anomalies during reading, listening and signing. Electroencephalogr Clin Neurophysiol 1987;(suppl 39): Kutas M, Hillyard SA: Reading senseless sentences: Brain potentials reflect semantic incongruity. Science 1980;207: Kutas M, Hillyard SA: Event-related brain potentials to semantically inappropriate and surprisingly large words. Biol Psychol 1980;11: Neville HJ, Kutas M, Chesney G, Schmidt AL: Event-related brain potentials during initial encoding and recognition memory of congruous and incongruous words. J Mem Lang 1986;25: Harbin TJ, Marsh GR, Harvey MT: Differences in the late components of the event-related potential due to age and to semantic and non-semantic tasks. Electroencephalogr Clin Neurophysiol 1984; 59: Bentin S, McCarthy G, Wood CC: Event-related potentials, lexical decision and semantic priming. Electroencephalogr Clin Neurophysiol 1985;60: Stuss DT, Leech EE, Sarazin FF, Picton TW: Event-related potentials during naming. Ann NY Acad Sci 1984;425: Noldy-Cullum N, Stelmack R: Recognition memory for pictures and words: The effect of incidental and intentional learning on N400. Electroencephalogr Clin Neurophysiol 1987;(suppl 40): Kutas M, Hillyard SA: Event-related brain potentials elicited by novel stimuli during sentence processing. Ann NY Acad Sci 1984;425: Besson M, Macar F: An event-related potential analysis of incongruity in music and other nonlingual contexts. Psychophysiology 1987;24: Stuss DT, Picton TW, Cerri AM: Electrophysiological manifestations of typicality judgment. Brain Lang 1988;33: Stuss DT, Sarazin FF, Leech EE, Picton TW: Event-related potentials during naming and mental rotation. Electroencephalogr Clin Neurophysiol 1983;56: Kutas M, Hillyard SA: The lateral distribution of event-related potentials during natural sentence processing. Neuropsychologia 1982;20: Kutas M, Van Petten C, Besson M: Event-related potential asymmetries during the reading of sentences. Electroencephalogr Clin Neurophysiol 1988;69: Middle and Long Latency ERPs 83

202 240 Fischler I, Bloom PA, Childers DG, Roucos SE, Perry NW Jr: Brain potentials related to stages of sentence verification. Psychophysiology 1983;20: Lovrich D, Novick B, Vaughan HG Jr: Topographic analysis of auditory event-related potentials associated with acoustic and semantic processing. Electroencephalogr Clin Neurophysiol 1988;71: Kutas M, Van Petten C: Event-related potential studies of language; in Ackles PK, Jennings JR, Coles MGH (eds): Adv Psychophysiol. Greenwich Conn, JAI Press, 1987, vol 3, pp Stelmach RM, Saxe BJ, Noldy-Cullum N, Campbell KB, Armitage R: Recognition memory for words and event-related potentials: A comparison of normal and disabled readers. J Clin Exp Neuropsychol 1988;10: Kraus N, McGee T: Auditory event-related potentials; in Katz J (ed): Handbook of Clinical Audiology. Baltimore, Williams & Wilkins, 1994, pp Jacobson GP: Magnetoencephalographic studies of auditory system function. J Clin Neurophysiol 1994;11: Gary P. Jacobson, PhD, Director, Division of Audiology, Henry Ford Hospital, 2700 West Grand Blvd, Detroit, MI (USA) Jacobson/Kraus/McGee 84

203 Alford BR, Jerger J, Jenkins HA (eds): Electrophysiologic Evaluation in Otolaryngology. Adv Otorhinolaryngol. Basel, Karger, 1997, vol 53, pp Objective Measurements and the Audiological Management of Cochlear Implant Patients Jon K. Shallop Research and Clinical Services, Denver Ear Institute, Englewood, Colo., USA Various behavioral and electrophysiological procedures have been utilized to evaluate cochlear implant candidates and to optimize speech recognition performance for patients with cochlear implant patients. These procedures include electrical promontory testing (PROM), verification of device and electrode integrity using real-time electrode voltages (EV) and averaged electrode voltages (AEV), whole nerve action potentials (EAP), electrically elicited stapedius reflexes (ESR), electrical auditory brainstem (EABR), middle latency (EMLR) responses and various electrically elicited cortical responses. This chapter presents an overview of these objective measures and how they are applied to the management of cochlear implant patients. These measurements can be especially helpful for young children. The AEV, ESR and EABR procedures can assist with device programming. The cortical responses, including color topographic brainmapping, provide insight into how stimulation from a cochlear implant may be processed by the brain. As additional patients receive cochlear implants and as additional devices are developed, the need will continue for objective measurement techniques for these patients, especially young children who may not be able to provide adequate behavioral responses. This chapter reviews various objective measurement techniques which are utilized with cochlear implant patients, before, during or after their surgery.

204 Electrical Promontory Testing Electrical PROM testing was one of the first procedures used in the selection of prospective patients for cochlear implantation. It is not an objective technique in the strictest sense since it requires behavioral cooperation and responses from the patient. However, this procedure has been utilized for a number of years and has resulted in the development of various objective procedures which do not require behavioral responses. The PROM test has been recommended for patients who do not have any known audiometric responses or in other situations where the potential benefit from a cochlear implant is questioned during preoperative evaluations. Instrumentation The most common technique for electrical PROM testing is to place a transtympanic needle electrode on the promontory. A second reference disk electrode is placed on the forehead. Charge-balanced biphasic electrical square waves are then presented via these electrodes. The current range necessary to produce auditory nerve stimulation with a promontory needle electrode is typically in the range of 10 to 1 ma. These charged-balanced stimuli are used to conduct several tests to evaluate the viability of neural elements of the auditory nerve. Promontory stimulation instruments are available for the various cochlear implant systems in use throughout the world. Procedures The measures which are most likely to be used during promontory testing include the following: (1) electrical stimulation threshold; (2) electrical stimulation comfort level; (3) frequency discrimination; (4) temporal discrimination, and (5) neural adaptation. Electrical stimulation threshold is determined by carefully increasing the output current until the patient can consistently detect the signal. Pulsed signals are usually easier for the patients to detect, especially if they have any tinnitus. Control presentations without a signal and having the patient count signal presentations can help the clinician to verify responses during promontory testing. Comfort level is established by providing the patient with a clear explanation of a loudness scale such as: 0> signal is not detected ; 1> first hearing or sensation, very soft (threshold); 2> soft ; 3> medium ; 4> loud & comfortable and 5> too loud. This is a simple loudness scale that can be used with a graphic presentation of the scale which enables the patient to track the relative loudness of presented signals with their finger. It is important to make sure that the patient s responses and perception are clearly understood by the clinicians. It is possible for patients to perceive nonauditory sensations, Shallop 86

205 Fig. 1. Mean PROM stimulation thresholds from a group of 550 adult deaf patients and adult patient (LN) illustrate the increasing current required to establish threshold as the frequency of the pulsatile stimuli are increased from 50 to 1,600 Hz. The normative data for this illustration are used with the permission of Battmer [1994]. such as pain perception down into the neck. Such nonauditory responses must be carefully evaluated. In some instances, it may be necessary to have the promontory electrode moved closer to the round window to eliminate these nonauditory sensations. Figure 1 shows some typical responses which may be expected with the Cochlear Corporation Promontory Stimulator. The mean thresholds 1SD are illustrated for the octave pulse rates between 50 and 1,600 Hz for preoperative testing on 550 adult cochlear implant candidates seen for evaluation at the Cochlear Implant Clinic of the Medizinische Hochschule in Hannover, Germany [Battmer, 1994]. The individual results for a 35- year-old male (LN) with a profound sensorineural hearing loss are shown in comparison to the Hannover normative data. Note how the threshold levels increase as the frequency increases. As mentioned above, occasionally patients will report nonauditory sensations during promontory testing. These sensations may include mild pain from the tympanic plexus on the promontory. In this case, the stimulating electrode should be moved closer to the round window which may reduce these sensations. Additional nonauditory responses have been observed in patients with congenital deafness and long-term acquired deafness. These responses may include sensations of dizziness and/or tingling sensations, typically in the arms, chest or head. Such sensations are probably false interpretations by the brain since the person lacks adequate auditory memory to associate with the electrical stimulation of the auditory nerve. When these responses occur, it can be difficult to distinguish valid responses for false-positive responses. Clinicians must be careful and certain about reporting no response. They must make certain that the electrodes have continuity and that there is in fact The Audiological Management of Cochlear Implant Patients 87

206 a signal being presented from the instrument output. An oscilloscope can be used to monitor the output of the promontory stimulator. If these technical points are assured, then the absence of a response may be factual across the range of current and frequencies available with the instrumentation used during testing. The absence of a promontory response is generally considered to be a definite contraindication for cochlear implantation. When doubt exists regarding behavioral promontory testing or when the patient is too young to use the procedure, then additional objective procedures may be required. These points will be described later in this chapter. In general it has been observed that low PROM thresholds and wide dynamic ranges correlate with speech recognition in adult cochlear implant patients [Fritze and Eisenwort, 1988; Kileny et al., 1991]. Frequency discrimination task results can assure the clinician that the patient is perceiving true auditory sensations from the electrical signals. Paired comparison presentations or alternative forced-choice paradigms of different frequencies at comfort level should be given to the patient with adequate randomization. If the patient is capable of distinguishing between paired presentations and effectively ranks 3 or 4 frequencies (e.g Hz), this should be considered as a favorable finding for implantation. Temporal discrimination tasks might include the measurement of gap detection between paired signal bursts and burst duration difference limens. The gap detection procedure is conducted with the presentation of control and gap signals. The total signal duration is constant for the control no gap and the measured gap conditions. Gap detection and burst duration discrimination tasks are hypothesized to relate to the number of surviving neural elements of the auditory nerve and potential benefits from a cochlear implant, but this correlation has not been firmly established [Hochmair-Desoyer and Klasek, 1987; Skinner, 1989]. For a good summary of temporal processing in persons with cochlear implants, see Shannon [1990]. Adaptation testing of electrical stimulation should be considered for all patients with suspected retrocochlear pathology, which could negatively affect the ultimate successful use of a cochlear implant. This test is conducted in the same manner as an auditory tone decay test, which is familiar to audiologists. The electrical stimulation should be presented at comfort level for one or more frequencies for 1 min. The patient should be able to continue to hear the signal without significant adaptation. If adaptation is noted, careful consideration regarding etiology should be considered before the final decision regarding implantation. If adaptation is ignored by the clinicians, the patient may be expected to experience adaptation of speech signals with their cochlear implant. Shallop 88

207 Promontory Electrode Impedances Promontory electrode impedances may need to be measured preoperatively, intraoperatively or postoperatively. A constant low level measurement current at a specific frequency (e.g. 30, 100 Hz) is applied to the active electrode which is referenced to a ground electrode. From the voltage applied to maintain the constant current, the impedance is measured using Ohm s law, E>I R (voltage equals current times resistance). The current to check electrode impedances must be kept very low (=5μA) in order to not produce auditory sensations. Instrumentation The clinician needs to be certain that the equipment used to measure electrode impedances produces safe levels of current which are used for the measurements. For example, a commercial promontory unit can produce very low current levels (e.g. 1 μa) that cannot be detected when the promontory needle electrode impedance is tested. However, other impedance meters or evoked potential systems used for checking surface electrode impedances may produce current levels which are easily detected and may in fact be uncomfortable or painful to the patient during transtympanic promontory testing. The impedance measurement circuit of an evoked potential system is typically designed for surface electrodes and may produce constant current which exceeds 10 μa. Such levels may produce detectable to uncomfortable sensations for some patients. Thus there is an advantage of using a promontory device as described above since the clinician can set the exact measurement current very low (1 μa) during the impedance check. Procedures The measurement of electrode impedance is a useful test to verify the function of specific electrodes in a cochlear implant. This procedure is possible in a hardwired device such as the Inneraid (Cochlear Corp.) and in a transcutaneous system such as the Clarion (Advanced Bionics) and Med-El devices. The Inneraid device uses a small impedance meter which can be used to safely check electrode impedances while the patient is awake or asleep. The Clarion and Med-El systems use reverse telemetry to receive measurements back from the internal device including all paired combinations of electrode impedances. This type of telemetry measurement is very useful and it is likely to be used in most cochlear implant devices developed in the future. For this procedure, the patient can be asleep or cooperatively awake. The Audiological Management of Cochlear Implant Patients 89

208 Electrode Voltages Electrode voltages are measured from surface electrodes placed on the head to optimize the measured voltages resulting from activation of the cochlear implant. Typically the recording electrodes are placed on the ipsilateral mastoid (reference the implanted ear) and on the forehead. A ground electrode can be placed on the opposite mastoid. Instrumentation Surface disk recording electrodes are taped to the mastoid of each ear and a ground electrode is placed on the forehead. These electrodes are connected to an isolation biological amplifier with a gain of about 10,000. The output signal from the amplifier is then connected to an oscilloscope (battery-powered for electrical isolation and safety). It is helpful to use an external trigger signal to synchronize signal presentation from the cochlear implant with the oscilloscope. The cochlear implant is then activated with an appropriate test signal and the device output or stimulation artifact can be measured on the oscilloscope. In this manner, any cochlear implant device can be checked as it is activated. Procedures The cochlear implant should be activated with a low-level signal which can then be gradually increased. From normative studies, the characteristics of the expected waveforms can be anticipated. The advantage of this procedure is that it is simple and requires minimal equipment to obtain the response waveforms. The disadvantages of this technique include the difficulty to measure the low-level signals from apical bipolar electrodes and testing children who are not fully cooperative, since movement (muscle potentials) can make it difficult to measure the responses. Averaged Electrode Voltages Averaged electrode voltages (AEVs) employ signal averaging to improve the recordings of stimulation artifact and has been referred to as averaged surface potentials or averaged electrode voltages. This enables the measurement of responses to as low as 10 μv [Heller et al., 1991; Shallop 1993a, b; Shallop et al., 1993; Almqvist et al., 1993; Mens et al., 1993, 1994a, b; Mahoney and Rotz Proctor, 1994; Peterson et al., 1995]. Shallop 90

209 Fig. 2. A schematic diagram illustrates the equipment used to record averaged electrode voltages. Surface electrodes are the input to a clinical evoked potential system which averages the voltages generated by the biphasic stimulation of specific electrodes of the Nucleus Mini- 22 cochlear implant. The implant is activated by the clinical Diagnostic Programming System (DPS) and appropriate software (DPS version 6.90) installed on an MS-DOS compatible computer. The output of the computer is from an interface card (IF3 or IF4) to a speech processor (wearable speech processor, WSP III or mini-speech processor, MSP or Spectra 22). The signal from the speech processor is conducted to a transmitting coil which transfers the signal to the internal receiver stimulator. Instrumentation Recording electrodes are taped in place at each mastoid tip; active positive on the implant side and a negative reference at the vertex (Cz) or on the forehead at FPz. A ground electrode is placed on the opposite mastoid. The mastoid to vertex placement of the electrodes assures that a large response will be obtained during activation of the implant. Intraoperative recordings during cochlear implant surgery utilize subdermal needle electrodes, taking care to avoid contamination of the surgical field by placing the positive electrode in front of the tragus. The surface recording electrodes serve as the input to a clinical evoked potential system as shown in figure 2. This figure shows the electrode montage as ipsilateral mastoid to the opposite mastoid. Analysis parameters should be selected to minimize distortion and this includes the placement of the active electrodes at the mastoid and vertex if possible, rather than mastoid to mastoid. The evoked potential system should be configured to be triggered externally by the control signal from the implant-programming system. Typical evoked potential system settings include: preamplifier sensitivity of 1 mv, The Audiological Management of Cochlear Implant Patients 91

210 Fig. 3. The biphasic negative phase leading ouput current of the Nucleus cochlear implant is shown along with the typical AEV patterns which are typically observed. The upper trace is the negative leading charged-balanced output. The middle trace is a surfacerecorded AEV, also negative leading. The lower trace shows the phase inversion which is sometimes observed on middle and apical electrodes. bandpass filtering of 1 10,000 Hz, analysis time of 10 ms and external averager trigger. The number of averages necessary will be dependent on the state of the patient. Procedures When patients are quiet or asleep, 25 averages will usually be adequate, which takes about 1 s/electrode. However, when the patient is awake and movement artifacts are likely, more averaged samples will need to be obtained. For the Nucleus cochlear implant, electrodes can be activated using the standard computer interface system for this device; a PC computer with the Cochlear Corp. MSP interface card (IF4), dual processor interface (DPI) and a mini-speech processor (MSP) or a Spectra 22 speech processor. The output of the speech processor is connected to the patient s headset (HS6) or a test headset (HS7). Stimulation parameters of the Diagnostic Programming Software (DPS) should be stimulation mode BP+1, pulse width 200 μs/phase, current level 126, pulse rate 250 Hz, stimulation on time of 1,000 ms and stimulation off time of 1 ms. This combination of stimulation parameters will result in a continuous pulse train at 250 Hz at a current of approximately 300 μa peak. In a few instances, this current may be above the patient s behavioral comfort level. In this instance, measurements can be obtained at comfort level for these electrodes. The output from the implant is a negative leading charge-balanced biphasic waveform. Shallop 92

211 Fig. 4. AEV responses from the 20 active electrodes of an adult Nucleus cochlear implant patient (DW) are illustrated. Stimulation was at a current of 300 μa at the rate of 250 pulses/s. Stimulation mode was BP+1. Note the variations in the AEV amplitudes for each of DW s electrodes. The amplitudes of these responses ranged from about 20 to 75 μv. Phase reversals and 2 null points (electrodes 9 and 17) are described in the text. Case Examples Figure 3 demonstrates the waveforms of the stimulation current, the expected normal AEV and an inverted AEV. Inverted waveforms are quite typical from the mid to apical electrodes of the Nucleus device when the stimulation mode is BP+1. The averaged waveforms typically show a slight distortion resulting from the capacitive effects of the stimulating electrodes. Each electrode can be tested in sequence, e.g. from base (electrode 1) to apex (electrode 20). This sequence is preferred since the largest responses will be obtained from the basal electrodes in bipolar modes. Total testing time will be typically 5 10 min. With an automated acquisition program on the evoked potential system, the testing time can be reduced. AEVs measured in CG The Audiological Management of Cochlear Implant Patients 93

212 Fig. 5. The mean and 1SD of the peak-to-peak amplitude of the averaged electrode voltages (AEV) are plotted for each electrode for 30 adult normative subjects. All responses were obtained with a stimulation current of 300 μa peak (pulse width>200 μs, current programming level>126) at a pulse rate of 250 Hz. Response amplitudes were measurable from about 1 μv on apical electrodes to the maximum values we observed on some basal electrodes of 700 μv. The response amplitude variability was the greatest in the basal region of the cochlea [Shallop, 1993a]. often demonstrate distorted waveforms due to the difference in phase 1 vs. phase 2 volume conduction of the electrode voltages. The stimulation rate of 250 Hz results in two measurable waveforms within the 10-ms analysis time since the interstimulus interval is 4 ms. Figure 4 shows the AEV responses for the 20 active electrodes in mode BP+1 for an adult cochlear implant patient (DW), who has a full insertion of all active and stiffening rings of the Nucleus Mini-22 cochlear implant. This patient lost his hearing as the result of cochlear otosclerosis and head trauma. The AEV waveforms for this patient illustrate normal and abnormal morphology. Electrodes 1 8 show a series of negative leading (noninverted) responses that vary in amplitude from base to apex. Typically the AEV amplitudes in BP+1 decrease consistently from base to apex since the current flows between paired electrodes which are successively deeper into the cochlea. The volume-conducted electrode voltages from each stimulated pair of electrodes must then flow out of the cochlea, presumably via the round window, to the surface recording electrodes. In the case of DW, the AEVs are phase inverted from electrode 10 to 16. The AEVs for electrodes return to negative leading waveforms. Note the voltage nulls of the AEVs for electrodes 9 and 17 where the phase reversals occur. This unusual AEV series for patient DW most likely results from the etiology (otosclerosis) of his deafness as pointed out by Mens et al. [1994b]. Shallop 94

213 Fig. 6. Stimulogram AEVs are shown for a fixed mode of stimulation using the most basal electrode (E1) as the indifferent electrode for all other electrodes. Stimulation current was fixed at about 35 μa. Note that the AEVs increase in amplitude from basal to apical cochlear stimulation sites in contrast to the BP+1 AEVs summarized in figure 5. These AEVs were obtained from an adult cochlear implant patient (Nucleus 22 channel) who had a complete insertion of all active electrodes. Stimulation parameters were: rate>700 Hz, amplitude of current level>20 (35 μa), pulse width>200 μs/phase. Acquisition was for 400 averages with the preamplifier filtering set at 1 10,000 Hz. Special thanks to the authors for the preparation and use of this figure [Almqvist et al., 1993]. The summarized BP+1 AEVs for 30 adult Nucleus cochlear implant patients are shown in figure 5. The mean 1 SD deviation of the peak-topeak amplitude of the AEVs are plotted for each electrode. Response amplitudes were measurable from about 5 10 μv peak on apical electrodes to the maximum values we observed on some basal electrodes of 700 μv peak. Note that response variability is greatest in the basal region. The small amplitude apical responses obtained in the BP+1 mode can be enhanced by another AEV technique as described by several authors [Mens et al., 1993; Almqvist et al., 1993; Heller et al., 1993]. In this technique, each active electrode is paired with a single or a series of fixed electrodes, e.g. electrode 1. The procedure can also be repeated with the next fixed electrode, e.g. electrode 2, etc. This technique causes the current to flow toward the fixed indifferent electrode (e.g. electrode 1) from each of the other electrodes (2 22). An example of the AEVs using the technique of Almqvist et al. [1993] is illustrated in figure 6. They The Audiological Management of Cochlear Implant Patients 95

214 Fig. 7. AEVs are shown for an Inneraid cochlear implant user. The AEVs demonstrate the results from a defective cable for the speech processor to the connecting plug. The AEVs were obtained by pairing each electrode (1 6) to an extracochlear electrode (8). In this monopolar configuration, stimulation current was set at 65 μa, pulse width at 400 μs/ phase and rate at 250 Hz. The AEV for electrode 1 (trace M1) had an amplitude of 1.13 mv and the AEV amplitude for electrode 5 (trace M5) was 1.56 mv. Note the abnormal AEV morphology for electrode 6 (trace M6) and reduced amplitude. refer to this technique as a Stimulogram since it represents the sequential stimulation of electrodes 1 22, always paired with electrode 1 as the indifferent. Thus electrode 1 is tested in CG since it is connected to all electrodes as CGs when the default-indifferent electrode is specified as electrode 1 for the active electrode 1. Thus by using a low level of current (35 μa in this example), welldefined AEVs can be obtained quickly from each electrode. Obviously the fixed indifferent electrode must be functional for this procedure to be effective. Mens et al. [1993] pair all electrode combinations which makes electrode problems very apparent in their three-dimensional graphic presentation showing the amplitude and leading phase of each response waveform. Examples of AEVs recorded from an Inneraid cochlear implant are shown in figure 7. These AEVs from an adult patient (KE) were recorded from the most apical electrode (1) to the remaining intracochlear electrodes 2 6. Each electrode was paired in a monopolar configuration to extracochlear electrode 8. KE had reported poor sound quality as a recent complaint but she had not experienced this problem previously. Her electrodes were activated with a6-μa pulse train at 250 Hz. Amplitudes of her AEVs were large ranging from 1.13 mv (electrode 1) to 1.56 mv (electrode 5). Note that the AEV for Shallop 96

215 electrode 6 has abnormal morphology and low amplitude (0.35 mv). This fault was traced to an intermittent cable from the speech processor. Additional Acquistion Parameters There are some additional acquistion parameters which should be highlighted at this point since they can have the effect of distorting AEVs. Effects of Amplifier Gain. It is important to use the proper level of preamplifier gain when assessing AEVs. We typically set the preamplifier gain at a sensitivity of 1,000 μv (gain>2,400). This gain is usually adequate to measure AEVs?100 and =1,000 μv. If the AEVs exceed 1,000 μv, then we suggest that the amplifier sensitivity must be reduced to avoid peak clipping. If the AEVs are =100 μv, the amplifier sensitivity should be increased to better resolve the waveforms. Amplifier Bandwidth Effects. AEVs can be easily distorted by using a restricted preamplifier bandwith (e.g ,000 Hz). The use of a wide amplifier bandwidth will reduce distortion of the waveforms. For our normative and clinical studies, we have consistently used 1 10,000 Hz as our recording bandwidth. We have also measured the effects of systematically changing the amplifier bandwidth for adult cochlear implant patients with complete insertion of all active electrodes and stiffening rings. These results demonstrated that high-frequency cutoffs of =3,000 Hz and low-frequency cutoffs?30 Hz will distort AEVs. These distortions include asymmetric biphasic AEVs and reduced peak-to-peak amplitudes. We recommend that a wide bandwidth should always be used without the use of a notch filter. Postmeasurement digital filters or smoothing can be used to selectively eliminate some interference signals but usually this is not necessary in most situations. We occasionally encounter high-frequency interference when recording AEVs intraoperatively which can be filtered out posthoc. Recording Electrode Montages. The largest AEV amplitudes will be obtained using an ipsilateral to Cz recording montage. When the inverting electrode (Ö) is moved from Cz to FPz there will be about a 10% reduction in the AEV amplitudes. An additional 10% amplitude reduction will result from moving the inverting electrode to the contralateral mastoid. Effects of Radiofrequency (RF) Interference. When the measured AEVs are very small (=10 μv p-p), or when recording electrodes and leads are close to the headset cable of the transmitting cable of a cochlear implant, artifact signals from the RF transmission carrier to the implant receiver-stimulator can interfere with the recorded waveforms as shown in figure 8. The RF signal used to transmit data instructions can be blocked by an RF-blocking filter between the surface recording electrodes and the evoked potential system The Audiological Management of Cochlear Implant Patients 97

216 Fig. 8. The transmission of the RF signals of a cochlear implant can result in a variety of unusual AEV waveform morphologies. Trace A shows a normal, biphasic AEV waveform. Traces B and C show RF distorts which may occur when RF filtering is not used or when the recording electrode leads are in close proximity to the headset cord. preamplifier or by an RF filter built into the headbox or preamplifier. Rectification of the RF signals can result in a variety of unusual AEV waveform morphologies as shown in figure 8. Trace A illustrates a normal AEV. Placement of the recording electrodes too close to the transmitter coil produced trace B. An increase in the stimulation current level on a more apical electrode produced trace C. Since the RF signal level effects can be influenced by the relative positions of the headset cord and the recording electrode leads, it is essential that the input of the evoked potential system have RF filtering to exclude the RF transmission picked up by the recording electrode leads. Without filtering, this RF interference will often distort and/or obliterate the AEVs. Effects of CG Mode. Since some clinicians may prefer to program young children in CG mode, AEVs could also be measured in CG mode. However, it must be stressed that this mode can distort AEVs. A CG stimulation mode in any cochlear implant system will cause significant distortion AEV waveforms. Whereas in bipolar modes, the current path is more restricted between the active and indifferent electrodes. It is always recommended to use wide bipolar modes of stimulation with a basal electrode as the indifferent electrode when assessing AEVs. If CG is used, the results must be compared to results from a bipolar mode. Summary of AEV Testing. Although various stimulation modes can be used to measure AEVs from a multichannel cochlear implant, the use of a basal or extracochlear electrode is recommended as the indifferent electrode. When this monopolar technique is used, AEV amplitudes will increase proportionally to the width of the stimulation mode. The AEV amplitudes from the Shallop 98

217 apical electrodes are significantly larger in these modes at a stimulation current of 65 μa in comparison to the AEV values of the apical electrodes obtained in BP+1 at a current of 300 μa. Thus we now prefer to use the widening bipolar modes for the measurement of AEVs rather than BP+1 [Shallop, 1993a; Shipp et al., 1993; Mahoney and Rotz Proctor, 1994] or CG as recommended by Kileny et al. [1995]. AEVs provide valuable information regarding specific electrode functioning as well as the operation of the internal receiver and stimulator device. A clinical evoked potential system enhances results through the averaging of electrode voltages. AEVs can be measured easily from children and adults intraoperatively or as a postoperative test whenever device or electrode failure is suspected. The Electrical Stapedius Reflex Another objective procedure which can be used to help confirm behavioral response levels is the ESR. The stapedius reflex to sound has been used in clinical audiology to predict hearing levels, slope of hearing loss and hearing-aid settings. Its use with cochlear implant patients can be useful as long as the reflex is intact. Several authors have noted that this response may be absent in as many as 25% of cochlear implant patients [Jerger et al., 1988; Battmer et al., 1990; Hodges, 1996]. The primary use of the ESR with cochlear implants to date, has been to predict comfort level settings for the speech processor [Jerger et al., 1986; Battmer et al., 1990; Spivak and Chute, 1994]. Instrumentation The ESR can be elicited with a promontory needle electrode or through electrodes of a cochlear implant. Electrical stimuli are presented from a promontory stimulator for the promontory needle technique or from the computeractivated speech processor of an implant system. The signal is typically a burst of 250 1,000 ms at a specific pulse rate (e.g. 200 pulses/s) within the burst. An appropriate duty cycle (e.g. 50%) provides adequate time for the ESR to recover and makes identification of the response easier. An electroacoustic impedance bridge is connected to the patient in the same manner as used for acoustic reflex measurements. The contralateral ear is typically used in preference to the ipsilateral ear. The instrumentation should include an output recording device (e.g. strip chart or computer) which enables the clinician to easily observe the responses. Computer averaging of the responses can also be utilized. The Audiological Management of Cochlear Implant Patients 99

218 Fig. 9. The correlation (r>0.85) between ESR threshold and programming electrical comfort level is evident in this figure. These measures were obtained from adult (n>17) Nucleus cochlear implant users. The ESR was determined by three different methods (see text for additional explanation). Procedures The time needed is minimal from a cooperative or sedated patient. If patients are to be tested with this technique intraoperatively, the patient must not be paralyzed with muscle relaxants which would inhibit the reflex arc of the stapedius muscle. The ESR shows amplitude growth and at amplitude saturation, the ESR has been suggested to be indicative of behavioral comfort levels. However, as with any electrophysiological technique, an absent response must be interpreted with caution. Jerger et al. [1986] reported a technique to elicit and average the ESR from a multichannel cochlear implant patient. They obtained the ESR from several electrodes and demonstrated its amplitude growth. They suggested that an initial dynamic for speech processor current range for a specific electrode may be predicted based on ESR measures on that same electrode. The saturation level of the ESR correlated well with this patient s preferred loudness level. Hodges [1996] reported the results of her investigation of 6 cochlear implant patients and correlated their ESR threshold with comfort level in programming units of their Nucleus implant. She measured the ESR on at least three electrodes per patient, using the same type of stimuli for both measures including stimulation mode, pulse rate and pulse width. Her results demonstrated that the current level needed to elicit the ESR was strongly correlated (r>0.91) with the comfort level settings of their speech processor program. The results of our own experience is summarized in figure 9. Our results were obtained using three methods of determining the patient s comfort level: adjustments by an audiologist (A), self-adjustments with the computer keyboard by the patient (S) and self-adjustments using a continuous turning Shallop 100

219 knob control by the patient (K). All three methods had a strong correlation (r>0.85) with the contralateral ESR [Shallop and Ash, 1995]. In another ESR study, Battmer et al. [1990] investigated the amplitude growth function of the ESR in 25 patients with the Nucleus 22 channel cochlear implant. They varied the stimulation mode from BP+1 to BP+3. The amplitude growth function shifted as the mode of stimulation was widened from 1.5 to 2.3 and 3.1 mm (BP+1, BP+2 and BP+3, respectively) and tended to saturate near the comfort level in programming units in the same stimulation mode. Their findings are in agreement with typical behavioral findings with the Nucleus device, i.e. as the stimulation mode widens, threshold and comfort levels generally decrease. They also reported that they were able to elicit the ESR in 76% of their patients studied. The absence of the ESR in some patients may be the result of inadequate current levels and/or the number of surviving nerve fibers of the VIIIth nerve. Middle ear pathology in the recording probe ear must be considered whenever the ESR is absent. Intraoperatively, the ESR may be influenced by anesthetic agents [Gnadeberg et al., 1994]. Electrically Evoked, Whole Nerve Action Potentials Electrically evoked, whole nerve action potentials (EAP) is a technique which has been developed primarily through the efforts of the cochlear implant program at the University of Iowa [Abbas and Brown, 1991]. It is difficult to record this response because the artifact from stimulation can easily overlap the short latency of the EAP which typically has a latency of =0.5 ms. The latency of the EAP (or wave I of the electrically evoked ABR (EABR) is shorter than the acoustically evoked ABR because the transmission and transduction properties of the middle ear and the inner ear have been bypassed. Instrumentation This technique requires customized equipment in order to present biphasic current pulses using a forward masking paradigm [Abbas and Brown, 1991]. The Abbas and Brown EAP procedure is an adaptation of the procedure developed in animal research by Charlet de Sauvage et al. [1983] which eliminates stimulus artifact using a subtraction technique. Through the use of this technique a residual response of the EAP elicited by the biphasic current probe provides a measure of response from the electrically stimulated auditory nerve. The Audiological Management of Cochlear Implant Patients 101

220 Fig. 10. An example of an EABR response for adult SG is shown for an apical electrode (E20) which was stimulated in a BP+1 mode using biphasic electrical pulses through a Nucleus cochlear implant at the rate of 17/s. Current level was the patient s comfort level for this slow rate stimulation. The patient was awake and relaxed during these recordings. A blanking amplifier was used to reduce stimulus artifact for these ipsilateral EABR tracings. Procedures Extracochlear stimulation is achieved by placing a ball electrode in the niche of the round window. Intracochlear stimulation is accomplished through the hardwired Inneraid cochlear implant electrode. In both instances, the subtraction technique enables the measurement of the EAP amplitudes in response to varied current levels and interpulse intervals. Biphasic current pulses are presented and the EAP is recorded from the same extracochlear ball electrode or from a separate electrode pair of the intracochlear Inneraid device. The resulting EAP is the compound action potential (N1 response) of the auditory nerve. To date, this technique has not been reported as a procedure with other cochlear implant devices. However, Heller et al. [1996] recently reported a technique of neural response telemetry for an experimental cochlear implant. This technique would allow the recording of intracochlear potentials using back telemetry circuits built into a cochlear implant receiver stimulator. Shallop 102

221 Electrical Auditory Brainstem Response (EABR) Electrical auditory brainstem response (EABR) has been used by several investigators as a method to aid in device programming and to correlate with future benefits as measured by speech recognition scores. An example of an EABR tracing is shown in figure 10. This congenitally blind patient (SG) was 34 years old at the time of implantation of the Nucleus device. These EABR tracings were recorded ipsilaterally, i.e. on the same side as the patient s cochlear implant device. These tracings were recorded at the patient s comfort level for click stimuli presented at 10/s. It is unusual to record wave I in an EABR due to its short latency and interference from stimulation artifact. We have been able to record these responses by using a custom-built stimulus blanking amplifier (Cochlear Corp.). Instrumentation Recording electrodes are taped in place at each mastoid tip; active negative on the implant side and a negative on the forehead at FPz. A ground electrode is placed on the opposite mastoid. The mastoid placement of the negative (active, noninverting) electrode assures that a large wave I response may be obtained during activation of the implant. This placement also means that the stimulus artifact will be prominent unless it is cancelled electronically or blocked by temporal electronic switching. Intraoperative recordings during cochlear implant surgery utilize subdermal needle electrodes, taking care to avoid contamination of the surgical field by placing the negative electrode in front of the tragus. The recording electrodes serve as the input to a clinical evoked potential system (Nicolet Compact 4 or Nicolet Viking II), essentially the same instrumentation as shown in figure 2. When a blocking amplifier is used, it is placed in between the recording electrodes and the preamplifier. Analysis parameters of the evoked potential system should be configured to be triggered externally by the control signal from the implant programming system. Typical evoked potential system settings include: preamplifier sensitivity of 100 μv, bandpass filtering of 100 3,000 Hz, analysis time of 10 ms and external averager trigger. The number of averages necessary will be dependent on the state of the patient. When patients are asleep, responses may be adequate. If patients are awake, 2,000 3,000 responses may need to be averaged. Procedures For the Nucleus cochlear implant, electrodes can be activated using the standard computer interface system for this device; a PC computer with the Cochlear Corp. interface card (IF4), dual processor interface (DPI) and a The Audiological Management of Cochlear Implant Patients 103

222 mini-speech processor (MSP) or Spectra 22 speech processor. The output of the speech processor is connected to the patient s headset (HS6) or a test headset (HS7). Stimulation parameters of the Diagnostic Programming Software (DPS version 6.90) might be stimulation mode BP+1, pulse width 200 μs/phase, current level as indicated, pulse rate Hz, stimulation on time of 1,000 ms and stimulation off time of 1 ms. This combination of stimulation parameters will result in a continuous biphasic pulse train of electrical stimuli. It is important to make sure that the test signals are not too loud in awake patients. In this instance, measurements can be obtained at the psychophysical comfort level for the specific electrode pairs which are activated. The detection level of the EABR will typically correlate directly with the behavioral threshold measures for the same stimuli. The EABR thresholds will be higher than the speech processor thresholds [Shallop, 1993b] as a result of the known temporal integration functions for electrical stimulation. Hodges [1996] found a good correlation between EABR thresholds and programming thresholds. She also observed a correlation between electrical stapedius muscle thresholds and programming comfort levels on specific electrodes. She advocated a combined use of both electrophysiological methods to aid in the programming of difficult cases. Similar procedures and findings should be obtainable with various cochlea implant devices. Electrical Middle Latency Responses Electrical middle latency responses (EMLR) is another evoked potential which has been used with cochlear implant patients. This response has been recorded preoperatively using a promontory needle electrode or round window ball electrode, and intraoperatively or postoperatively from various cochlear implant devices. Instrumentation The instrumentation for the EMLR is essentially the same as for the EABR. However, there are a few equipment acquisition parameters which must be changed. Typical evoked potential system settings include: preamplifier sensitivity of 250 μv, bandpass filtering of Hz, analysis time of 80 ms and external averager trigger. The number of averages necessary will also be dependent on the state of the patient. When patients are asleep, responses may be adequate; however sleep stage will affect the amplitude of the EMLR quite dramatically. There are also known age-dependent maturational effects on the morphology and detectability of the middle latency responses. If patients are awake, more responses will need to be averaged. Shallop 104

223 Fig. 11. An example of an EMLR response for adult EM is shown. Stimulation was biphasic electrical pulses through a Nucleus cochlear implant at a rate of 9/s. The current level was equal to the patient s comfort level for the same stimuli. The patient was awake and relaxed during these recordings. The two tracings show good replication on successive trials of 1,000 sweeps. Note the EABR waveforms at the beginning of the tracings, waves III and V are evident. Procedures Surface disk or subdermal needle electrodes are typically placed at Cz (positive), ipsilateral mastoid (negative) and an appropriate ground electrode. Stimulation of specific electrodes is identical to the EABR procedures. However, the stimulation rate must be slow enough to present a single stimulation for each analysis period, e.g. 9/s when the analysis period is 80 ms. An example of an EMLR intensity series is shown in figure 11. These responses were recorded from an awake, relaxed adult using a Nucleus 22 channel cochlear implant. The stimulation was with biphasic click pulsatile stimuli. It is possible to also use longer stimulation bursts for EMLR procedures. Electrical Late Latency Responses Electrical late latency responses (ELLR) are the final group of evoked potentials to be discussed in this chapter. The cortical evoked potentials have had limited application with cochlear implant patients. However, in the past few years, there has been a renewed interest in studying these potentials with The Audiological Management of Cochlear Implant Patients 105

224 this patient population. This is especially true for the event related cortical potentials, the mismatch negativity (MMN) and the P300 responses. Instrumentation The instrumentation for cortical evoked potential studies includes an evoked potential system that is capable of having parameter settings to optimize the acquisition of these responses. In contrast to the settings for EABR and EMLR studies, ELLR techniques require longer analysis times and different preamplifier settings. The analysis time period for ELLRs should be adjustable in the range of 500 2,000 ms. The preamplifier gain can be reduced since the response amplitude of the ELLRs is times larger than the EABR. Filter settings need to be adjusted for the lower EEG spectral energy in the range of 1 40 Hz. Multichannel preamplifiers and processing are required for topographic brainmapping, usually channels depending on the equipment specifications. Procedures ELLR techniques are typically done only on awake patients. There can be some exceptions. Cortically evoked potentials are known to be dramatically affected by sleep stages. Stages 3 and 4 can especially interfere with and reduce cortical responses due to the large amplitude low-frequency EEG energy =10 Hz. Stimuli of ELLRs with cochlear implant patients can be generated directly from the interface system used to control and program the speech processor or stimuli can be presented soundfield. A simple technique for recording cortical event related potentials will be described to further illustrate the procedures for ELLRs. Event Related Potentials (ERPs) ERPS are a class of evoked potentials which are the result of unique stimulus paradigms, most commonly the odd-ball paradigm. The events of this paradigm are two different stimuli presented in a randomized sequence. One of the stimuli is presented as the frequent signal and the second stimulus, less frequently, as the rare stimulus. The evoked responses to the two contrasting stimuli are averaged in separate memories of an evoked potential system. If the stimuli are processed differently by the brain, the responses will be distinctly different. Some examples of these differences include the P300 response and the MMN response. A method to obtain ERPs for individuals using the Nucleus 22 channel cochlear implant will now be described. This method utilizes a simple twoelectrode program MAP in which specific electrodes will be stimulated at a precise current level. The odd-ball paradigm ERP requires a frequent stimulus Shallop 106

225 Table 1. Sample threshold (T) and comfort level (C) current levels are listed for 6 selected electrodes for a patient using the Nucleus 22 channel cochlear implant Electrodes E1 E5 E9 E13 E17 E21 T C The stimulation mode in this instance is bipolar. Each comfort level should be carefully assessed and balanced for loudness against the adjacent electrode(s). Sweeping all of the electrodes in both pitch directions at comfort level will assure the best possible agreement of equal loudness for the selected electrodes. The threshold level is then arbitrarily set to equal the current level of the comfort level. These values are then used to make a two-electrode map which is then activated by the output tones from an evoked potential system. This method assures discrete stimulation of specific electrodes for the oddball paradigms used to measure ERPs such as P300 and the MMN responses. and a rare stimulus which are presented in a specified ratio, e.g. 80% frequent and 20% rare. Tones presented soundfield from the evoked potential system can be used as the frequent/rare stimuli using the individual s regular program MAP. However, the activation of specific electrodes at the desired current level may be inaccurate and erratic as the speech processor codes the input tones. Our method utilizes a simple two-electrode MAP which will activate electrodes in response to puretone stimuli. The desired electrodes for stimulation are selected in the preferred stimulation mode using current level rather than stimulus level. If stimulus level is used, this introduces the additional variable of pulse width changes. The number of electrodes to be used may be as few as two and as many as all of the active electrodes. Each selected electrode is tested in psychophysics using the standard software (DPS version 6.90 or higher). We carefully assess and balance comfort level for each electrode. We then set the threshold (T) level at one current level below the comfort level (C). Table 1 illustrates sample T/C values that can be used for a sample ERP MAP for the Nucleus cochlear implant. It is apparent that activation of the selected electrodes in table 1 from any microphone or external input will be at comfort level since the dynamic range is zero for each electrode. The electrodes to be used as the frequent and rare stimuli are then selected by the experimenter, e.g. E1 as frequent and E21 The Audiological Management of Cochlear Implant Patients 107

226 Table 2. A sample MAP (bipolar mode) for ERPs was created using Cochlear Corp. DPS software version 6.90 using the T and C values listed in table 1 Active Reference T C Frequency electrode electrode boundaries E21 E ,400 E1 E ,401 4,000 The frequency boundaries have been adjusted to optimize the stimulation of the desired electrode in response to an acoustic microphone input to the speech processor (MSP or Spectra 22). In the create map (F5) section of the software, the frequency boundaries can be adjusted and in this case the F2 cutoff frequency was adjusted to 1,400 Hz to create this map. The coding strategy selected should be F0F2 which will then activate only one electrode for each tonal signal. In this example, a 500-Hz tone will activate apical electrode 21 and a 2,000-Hz tone will activate basal electrode 1. as rare. A MAP is then created in the desired mode, in this case bipolar as shown in table 2. The coding strategy typically used is F0F2 in order to assure that a single puretone signal will cause stimulation on a specific electrode at a known current level, comfort level in this example. In the example MAP, a 1,000-Hz tone will activate E20, and 3,000 Hz will activate E1. The parameters of the evoked potential system are then set for the desired frequent and rare acoustic stimuli; e.g. 1,000 Hz frequent and 3,000 Hz rare. An example of P300 and MNN responses are shown in figure 12. These responses were obtained from a 35-year-old male cochlear implant patient (SG) who is congenitally blind due to maternal rubella. SG is also congenitally hearing impaired and became profoundly deaf in his left ear 4 years prior to his cochlear implant surgery in May These ERP responses were obtained using the NeuroScience, Inc. Brain Imager. The averaged responses were also analyzed as color topographic images (not shown). The 32 surface electrodes were applied using an electrode cap (Electrocap) and input to the preamplifier and averaged. The acoustic (puretone bursts) output of the earphones from the evoked potential system (Neuroscience Brain Imager) was coupled to a small external input microphone for the speech processor. The external microphone was placed between the earphones and taping them together. The speech processor sensitivity control was set to 1 Shallop 108

227 Fig. 12. An example of an ELLR from cochlear implant patient SG is shown in to a series of odd-ball stimulations of apical electrode 20 as the frequent signal and mid-electrode 12 as the infrequent signal. These responses were obtained while SG was awake and alert. Stimulation was at SG s comfort level for a 50-ms signal having a pulse rate of 250 pps. Responses were obtained at 28 electrode sites with 4 being displayed (Pz, PO1, PO2 and OZ2). The frequent response waveform (F) shows a clear N1-P2 complex. The infrequent response (R) shows a strong P300 response at about 350 ms. The shaded area at about 200 ms is a MMN response. in order to produce consistent stimulation of the frequent and rare electrodes in the ERP MAP. We have observed that setting the sensitivity to typical use settings of a conventional MAP (sensitivity>3.5) produces spurious signals which are reported as two tones for each single stimulus. It is likely that the tone input can overdrive the input of the MSP. Thus by setting the sensitivity to the low value of 1 for the 80-dB earphone signals, cochlear implant patients The Audiological Management of Cochlear Implant Patients 109

228 report distinct signals equivalent to stimulation of these same electrodes in the psychophysics section of the DPS software. This method provides precise control for electrode stimulation of the Nucleus cochlear implant. Conclusion Cochlear implants have advanced considerably over the past 20 years. Levels of speech recognition without lipreading have improved so that typical adult cochlear implant users achieve sentence recognition scores of 70 80% and word recognition scores of 35 45%. Selected users may perform better than these scores, but at present, these are the values we use when counselling patients who are considering a multichannel cochlear implant. We do not know the full potential of children, but we should expect similar levels of speech recognition when parental and educational support are good. This chapter has discussed various objective procedures which can be used to assist in the management of cochlear implant patients. These methods are used in conjunction with good medical and audiological management of these patients. References Abbas PJ, Brown C: Assessment of the status of the auditory nerve; in Cooper H (ed): Cochlear Implants: A Practical Guide, chap 8. San Diego, Singular Press, 1991, pp Almqvist B, Harris S, Jonsson KE: The stimulogram; in Hochnair-Desoyer IJ, Hochmair ES (eds): Advances in Cochlear Implants. Wien, Manz, 1993, pp Battmer R-D: Electrical promontory thresholds and comfort levels for 550 patients at the Cochlear Implant Clinic of the Medizinische Hochschule in Hannover, Germany. Pers commun, July Battmer R-D, Laszig R, Lehnhardt E: Electrically elicited stapedius reflex in cochlear implant patients. Ear Hear 1990;11: Charlet de Sauvage R, Cazals Y, Erre JP, Aran JM: Acoustically derived auditory nerve action potential evoked by electrical stimulation: An estimation of the waveform of single unit contribution. J Acoust Soc Amer 1983;73: Fritze W, Eisenwort B: Zur Vorhersagbarkert des Ergebnisses nach Cochlearimplantation. HNO 1988; 36: Gnadeberg D, Battmer RD, Lüllwitz E, Laszig R, Dybus U, Lenarz Th: Der Einfluss der Narkose auf den intraoperativ elektrisch ausgelösten Stapediusreflex. Laryngorhinootologie 1994;73: Heller JW, Dillier N, Abbas PJ: Neural response telemetry. 3rd Eur Symp on Pediatric Cochlear Implantation, Hannover June Heller JW, Shallop JK, Abbas PJ: Cochlear implant assessment by averaged electrode voltages; in Hochnair- Desoyer IJ, Hochmair ES (eds): Advances in Cochlear Implants. Wien, Manz, 1993, pp Heller JW, Sinopoli T, Fowler-Brehm N, Shallop JK: The characterization of averaged electrode voltages from the Nucleus cochlear implant. IEEE Trans, Nov Hochmair-Desoyer IJ, Klasek O: Comparison of stimulation via transtympanic promontory electrodes, implanted electrodes and salt electrodes in the ear canal. Proc Int Cochlear Implant Symposium, Düren Hodges AV: Electrical middle ear muscle reflex: Use in cochlear implant programming. Proc 6th Symp on Cochlear Implants in Children, Univ. of Miami, 1996, p 61. Shallop 110

229 Jerger JF, Jenkins H, Fifer R, Mecklenburg D: Stapedius reflex to electrical stimulation in a patient with a cochlear implant. Ann Otol Rhinol Laryngol 1986;95: Jerger JF, Oliver TA, Chmiel RA: Prediction of dynamic range from stapedius reflex in cochlear implant patients. Ear Hear 1988;15: Kileny PR, Meiteles LZ, Zwolan TA, Tilian SA: Cochlear implant device failure: Diagnosis and management. Am J Otol 1995;16: Kileny PR, Zimmerman-Phillips S, Kemink JL, Schmaltz SP: The effects of preoperative electrical stimulability and historical factors on performance with multichannel cochlear implant. Ann Otol Rhinol Laryngol 1991;100: Mahoney MJ, Rotz Proctor LA: The use of averaged electrode voltages to assess the function of Nucleus internal cochlear implant devices in children. Ear Hear 1994;15: Mens HM, Oostendorp T, van den Broek P: Electrode-by-electrode mapping of cochlear implant generated surface potentials: (Partial) device failures; in Fraysse B, Deguine O (eds): Cochlear Implants: New Perspectives. Adv Otorhinolaryngol. Basel, Karger, 1993, vol 48, pp Mens HM, Oostendorp T, van den Broek P: Identifying electrode failures with cochlear implant generated surface potentials. Ear Hear 1994a;15: Mens HM, Oostendorp T, van den Broek P: Cochlear implant generated surface potentials: Current spread and side effects. Ear Hear 1994b;15: Peterson AM, Brey RH, Facer GW: Averaged electrode voltages used to identify nonfunctioning electrodes in cochlear implants: Case study. J Am Acad Audiol 1995;6: Shallop JK: Objective electrophysiological measures from cochlear implant patients; in Hochnair-Desoyer IJ, Hochmair ES (eds): Advances in Cochlear Implants. Wien, Manz, 1993a, pp Shallop JK: Objective electrophysiological measures from cochlear implant patients. Ear Hear 1993b;14: Shallop JK, Ash KR: Relationships among comfort levels determined by cochlear implant patient s selfprogramming, audiologist s programming and electrical stapedius reflex thresholds. Ann Otol Rhinol Laryngol 1995;104(suppl 166): Shallop JK, Kelsall DC, Turnacliff KA: Multichannel cochlear implant in children with labyrinthitis; in Hochnair-Desoyer IJ, Hochmair ES (eds): Advances in Cochlear Implants. Wien, Manz, 1993, pp Shannon RV: A model of temporal integration and forward masking for electrical stimulation of the auditory nerve; in Miller JM, Spelman FA (eds): Cochlear Implants: Models of the Stimulated Ear. New York, Springer, 1990, pp Shipp DB, Murad C, Nedzelski JM: Test-retest reliability of averaged electrode voltage measurements with the Nucleus 22-channel cochlear implant; in Hochnair-Desoyer IJ, Hochmair ES (eds): Advances in Cochlear Implants. Wien, Manz, 1993, pp Skinner MA: Relation between pre-operative electrical stimulation and post-operative speech recognition performance with a cochlear implant. Annual Conference of the New Zealand Audiological Society, Hamilton Spivak LG, Chute PM: The relationship between electrical acoustic reflex thresholds and behavioral comfort levels in children and adult cochlear implant patients. Ear Hear 1994;15: Jon K. Shallop, PhD, Director of Research and Clinical Services, Denver Ear Institute, 799 East Hampden Ave 520, Englewood, CO (USA) The Audiological Management of Cochlear Implant Patients 111

230 Alford BR, Jerger J, Jenkins HA (eds): Electrophysiologic Evaluation in Otolaryngology. Adv Otorhinolaryngol. Basel, Karger, 1997, vol 53, pp Electroneuronography J. Michael Dennis a, Newton J. Coker b a Department of Otorhinolaryngology, University of Oklahoma College of Medicine, Oklahoma City, Okla., and b Department of Otorhinolaryngology and Communicative Sciences, Baylor College of Medicine, Houston, Tex., USA Facial Electroneuronography Facial electroneuronography (ENoG) is one in a family of electrodiagnostic tests available for the clinical evaluation of the patient with acute facial nerve paralysis. Procedurally, this test is performed by applying percutaneous electrical stimulation to the facial nerve in order to produce a recordable compound muscle action potential (CMAP) in facial musculature. In general, a supramaximal stimulus (a current threshold exceeding that level necessary to produce a maximal CMAP response), delivered via bipolar electrodes, generates an electrical field in the tissues surrounding the nerve which is sufficient to alter its membrane permeability and recruit available fibers for synchronous depolarization. The resultant whole nerve action potential transmits the distal course of the motor axons to innervated muscle endplates. The endplates release neurotransmitter (acetylcholine) which opens calcium channels to produce muscle action potentials and contraction of facial muscle fibers. Suitably arranged bipolar electrodes record this bioelectric event as an orthodromic compound muscle action potential or ENoG response. The comparison of ENoG recording amplitudes derived from the involved and noninvolved sides of the face provides an index of facial nerve degeneration. This concept is illustrated by figures 1 and 2. The purpose of these illustrations and related discussion is to introduce the concept of ENoG as a test of facial nerve integrity. A more detailed presentation of rationale, procedure, and interpretation of ENoG will follow later in the chapter. Figures 1 and 2 assume that supramaximal electrical stimulation is delivered separately to the main trunk of each facial nerve. ENoG is recorded by means of bipolar electrodes situated over perioral musculature in these

231 Fig. 1. Facial nerve testing by means of ENoG. The schematic illustrates percutaneous electrical pulse stimulation of the nerve, locations of stimulating and recording bipolar, surface electrode pairs, and bilateral CMAP waveforms of normal latency and peak-to-peak (absolute) amplitude. particular examples. The evoked ENoG response (CMAP) presents as a diphasic potential several milliseconds after stimulation. Amplitude in microvolts and latency in milliseconds are plotted, respectively, on the ordinate and abscissa of the graph. The amplitude result from one side is compared to the other and the quantified difference is the determinant of normal/abnormal outcome. Figure 1 shows symmetrical ENoG responses when right and left sides are compared. Figure 2, on the other hand, shows the left ENoG amplitude diminished when compared to the opposite side. The interpretation of these findings could be that fewer, functional facial nerve fibers were available for recruitment from the left versus the right side (fig. 2) while an equivalent Electroneuronography 113

232 Fig. 2. Facial nerve testing by means of ENoG. The schematic illustrates percutaneous electrical pulse stimulation of the nerve, locations of stimulating and recording bipolar, surface electrode pairs, and CMAP waveforms. The response from the right side is normal in peak-to-peak amplitude. The response from the left side has reduced peak-to-peak amplitude. number of fibers were available, bilaterally, for the example in figure 1. Moreover, a general clinical interpretation would be bilaterally normal ENoG (fig. 1) and abnormal left ENoG (fig. 2), i.e. findings consistent with nerve degeneration. Terminology ENoG and electroneurography have been used to describe this particular test of facial nerve function. These terms imply that ENoG, as a procedure, records activity directly from the facial nerve. In reality, the ENoG response results from direct measurement of muscle (myogenic) potentials that occur subsequent to an electrically stimulated facial nerve. Accordingly, the term Dennis/Coker 114

233 facial evoked electromyography (EEMG) also appears as a descriptor of the procedure and response. Facial EEMG is technically correct since the response is recorded from evoked muscle activity. The term, ENoG, however, has a more universal usage and acceptance. While admittedly inexact, the term is not particularly onerous, and is used commonly as the name of the test on an international basis. Facial Nerve Electrodiagnostic Testing The evaluation of muscular response to facial nerve stimulation is not new. One of the earlier reports describing electrical testing of the facial nerve appeared in the late 1800s. Duchenne [1] was one of the first to note that patients with facial paralysis who had visible but reduced muscular contractability from electrical stimulation were more likely to regain function than those who had no movement. Over the years a number of techniques have evolved to evaluate the electrical excitability of the facial nerve and several contemporary tests are available for this purpose. Chief among these are the minimal nerve excitability test (NET), the maximum stimulation test (MST) and ENoG. These procedures have features that are mutual as well as different. All three use percutaneous electrical stimulation to depolarize the facial nerve. NET determines the minimal electric stimulus (current level) in milliamperes as threshold for muscle contraction. MST and ENoG, however, use the concept of maximal excitability by delivering a derived superthreshold stimulation that presumably saturates the nerve for complete and synchronous depolarization. Test outcome for the three tests is determined by comparing the responses obtained from both sides of the face. NET and MST are, however, subjective in nature since the response is limited to visual detection and visual grading, respectively, of evoked muscle movement. ENoG is more objective because the evoked response is a permanently recorded bioelectric potential whose parametric characteristics can be quantified using an interval scale of measurement. NET, MST and ENoG have their particular advocates and each enjoys relative degrees of application as an electrodiagnostic test for facial nerve evaluation. ENoG is the newest of the procedures and has gained popularity because of the objectivity inherent in procedure as well as derivation and expression of outcome measures. Clinical Electroneuronography Fisch and Esslen [2] used intraoperative electrical stimulation of the facial nerve as a method to locate the site of the lesion producing conduction block in neuropraxic patients with Bell s palsy. They stimulated the nerve at the Electroneuronography 115

234 stylomastoid foramen as well as more proximal levels and recorded corresponding electromyographic (EMG) activity in distal facial muscles. The EMG results and their conclusions from observations of surgical pathology helped establish the transition zone between the meatal and labyrinthine segments of the facial nerve as the principal site of lesion in Bell s palsy. Importantly, the methodology used for electrical stimulation and distal recording of evoked EMG activity served as a precursor to the ENoG procedure. Esslen [3] introduced ENoG as an electrodiagnostic test to clinically describe the degenerative state of the facial nerve in cases of acute palsy by relating the number of motor fibers that are functional or neuropraxic to the number that are degenerating (axonotmesis). He contended that existing electrodiagnostic test results including those from electromyography were imprecise for reliable determination of three important factors: the proportion of degenerated nerve fibers; the endpoint of denervation, and, consequently, prognosis of recovery from facial palsy. ENoG, he concluded, overcame these difficulties with a clarity and precision which has not been previously possible. This seminal article outlined the essential features of the test including its name, purpose, procedure, interpretation and limitations. Esslen elaborated these features in following publications [4, 5]. However, his colleague Fisch is also largely responsible and properly credited for the early work that demonstrated the viability of ENoG as a test of facial nerve function [6 10]. Esslen and Fisch are recognized as pioneers in ENoG development and their separate and combined publications are alike with regard to test rationale and procedure. Consequently, their work concerning ENoG is combined and condensed for the reader in order to present the test as it was offered in its original format. The stated purpose of ENoG as a test of facial nerve function for acute facial palsy was to evaluate the status of the motor axon. Accordingly, it was proposed that recorded facial summation potentials or CMAPs be derived from both sides of the face and compared in terms of amplitude. Supramaximal electrical stimulation was thought necessary in order to stimulus saturate and, therefore, depolarize all available motor fibers. Surface recording electrodes were recommended to register the CMAP or ENoG response because intramuscular needle electrodes would not sample a sufficient number of motor units to yield a representative, i.e. maximal, amplitude. In their experience, ENoG recorded in the vicinity of the perioral (nasolabial) muscles was superior to responses from other areas of the face. The details of the Esslen-Fisch ENoG procedure are outlined in figure 3. The galvanic stimuli were specified as rectangular pulses with a duration of 200 μs and an interpulse interval of 1 s. These electrical pulses were delivered to the facial nerve by means of bipolar surface electrodes with a diameter of Dennis/Coker 116

235 Fig. 3. Esslen-Fisch ENoG procedure. The illustration depicts the electrical pulse stimulation pattern, locations of stimulation and recording bipolar, surface electrode pairs, electrode size and spacing distance within a pair and the evoked CMAP waveform. The stippled areas at the stimulating and recording sites represent approximated boundaries for small electrode pair position shifts to optimize peak-to-peak amplitude. 7 mm and an interelectrode centerpoint difference of 15 mm. The electrodes were encased in a plastic housing with tips exposed for skin surface contact. They were hand held and initially positioned so that the cathode was anterior to the tragus with the anode placed between the ascending ramus of the mandible and the mastoid tip in the vicinity of the stylomastoid foramen. The bipolar recording electrodes were identical to the stimulating pair in size, interelectrode distance and plastic encasement. They were hand held online in the nasolabial fold with the superior electrode just lateral to the nasal ala. When stimulating and recording electrodes were in place and registering low impedance values, the electrical stimulus was introduced and gradually increased to a point where there was no additional increment in CMAP amplitude on the oscilloscope. The stimulus intensity was then increased by 10% to achieve supramaximal stimulation and recruitment of all motor units. The CMAP amplitude and phase were maximized or optimized by small positional or pressure changes in stimulating and recording electrodes. Maneuvering Electroneuronography 117

236 Fig. 4. Method of calculating the percentage of degenerated facial nerve fibers. The ratio of the reduced peak-to-peak amplitude of the involved side (CD) to the peakto-peak amplitude of the noninvolved side (AB) expressed as a percentage, equals the number of fibers that are blocked for neural transmission at the site of injury but still able to be stimulated. The percentage of blocked or intact fibers subtracted from 100 equals the proportion of degenerated fibers. both sets of electrodes to attain maximal responses was referred to as optimized lead placement (OLP) by later authors. This concept of OLP is illustrated by the stippled areas surrounding the stimulation and recording points in figure 3. CMAPs obtained after the twentieth stimulus were accepted for measurement. This practice was thought to assure greater synchronization of action potentials and, hence, increased amplitudes. The CMAP response was graphically recorded and analyzed for amplitude. Figure 3 also shows the typical recorded ENoG with an initial positive peak followed by a negative peak. Amplitude was expressed as the calibrated distance in microvolts between the positive and negative peaks (peak-to-peak amplitude). An arithmetic manipulation of amplitude from both sides was proposed in order to provide a statistical assessment of the status of the nerve. It was hypothesized, in general, that the CMAP amplitude obtained by means of their test protocol was proportional to the number of activated facial muscle fibers. Consequently, any substantial decrease in CMAP amplitude due to nerve fiber degeneration was proportional to the number of denervated motor units or degenerated motor axons. This was concluded because degeneration of facial axons results in denervation of the motor muscle fibers corresponding to the motor units innervated by the nerve fibers. Procedurally, the peak-topeak amplitude of the paralyzed side was expressed as a percentage of the noninvolved side in order to quantitate the number of intact facial nerve fibers (figure 4). This number represented the proportion of axons still provocable Dennis/Coker 118

237 Fig. 5. Method of calculating the percentage of degenerated facial nerve fibers using actual numbers. Ratio of 1:10 100> 10% blocked fibers. This value subtracted from 100% equals 90% degeneration of facial nerve fibers. distally, although blocked at the point of injury for neural propagation. This value subtracted from the nonparetic side (assumed at 100% stimulable) indicated the number of degenerated fibers (fig. 5). On the basis of their vast experience using ENoG to evaluate patients with acute, complete facial paralysis, Esslen and Fisch concluded that the technique, while not perfect, adequately quantified nerve degeneration which related to prognosis for recovery of function when interpreted in the clinical context of the disease process. A good correlation was reported between degree of amplitude asymmetry and prognosis from Bell s palsy patients. They determined that less than 90% fiber degeneration within the nerve at 2 weeks from onset of paralysis indicated a good recovery of function for facial expression. In fact, the smaller the percentage of degeneration the better the chance for satisfactory recovery. On the other hand, greater than 90% degeneration corresponded to a severe injury and at least a 50% chance of poor recovery for these patients. It was also contended that the temporal evolution of degeneration elucidated by ENoG evaluation was important for prognosis. Serial ENoG begun after the fourth day of paralysis onset could profile the rapidity of degeneration. Patients with traumatic facial nerve injury having greater than 90% degeneration at days 5 or 6 would have a poorer chance for recovery of function than those who reached this point at 14 days. They noted instances where CMAP peak-to-peak amplitude remained reduced in some cases that attained good recovery of facial function. Latency and duration of the CMAP Electroneuronography 119

238 response were evaluated as indicators of facial nerve degeneration and recovery of function but were found to be clinically unreliable. These authors did not consider ENoG a de facto test, in the absolute sense, for differential selection of patients who needed an operation versus those who did not. It was an electrodiagnostic procedure whose results expressed a likelihood statement about functional return of facial movement and was to be interpreted in the context of the patient s condition, disease process and treatment. Esslen and Fisch presented ENoG as an electrodiagnostic test of facial nerve function that surpassed the existing methods. Like many newly introduced techniques, ENoG prompted considerable interest among clinicians especially otolaryngologists and audiologists. Many centers and practices began to use ENoG for the evaluation of acute facial paralysis. Appropriately, this clinical activity led to critical evaluation of the technique. In general, normal variability, prognostic ability and validity of the test were subjected to scrutiny. Interside Amplitude Differences in Normal Subjects The side-to-side CMAP amplitude difference in normals has received attention in the literature since this comparison is the basis for clinical interpretation of the test. Early in the history of ENoG, Esslen [4] reported an average between sides amplitude difference of 3% in a group of 30 normal subjects. This difference was considered small and of no significance in terms of effect on test accuracy and application. Subsequently, a number of investigations have reported average side-to-side amplitude difference values in normals that were similar to Esslen s results [11 16]. There are fewer reports that describe side-to-side amplitude difference values in normals that are substantially different from Esslen, usually by clinical investigators who have modified the original technique. May et al. [17] found a 24% median interside amplitude difference in normals with the highest value at 50%. Kartush et al. [18] found interside an amplitude variance value of 21.2% for a nonoptimized stimulation and recording technique. Test-Retest Consistency in Normal Subjects Adour et al. [19, 20] presented early reports that were critical of ENoG. They evaluated the test-retest reliability in normals and compared the prognostic value of ENoG to the MST in patients with facial paralysis. These authors concluded that ENoG had an unacceptable reproducibility with an average amplitude test-retest difference of 16%. In addition, they maintained, on the basis of three case studies, that MST was superior to ENoG for prognosis of outcome. Fisch [8] responded with a detailed analysis of the data of Adour et al. [19, 20] and concluded that error was introduced into the Dennis/Coker 120

239 reliability measures because OLP (small shifts in electrode positions) was not used to ensure maximum CMAP amplitude and consistent phase orientation of the response. He further examined and discussed the case reports of Adour et al. and concluded their statements concerning prognosis were in error because of inappropriate application of ENoG principles and interpretation. Additional criticism not stated by Fisch would include their use of an unorthodox stimulating electrode pair arrangement (anode and cathode reversed with anode oriented anteriorly) which may have influenced amplitude. Also there is evidence of contamination by masseter artifact on some of their CMAP waveforms. This distortion typically presents as a bifid component to the negative peak and its presence can affect the amplitude of the response [14, 18, 21, 22]. Thomander and Stalberg [15] repeated examinations 2 6 times in a group of normals and reported a test-retest amplitude variation of 4.3% with a range of 0 11%. Their overall technique was similar to that of Esslen-Fisch with the major differences being the use of 25% supramaximal stimulation and a recording electrode configuration which placed the active lead in the nasolabial fold lateral to the ala and the reference on the tip of the nose. These authors concluded that ENoG has a clinically acceptable accuracy for facial nerve assessment and monitoring. Hughes et al. [14, 23] conducted two separate studies on variability of ENoG using normal subjects. These authors introduced the standard stimulating and recording lead placement (SLP) which was intended to standardize ENoG electrode placement for purposes of consistency. Their electrode montage always placed the anode between the tip of the mastoid and the condyle of the mandible. The cathode was placed 2 cm anterior to the anode. The superior recording electrode was placed lateral to the nasal ala in a straight line arrangement with the stimulating pair. The other recording electrode was 2 cm inferior in the nasolabial fold. All electrodes remained fixed in these positions. The standard lead placement is illustrated in figure 6. They reported fluctuations of 11.4% and 6.2%, respectively on repeated measures. They concluded that their results compared favorably with the 10% allowable variation reported by Esslen [4] and that ENoG variability was within acceptable limits for clinical practice. According to these authors, the variations inherent in ENoG results were the result of instances of trigeminal nerve artifact, changing skin resistance and possible submaximal nerve stimulation. May et al. [24] reported up to 20% test-retest amplitude variation in 3 normals and 10% in 7 others for an approximate average of 13%. They used a supramaximal, branch (zygomatic and buccal) stimulation with the electrodes placed under the zygomatic arch. Recording electrodes were applied over each nasal ala. These workers concluded that the extent of test-retest variation in normals Electroneuronography 121

240 Fig. 6. Standard stimulating and recording lead placement. Interelectrode distance is constant at 2 cm for each stimulating and recording pair. The superior recording electrode is always placed lateral to the nasal ala in a straight line with the stimulating pair. does not seem to preclude the prognostic value of ENoG in the clinical evaluation of acute facial paralysis. Kartush et al. [18] used supramaximal stimulation at the nerve trunk and reported a mean 17.8% amplitude difference for repeated ENoG tests using an OLP technique. The variability associated with SLP was higher but not statistically significant. These authors stressed the importance of controlling the technical factors that are necessary for reliable results. Silverstein et al. [11] tested 5 patients on three different occasions. Maximal stimulation was applied under the zygomatic arch with recording electrodes located at the nasal ala. They reported an average ipsilateral amplitude variation of 3% and stated that ENoG is a repeatable test of facial nerve function. Gavilan et al. [13] performed ENoG on 25 normal adults using a technique similar to Esslen- Fisch. The results of the study indicated minimal test-retest ENoG amplitude variability with an average intrasubject coefficient of variation of 3.15%. Gutnick et al. [25] performed serial ENoG on seven adults using supramaximal branch stimulation under the zygomatic arch and several recording montages. An analysis of variance of their results showed no significant differences in amplitude as a function of test day. There are obvious disparities among the findings of the studies evaluating ENoG results in normal subjects as they relate to ENoG amplitude variation between sides of the face and especially intrasubject test-to-test variation. There is a trend (with some exceptions) for those studies that used methodology resembling that of Esslen-Fisch to show less variability. Interstudy comparisons, however, are replete with technique differences as well as technical influences which may effect ENoG outcome. Principal among these variables Dennis/Coker 122

241 are different stimulating and recording sites, optimized versus standardized lead placement, and various levels of supramaximal stimulation leading to possible contamination of ENoG amplitude by means of masseter muscle excitation. Supramaximal stimulation, site of stimulation and potential for masseter artifact are likely related variables in ENoG assessment. In more recent work, these features as they relate to ENoG have been evaluated in humans by Coker and Salzer [21] and animals by Salzer et al. [22]. These authors used optimized stimulation and recording techniques. They evaluated facial main trunk, pes anserinus region, and buccal branch stimulation in humans. Main trunk and buccal branch stimulation were scrutinized in cats. ENoG recordings were obtained in humans from the nasolabial fold and, in cats, the whisker pad. Intramuscular masseter EMG activity was monitored simultaneously during ENoG. Stimulus intensity-enog amplitude functions were obtained. Both studies found that smaller amounts of current intensity produced masseter activity at stimulation sites distal to the main trunk, i.e., branch stimulation. Additionally, it was more common with branch stimulation to see masseter excitation prior to obtaining ENoG amplitude maximum. These authors recommended facial trunk stimulation for ENoG testing to avoid stimulation of nonfacial musculature and distortion of the facial CMAP. As a consequence of their findings, they defined supramaximal stimulation as the current level that produces ENoG amplitude maximum or the highest achievable level without evidence of masseter activity. Coker [26] evaluated in normal subjects three different ENoG techniques as they relate to reliability. He examined the optimized technique as proposed by Esslen-Fisch and several standardized recording placement methods. The SLP methods included paired electrode montages on the nasofacial junction [14, 23], the forehead, the chin, and the alar rims of the nose [11, 24]. Stimulation at the main trunk was optimized for all conditions with control for masseter activation. Repeat examinations were given to a subset of the normal group to examine test-retest and intrasubject variance. Statistical analysis of repeated measures showed significantly smaller CMAP changes and more consistent amplitude values recorded with the OLP and one SLP location, the nasolabial area. Side-to-side amplitude differences were also smaller with these two recording derivations. Additionally, there was a trend for larger amplitudes with OLP. It was concluded overall that ENoG was a reliable test and that less variability of results could be expected with OLP and SLP at the nasolabial fold. ENoG using the OLP technique for the recording leads offers the most accurate means of calculating the degree of degeneration in advanced paralysis. Standardized placement of leads in a predetermined position on the face may Electroneuronography 123

242 Table 1. Calculations of ENoG estimates of blocked and degenerated facial nerve fibers using Fisch-Esslen method: hypothesized actual versus worst case amplitude analysis at 23% error [adapted from 18] Actual amplitude Left ENoG Right ENoG 650 μv 4,500 μv ENoG estimates 650/4,500>14% blocked fibers %>86% degenerated fibers Worst case amplitude Left ENoG 500 μv (650 23% of 650) Right ENoG 5,536 μv (4,500+23% of 4,500) ENoG estimates 500/5,536>9% blocked fibers 100 9%>91% degenerated fibers fail to detect an underlying myogenic event of nominal activity. The presence of evoked myogenic activity signifies an incomplete lesion, i.e., intact motor axons, and in some situations may guide treatment, e.g. the decision whether or not to explore a traumatic facial nerve paralysis. For this reason the present authors prefer the Fisch-Esslen technique, one that optimizes placement of both stimulating and recording leads. Taken as a composite, the preponderance of the evidence in the literature shows ENoG as an acceptably reliable test of facial nerve function in normals in terms of amplitude consistency on repeated measures and minimal sideto-side CMAP differences. It is apparent, however, that direct control of procedural and technical features of ENoG is requisite for reliable results. Clinical application of ENoG methodology requires arithmetic manipulation of the amplitudes from both sides of the face to derive a quotient representing the interside percentage difference. It is recognized that the test variability has less influence as nerve degeneration progresses and the amplitude of the paralyzed side decreases [17, 18, 26]. Inherent error is minimized in these clinical presentations by the ratio of a relatively small dividend to a larger divisor. This fact does not at all, however, diminish the importance of applying only those ENoG techniques that reduce error to a minimum. Table 1 illustrates a worst case scenario where the assumptions are a high level of inherent test error (23%) and clinically significant degeneration that is less than 90%. This example is intended to present the possibility of deriving a higher than actual degenera- Dennis/Coker 124

243 tion value if test protocol is not sufficiently rigorous to minimize error. An outcome such as the one shown in table 1 could inadvertently lead to a recommendation for surgical management if degeneration greater than 90% was a rigid ENoG criterion for facial nerve decompression and not interpreted in the context of the clinical examination and serial ENoG testing. ENoG Validity Esslen and Fisch stated that the CMAP amplitude of the involved side directly related to the number of facial nerve axons capable of being galvanically stimulated, i.e., a quantification of those fibers not having undergone Wallerian degeneration at the time of testing. There is a relative paucity of histologic studies in animal models that have examined this hypothesis. However, data do exist that support this contention. In related studies, Coker [26] and Halvorson et al. [27] evaluated the histologic correlation between facial nerve degeneration and the CMAP amplitude in mongrel cats. The animals received unilateral axotomy in the tympanic segment of the facial nerve subsequent to normative ENoG testing. Serial ENoG was performed with the data expressed in the usual ratio fashion. The peripheral nerve was harvested and examined using the Marchi-Algeri method [28] to determine the ratio of intact to total (intact and degenerated) axons. Statistically significant correlations were found between histologic counts of viable axons and amplitude. Stated differently, the histologic counts of viable axons correlated with the percentage of intact fibers calculated by ENoG. These authors conclude that ENoG reliably estimates neural integrity following traumatic lesion to the facial nerve. Prognostic Value of ENoG Fisch and Esslen observed many patients on a longitudinal basis who had been evaluated with ENoG during the acute phase of facial palsy. Many of their patients were stratified according to Bell s palsy, facial nerve trauma, and herpes zoster oticus. They maintained from this experience that ENoG was a reasonably accurate prognostic guide early in the course of the paralysis provided the test was performed within 21 and preferably 14 days from onset of the paresis. Table 2 lists the prognostic findings which have been collapsed across several of their studies. The chances of a spontaneous recovery were very good to excellent if the ENoG-derived percentage of degeneration was between 50 and 70%. Values from 71 to 90% indicated a good chance of recovery with 85 98% of those cases achieving satisfactory return of function. While there might be some degree of functional recovery for patients with an ENoG value of 91 98%, generally they would have less than a satisfactory return of facial motility. A degeneration of greater than 98% predicted unsatis- Electroneuronography 125

244 Table 2. Generalized ENoG prognostic guidelines according to Esslen- Fisch of final outcome in acute facial palsy (due to Bell s palsy, herpes zoster, or trauma) ENoG percentage degeneration Predicted outcome (recovery) 50 70% Very good 71 90% Good 91 98% Less than satisfactory?98% Poor factory recovery. In general, their results indicated a greater than 50% chance for less than satisfactory recovery if degeneration of the nerve was beyond 90%. It is important to state that Esslen and Fisch offered these prognostic statements in relative not absolute terms. They were intended as best estimates of recovery likelihood based on longitudinal observations of outcome and their articles are replete with commentary about exceptions to these guidelines. Yet, the ENoG guidelines concerning likelihood for spontaneous recovery have stood the test of time reasonably well. With the exception of early criticisms [19, 20] a plethora of studies have examined and evaluated ENoG prognostic value and have reached conclusions similar to those of Esslen- Fisch [10, 11, 15, 17, 23, 24, 29]. A more recent study evaluating the prognostic value of ENoG has been reported by Sillman et al. [30]. These authors retrospectively analyzed 62 and 29 cases, with idiopathic and traumatic facial paralysis, respectively. ENoG was performed in close accordance with the Esslen-Fisch method and their follow-up exceeded 12 months. Incomplete recovery for idiopathic patients was significantly related to degeneration in excess of 90% while functional recovery was significantly associated with ENoG percentages less than 90%. ENoG was predictive but to a lesser degree for patients with temporal bone trauma. Interestingly, 8 patients with ENoG side-to-side differences of greater than 90% had voluntary motor potentials on standard EMG. All 8 patients obtained satisfactory spontaneous recovery of facial function. The results of Sillman et al. [30] support the prognostic value of ENoG in evaluation of acute facial palsy. These authors recommended including EMG evaluation for voluntary motor potentials in those cases where ENoG difference is greater than 90%. They contended this practice would increase the prognostic precision of the test and avoid unnecessary surgical decompression. ENoG is most appropriately applied during the acute phase of degeneration of the facial nerve. Summation of the CMAP amplitude depends on the Dennis/Coker 126

245 synchronous depolarization of intact motor axons. During recovery from injury, synchronous depolarization of regenerating axons may not be achieved, and the nerve conduction velocities of regenerating axons or of axons recovering from neuropraxia vary to such a degree as to produce a CMAP amplitude of reduced amplitude. Such false positive results can mislead the clinician into surgical intervention or lead to poor prognostication for a process in the early states of recovery. For this reason ENoG is most accurate when used to evaluate Bell s palsy, herpes zoster oticus, or paralysis secondary to trauma within 3 weeks of the onset. Once recovery begins, ENoG results may be suspect and have to be interpreted in the context of the disease process, the clinical examination, and, occasionally, the EMG findings. Specifically, the CMAP response may be absent, yet the patient exhibits voluntary facial motion on clinical examination or demonstrates volitional motor units on EMG during recovery. For this reason the clinician should never use the results of the ENoG procedure alone to guide treatment decisions and should consider EMG studies after the second week of paralysis. ENoG results obtained on patients with facial paralysis secondary to tumors are suspect, as most tumors in contact with the facial nerve grow slowly. Simultaneously, some populations of motor axons may undergo degeneration and others regeneration such that the CMAP amplitude may not truly reflect the degree of facial nerve degeneration. Therefore, one cannot quantitate the degeneration of a nerve because of neoplastic involvement. A reduction in the CMAP amplitude, however, does signify facial nerve involvement by the tumor and may have prognostic significance in regard to surgical outcome. Final Statements ENoG was developed as a test to provide an index of facial nerve injury by deriving the proportion of motor axons that have degenerated. As such, ENoG has been extensively evaluated over the past 15 years. There is ample evidence that the test is reliable and prognostic provided meticulous control is maintained over those variables that are known to inflate measurement error. The sagacious clinician designs and follows a protocol that maximizes the opportunity for recording actual absolute amplitude in each patient. Factors that might be considered to reduce error would be stimulation of the nerve at the main trunk, recording in the nasolabial fold, minute shifts in stimulating and recording electrode positions to optimize CMAP amplitude, use of maximal stimulation values that preclude masseter artifact, and consistent use of peak-to-peak measurements to express amplitude. There is no universally accepted, standard technique for performing ENoG. The method Electroneuronography 127

246 Table 3. Suggested ENoG protocol Pretest considerations Indication for test Test sequence Test preparation Stimulation parameters Electrodes Location Placement Stimulus type Stimulus generator Stimulus intensity Acute, complete facial palsy; onset within past 21 days Serially beginning 4 days postonset or single test at days; repeat test every 1 3 days to determine endpoint of degeneration Explain test and assure patient; relax jaw and avoid contact between upper and lower teeth; prepare facial skin to reduce impedance Bipolar; centerpoint interelectrode distance of cm Over truncal region of nerve below earlobe with cathode anterior to anode Hand held and position shifted for maximum response amplitude Direct current electrode pulse; duration of 200 μs; rate of 1.1/s Constant current Highest current level producing maximum response amplitude without masseter excitation of choice for each clinician will relate to his/her knowledge, experience, and philosophy. Examination of the literature, however, seems to support the use of methodology similar to that originally proposed by Esslen-Fisch in order to increase consistency and accuracy. Tables 3 and 4 list a suggested protocol for ENoG that is based on our combined experience with the test. ENoG is used to evaluate complete facial paralysis. As long as the patient demonstrates voluntary facial movement on the affected side, i.e. paresis, facial nerve compromise is incomplete and the prognosis for recovery is good at that point in time. ENoG performed during paresis rarely directs treatment. Additionally, the testing must be performed within 21 days from the onset of paralysis. In some cases serial testing is begun at 4 days and continued until the endpoint of degeneration is apparent. On other occasions, a single test may be administered at approximately days preferably close to day 14. It is important to explain the details of the test and assure the patient that the procedure is not harmful or unduly uncomfortable. During the test it is important that the patient s jaw be relaxed with avoidance of contact between upper and lower teeth. Bipolar stimulating electrodes are initially placed over the truncal region of the nerve just below the earlobe with the cathode anterior to the anode. The electrodes are hand held with a fixed centerpoint interelectrode distance of cm. A constant current stimulus generator delivers direct current electrical pulses with a duration of 200 μs to the electrodes at a rate of 1.1/s. The use of a constant current generator reduces ENoG variability since its Dennis/Coker 128

247 Table 4. Suggested ENoG protocol Continued Recording parameters High-pass filter setting 1 5 Hz Low-pass filter setting 500 1,500 Hz Amplification Adjusted according to size of response Epoch 20 ms Poststimulus averaging delay 1 ms Number of averages Up to 20 Electrodes Bipolar; centerpoint interelectrode distance of cm Location Noninverting electrode placed lateral to nasal ala in nasolabial fold; inverting electrode placed in nasolabial fold inferior to noninverting; ground electrode at forehead Placement Hand held and position shifted for maximum response amplitude Electrode impedence Less than 5,000 ohm; interelectrode impedance 1,000 ohm or less ENoG amplitude measurement Procedure Peak-to-peak (positive peak to following negative peak) amplitude in microvolts Percentage estimate of degenerated fibers Procedure 100 (μv amplitude of paralyzed side/μv amplitude of normal side 100) Additional electrodiagnostic assessment ENoG result?90% Facial EMG at perioral and periocular muscles to determine degeneration presence of voluntary motor potentials very high internal resistance relative to the lower external load resistance results in constant current delivery at the electrode-skin interface. Stimulus intensity is generally the highest achievable current level that produces maximal CMAP amplitude without EMG or clinical detection of masseter activity. Most ENoG measurements today are obtained by the use of an evoked response averaging system. The high-pass filter setting is generally 1 5 Hz although higher values can be used if there is excessive myogenic activity. The low-pass filter setting can be 500 1,500 Hz. The overall amplification of the system is adjusted according to the amplitude of the response. The poststimulus analysis time is generally 20 ms. A poststimulus-averaging delay of 1 ms will reduce the presence of stimulus artifact. Generally less than 20 averages are necessary since the signal-to-noise ratio for this potential is relatively large. Recording electrodes are bipolar with a centerpoint interelectrode distance of approximately cm. The noninverting electrode is positioned lateral to Electroneuronography 129

248 the nasal ala in the nasolabial fold and the inverting electrode is placed online, inferior to the noninverting lead. The ground electrode can be placed at the forehead. Electrode impedance should be less than 5,000 ohm with interelectrode impedance values maintained at 1,000 ohm or less to assure maximum common mode rejection. During the test, stimulating and recording electrodes are hand held and position shifted to find the exact locations that produce maximum CMAP amplitude. The amplitude from the involved side is expressed as a percentage of the noninvolved side in order to estimate the number of intact fibers. EMG is conducted to determine presence of voluntary motor potentials from perioral and periocular muscles if ENoG results indicate greater that 90% degeneration. ENoG plays an important role in the clinical evaluation of acute facial paralysis. Niparko [31] has recently summarized the utility of the test. He states that ENoG is now recognized as the most straightforward and accurate means of assessing the degree of nerve injury associated with Bell s and herpes zoster oticus facial paralysis. Accurate results depend upon complete evaluation incorporating historical and physical findings prior to testing as well as care in administering and interpreting results. While other electrophysiologic tests have not established a clear correspondence between response profile in the acute phase and functional outcome, ENoG identifies early those patients who are at greater risk for unsatisfactory recovery of function. References 1 Duchenne GB: De l Electrisation localisée, ed 3. Paris, Bailliére, 1872, pp Fisch U, Esslen E: Total intratemporal exposure of the facial nerve. Arch Otolaryngol 1972;95: Esslen E: Electrodiagnosis of facial palsy; in Miehlke A (ed): Surgery of the Facial Nerve. New York, Saunders, 1973, pp Esslen E: Electromyography and electroneurography; in Fisch U (ed): Facial Nerve Surgery. Birmingham, Aesculapius, 1977, pp Esslen E, Fisch U: The acute facial palsies. Berlin, Springer, 1977, p 7. 6 Fisch U: Facial paralysis in fractures of the petrous bone. Laryngoscope 1974;84: Fisch U: Total facial nerve decompression and electroneurography; in Silverstein H, Norrell H (eds): Neurological Surgery of the Ear. Birmingham, Aesculapius, Fisch U: Maximal nerve excitability testing vs. electroneuronography. Arch Otolaryngol 1980;106: Fisch U: Surgery for Bell s palsy. Arch Otolaryngol 1981;107: Fisch U: Prognostic value of electrical tests in acute facial paralysis. Am J Otol 1984;5: Silverstein H, McDaniel AB, Hyman SM: Evoked serial electromyography in the evaluation of the paralyzed face. Am J Otol 1985(Nov suppl): Redhead J, Mugliston T: Facial electroneuronography: Action potential amplitude and latency studies in 50 normal subjects. J Laryngol Otol 1985;99: Gavilan J, Gavilan C, Sarria J: Facial electroneurography: Results on normal humans. J Laryngol Otol 1985;99: Dennis/Coker 130

249 14 Hughes GB, Josey AF, Glasscock ME, Jackson CG, Sismanis A: Clinical electroneurography: Statistical analysis of controlled measurements in twenty-two normal subjects. Laryngoscope 1981; 91: Thomander L, Stalberg E: Electroneurography in the prognostication of Bell s palsy. Acta Otolaryngol 1981;92: Kelleher MJ, Gutnick HN, Prass RL: Waveform morphology and amplitude variability in facialnerve electroneurography. Laryngoscope 1990;100: May M, Blumenthal F, Klein SR: Acute Bell s palsy: Prognostic value of evoked electromyography, maximal stimulation, and other electrical tests. Am J Otol 1983;5: Kartush JM, Lilly DJ, Kemink JL: Facial electroneurography: Clinical and experimental investigations. Otolaryngol Head Neck Surg 1985;93: Adour KK, Sheldon MI, Kahn ZM: Comparative prognostic value of maximal nerve excitability testing versus neuromyography in patients with facial paralysis. Trans Pac Coast Otoophthalmol Soc Annu Meet 1977;58: Adour KK, Sheldon MI, Kahn ZM: Maximal nerve excitability testing versus neuromyography: Prognostic value in patients with facial paralysis. Laryngoscope 1980;90: Coker NJ, Salzer TA: The use of masseter electromyography with electroneurography in the evaluation of facial paralysis. Otolaryngol Head Neck Surg 1990;103: Salzer TA, Coker NJ, Wang-Bennett LT: Stimulation variables in electroneurography of the facial nerve. Arch Otolaryngol Head Neck Surg 1990;116: Hughes GB, Nodar RH, Williams GW: Analysis of test-retest variability in facial electroneurography. Otolaryngol Head Neck Surg 1983;91: May M, Klein SR, Blumenthal F: Evoked electromyography and idiopathic facial paralysis. Otolaryngol Head Neck Surg 1983;91: Gutnick HN, Kelleher MJ, Prass RL: A model of waveform reliability in facial nerve electroneurography. Otolaryngol Head Neck Surg 1990;103: Coker NJ: Facial electroneurography: Analysis of techniques and correlation with degenerating motoneurons. Laryngoscope 1992;102: Halvorson DJ, Coker NJ, Wang-Bennett LT: Histologic correlation of the degnerating facial nerve with electroneurography. Laryngoscope 1993;103: Marchi V, Algeri G: Pathological technique; in Mallory FB (ed): New York, Hafner, 1968, pp May M, Klein SR, Taylor FH: Idiopathic (Bell s) facial palsy: Natural history defies steroid or surgical treatment. Laryngoscope 1985;95: Sillman JS, Niparko JK, Lee SS, Kileny PR: Prognostic value of evoked and standard electromyography in acute facial paralysis. Otolaryngol Head Neck Surg 1992;107: Niparko JK: The acute facial palsies; in Jackler RK, Brackman DE (eds): Neurotology. St Louis, Mosby-Year Book, 1994, pp J. Michael Dennis, PhD, Department of Otorhinolaryngology, University of Oklahoma Health Sciences Center, 800 N.E. 13th Street, Room 6NP522, Oklahoma City, OK (USA) Electroneuronography 131

250 Alford BR, Jerger J, Jenkins HA (eds): Electrophysiologic Evaluation in Otolaryngology. Adv Otorhinolaryngol. Basel, Karger, 1997, vol 53, pp Testing the Vestibulo-Ocular Reflex G. Michael Halmagyi, Robyn A. Yavor, Leigh A. McGarvie Department of Neurology, Royal Prince Alfred Hospital, Camperdown, N.S.W., Australia In this chapter, we describe our approach to routine laboratory testing of vestibular function (i.e. vestibulometry) by measuring the vestibulo-ocular reflex (VOR). Aims of Vestibulometry The aims of vestibulometry are similar to those of audiometry: to make a site-of-lesion diagnosis as well as a quantitative evaluation of deficit; in other words, Where is the vestibular lesion and how bad is it? As with audiometry, the lesion responsible for loss of function can be at the level of the inner ear, the 8th cranial nerve or the brainstem. There is, however, one important difference between audiometry and vestibulometry. Because cochlear nerve lesions are so much more common than cochlear nucleus lesions, and since lesions at these two sites can be audiometrically indistinguishable from each other, the main problem in diagnostic audiometry, the distinction between cochlear and retrocochlear lesions, is in fact the distinction between cochlear end-organ and cochlear nerve lesions. In contrast, labyrinthine end-organ lesions are vestibulometrically indistinguishable from vestibular nerve lesions; hence in vestibulometry, the main distinction is between peripheral i.e. vestibular end-organ/vestibular nerve lesions and central i.e. brainstem vestibular nucleus lesions/vestibulocerebellar lesions.

251 Methods of Vestibulometry What We Do This chapter is based on the accumulated experience of our Balance Disorders Clinic over the last 15 years. We now see about 2,000 new patients a year. Our ideas and practices continue to evolve and what follows is an outline of our approach to evaluating the VOR. Our vestibular evaluation is in five parts: (1) a clinical history and examination; (2) a search for spontaneous, gaze-evoked, positional and rebound nystagmus in light and in darkness; (3) a caloric test of lateral SCC function; (4) a rotational test of lateral SCC function, and (5) a subjective visual horizontal test of otolith function. A basic vestibular evaluation consists of stages 1 3; an advanced vestibular evaluation consists of stages 1 5. Since almost all routinely scheduled patients are symptom-free at the time of testing, we strongly encourage them to report to the clinic as soon as possible after the start of another attack. Experience of examining patients during acute vertigo attacks has shown that it is usually possible to make a diagnosis if the patient can be examined during, as well as in between, vertigo attacks. Our aim is to be able to categorize vestibular dysfunction into 1 of 5 diagnostic groups: (1) normal; (2) unilateral peripheral vestibular lesion acute or compensated; (3) bilateral peripheral vestibular lesion; (4) central vestibular lesion, or (5) combined peripheral and central vestibular lesions What We Do Not Do Apart from the VOR we do not evaluate other eye movement systems in our routine test battery. Subtle smooth pursuit abnormalities are too common and nonspecific to be diagnostically useful, and marked pursuit abnormalities are obvious on clinical examination and in any case correlate closely with abnormalities of VOR suppression (which is part of our laboratory testing). Perhaps the only diagnostic value of pursuit testing is when a previously unrecognized pursuit-induced, gaze-evoked congenital nystagmus confounds diagnosis. We no longer routinely evaluate optokinetic nystagmus, since in our experience it is rarely a source of diagnostic information. Saccadic system abnormalities, apart from primary-position saccadic oscillations such as square-wave jerks, are too rare among patients with vertigo or other balance disorders to make routine testing of saccade metrics worthwhile. We do not evaluate vertical SCC function because there are no routine tests available for this. Testing the Vestibulo-Ocular Reflex 133

252 Clinical Evaluation A thorough clinical vestibular history and examination is as important to the proper laboratory evaluation of a patient with a balance disorder as an auditory history and examination is to the evaluation of a patient with a hearing disorder. Details of the method are beyond the scope of this chapter but are covered in detail elsewhere [Baloh and Halmagyi, 1996]. Nystagmography Clinical Testing for Nystagmus As part of the routine clinical vestibular examination (after the history is taken and before any laboratory testing is done), spontaneous, gaze-evoked, head-shaking and positional/positioning nystagmus are sought with visual fixation and without, using Frenzel glasses. This way, it is possible to observe and diagnose all but the most subtle peripheral vestibular nystagmus (which is present only in darkness). The diagnostic value of nystagmography is documentation and quantification of any horizontal peripheral vestibular nystagmus. Positional nystagmus and vertigo is evaluated clinically before any laboratory testing. We do not routinely evaluate positional nystagmus with oculography because subtle positional nystagmus is too common (and therefore too nonspecific) to be diagnostically useful. A detailed description of the diagnostic method in a patient with obvious nystagmus in light is beyond the scope of this chapter. It is, however, possible to diagnose clinically, without electronystagmography (ENG), just about any nystagmus that is present in light [Halmagyi, 1994]. Possible exceptions to this rule are subtle cases of pursuit-induced congenital nystagmus and of rebound nystagmus. Here we deal with the evaluation of spontaneous or gaze-evoked nystagmus with and without visual fixation, in a patient without much spontaneous primary-position nystagmus in light. The routine of laboratory testing is as follows: The patient looks straight ahead for 20 s or so at a fixation light, and then for another 20 s in complete darkness at where the light was after it is extinguished. The same process is repeated with the patient looking left or right: anywhere from 15 to 30º eccentrically depending partly on the eye movement measurement system used (infrared systems have a limited linear range, usually 15 20º). Before caloric testing, nystagmography is carried out with the patient supine, before rotational testing with the patient upright. Three points need to be emphasized: Halmagyi/Yavor/McGarvie 134

253 (1) All spontaneous peripheral vestibular nystagmus will be directionfixed in all gaze positions; all induced vestibular nystagmus will be directionfixed under any particular stimulus condition. (2) All peripheral vestibular nystagmus has a linear waveform and is suppressed by visual fixation. A low-velocity (1 2º/s) direction-fixed or directionchanging gaze-evoked nystagmus, present only in darkness, particularly during testing in the supine position, can occur as a nonspecific finding in many otherwise normal individuals, as well as in patients with organic peripheral or central vestibular lesions. This does not mean that such findings can be automatically discounted, or conversely, that any patient with these findings needs extensive neuro-otologic investigation. It does mean that such findings need to be carefully considered in the context of the clinical, the audiometric and the other vestibulometric findings. (3) It is essential to be completely familiar with the characteristics and natural history of the nystagmus that is due to acute, total, permanent deafferentation of one intact labyrinth (unilateral vestibular deafferentation, uvd). The nystagmus is always direction-fixed, largely horizontal, partly torsional, and always beats away from the side of the lesion. In the first day or so after uvd, the horizontal component of nystagmus slow-phase velocity can reach 30 40º/s in dark and about 10º/s when the patient is trying to fix straight ahead in light. The nystagmus is usually present even during gaze away from the fast-phase direction and can thus be described as third degree. Inexperienced observers sometimes mistake a third-degree direction-fixed nystagmus for a directionchanging gaze-evoked nystagmus, that is, second-degree nystagmus in one direction and first-degree in the other. A torsional component in the primary position or on gaze in the fast-phase direction indicates involvement of the vertical semicircular canals. Horizontal slow-phase velocity will always increase with gaze in the direction of the fast phases as predicted by Alexander s law [Robinson et al., 1984], and torsional components will appear or increase during upward or downward gaze a consequence of Listing s law [Misslich et al., 1994]. The nystagmus will always diminish with time and will be unapparent in light after about 1 week. A low velocity (=3º/s) primary-position nystagmus only in the absence of visual fixation will remain as a permanent stigma of the uvd. A spontaneous nystagmus in darkness of 5º/s or more in a patient with a chronic peripheral vestibular lesion generally indicates poor compensation. There are several other types of nystagmus of peripheral vestibular origin: (1) During the first hour or so of an acute Ménière s attack, there can be a high-velocity spontaneous nystagmus beating toward the side of the responsible labyrinth, the so-called irritative nystagmus [Brown et al., 1988]. (2) Late during the recovery phase of a Ménière s attack there can be a low-velocity horizontal nystagmus also beating toward the responsible laby- Testing the Vestibulo-Ocular Reflex 135

254 rinth, the so-called recovery nystagmus [McClure et al., 1981]. It follows that it can be difficult to be sure which ear is responsible for an acute Ménière s attack from the characteristics of the spontaneous nystagmus only. (3) Testing for spontaneous nystagmus (which is carried out in the supine position) before caloric testing can reveal persistent nystagmus that is not accompanied by vertigo, and is either not present (or is much less apparent) in the upright position. Some of these patients will have other evidence of peripheral vestibular disease, and presumably this is a form of peripheral positional nystagmus. A few will have evidence of brainstem or cerebellar disease involving central vestibular pathways. Central vestibular nystagmus has characteristics that are different from those of peripheral vestibular nystagmus. It can be not only horizontal but also vertical or torsional or almost any combination of these axes. The nystagmus will change with gaze direction; it will be left-beating in leftward gaze and right-beating in rightward gaze. It will not be suppressed by visual fixation and might not have a linear, but an exponentially decreasing, or sometimes even exponentially increasing, velocity waveform. Central vestibular nystagmus of cerebellar origin will often show the rebound phenomenon a 20-second or so period of gaze-evoked nystagmus will induce a 5- to 10-second period of primary-position nystagmus in the opposite direction after the eyes saccade back to the primary position. A patient with obvious primary-position spontaneous nystagmus in light probably does not need vestibular function testing for diagnosis. The patient might have congenital nystagmus, in which case any vestibular function tests that measure nystagmus will be uninterpretable [Gresty et al., 1985]. If the patient has an acquired primary position spontaneous nystagmus then it is already obvious that there is a brainstem or cerebellar lesion and vestibular function testing will be unnecessary. Caloric Testing Caloric testing remains the mainstay of all vestibular function evaluation, since it is still the best way to test one labyrinth at a time, and since all vertigo is due to a unilateral or asymmetrical vestibular function, albeit intermittent. It needs to be emphasized that meticulous attention to technical detail is required to produce reproducible results. Nevertheless, there will still be patients from whom it is not possible to acquire reliable data, because of ear canal problems, inability to fixate, blinking, too much nausea, etc. For such patients rotational or other forms of vestibular testing might be suitable. Halmagyi/Yavor/McGarvie 136

255 Mechanisms (1) At the end-organ level: Warming or cooling the external auditory canal creates a temperature gradient in the temporal bone. Since the lateral SCC duct is closer to the stimulus than any other part of the inner ear, it is in the best position to receive the stimulus [O Neill, 1995]. If the head is positioned so that the lateral SCC is gravitationally vertical, the thermal gradient will create a convection current in the lateral SCC duct and thereby deflect its cupula. Heating the lateral SCC endolymph above its normal 37 ºC when the subject s nose is pointing up will deflect the cupula towards the ampulla (ampullopetal deflection). This will then produce a horizontal nystagmus with slow phases drifting away from the stimulated ear (i.e. quick phases beating toward the stimulated ear). Cooling the lateral SCC will produce the opposite nystagmus reaction (ampullofugal deflection). Heating the lateral SCC with the subject s nose pointing down will also produce the reverse nystagmus reactions. Heating or cooling the lateral SCC when it is earth-horizontal (i.e. with the subject seated and the head inclined about 30º forward) will produce no horizontal nystagmus. It is possible that there is a small contribution to the caloric response from direct cooling or heating of the vestibular nerve. In clinical practice this is not important, since there is no caloric response after the vestibular receptors are destroyed but the vestibular nerve is preserved (i.e. after labyrinthectomy). It should be remembered that the caloric response is a low-frequency stimulus, equivalent to about Hz [Barnes, 1995]. (2) At the vestibular nucleus level: Ampullopetal deflection of the lateral SCC cupula, as produced by warm caloric stimulation in the standard noseup, head 30º forward supine position, increases the firing rate of primary vestibular neurons from their normal resting rate (fig. 1). This increase in primary vestibular neuron activity directly increases the activity of excitatory type 1 secondary vestibular neurons in the ipsilateral medial vestibular nucleus, and indirectly, through commissural connections, decreases the activity of type 1 neurons in the contralateral medial vestibular nucleus. This happens because type 1 neurons also excite contralateral type 2 neurons, which then inhibit the resting activity of contralateral type 1 neurons. Conversely, cool caloric stimulation in the same position decreases activity in ipsilateral primary and type 1 secondary vestibular neurons, and then increases activity in contralateral type 1 neurons by decreasing activity in inhibitory contralateral type 2 neurons. This means that cool caloric stimulation acts by producing activation of excitatory secondary vestibular neurons in the contralateral medial vestibular nucleus. (3) At the ocular motor nucleus level: Type 1 secondary vestibular nucleus neurons excite contralateral abducens motoneurons and interneurons. For example, warm caloric stimulation of the left ear produces rightward slow- Testing the Vestibulo-Ocular Reflex 137

256 Fig. 1. The mechanism of the caloric test. The mechanism of the caloric test deduced from the behavior of primary and secondary vestibular neurons in the guinea pig. In response to cold water stimulation of the left lateral semicircular canal there is ampullofugal displacement of hair cell processes leading to a decrease in the activity of left vestibular nerve primary afferents from their normal tonic resting level. This in turn reduces the activity of left vestibular nucleus type I excitatory secondary neurons from the normal tonic resting level; through commissural connections this reduces the tonic resting activity of right vestibular nucleus type II inhibitory neurons, resulting in an increased activity of right vestibular nucleus type I excitatory neurons. In effect, cold water stimulation of the left ear results in excitation of the right vestibular nucleus. The result of increased activity of right vestibular nucleus type I neurons is activation of left abducens and right medial rectus motoneurons which produces a slow phase of nystagmus to the left and eventually, through circuitry not shown here, a quick phase to the right. [Courtesy of Dr. Ian S. Curthoys.] phase eye movements by excitation of the right lateral rectus and of the left medial rectus via excitation of the left medial longitudinal fasciculus. The generation of fast phases is more complicated. The burst of neural activity required to produce a leftward fast-phase eye movement is produced by the left pontine paramedian reticular formation exciting left abducens motoneurons and interneurons. Just how the fast phases are initiated and linked to slow phases involves a complex relationship between burster-driver neurons, Halmagyi/Yavor/McGarvie 138

257 inhibitory burst neurons and pause neurons. A discussion of these mechanisms is beyond the scope of this chapter, but for a review see Markham [1996]. (4) Visual suppression: Vestibular nystagmus is normally suppressed, up to a certain limit, by visual fixation. It is possible to express this function quantitatively as a fixation index, which is the difference between slow-phase velocity in the dark and in the light, divided by the slow-phase velocity in the dark (dark-light/dark). The normal value in our laboratory for visual suppression of caloric nystagmus is?70%. Patients with certain cerebellar disorders, particularly those involving the flocculus, have impaired visual suppression of vestibular nystagmus. Defects in visual suppression of vestibular nystagmus are closely related to disorders of smooth pursuit [Moschner et al., 1994]. (5) The effect of eye position on eye velocity: Horizontal slow-phase eye velocity is influenced by horizontal and vertical eye position. Eye deviation in the direction of the horizontal quick phases increases the horizontal slowphase velocity, as predicted by Alexander s law. Vertical eye deviation will introduce a torsional component which reduces the horizontal component of slow-phase eye velocity, as described by Listing s law. Practical Considerations (1) The stimulus: Without a correct reproducible stimulus the caloric test will be meaningless or misleading. There are arguments for and against various stimulation methods: air vs. water irrigators, open- vs. closed-loop irrigators. In our view, the traditional open-loop water irrigator gives the most consistently reliable and reproducible results. Care has to be taken to ensure that all the water enters and exits the ear canal freely. There are many ways to introduce the water; we use urethral catheters. The delivered water has to be at the correct temperature: 30 or 44 ºC. We do this by lagging the connecting tubing and by flushing it thoroughly immediately before stimulating (fig. 2). It is critical to check the temperature of the delivered water (not only the tank water) and to ensure that it does not change during the irrigation (as it does with some closed-loop systems). In patients who have had mastoidectomies, closed-loop balloon systems are not easy to use. In patients with perforations, an air or closed-loop stimulator should be used. While it is reasonable to have a standard stimulus duration (e.g. 40 s), longer or shorter durations should be used in patients whose responses are too small (say=8º/s) or are too large (say?80º/s). The results can be influenced by the irrigation sequence, particularly with closed-loop irrigators [Furman and Jacobs, 1993]. Irrigation with water at 0 ºC can be helpful in deciding whether or not there is any residual lateral canal function in an ear with no response to 30 or 44 ºC irrigation for 80 s. Testing the Vestibulo-Ocular Reflex 139

258 Fig. 2. Performing the caloric test. Important practical features to note are: the comfortable (for both patient and for operator) hydraulically operated test bed; the firm head restraint; the heat-insulated tubing from the open-loop irrigator; the light-excluding hood that covers the patient s head and shoulder during nystagmus recording; the infrared eye movement recording spectacles; the infrared video camera to monitor eye position in the dark. [Courtesy of VestiTest Ô.] (2) The operator: As with audiometry, a thorough knowledge of theory and extensive practical experience are required in order to produce reliable, reproducible results. The inadequately trained individual doing 3 quick ENGs a week will not produce any better data than an inadequately trained person doing 3 quick audios a week. (3) Head position: The duct of the lateral SCC is close to earth-vertical, and the caloric response is maximal when the supine subject s head is elevated by 30º. It is essential to restrain the head (fig. 2) in order to keep it in this position, since any deviation of the head will introduce at least two sources of error: (a) The magnitude of the response will decrease by the sine of the angle that the duct of the lateral SCC deviates in yaw or in pitch from the gravitational vertical; (b) If the head deviates in yaw while the subject continues to try to look straight ahead, mean eye position will deviate in the fast- Halmagyi/Yavor/McGarvie 140

259 phase direction, spuriously increasing slow-phase velocity as described by Alexander s law. (4) Patient cooperation: The level of cooperation required for caloric testing is about the same as that required for an audiogram. The subject has to be able to follow instructions, fixate and not blink much. It is rarely possible to obtain meaningful results from uncooperative adults or from children under 6 years of age. It is unwise to attempt caloric testing without an interpreter if the tester and the patient do not speak the same language. It is useful to have instruction cards ready for profoundly deaf patients. Poor vision can also make testing difficult. (5) Patient alertness: Drowsiness reduces the nystagmus response. The reticular formation must be continually activated throughout the test; having the patient do mental arithmetic is a good way to achieve this. (6) No drugs: Patients should abstain from psychoactive drugs, alcohol and tobacco, as each can produce spontaneous nystagmus or reduced vestibular responses or both. If there is doubt about abstinence, breath, blood and urine tests can be requested. (7) Visual fixation: There must be no visual fixation point whatsoever visible during the nystagmus recording period. Testing with the eyes open in darkness (fig. 2) is preferable to testing with the eyes closed and to testing with the eyes open behind Frenzel glasses. (8) Video monitoring: Continuous infrared video monitoring of the eye being recorded helps identify and thereby reduce artifacts caused by eye-blinks, loss of attention, loss of alertness, eye position offsets, etc. (fig. 2). (9) Measuring eye movement: There is no ideal method for eye movement measurement. Electro-oculography (EOG), the traditional method, has three main limitations: high-frequency noise, which can make deriving slow-phase eye velocity difficult; low-frequency drift, which can make determining absolute eye position difficult; and insensitivity to vertical eye position. Infrared methods are less noisy but have a smaller dynamic range ( 20º) than EOG. The sampling rates of video methods are too slow to allow eye velocity to be derived. The scleral search coil method is the current gold standard of eye movement measurement but is not practical for routine clinical use. Whichever method is used, it is essential to record the slow-phase velocity envelope of the entire response. Measuring the slope of a few selected slow phases near the estimated culmination velocity allows the operator too much freedom in data selection. (10) Normal values: The normal range of values for the peak absolute eye velocity response to a caloric stimulus is large: from about 8 to 80º/s [Sills et al., 1977]. Values of 6º/s or less indicate defective function; values greater than 80º/s are usually seen only in patients with cerebellar disorders or with migraine. Testing the Vestibulo-Ocular Reflex 141

260 The caloric response can also be large from an ear that has had a large mastoidectomy. In contrast, the normal range for relative eye velocity is narrow. Using the traditional Jongkees formulae, the normal value for unilateral weakness is less than 25% and for unidirectional weakness is less than 30%. The lower limit for visual suppression of caloric nystagmus is about 70% and is age-dependent. Each laboratory has to develop its own normal control range: Unilateral weakness (%) > (L30+L44)Ö(R30+R44) ( canal paresis ) R30+R44+L30+L44) 100 Unidirectional weakness (%) ( directional preponderance ) >(L30+R44)Ö(R30+L44) (R30+L44+L30+R44) 100 Common Patterns of Dysfunction and Their Interpretation (1) The two responses from one ear are smaller than those from the other: This pattern has been called canal paresis, unilateral weakness or reduced vestibular response (fig. 3). This is the single most valuable localizing result, and almost always indicates decreased sensitivity (i.e. function) of the lateral SCC from the ear giving the lower values. The only exception to this rule is the patient with one large mastoidectomy, who might give spuriously large responses from that operated ear. A canal paresis does not necessarily indicate that lateral SCC function is defective at higher frequencies of stimulation (e.g. during impulsive stimulation) or that vertical canals or the otoliths are also involved. (2) The 30 ºC response from one ear and the 44 ºC response from the other are higher than the other two responses: In other words, the two responses in one direction are higher than the two responses in the other direction. Originally called directional preponderance, this pattern is also called directional asymmetry in recognition of the fact that it can be due to reduced responses to Fig. 3. Routine caloric test results in a patient with right Ménière s disease. Top row shows spontaneous and gaze-evoked (15º right and left) nystagmus in light and in dark. There is blink artifact. Below this are the caloric results (30 ºC above, 44 ºC below, right ear on left, left ear on right). Note that the entire slow-phase velocity envelope is displayed. The operator uses a cursor to select the 4 s of peak slow-phase velocity; the position traces for this epoch are displayed below the velocity curves; the peak velocities are calculated as the mean for that 4-second epoch. Towards the end of the response the fixation light is reilluminated and the suppression index (SI) is calculated; in this case all SIs are greater than 87%. The values for spontaneous nystagmus in dark, for the peak slow phase velocity of each caloric irrigation, the calculated canal paresis (CP in this case right 65%) and directional preponderance (DP) are given at the bottom of the page. Halmagyi/Yavor/McGarvie 142

261 3 Testing the Vestibulo-Ocular Reflex 143

262 one direction ( directional deficit ) as well as increased responses in the other. While this is an important abnormal result, it is by itself nonlocalizing. It can simply indicate an ongoing spontaneous nystagmus, but it can also occur without spontaneous nystagmus, in which case it might indicate asymmetrical velocity sensitivity of type I neurons in the vestibular nucleus. This pattern can also occur after a unilateral weakness of peripheral origin has resolved, or after central lesions affecting the vestibular nucleus or vestibulocerebellum. (3) One 44 ºC or one 30 ºC irrigation gives a much stronger response than any of the other three: The other three responses might even be almost identical. This pattern is usually due to a combination of patterns 1 and 2 above. For example, a right unilateral weakness combined with a right (uni)directional weakness could occur in the early recovery phase after an acute right peripheral (much less commonly central) vestibular lesion. A right unilateral weakness combined with an apparent leftward (uni)directional weakness, which is actually a rightward (uni)directional preponderance, can indicate an irritative right peripheral lesion (as occurs in the early phase or in the recovery phase of a Ménière s attack or in cases of benign positioning vertigo). (4) One 44 ºC or one 30 ºC irrigation gives a much weaker response than the other three: This is not usually a diagnostic pattern and can be assumed to be an artifact due to one inadequate irrigation. (5) Both 44 ºC or both 30 ºC responses are weaker than the other two responses: This is also a nondiagnostic pattern and can be assumed to be an artifact caused by the 44 ºC irrigation being too cold or the 30 ºC irrigation being too warm. At average room temperature (20 ºC), the 44 ºC water tank loses heat more quickly than the 30 ºC tank, and therefore with this type of artifact the 44 ºC responses are more likely to be spuriously weak than 30 ºC responses. (6) All four responses less than 6º/s: In the absence of systematic technical error, this means bilateral impairment of sensitivity. In the absence of any other neurologic deficits, the site of the lesion is likely to be peripheral. This finding needs to be confirmed by rotational tests, which should show low maximum velocities and low time constants to velocity steps and a phase advance on sinusoidal testing [Hess, 1996]. (7) Visual suppression less than 50%: While visual suppression of caloric nystagmus is normally more than 70%, in our experience, values between 50 and 70% can indicate such nonspecific factors as fatigue or undisclosed substance use. Values of less than 50% on all four irrigations generally indicate a diffuse cerebellar disorder. A directional deficit of visual suppression can indicate a lateralized cerebellar lesion on the side of the suppression deficit. Halmagyi/Yavor/McGarvie 144

263 Rotational Testing We consider rotational testing to be a component of an advanced vestibular evaluation, a useful adjunct to caloric testing but not an alternative. Rotational testing has three main uses: (1) to confirm bilateral impairment of lateral SCC function; (2) to show evidence of a central vestibular dysfunction; (3) to quantify progress of a known vestibulopathy. Mechanism Understanding of the mechanisms of VOR in response to rotational stimulation follows from an understanding of the responses to caloric stimulation. The principal difference is that the stimulus acts simultaneously on both lateral SCCs. It excites the lateral SCC ipsilateral to the rotation and inhibits (or rather disfacilitates) the lateral SCC contralateral to the direction of the angular acceleration. For example, during a rightward angular acceleration, the activity of type 1 neurons in the right vestibular nucleus is increased from the resting level both by excitation from the right vestibular nerve and by disinhibition from the left vestibular nerve, through reduced action of type 2 neurons in the right vestibular nucleus. The effects of visual fixation on slow-phase eye velocity are similar to the effects on caloric-induced nystagmus. Practical Considerations (1) Stimulus parameters: We use 0.1 and 0.3 Hz sinusoidal acceleration and a constant acceleration of 20º/s 2 for 5 s, or 100º/s 2 for 1 s. Other laboratories use either a sum-of-sines stimulus, a white noise stimulus or shorter faster constant accelerations. There is not much evidence that one pattern of acceleration gives more useful results than any another [Furman and Cass, 1996]. (2) Head position: For optimum stimulation, the lateral canals should be close to the rotation plane of the stimulus, that is, at gravitational horizontal. To achieve this, the head needs to be tilted forward by about 30º. While this sounds easy enough, in practice it is difficult to record nystagmus in this head position, since the calibration lights then would need to be dropped 30º in order for the eyes to remain in the cardinal horizontal meridian of the eye in orbit; otherwise systematic errors would be introduced owing to elevation of the eye in orbit. In practice, it is easier to accept the reduced activation of lateral SCCs as a result of being pitched back about 30º with respect to the rotation plane, since the reduction in activation can in any case be predicted as (cos 30) of maximal activation. (3) Head must be restrained: If the chair velocity signal is taken as equivalent to head velocity, the head must be effectively fixed to the chair. This assumes particular importance at high accelerations and frequencies. Testing the Vestibulo-Ocular Reflex 145

264 (4) Alertness, visual fixation, measuring and monitoring eye movements: The comments made concerning these effects on caloric testing apply equally to rotational testing. (5) Normal values in our laboratory: (a) 0.1 Hz sinusoids?gain: ?phase: 5º lag to 15º lead?suppression (dark-light/dark):?80% (b) 0.3 Hz sinusoids?gain: ?phase: 10º lag to 10º lead?suppression (dark-light/dark):?70% (c) constant acceleration (20º/s 2 for 5 s)?maximum velocity: 42 16º/s?time constant: s?asymmetry (right-left/right+left) maximum velocity: =30% time constant: =30% Common Patterns of Dysfunction and Their Interpretation There are three common abnormal patterns on rotational testing; no pattern is specific for a particular site of lesion: (1) High-peak velocities (?75º/s), with normal or long time constants (?25 s), especially combined with impaired VOR suppression, suggest a central, usually cerebellar, disorder. This pattern can also occur in migrainous individuals but then visual suppression is normal (fig. 4). (2) Normal or low-peak velocities (=25º/s) with long time constants (?20 s) suggest that benzodiazepine or similar drugs are being used. (3) Low-peak velocities (=25º/s), low time constants (=10 s) and a phase advance on sinusoids (?20º) suggest either a bilateral peripheral lesion or a high degree of adaptation which can be a consequence of a unilateral peripheral lesion. Fig. 4. Routine rotational test results in a patient with cerebellar ataxia. There is firstdegree left and right beating gaze-evoked nystagmus in light only. The nystagmus decays with gaze-holding, suggesting that there might be rebound nystagmus as well (there was). There are some square-wave jerks in the dark. The gain of the VOR to sinusoidal testing is normal but there is no visual suppression whatsoever (5 cycles in each direction, medianstacked). The responses to a constant acceleration ( trapezoidal stimuli ) are normal 3 responses in each direction, also median-stacked. Optokinetic nystagmus (not routinely measured) is almost absent in this case. Halmagyi/Yavor/McGarvie 146

265 4 Testing the Vestibulo-Ocular Reflex 147

266 Table 1. Effect of the rotation test on the interpretation of the caloric test Caloric test results Rotation test result a PV TC DP PV TC DP PV TC DP PV TC DP PV TC DP PV TC DP N b NN HiHiN HiLoN LoLoN LoHiN X c XHi Normal n Absolute?6º/s consistent normal central bilateral central central Canal paresis =25% normal? central Directional normal? central asymmetry =30% Unilateral n Canal paresis =25% consistent inconsistent consistent bilateral unilateral consistent Directional unilateral? caloric unilateral and cen- unilateral asymmetry =30% =80% tral Bilateral n All =6º/s inconsistent inconsistent bilateral?? caloric? caloric Directional preponderance n Directional consistent inconsistent consistent preponderance?30%? unilateral? caloric? unilateral? central? central a Step response only; b N>normal; c X>any value. Normal values: Caloric: absolute?6º/s, canal paresis =25%, directional asymmetry =30%, and Rotation: peak velocity (PV) 35 45º/s, time costant (TC) s, directional asymmetry =20%. In order to describe how rotational tests influence vestibular diagnosis and evaluation, we analyzed the impact of rotational tests on the interpretation of caloric tests in 1,000 consecutive patients referred to our Balance Disorders Clinic. Table 1 shows how the peak velocity, time constant and directional asymmetry (i.e. preponderance ) of the response to an acceleration step influences the assessment that has been made after the clinical evaluation and the caloric tests. For simplicity, table 1 does not include data from the sinusoidal tests. If sinusoidal data are also considered, then the results of the rotational tests influence the diagnosis or evaluation in about 30% of the patients in whom the test is done. Halmagyi/Yavor/McGarvie 148

267 Subjective Visual Horizontal Consider a subject sitting upright in a room that is totally dark, apart from a just-visible light-bar that can be rotated about its midpoint. Viewing the bar and using a remote control device, the subject is required to rotate the bar in order to align it parallel to the perceived gravitational vertical or horizontal. Normal subjects can set the bar to within 1º of the gravitational horizontal [Dai et al., 1989]. Friedmann [1971] first showed that patients with various unilateral vestibular lesions set such a bar so that it was no longer aligned with gravitational vertical, but was consistently tilted toward the side of the lesion. Following acute total unilateral deafferentation of a previously normal labyrinth, patients invariably set the bar rotated toward the lesioned side, in some cases by up to 15º. They set the bar rotated toward the lesioned side because they saw the earth horizontal bar as tilted toward the intact side. Although the setting of the bar returned toward the earth gravitational with time, the setting was still tilted by a mean of 4º, 6 months or more after uvd. It appears, therefore, that a slight ipsilesional offset of the subjective visual horizontal (SVH) is a permanent legacy of uvd [Curthoys et al., 1991; Boehmer and Rickenmann, 1995]. The cause of the offset of the SVH appears to be an offset of torsional eye position. Following uvd, there is also an ipsilesional deviation of ocular torsional position: the 12 o clock meridians of both eyes are invariably rotated toward the side of the uvd [Curthoys et al., 1991]. One week after uvd, there is up to 15º of ipsilesional ocular torsion, and the magnitude of the ocular torsion closely correlates with the magnitude of the offset of the SVH. Furthermore, the torsional deviation gradually resolves, with a temporal pattern identical to that of deviation of the SVH. One month after uvd, both the ocular torsion and the tilting of the SVH are at half the 1-week value. A slight but statistically significant ocular torsion (4 5º) is also a permanent legacy of uvd (fig. 5). The mechanism of the ocular torsion and therefore of the deviation of the SVH could be similar to the mechanism of the spontaneous nystagmus that occurs after uvd: decreased resting activity in secondary vestibular neurons in the ipsilesional vestibular nucleus, because of loss of tonic input from primary vestibular neurons originating in the utricle. The evidence that tonic ocular torsion is utricular in origin depends in part on the argument that ocular torsion represents a tonic offset of the dynamic ocular counterrolling mechanism. It is generally accepted that dynamic counterrolling is under utricular control [Diamond and Markham, 1983]. Patients with certain acute focal brainstem lesions can also show a deviation of the subjective visual horizontal or subjective visual vertical (SVV) Testing the Vestibulo-Ocular Reflex 149

268 Fig. 5 a. Torsional eye position before and after unilateral vestibular deafferentation. Fundus photographs of the left and right eye of a patient before (top row) and 1 week after (bottom row) right vestibular neurectomy. After operation, there is tonic torsion of each eye toward the patient s right side. This change in torsional position measures 17º in the right eye and 15º in the left eye. That is, the right eye develops 17º of excyclotropia while the left eye develops 15º of incyclotropia. Note that before operation both eyes are slightly excyclotropic by an amount that is within the normal range. When the patient was asked to set a luminous bar to the perceived visual horizontal in an otherwise darkened room, he set the bar tilted down on his right side by 14.2º when viewing with the right eye and 15.1º when viewing with the left. [Halmagyi et al., 1990; Brandt and Dieterich, 1994]. Patients with lower brainstem lesions involving the vestibular nucleus (e.g. lateral medullary infarcts) offset the SVV towards the side of the lesion, whereas patients with upper brainstem lesions involving the interstitial nucleus (e.g. paramedian thalamic infarcts) offset the SVV away from the side of the lesion. In most patients, Halmagyi/Yavor/McGarvie 150