CENTRAL AUDITORY NEUROPLASTICITY IN SUDDEN HEARING LOSS: HEALTHY-SIDE DOMINANCE OF MIDDLE LATENCY AUDITORY EVOKED NEUROMAGNETIC FIELDS

Transcription

1 CENTRAL AUDITORY NEUROPLASTICITY IN SUDDEN HEARING LOSS: HEALTHY-SIDE DOMINANCE OF MIDDLE LATENCY AUDITORY EVOKED NEUROMAGNETIC FIELDS Abstract It is known that any lesion at different levels may induce a subsequent functional reorganization along the whole neural axis. Most of the neuroelectric and neuromagnetic studies on hearing impairment were limited to the investigation of the cerebral responses by auditory stimulation of the intact ear owing to the profound degree of hearing loss of the affected ear of the patients studied. By concurrent measurements of P50m and N100m, this study aimed to investigate functional plasticity in the cortical representations by magnetoencepalography (MEG). Intra-group and inter-group interhemispheric differences in peak dipole strengths and latencies of P50m and N100m to monaural tones were evaluated in 16 patients with acute unilateral idiopathic sudden sensorineural hearing loss (ISSNHL; moderate degree) and 16 controls. Auditory tone was applied to affected and intact ears in different sessions. Healthy-side dominance of both P50m and N100m was found in ISSNHL, i.e., preservation of contralateral dominance on affected-ear stimulation but ipsilateral dominance on healthy-ear stimulation. The mechanisms might be attributed to a functional retune of auditory pathways which in turn is registered in the cortical responses. It is speculated from animal studies that the wide ranges of neuroanatomical and neurochemical changes along the central auditory pathway following peripheral injury and hearing loss might underpin such neuromagnetic changes.

2 Article text Introduction Idiopathic sudden sensorineural hearing loss (ISSNHL) is one of the few inner ear hearing disorders of which recovery can be observed. Incidence of ISSNHL increases from 4.6/100,000 per year in the 2nd decade to 47.2/100,000 in the 7th decade {Byl, 1984 #148}. One third of patients may, either spontaneously or after appropriate interventions, achieve complete recovery of hearing {Byl, 1984 #148}. However, precise localization of lesion(s) of ISSNHL and the functional modulation of the auditory pathway after insult remain unresolved {Ota, 1999 #43;Busaba, 1995 #44}. Albeit the possibility of neural deficit(s) at higher level of the auditory pathway, the cochlea has been considered the most probable lesion site of ISSNHL {Biavati, 1994 #45}. It is suggested by auditory evoked potentials (AEPs) and auditory evoked fields (AEFs) studies that any lesion along the whole axis may induce a subsequent functional reorganization at the level above {Irvine, 2000 #119; Morita, 2003 #149; Wang, 1996 #150}. A normal AEF or AEP relies upon the integrity of both transmission of auditory signal along the auditory pathway and processing in the cortex. It is conceivable that the site(s) of auditory neuroplasticity may not necessarily be the primary site of lesion and the reorganization as expressed in the auditory cortex might originate from more peripheral loci along the auditory pathway. The long-latency N100 (peak latency at around 100 ms) component of AEPs, for example, may reflect the lower-level sensory processing in the cortex {Oates, 2002 #24}. Amplitude reduction of N100 may indicate a compromised cortical processing of auditory signal in patients with mild-to-severe hearing loss of peripheral origin {Oates, 2002 #24}. The magnetoencephalographic (MEG) studies of long-latency AEFs, e.g., N100m, in patients with acute ISSNHL or chronic unilateral deafness of various etiologies evidenced a dynamic plasticity in the central auditory pathway {Vasama, 1995 #153;Vasama, 1995 #21;Vasama, 1998 #48; Fujiki, 1998 #11; Po-Hung Li, 2003 #18}{Dietrich, 2001 #154}. Most of the aforementioned MEG studies were limited to the investigation of the cerebral responses by auditory stimulation of the intact ear owing to the profound degree of hearing loss of the affected ear {Vasama, 1995 #153;Vasama, 1995 #21;Vasama, 1998 #48;Fujiki, 1998 #11; Dietrich, 2001 #20}. Components of middle-latency AEFs (MLAEFs) and middle-latency AEPs

3 (MLAEPs), e.g. P30m/P50m and P30/P50, are critical for the initial cortical representations of perceived transient sounds {Kanno, 2000 #25} and may mirror the neurophysiological correlates for auditory recognition {Ozdamar, 1982 #128}. It has been reported in patients with temporal lobe lesions that the P30-amplitude decreased on the lesion side regardless of the side of auditory stimulation {Kaseda, 1991 #101}, contrasting the contralateral dominance of MLAEFs to monaural stimulation in normal hearing subjects {Ackermann, 2001 #26}. Nevertheless, it is unknown whether there is altered responsiveness antecedent to LLAEFs after ISSNHL or hearing impairment in general. We set out in this study to investigate both the MLAEFs (P50m) and LLAEFs (N100m) by means of MEG in a group of sixteen acute unilateral ISSNHL patients. P50m is the magnetic counterpart of P50 component of middle-latency AEPs peaking at around 50~70 ms and emanates from an area different from that of the N100m in the auditory cortex {Kanno, 2000 #25}{Reite, 1988 #17}. P50m represents the cortical event for pure tone processing just ahead of the N100m {Pekkonen, 2001 #27}. We had electively chosen ISSNHL patients with mild-to-moderate hearing impairment so that P50m and N100m were concurrently detectable on either affectedor healthy-ear stimulation, which in turn promised the possibility of addressing profoundly the temporal scenario of functional plasticity in the primary auditory cortex.

4 Method Subjects: Sixteen right-handed, previously untreated adult patients with acute unilateral left (n=8) or right (n=8) ISSNHL (8 males; years of age, mean=51) were studied (Table 1 & 2). Patients are normal for age in hearing of the opposite ear. Sixteen right-handed healthy volunteers with normal hearing (8 males; years of age, mean=39) served as control (Table 1 & 2). Diagnosis criteria were a sensorineural hearing loss with the threshold of not less than 30 db HL over three contiguous frequencies in octave within three days or less {Wilson, 1980 #29}. No other neurological deficits or traumatic history were identified. Elapsed time for MEG examination after disease onset ranged from 3 days to 3 weeks. Written informed consent was obtained from each participant with a protocol approved by the Institutional Ethics and Research Committee of Taipei Veterans General Hospital. Audiometric and Electrophysiological Examinations: All participants underwent pure tone audiometry (PTA) examination to determine both air and bone conduction threshold, using test frequencies between 250 Hz to 8000 Hz. Controls had normal PTA results (threshold < 20 db HL for all frequencies). A unilateral sensorineural hearing loss was impressed in all ISSNH patients, characterized as cochlear in site of lesion by results of reduced distortion-product otoacoustic emissions (DPOAEs) and within-normal-limit age-adjusted interaural latency difference of ABRs {Foster, 2002 #33; Gstoettner, 1992 #152}. Since for all patients, air and bone conduction thresholds were less than 60 db HL at 1000 Hz (Figure 1), the probing auditory stimulus was set at this frequency with an intensity of 70 db SPL for the MEG experiment. This moderate intensity was chosen to avoid further acoustic damage and cross-hearing contamination. MEG Paradigm: MEG measurements were performed in a magnetically shielded room using a whole-head 306-channel neuromagnetometer (Vectorview 4-D Neuroimaging, Helsinki, Finland). Subjects were seated upright with eyes open and were instructed to pay attention to the auditory stimulation during measurements. Simple tones (1000 Hz, 50 ms duration with 10 ms for ramp up and down, respectively, 70 db SPL at the exit end of the plastic tube, and interstimulus interval of about 4 s) were delivered monaurally via molded earpieces using the SoundProbe program on a McIntosh computer. Affected and intact ears were monaurally stimulated in separate sessions separated by two minutes of rest. Trials with electro-oculographic amplitudes exceeding 150 μv were rejected. MEG signals were sampled at 1000 Hz and band-pass filtered at 0.03 to 100 Hz. About 90

5 artifact-free trials were averaged. Off-line digital low-pass and high-pass filtering was performed at 30 Hz and 1 Hz, respectively. An equivalent current dipole (ECD) consisting of bilateral sources was used to explain the MEG signals {Hämäläinen M. Rev Mod Phys 1993;65:413-97}{Kanno, 2000 #25}. Each ECD was fitted to a subset of sensors in one hemisphere and was required to reach a goodness-of-fit larger than 80% to be accepted {Kaukoranta, 1986 #52}. The peak latency for these ECDs was extracted. T1-weighted MR images of subject brains were acquired using a 3.0 T Bruker MedSpec S300 system (Bruker, Kalsrube, Germany) for MEG-MRI co-registration. Data Analysis: The epoch analyzed ranged from 50 ms before to 350 ms after stimulation onset. The interval between -50 ms and 0 ms (trigger onset) was used as baseline. The time windows for P50m and N100m measurements were ms and ms, respectively {Woldorff, 1999 #73;Kanno, 2000 #25}. Should two or more identifiable peaks were observed within the defined P50m interval, the one nearest to the N100m peak was coined as the P50m {Onitsuka, 2000 #19}. Within-group inter-hemispheric differences of peak dipole strength and latency of P50m and N100m observed in different hemispheres were evaluated using the Wilcoxon signed rank test (threshold at p < 0.05). Differences of peak dipole strength and latency of P50m and N100m between groups over the same side of the brain (i.e. contralateral or ipsilateral hemisphere with reference to the ear stimulated) were analyzed using one way analysis of variance (ANOVA) (threshold at p < 0.05) {Ponton, 2001 #85}. Peak dipole moments and latency of P50m and N100m were grouped into three sets for the statistical treatment according to the ear stimulation type: on either (i.e. left or right) ear stimulation in normal-hearing subjects, on affected-ear stimulation in ISSNHL patients, and on healthy-ear stimulation in ISSNHL patients, respectively.

6 Results In all participants, the controls and patients, a P50m and an N100m dipole were detectable over each hemisphere (Table 1 & 2). Sources for P50m and N100m were separable and were localized bilaterally on the superior temporal plane with orientations of P50m and N100m ECDs opposite to each other, i.e., centripetal and centrifugal to the auditory cortex, respectively (Figure 1). Within-group differences P50m When P50m activities for contralateral and ipsilateral hemispheres across all control subjects were respectively pooled from ear stimulation on both sides (32 measurements for each hemisphere), a contralateral dominance was noted (p<0.001; Table 1). A faster P50m response was also noted in the contralateral hemisphere (p<0.001; Table 1). A subset analysis (n=16) of peak P50m moment made according to the ear stimulated revealed a significant contralateral preponderance upon left ear stimulation (p=0.007; Table 1) and right ear stimulation (p=0.013; Table 1). Interhemispheric latency differences (contralateral responses faster than ipsilateral responses) were significant for both left ear stimulation (p=0.016; Table 1) and right ear stimulation (p=0.001; Table 1) on the subset level. In ISSNHL patients, we observed that the contralateral hemisphere was significantly shorter in response latency (p<0.001; Table 1) at P50m as compared to that of ipsilateral hemisphere, but did not observe a pattern of contralateral dominance (p=0.379 for dipole moment; Table 1) on a pooled data set from stimulation of both ears (responses from the hemisphere opposite the stimulated healthy or deaf ear vs. those from the ipsilateral hemisphere, 32 measurements). However, a healthy-side dominance of dipole moment was observed when responses from hemispheres ipsilateral to the healthy ears were pooled (32 measurements) and compared with that from hemispheres ipsilateral to the deaf ears, irrespective of the ear stimulated (p<0.001; Table 1, Figure 1). No interhemispheric difference in latency was observed (p=0.517; Table 1). On a subset level (n=16), P50m dipoles were significantly stronger over the ipsilateral hemisphere but faster over the contralateral hemisphere upon healthy ear stimulation (p<0.001 for dipole moment & p=0.002 for latency; Table 1). On deaf ear stimulation, P50m dipoles were both significantly faster and stronger over the contralateral hemisphere (p=0.004 for dipole moment & p=0.012 for latency; Table 1).

7 N100m When N100m activities for contralateral and ipsilateral hemispheres of all control subjects were respectively pooled from ear stimulation on both sides (32 measurements for each hemisphere), a contralateral dominance was noted (p<0.001; Table 2). A faster N100m response was also noted in the contralateral hemisphere (p<0.001; Table 2). A subset analysis (n=16) of peak N100m moment made according to the ear stimulated revealed a significant contralateral preponderance upon left ear stimulation (p=0.001; Table 2) and right ear stimulation (p=0.034; Table 2). Interhemispheric latency differences were significant for both left ear stimulation (p=0.001; Table 2) and right ear stimulation (p=0.001; Table 2) on the subset level. In ISSNHL patients, we noted that the contralateral hemisphere was significantly shorter in response latency (p=0.002; Table 2) at N100m as compared to that of ipsilateral hemisphere, but did not observe a pattern of contralateral dominance (p=0.204 for dipole moment; Table 2) on a pooled data set from stimulation of both ears (32 measurements). However, a healthy-side dominance of dipole moment was observed when responses from hemispheres ipsilateral to the healthy ears were pooled (32 measurements) and compared with that from hemispheres ipsilateral to the deaf ears, irrespective of the ear stimulated (p<0.001; Table 2, Figure 1). No interhemispheric difference in latency was observed (p=0.427; Table 2). On a subset level (n=16), N100m dipoles were significantly stronger over the ipsilateral hemisphere but faster over the contralateral hemisphere upon healthy ear stimulation (p=0.004 for dipole moment & p=0.041 for latency; Table 2). On deaf ear stimulation, N100m dipoles were both significantly faster and stronger over the contralateral hemisphere (p<0.001 for dipole moment & p=0.014 for latency; Table 2). Between-group differences Hemispheres contralateral to ears of stimulation The P50m and N100m peak dipoles were significantly weaker over contralateral hemispheres, on healthy ears stimulation in ISSNHL patients (n=16) than on either ears stimulation in normal-hearing subjects (pooled data from both left and right ear stimulation, n=32) (F(1,46) = 6.743, p=0.013 for P50m; F(1,46) = 5.848, p=0.020 for N100m) (Figure 2). However, the amplitudes of P50m and N100m peak dipoles over contralateral hemispheres on affected ears stimulation in ISSNHL patients (n=16) were not significantly different from those on either ears stimulation in normal-hearing subjects (n=32) (F(1,46) = 0.072, p=0.789 for P50m; F(1,46) = 0.046, p=0.831 for N100m) (Figure 2). The peak latencies of P50m and N100m dipoles over contralateral hemispheres

8 on healthy ears stimulation in ISSNHL patients (n=16) were not significantly different from those on either ears stimulation in normal-hearing subjects (n=32) (F(1,46) = 0.115, p=0.736 for P50m; F(1,46) = 0.948, p=0.335 for N100m) (Figure 3). Similarly, the peak latencies of P50m and N100m dipoles over contralateral hemispheres on affected ears stimulation in ISSNHL patients (n=16) were not significantly different from those on either ears stimulation in normal-hearing subjects (n=32) (F(1,46) = 1.052, p=0.310 for P50m; F(1,46) = 1.028, p=0.316 for N100m) (Figure 3). Hemispheres ipsilateral to ears of stimulation The P50m and N100m peak dipoles were significantly stronger over ipsilateral hemispheres, on healthy ears stimulation in ISSNHL patients (n=16) than on either ears stimulation in normal-hearing subjects (n=32) (F(1,46) = , p=0.001 for P50m; F(1,46) = 9.138, p=0.004 for N100m) (Figure 2). However, the amplitudes of P50m and N100m peak dipoles over ipsilateral hemispheres on affected ears stimulation in ISSNHL patients (n=16) were not significantly different from those on either ears stimulation in normal-hearing subjects (n=32) (F(1,46) = 0.594, p=0.445 for P50m; F(1,46) = 2.365, p=0.131 for N100m) (Figure 2). The peak latencies of N100m dipoles were significantly longer over ipsilateral hemispheres, on healthy ears stimulation in ISSNHL patients (n=16) than on either ears stimulation in normal-hearing subjects (n=32)(f(1,46) = 7.145, p=0.010) (Figure 3). However, the peak latencies of P50m dipoles over ipsilateral hemispheres on healthy ears stimulation in ISSNHL patients (n=16) were not significantly different from those on either ears stimulation in normal-hearing subjects (n=32)(f(1,46) = 0.877, p=0.354). The peak latencies of P50m and N100m peak dipoles over ipsilateral hemispheres on affected ears stimulation in ISSNHL patients (n=16) were not significantly different from those on either ears stimulation in normal-hearing subjects (n=32) (F(1,46) = 0.216, p=0.644 for P50m; F(1,46) = 0.838, p=0.365 for N100m) (Figure 3).

9 Discussion Relative positions of P50m and N100m dipole sources Controversy exists regarding the origins of the middle and late responses {Reite, 1994 #77;Reite, 1988 #17;Onitsuka, 2000 #19}{Pekkonen, 1995 #78}. Our findings are in line with previous MEG studies that the locations for P50m and N100m generators are different {Huotilainen, 1998 #84;Kanno, 2000 #25;Borgmann, 2001 #23; Onitsuka, 2000 #19}. The P50m source was in general slightly medial to the N100m source in the supratemporal plane {Kanno, 2000 #25} (Figure 1). Of note, the stimuli given and the MEG instrumentation used (a whole-head neuromagnetometer) in the study by Kanno et al. (2000) were similar to those employed in the current study {Kanno, 2000 #25}. The converging findings indicate a progressive activation of neural substrates in the primary auditory cortex corresponding to the time course of the AEFs {Borgmann, 2001 #23}. Numbers of recording channels and types of acoustic stimuli as employed in different studies might have contributed to the equivocal source locations among the reported MEG studies. Contralateral dominance of P50m and N100m in normal hearing subjects and ISSNHL patients The finding of a contralateral dominance of both P50m and N100m in terms of peak dipole strength by monaural stimulation on normal subjects in the present study is congruent with previous MEG and fmri reports {Ackermann, 2001 #26;Suzuki, 2002 #51;Jacobson, 1994 #5} (Table 1 & 2). This hemispheric lateralization can be attributed to the prevailing cross-hemispheric projections in the auditory pathway and has been suggested to subserve in part the function of sound localization {Moore, 1991 #53}{Casseday, 1977 #117}. In fact, this pattern of contralateral dominance can be observed at level as low as the inferior colliculus {Shepherd, 1999 #54; Moore, 1984 #114;Shmigidina, 1981 #116} which is upstream of the auditory pathway receiving cross-hemispheric projections from cochlear nucleus in the brainstem {Hausler, 2000 #47}. Although the crossing is incomplete with bilateral projections, a large body of evidence has shown that contralateral pathways and the contained excitatory representations are preponderant than ipsilateral ones {Park, 1994 #112;Moore, 1983 #113}. At the cortical level, there are additional crossings from ipsilateral to contralateral auditory cortex via the posterior corpus callosum {Hausler, 2000 #47;Woldorff, 1999 #73}. It is reasonable to infer that the number of subpopulations of neurons can be also more abundant in the contralateral hemisphere

10 {Rojas, 2001 #88}{Murakami, 2003 #156}. Such anatomical architecture may underlie the enhanced P50m- and N100m-neuromagnetic activity (amplitude) of the contralateral auditory cortex upon monaural acoustic stimulation. Faster P50m and N100m responses over contralateral hemispheres in controls and ISSNHL Cortical auditory processing of monaural auditory input has been suggested to evolve across two stages: (a) initial excitation of larger contralateral and smaller ipsilateral pool of cortical neurons, yielding a larger response over the hemisphere opposite to the ear stimulated (contralateral dominance); (b) subsequent activation of the additional neurons at either side via transcallosal connections {Ackermann, 2001 #26}. It is known that the latencies of ipsilateral ABRs, MLAEFs, and LLAEFs are longer than the homologous ones of contralateral hemisphere upon monaural stimulation in normal-hearing subjects {Quaranta, 1986 #102;Makela, 1993 #87;Jacobson, 1994 #5}. This longer peak latencies of ipsilateral AEPs/AEFs can be attributed in part to the aforementioned delayed transcallosal activation in the ipsilateral auditory cortex {Ackermann, 2001 #26;Woldorff, 1999 #73}. Abnormally prolonged peak latencies for components of ABRs may indicate a central conduction defect {Hansen, 1989 #99} with an implication of organic lesion, e.g., acoustic neuroma {Cheng, 2003 #98} or inflammatory process {Jacobson, 1986 #120}. Ipsilaterally localized central lesions may result in a significant delayed middle-latency auditory-evoked cortical response {Kaseda, 1991 #101}. The observations that all our ISSNHL patients had normal latencies of ABRs, P50m, and N100m (Table 1 & 2, Figure 3) may imply that the latency alone may be not as a sensitive parameter as amplitude to index for the subtle functional modulation/plasticity in the ISSNHL of slight to moderate degree albeit the possibility of structural changes at different levels of auditory pathways. Healthy-side dominance of P50m and N100m in patients with ISSNHL One major and novel finding in the present study is the healthy-side dominance for P50m in the studied ISSNHL patients (Table 1, Figure 1). This is the first MEG study reporting such observation of middle-latency neuromagnetic responses to monaural stimulation on both healthy- and affected-ear in patients with acute unilateral ISSNHL. The contralateral dominance of P50m on monaural stimulation in normal-hearing subjects was lost in the unilateral ISSNHL and was replaced by the phenomenon of healthy-side dominance. P50m dipoles were significantly stronger

11 in ipsilateral hemisphere to the healthy ear irrespective of the side of monaural stimulation, i.e., either intact or affected ear (Table 1, Fig 1). P50m functionally index automatic auditory processing underlying stimulus detection {Pekkonen, 2004 #74}, and is one of the initial cortical representations of transient sounds {Rupp, 2002 #3}. Our finding thus confirmed that the functional modulation of the central auditory pathway, i.e., the loss of contralateral dominance on healthy ear stimulation, can occur within the first few tens of milliseconds as transient sound arrives at the auditory cortex in patients with acute unilateral ISSNHL. The emergence of healthy-side dominance of N100m in a small group of patients with acute unilateral ISSNHL was previously reported in our recent MEG study {Po-Hung Li, 2003 #18} and was verified again herein with a larger sample size. N100m dipoles were significantly stronger over ipsilateral hemispheres to healthy ears irrespective of the side stimulated (Table 2, Figure 1). Patients in other related MEG studies were all chronic in disease course and were either deaf or with profound hearing loss {Vasama, 1995 #21;Fujiki, 1998 #11}. The severity of hearing deficit (also structural insult) was neurophysiologically confirmed by the compromise of N100m responses to affected-ear stimulation since the presence of N100m implies the cortical detection and processing of sound given {Parasuraman, 1980 #76;Naatanen, 1987 #56;Oates, 2002 #24}. Therefore, the authors reported only a stronger response over the hemisphere ipsilateral to the stimulation of healthy ear. On the contrary, patients studied in the current study had mild to moderate degree of hearing loss only (threshold of affected ears at 1000 Hz 60 db HL), giving the opportunity to study the cortical reactions in response to the stimulation of the affected ear. The intensity of stimuli used (70 db SPL at 1000 Hz) was about 10 db above the hearing threshold of our ISSNHL patients. Stimuli with the intensity of 10 db or so above the hearing threshold would be clearly audible to patients with moderate degree of hearing loss as is indexed by the auditory evoked responses {Oates, 2002 #24}. N100m responses to affected ears stimulation were clearly identified in all patients in our study. It should be born in mind that the AEFs measured by MEG stand for the final representations of the activity along the auditory pathway. Without segmental information of the entire pathway, it can be difficult to precisely posit where the origin of plasticity occurs, e.g., cortical or subcortical levels {Garcia, 2000 #107}. One possibility for the explanation of the loss of contralateral dominance in AEFs upon stimulation of healthy ear in the absence of cortical lesion is that the effect of cochlear lesion(s) might be bilateral through retrocochlear crossing fibers to influence the function of the auditory pathway ipsilateral to the healthy ear. Plasticity

12 in the expression, placement or composition of some molecular elements, e.g. receptors and/or neurotransmitters, as a result of changes in sensory input, e.g., deafness, had been reported {Sato, 2000 #38; Potashner, 2000 #34}. Chemical cues signaling auditory plasticity, probably in terms of changes in neurotransmission/neuromodulation generated by the cochlear nuclei of affected side, can be carried to neuronal substrates in the intact side of central auditory pathway through direct and/or indirect fiber projections within 2 days after insult {Potashner, 2000 #34;Smith, 2002 #105}. This provides auditory system with a capacity of synaptic fine tuning for an optimization of processing requirements and to react/adapt to changes of input {Sato, 2000 #38}. Another possible explanation on the loss of contralateral dominance in ISSNHL patients in response to healthy-ear stimulation is the involvement of the corticofugal auditory pathway {Suga, 2002 #58;Casseday, 1977 #117}. This descending auditory pathway encompasses bilateral fibers coming from the auditory cortices and mediates physiological feedbacks to fine tune the subcortical neurons {Yan, 1999 #32}. The aforementioned chemical cues might also be carried to cortical auditory neurons of corticofugal projections {Potashner, 2000 #34}, which in turn may in the presence of peripheral lesion modulate the hearing function by redistributing the information processed in the auditory cortex to subcortical centers {Morand, 2001 #75}{Khalfa, 2001 #60}. The modulation may have effect on the auditory processing at level as low as the hair cell of the cochlea {Xiao, 2002 #59;Huffman, 1990 #82}. This descending influence may be either transient or permanent {Suga, 2002 #58}. The observation of ipsilateral dominance on healthy-ear stimulation for both P50m and N100m dipole strength (Table 1 & 2) could possibly be ascribed to a conjoined contralateral inhibition (or loss of excitation) and an enhanced ipsilateral excitation (or loss of inhibition) in response to healthy-ear stimulation {Hsieh, 2002 #62} (Figure 2). In an operational context, such readjustment could be one facet of overall adaptive process of ISSNHL and mirror the functional status of the patients. Animal studies have revealed a down-regulation of both ipsilateral excitatory receptor expression/binding (loss of excitation) {Sato, 2000 #38} and contralateral inhibitory neurotransmitters synthesis (loss of inhibition) {Mossop, 2000 #83} with respect to the affected ear in the central auditory pathway, i.e. contralateral inhibition and enhanced ipsilateral excitation with respect to the healthy ear. Hence, central auditory neurons can up- or down-regulate their firing rates for changes in the number and strength of synaptic inputs {Salvi, 2000 #124}. The deafness-related changes after cochlear ablation can emerge along the auditory pathway up to the level of inferior

13 colliculus and can occur within minutes after cochlear damage {Mossop, 2000 #83}. In turn, the effect of these changes might affect subcortical and/or cortical auditory neuronal substrates through projecting fibers from the inferior colliculus {Hausler, 2000 #47}. The above changes may contribute to alterations in auditory processing following sensory deprivation {Vale, 2002 #46}. It is noteworthy that multi-unit recordings of responses to stimulation of intact ears also showed a greater excitation in neurons of ipsilateral central auditory pathway after contralateral cochlear ablation {Mossop, 2000 #83}. Functionally, this enhanced ipsilateral excitation might be a compensatory mechanism operating between the cortex and cochlea meant to increase the gain of the system and partially correct for the reduced cochlear input {Salvi, 2000 #124}. Since the contralateral dominance in the normal subjects services in part the function of sound localization, this specific pattern of plasticity might have some relevance in preventing the neural network for locating sounds in the environment from delivering erroneous signals central-ward {Michler, 2002 #129}. Although the audiometry exams in the present study pointed toward a possible lesion in the cochlea, the auditory plasticity might be coupled with anatomical changes at different levels of auditory pathway. Decreased afferent inputs, e.g., cochlear destruction, can cause dramatic adverse molecular effects on neurons in central auditory pathway within hours of cochlear damage {Durham, 2000 #35;Born, 1985 #39}. Some of those neurons will even die or shrink in size within days {Durham, 2000 #35;Born, 1985 #39}. Besides, the increased activity may reflect the formation of new synapses and even the emergence of additional afferent fibers in the ipsilateral pathway {Salvi, 2000 #124}{Kitzes, 1995 #155}. These may be initiated by the increased synthesis of growth factors in response to the damage {Smith, 2002 #105}. Conclusions Our data has illustrated that central auditory plasticity can be induced by peripheral lesion. The neurophysiological evidence of functional reorganization of central auditory pathway in acute unilateral ISSNHL patients can be found at the very early central processing of transient sounds arriving at the auditory cortex. The wide ranges of neuroanatomical and neurochemical changes observed in the central auditory pathway following peripheral hearing loss might underpin the neuromagnetic changes. The convergence of neurochemical, neuroanatomical, and electromagnetophysiological studies at all levels of the auditory pathway can be a promising and mandatory approach to thoroughly explore the mechanisms of

14 functional neuroplasticity in ISSNHL. Further longitudinal studies are elucidative to address whether the temporal changes of dominance expression can serve as a prognostic indicator in clinical settings.