C with magnetoencephalography (MEG), which offers

0145-6008/98/2203-0605$03.00/0 AI.COHOLISM: CLINICAL AND EXPFRIMENTAL RESEARCH Selective Acceleration of Auditory Processing in Chronic Alcoholics during Abstinence Eero Pekkonen, Jyrki Ahveninen, liro P. Jaaskelainen, Kaija Seppa, Risto Naatanen, and Pekka Sillanaukee Simultaneous auditory processing between the hemispheres was studied with a whole-head magnetometer in 13 abstinent chronic alcoholics and 10 healthy control subjects. Auditory stimuli were presented monaurally with interstimulus intervals of and sec in different blocks. The NlOOm response, which contributes to stimulus detection, was significantly accelerated in the hemisphere ipsilateral to the ear stimulated in abstinent alcoholics. The MMNm response reflecting automatic stimulus-change detection peaked earlier in alcoholics, and the ipsilateral NlOOm latency correlated significantty with the abstinence duration. These results suggest that auditory processing is accelerated in the auditory cortex ipsilateral to the stimulated ear in chronic abstinent alcoholics and that the accelerated processing is at least partly reversible. This may be caused by the hyperexcitation in the brain related to the ethanol withdrawal. Key Words: Alcoholism, Auditory-Evoked Fields, Magnetoencephalography, Auditory Processing, Event-Related Potentials. EREBRAL ACTIVITY can be studied noninvasively C with magnetoencephalography (MEG), which offers high spatial and temporal resolution.' Repeated auditory stimuli elicit in humans two prominent auditory evoked magnetic field responses (AEiFs) called P50m and NlOOm, which peak at -50 and 100 msec after the stimulus onset, respectively.2 These responses appear even when no attention is paid to the tones and, therefore, they reflect automatic stimulus processing preceding stimulus detection. When deviant tones are embedded randomly in a sequence of repetitive standard tones, they evoke a specific response called the magnetic mismatch negativity (MMNm), peaking at -100 to 200 msec after stimulus onset.* The MMNm is elicited by the deviant stimuli irrespective of whether attention is paid to the tones, presumably reflecting preconscious stimulus-change dete~tion.~.~ Previous MEG studies have found that P50m, NlOOm, and MMNm are mainly From the Cognitive Brain Research Unit, Department of Psychology (E.P., J.A., I.P.J., R.N.), and the Department of Neurology (E.P.), Universip of Helsinki, Helsinki, Finland; BioMag Laboratoty (E. P., I. P.J.), Medical Engineering Centre, Helsinki University Central Hospital, Helsinki, Finland; Medical School (KS., P.S.), University of Tampere, Tampere, Finland; Department of Psychiatry (KS.), Tampere University Hospital, Tampere, Finland; and Alcohol Related Diseases (P.S.), PhannaciaUpjohn AB Diagnostics, Uppsala, Sweden. Received for publication May 15, 1997; accepted December 27, 1997 This work was supported by the Finnish Foundation for Alcohol Studies and the Academy of Finland. Reprint requests: Eero Pekkonen, M. D., Ph. D., BioMag Laboraioly, Medical Engineering Centre, Helsinki Universip Central Hospital, P. 0. Box 508, 00029 HYKS Helsinki, Finland. Copyright 0 1998 by The Research Sociep on Alcoholism. Alcohol CIin Exp Res, Vol 22, No 3, 1998: pp 605-609 generated in or near the primary auditory cortex in the temporal lobe. In addition, P50m and especially NlOOm appear somewhat earlier over the contralateral than the ipsilateral auditory cortex to the ear stimulated in healthy subjects.495 Previous event-related potential (ERP) studies have found increased latencies of the brainstem [brainstem event-related potential (BAEP)] responses, which peak at -2 to 10 msec after stimulus onset, and decreased amplitudes of the N100, MMN, and P300 after acute administration of The P300, unlike NlOO and MMN. usually appears to the deviant tones only when subjects actively detect deviant tones in a sequence of standard tones. Together, these findings suggest that acute alcohol intake impairs both the preconscious and the subsequent conscious auditory processing. ERP studies have also shown that, during withdrawal soon after chronic alcohol abuse, there is a decrease in BAEP latencies and an increase in the amplitudes of the cortical ERPs, whereas after >3 weeks of abstinence, there is an increase in BAEP latencies and decreases in the MMN and P300 amplitude~.',~-'' We used a whole-head magnetometer to determine whether the preconscious parallel auditory processing and the automatic stimulus-change detection are affected by withdrawal in chronic alcoholics. MATERIALS AND METHODS Thirteen abstinent male alcoholics (mean age: 33 years, range: 33-55 years) and 10 healthy male age-matchcd control subjects (mean age: 41 years, range: 32-59 years) with normal hcaring were studied with the approval of the local ethical committcc. Patients had becn diagnosed a) alcoholics according to the DSM-IV critcria, and written informed c~nscnt was obtained from all subjects. Control subjects had no history of ncurological, psychiatric, or any other scvcrc diseases, and they did not use any drugs affecting the central nervous system. Their sclf-reported ethanol consumption did not exceed 18 standard drinks (12 g of ethanol.'drink) a week. Alcoholics had no history of severe head trauma, stroke, cpilepsy. Werniche-Korsakoff psychosis, severe psychiatric diseases, or any other system diseases. They had a history of heavy drinking - 17 years bcfore thc study (range: 5-25 years), with self-reported alcohol intake being 300 to 3156 giweek. They were abstinent on an average of 27 days (SD = 9. range: 13-43) before the MEG measurement. During the recording. seven patients were using antidepressant mcdication: three had citalopram (mean dose: 20 mgiday), two mianserin (mean dose: 75 mg in thc cvcnings), and two fluoxetine (mean dose: 15 mgiday). Recordings were performed between 9 AM and 1 PM in a magneticall) shielded room where the subject sat undcr the helmet-shaped dewar with his head against the bottom of the instrument. Each subject watched a 605

606 PEKKONEN ET AL. Alcoholic 61 r" Control Alcoholic Control r Fig. 1. Gradient field maps of the NlOOm for one healthy control and one alcoholic when the tones were presented to the left ear with the IS1 of sec. The helmet-shaped sensor array is viewed from the left and right sides. The magnetic field patterns with 5 ft isocontour lines show that the standard auditoty stimuli elicit maximal activity in the contralateral temporal lobe. Arrows demonstrate the sites and orientations of the equivalent current dipoles of the N100m. Maxmum responses for the standard tones over each hemisphere are shown enlarged. The NlOOm peaked earlier in the alcoholic than in the control over both hemispheres, but the difference was significant at the group ievel only over the ipsilateral cortex. o m w m s 0 silent video and was instructed not to attend to the tones presented monaurally through a plastic tube and earpiece. Subjective hearing threshold was measured before the recording separately for each ear, and the stimulus intensity was adjusted to 60 db above the threshold. Each stimulus block consisted of standard (80%) and randomly embedded deviant tones (20%), both 700 Hz in frequency. The duration of the standard tone was 50 msec and that of the deviant tone 25 msec with 5-msec rise and fall times. In all subjects, the stimulus block of sec interstimulus intervals (ISIS) to the left ear was first presented, followed by the sec IS1 to the same ear. Subsequently, the same stimulus blocks were separately presented to the right ear in the same order. In every block, the first 20 responses were omitted from the analysis. AEFs were recorded using a 122-channel, whole-head magnetometer (Neuromag Ltd.) measuring two orthogonal tangential derivatives of the magnetic field component normal to the scalp, at 61 locations over the head. The planar gradiometers of this device detect the strongest signal directly above a cerebral source. The accurate position of the subject's head relative to the gradiometers was determined by measuring the magnetic field produced by three marker coils attached to the scalp. Over 200 responses were averaged for the standard tone in the left-ear conditions with each IS1 and in the right-ear condition with sec ISI. Approximately 100 responses for the standard tone were in turn averaged in the right-ear condition with sec ISI. The total time for recording and hearing level measurements was -1 hr. For the deviant tone with sec ISI, >lo0 responses were averaged in the right-ear and left-ear conditions; in the left-ear condition with sec ISI, >40 responses were averaged. The analysis period was 750 msec, including a 150-msec prestimulus period. The recording bandpass was 0.03 to 100 Hz, with a sampling rate of 397 Hz. The vertical and horizontal electro-oculograms were recorded, and epochs coinciding with electro-oculogram or MEG changes exceeding 150 FV or 3000 ff/cm, respectively, were rejected from averaging. Digital bandpass-filtering was performed offline at 1 to 30 Hz. Peak latencies and amplitudes of the standard P50m and NlOOm were measured from the channel showing the largest response in four conditions. In contrast, MMNm was measured only at the left-ear condition with both ISIs, because in the right-ear condition with sec ISI, there were too few averaged deviant responses. MMNm was obtained by subtracting the standard AEF response from the deviant AEF response. The dipole locations were fitted at the latency maximum amplitude over each hemisphere separately with a fixed subset of 34 channels over each auditory cortex. The P50m and NlOOm responses were modeled as equivalent current dipoles' by a least-squares fit to the sec IS data. Correspondingly, the MMNm responses were modeled as ECDs by a least-squares fit to the sec data. The selection of the conditions for the modeling was based on the fact that P50m and NlOOm are usually larger for longer ISIs, whereas MMNm is usually larger for short ISIS.' A spherical head model was used for the dipole fitting. The center of symmetry was at (x, y, z) = 0, 0, 45 mm. The fitting was considered successful if the dipole explained >80% of the data of the selected subset of channels. MEG data were analyzed with the multivariate analysis of variance (MANOVA) for repeated measures to assess possible group and IS1 effects on the amplitudes and latencies of AEF responses. Unpaired and paired t tests were used when appropriate. Correlations between the AEF responses and abstinence duration were calculated with the Pearson correlation. RESULTS Figure 1 demonstrates the AEFs of one healthy control subject and one alcoholic to the standard tones with sec ISI, in which the responses were largest. Both subjects showed clear P50m and NlOOm responses over each hemisphere, with the contralateral responses being larger and earlier than the ipsilateral responses. In the alcoholic, the contralateral and ipsilateral NlOOm peaked earlier than in the control subject. MANOVA (group by ISI) was performed to assess possible group and IS1 effects on the absolute AEF peak latencies in the right-ear and left-ear conditions. The ipsilateral standard NlOOm peaked significantly earlier in the alcoholic group than in the control group in both the right-ear and left-ear conditions {right-ear condition [F(1,21) = 4.66,~ < 0.051 and left-ear condition [F(1,21) = 4.93,~ < 0.051). Additional unpaired t test showed that the ipsilateral NlOOm peaked significantly earlier in the alcoholics than in the controls with sec IS1 in the right-ear condition [t = 2.62, df = 20.1,~ < 0.05, 2-tail probability]; a similar trend was found in the left-ear condition [t = 2.07,

AUDITORY PROCESSING IN CHRONIC ALCOHOLICS 607 Table 1. lpsilateral and Contralateral Peak Latencies (+SD) in msec for P5Om and N100m in Each Group ~ Group Ear IS1 P50m N1 OOm P50m N100m (set) Alcoholics 55.7 2 9.9 50.0 + 8.9 51.6? 6.4 47.7 t 9.3 99.0 2 21.9 92.1 2 9.3 107.7 2 29.3 92.1 2 9.3 60.6 f 11.9 58.3 2 12.1 62.9 2 11.0 53.9 f 12.4 116.9 z 26.7 101.5 2 9.3' 111.7 2 21.4 105.6 r 13.2' Controls 54.9 2 9.1 40.0 2 10.8 54.7 2 9.5 48.0 5 8.8 108.9 -t 33.1 104.8 2 16.2 118.7 2 33.1 103.9 2 17.4 61.2 z 9.9 59.2 z 13.5 65.2 t 9.7 56.5 2 12.2 143.4 z 38.7 113.5 2 16.4 125.7 2 26.2 119.8 2 12.4 MANOVAs showed that the ipsilateral NlOOm peaked significantly earlier in the alcoholic group than in the control group in both the right-ear and left-ear conditions. 'p < 0.05. NIOOm peak latency (ms) 135 125 115 105 95 85 10 15 20 25 30 35 40 45 50 Abstinence (days) Fig. 2. Scatterplot shows the individual data points of the ipsilateral N1 OOm latencies with sec IS1 in the right-ear condition and the duration of abstinence in 13 alcoholics. In healthy controls, the ipsilateral N100m latency range was 119.8? 12.4 msec. There was a significant positive correlation between the NlOOm latency and the duration of abstinence (Pearson correlation). df = 13.36, p = 0.0591. Although the contralateral NlOOm peaked earlier in the alcoholics, the group differences were not significant: right-ear condition [F( 1,21) = 2.43, NS] and left-ear condition [F( 1,21) = 2.06, NS]. The contralateral, but not the ipsilateral NlOOm peak latency, decreased as a function of longer IS1 in the right-ear condition [F(1,21) = 4.90, p < 0,051, whereas the group X IS1 interactions were not significant. In the left-ear condition, the ipsilateral, but not the contralateral, NlOOm peaked earlier with longer IS1 [F(1,21) = 15.94,~ < 0,011. The group effect and group X IS1 interactions for the P50m latencies were not significant. Table 1 shows that there was considerable variation between individuals in the latency of the P50m and NlOOm peaks, and that AEFs peaked significantly earlier contralaterally than ipsilaterally in each group. Figure 2 demonstrates that there was a positive correlation between the ipsilateral NlOOm latency and the duration of ethanol withdrawal in the right-ear condition with sec IS1 (Pearson correlation = 0.8049, p < 0.001). The collapsed ipsilateral NlOOm latency had also significant correlation (Pearson correlation = 0.6554, p < 0.05), whereas correlations between the collapsed ipsilateral NlOOm latency with sec IS1 and contralateral NlOOm latencies with both ISIs in each condition were insignificant. Table 2 shows that the amplitudes of the P50m and NlOOm had a tendency to be larger over the contralateral than ipsilateral auditory cortex to the ear stimulated in both groups. In both the right- and left-ear conditions, the ipsilateral P50m amplitude increased significantly with longer IS1 (right-ear condition [F(1,21) = 6.73, p < 0.051 and left-ear condition [F(1,21) = 7.16, p < 0.051). The NlOOm peak amplitude increased significantly with longer IS1 and ipsilateral NlOOm {right ear-condition [F(1,21) = 49.01, p < 0.0011 and left-ear condition [F(1,21) = 76.71, p < 0.0011). The group effect or group X IS1 interactions for P50m and NlOOm amplitudes were insignificant. Table 3 shows the latencies and amplitudes of the MMNm in each group. MMNm latency had a significant group X IS1 interaction [F(1.21) = 9.77,~ < 0.011. Additional unpaired t test showed that the MMNm latencies were very similar with sec IS1 in each group, whereas with sec IS1 the alcoholic group had significantly earlier MMNm [p < 0.05, 2-tail probability]. The peak MMNm amplitudes did not differ between the groups (Table 3). Subanalysis between alcoholics with and without medication with unpaired t test found no significant differences in the amplitudes and latencies of the AEFs between ipsilateral and contralateral hemispheres, between right and left hemispheres, and between right-ear and left-ear conditions. The sources of the NlOOm could be modeled from all control subjects and from 11 alcoholics over each hemisphere in the right-ear and left-ear conditions with sec ISI. It was not possible to perform the source modeling in the two alcoholics because of a dysfunction of the marker coils during the recording. The P50m sources could be modeled from 5 controls and 7 alcoholics over the right hemisphere, and from 3 controls and 5 patients over the left hemisphere. The position of the NlOOm source (ZSD) from the midline in the right hemisphere was 54.9? 4.7 mm and in the left hemisphere 53.3 t 6.0 mm in alcoholics;

~ - 608 PEKKONEN ET AL. Table 2. Peak Amplitudes in ff/cm (+SD) for the Standard P50m and N100m Over the lpsilateral and Contralateral Auditory Cortices in Both Groups Group Ear IS1 P5Om NlOOrn P5Om NI OOrn Is=) Alcoholics 22.4 2 13.2 32.1 2 24.1 14.62 7.7 20.2 5 12.3 21.3? 10.4 115.1 2 57.3 22.8 t 14.0 73.0 t 28.0 17.0 -t 10.1 26.9 2 13.4 14.8 c 8.1 21.6? 14.9 26.4 2 15.6 87.3 c 42.9 18.7 6.8 62.6 2 37.2 Controls 16.6 c 9.8 26.8 -t 14.1 11.3 ;t 5.8 15.4 t 3.7 18.8 c 8.4 102.2 2 39.3 13.7 2 4.3 63.3 2 29.0 18.3? 14.0 21.2 c 9.9 9.5 2 7.1 19.0 c 9.0 20.0 c 11.3 95.3? 43.2 14.0 2 6.4 75.0 2 30.6 Tones were presented separately to the lefl and right ear in all subjects. AEFs were larger contralaterally in both groups, except for the alcoholics' P50m with sec IS1 in the left-ear condition. There were no significant group effects. Table 3. Peak Amplitudes and Latencies of the MMNm Elicited by the Deviant Tones in the -Ear Condition MMNm Latency Group IS1 Amplitude (fflcm) (msec) (SS) Alcoholics 29.5 c 7.7 185.2 c 27.9 30.3 2 12.1 165.5? 29.3' Controls 3? 15.7 178.2 -c 29.1 30.1 2 8.6 211.5 2 47.6 MMNm was measured over the hemisphere where it was largest. MANOVA showed a significant group x IS1 interaction of the MMNm latency. Alcoholics had a significantly earlier peak MMNm with sec IS1 than controls. The MMNm amplitudes were similar in both groups. 'p < 0.05. corresponding values were 53.7 2 7.8 mm and 53.7 2 6.5 mm in the controls. Accordingly, the P50m source from the midline in the right hemisphere was 59.1? 4.3 mm and in the left hemisphere was 45.2 2 3.9 mm in alcoholics, whereas corresponding values in the controls were 57.4 2 6.9 mm and 49.1 _t 9.8 mm. The NlOOm source in the right hemisphere was 7 2 4.7 mm posterior and in the left hemisphere 4? 0.6 mm posterior in the alcoholics than controls. The P50m source in the right hemisphere was about the same for each group, whereas the P50m source in the left was 4? 3.1 mm posterior in the alcoholic group. However, the sites of P50m and NlOOm in each hemisphere did not differ significantly between the groups. The MMNm sources could be modeled in 6 control subjects and 3 alcoholics in the left-ear condition with sec ISI. One subject in each group had larger MMNm over the ipsilateral temporal lobe. The MMNm sources (?SD) were, on average, 54 2 6 mm from the midline in the control group and 52 2 2 mm in the alcoholic group. The MMNm source was -7 mm more posterior in the alcoholic group than the control group. The MMNm sources did not differ significantly between the groups. DISCUSSION This is the first MEG study demonstrating that preconscious parallel auditory processing between the hemi- spheres, which precedes the higher cerebral functions, is selectively altered in chronic alcoholics after abstinence of -4 weeks. Specifically, the NlOOm latency differences between the groups point to accelerated auditory processing in the ipsilateral auditory cortex to the ear stimulated in chronic alcoholics. Although the ipsilateral processing is speeded up in alcoholics, they still process auditory information the same way as healthy subjects (i.e., information is processed in the contralateral auditory cortex earlier than in the ipsilateral auditory cortex).475 Our study also demonstrated that ipsilateral NlOOm latency increases with the duration of abstinence (i.e. that the difference between groups gradually disappeared), suggesting at least a partly reversible nature of auditory dysfunction in abstinent alcoholics. This finding supports previous results that alcohol withdrawal is accompanied by cerebral hyperexcitation, causing auditory responses to be accelerated at the beginning of the abstinence peri~d.""~ The present results suggest that withdrawal hyperexcitation affects ipsilateral auditory processing more intensively than contralateral processing. Even the contralateral NlOOm tended, although not significantly, to peak earlier in the alcoholic group. In this study, the range of the abstinence duration was 13 to 43 days. An interesting question, which merits further study, is also whether contralateral processing is speeded up with shorter abstinence. The present results did not show significant differences between alcoholics and controls in the peak amplitudes of the P50m and NlOOm, although the mean amplitudes of both AEFs were larger for 7 of 8 comparisons in the alcoholics. Furthermore, the NlOOm source was slightly more posterior in the right hemisphere in the alcoholic group. Because of the relative small sample size in our study, we cannot exclude other possible effects on the activity and position of the AEF generators in alcoholics. Interestingly, a previous MEG study showed that ipsilatera1 auditory processing is delayed in patients with Alzheimer's disease (AD),12 whereas it was accelerated in alcoholics in this study. One possible explanation for the functional difference between AD patients and alcoholics may be that, although both AD patients and alcoholics have

AUDITORY PROCESSING IN CHRONIC ALCOHOLICS OII I a loss of neurons, the diseases affect different neural networks in the brain.i3 In this study, 7 of 13 alcoholics used antidepressant medication during abstinence. However, subanalysis showed that the medication did not cause the significant latency and amplitude differences of the AEFs of the alcoholic group. Therefore, it is unlikely that medication alone can explain the accelerated auditory processing in alcoholics. Previously, it has been shown that acute ethanol exposure decreases MMN amplitude, implying that ethanol impairs automatic detection of acoustic changes. On the basis of the present data, it seems that chronic alcoholics have unimpaired automatic stimulus-change detection and, furthermore, their auditory system can automatically store a memory trace for at least sec. This finding somewhat contradicts the results obtained by Realmuto et al., who showed in their ERP study that MMN was reduced in alcoholics. They measured, however, MMN directly from the deviant response wave calculating peak-to-peak amplitude, whereas in this study MMNm was measured from the subtraction wave with respect to the prestimulus baseline. Furthermore, they presented tones binaurally using an IS1 of 1.5 sec. Thus, differences in methods may explain at least partly the differences in the results. Previous studies have demonstrated that the contralateral NlOOm appears about 10 msec earlier than the ipislateral response in young healthy subjects, with ISIs longer than 1 sec.5314 A hemisphere latency differences of -20 msec has been reported in older subjects with sec ISI. The present results showed an almost 35 msec difference between the latencies of ipsilateral and contralateral NlOOm in the left-ear condition, with a sec IS1 in middle-aged controls. With a sec ISI, however, this difference was decreased to 8.7 msec. This suggests that there are refractory differences between the ipsilateral and contralateral NlOOm generators. In other words, the recovery period of the neuron population of the ipsilateral NlOOm generator seems to be lengthened, compared with the contralateral NlOOm generator. The majority of the fibers in the auditory system cross the midline and ascend to the contralateral auditory cortex, whereas only a relatively small proportion of axons reach the ipsilateral auditory cortex.16 Fibers of both nerve bundles relay in the thalamus, which is the main gating structure being modulated by the GABAergic inhibitory transmission from the basal ganglia. It has been proposed that chronic ethanol exposure decreases the GABAergic activity, which is the major inhibitory transmitter in the brain, and that alcohol withdrawal enhances glutaminergic activity, which is the most important excitatory transmitter in the ~ortex. ~ ~ ~ The inhibition of the GABAergic system, together with the enhanced glutaminergic activity, leads to excitotoxic damage in the brain. That greater changes are found in the ipsilateral auditory processing may be caused by it being mediated by the smaller nerve bundle, making it more vulnerable to the alcohol-related excitotoxic damage in the brain. Heavier myelination and better neural synchrony along the contralateral auditory pathway might also make it more resistant to toxicological influences. In summary, our results suggest that auditory processing is accelerated in the auditory cortex ipsilateral to the ear stimulated in chronic abstinent alcoholic5. and that accelerated processing is at least partly revcrsihle. 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