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OPEN a.•ACCESS Reidy Vialliblit Online .OPL0S ONE Dissociation of Detection and Discrimination of Pure Tones following Bilateral Lesions of Auditory Cortex Andrew R. Dykstra w a, Christine K. Koh2'3, Louis D. Braida w , Mark Jude Tramol ' 2'3° 1 Program in Speech and Hearing Bosoences and Technology, Harvard-MIT Division of Health Sciences and Technology, Cambridge• Massachusetts, United States of America, 2 The Institute for Music and Brain Science, Auditory Neuroscience Program, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston• Massachusetts. United States of America, 3 Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America Abstract It is well known that damage to the peripheral auditory system causes deficits in tone detection as well as pitch and loudness perception across a wide range of frequencies. However, the extent to which to which the auditory cortex plays a critical role in these basic aspects of spectral processing, especially with regard to speech, music, and environmental sound perception, remains unclear. Recent experiments indicate that primary auditory cortex is necessary for the normally- high perceptual acuity exhibited by humans in pure-tone frequency discrimination. The present study assessed whether the auditory cortex plays a similar role in the intensity domain and contrasted its contribution to sensory versus discriminative aspects of intensity processing. We measured intensity thresholds for pure-tone detection and pure-tone loudness discrimination in a population of healthy adults and a middle-aged man with complete or near-complete lesions of the auditory cortex bilaterally. Detection thresholds in his left and right ears were 16 and 7 dB HL, respectively, within clinically- defined normal limits. In contrast, the intensity threshold for monaural loudness discrimination at 1 kHz was 6.512.1 dB in the left ear and 6.511.9 dB in the right ear at 40 dB sensation level, well above the means of the control population (left ear: 1.6=0.22 dB; right ear: 1.710.19 dB). The results indicate that auditory cortex lowers just-noticeable differences for loudness discrimination by approximately 5 dB but is not necessary for tone detection in quiet. Previous human and Old- world monkey experiments employing lesion-effect, neurophysiology, and neuroimaging methods to investigate the role of auditory cortex in intensity processing are reviewed. Citation: Dykstra AR, Koh CK, Breda LD, Tramo Ml 12012) Dissociation of Detection and Discrimination of Pure Tones following Bilateral Lesions of Auditory Cortex. PLoS ONE 7(9): e44602 dol:10.1371/joumalpone.0044602 Editor. Jun Vail, Hotchkiss Brain Institute, University of Calgary• Canada Received November 19. 2011; Accepted August 9, 2012; Published September 5, 2012 Copyright C 2012 Dykstra et al Ibis is an open-access ankle distributed under the teems of the Creative Commons Attribution License, whkh permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This wait was supported by NIH (http://lwrw.nih.gova DC03328• DC006353, DC00117, T32-DC00038, The Harvard.MIT Division of Health Sciences and Technology (httpd/hst.miLedu/indexisp). and The Institute for Musk and Brain Science Ihnp/Neww.brainmusk.org/). The funders had no role in study design• data collection and analysis, decision to publish, or preparation of the manuscript Competing Interests: the authors have declared that no competing interests exist. • E-mail: Andrew.Dykstratlmeduni-heidelbergde Current address: Departments of Neurology and Music, University of CalWomia Los Angeles, Los Angeles, California. United States of America Introduction about its size, location, movement, significance, and identity. Humans and animals modulate the loudness of vocal communi- By the close of the 20th century, it seemed reasonably well- cation sounds to convey meaning and emotion, and musical established on the basis of neuropsychology studies in patients and dynamics is a key ingredient of musical aesthetics. Normal adults selective-ablation experiments in animals that auditory• cortex was demonstrate remarkably high perceptual acuity for loudness devoted to higher functions such as pattern recognition but played changes under optimal listening conditions: the just noticeable little or no role in elementary functions invoking discrimination of difference (jnd) for two-tone loudness discrimination is less than a single acoustic feature and its corresponding percept (e.g., pure- 1 dB at moderate and higher intensities throughout almost the tone intensity and loudness; for review see [1,2]). However, entire audible spectmm (for review see [7]). Given recent evidence experiments with neurological patients employing rigorous that auditory cortex supports high perceptual acuity for pure-tone psychoacoustic methods and in vivo lesion localization have since pitch perception [3,6], we hypothesized that it also subserves fine- demonstrated that lesions of auditory• cortex impair pure-tone grained loudness perception. frequency processing and pitch discrimination, even when pure- This idea is supported by recent studies utilizing functional tone audiograms are within normal limits [3-6]. These observa- neuroimaging which showed increased IMR1 activation in the tions suggest a dissociation between the effects of auditory cortex auditory• cortex with increasing sound level (see, e.g., [8-11]), lesions on auditory sensation (i.e., detecting the presence of particularly in posteromeclial portion of the tranverse gyms of a sound) and auditory perception (i.e., determining whether and Heschl (TG) [8,11], the presumed core area of human auditory how two sounds differ in one or more attributes). cortex [12-14]. However, such correlational studies cannot The present study focuses on pure-tone intensity processing in establish the necessity Ma given structure for a particular function, relation to tone detection and loudness perception. The loudness and psychoacoustic experiments with neurological patients who of a sound source and its change over time conveys information have bilateral auditor• cortex lesions provide strong tests of PLOS ONE I www.plosone.org September 2012 I Volume 7 I Issue 9 I e44602 EFTA01100139  Auditory Cortex and Loudness Perception hypotheses about the functional role of human auditory cortex in 35 auditory sensation and perception. While the rarity of cases with - Right Ear bilateral lesions limits the inferences one can draw about structure- function correlates in the general population, single-case studies - Left Ear 30 - - ANSI 3.6-2004 provide an important means of establishing existence proofs. This paper reports the results of a series of original experiments examining loudness perception in a population of normal adults 2 25 and a middle-aged, mixed-handed man, Case Al+, with chronic, C- bilateral middle cerebral artery (MCA) infarcts that include all of (r) kft and right primary auditory cortex (Al) and much of auditory -C 20 association cortex (AA). We predicted that: I) jnd's for tone loudness discrimination ("louder"-"softer" judgments) would be greater in Case Al+ than normals; 2) his jnd's would be greater in the ear contralateral to the larger (right MCA) lesion; and 3) his tone loudness discrimination would be impaired out of proportion to tone detection. Materials and Methods 5 Ethics Statement All procedures were approved by the Institutional Review Boards at the Massachusetts General Hospital (MGH) and the 0 • 125 250 500 1000 2000 4000 Massachusetts Institute of Technology (MIT), and mitten in- formed consent was obtained from all participants prior to their Frequency (Hz) participation. Figure 1. Case AI+ pure-tone audiogram for left-ear (filled Participants symbols) and right-ear (open symbols) presentation. Clinically. defined normal limits extend 25 dB above the dotted line, which Case Al+. Case Al+ is a 46-year old mixed-handed man who indicates the average threshold from the ANSI standard. suffered ischemic infarcts in the distribution of the right middle doi:10.1371/joumal.pone.0044602.9001 cerebral artery in 1980 and the left middle cerebral artery in 1981. He has twelve years of education and is not trained in music on the telephone as well as difficulty localizing sounds. He was performance or theory. At the time of the present experiments, he alert, attentive, and without complaints throughout the psycho- was the primary caretaker of his and his wife's three young acoustic experiments. children and was on warfarin anti-thrombotic therapy and Normal controls. Eleven age-matched right-handed adults phenytoin anti-convuisant therapy. (7 female, 4 male) participated as normal controls (median Details of the clinical history, neurological and audiological age = 41 years, range = 32 50 years). None reported a history of examinations, and radiographic findings have been reported neurological disease or hearing impairment, and none were previously [4,6,15,16]. In brief, the first cardioembolic stroke formally-trained musicians or actively performing music. presented with left hemiplegia and left hemisensory loss; the second presented only with complete km of hearing. Detection of tones and natural sounds at moderate and high intensities returned Stimulus Delivery and Data Collection within a month, but perception of speech, music, environmental Participants sat in a double-walled sound-attenuated booth and sound, and sound source location remain impaired. At the time faced a computer monitor on which instructions, visual cues, and the current study was conducted, Case Al+ had thresholds which feedback were given. Participants entered their responses using were within clinically-defined normal limits (Fig. I). a computer keyboard. All stimuli, except for pure tone audiometry Multi-planar MRI sections were acquired four months after the in normal control subjects, were generated digitally using present psychoacoustic experiments using a Siemens TIM Trio MATLAB (The Mathwodcs) and converted to analog waveforms Tr. Lesion localization was analyzed on fluid-attenuated in- by a LynxOne (LynxStudio) 24-bit soundcard with a sampling version-recovery (FLAIR) sequences. Contiguous sections were frequency of 32 kHz. The stimuli passed through programmable 1.0 mm-thick with an in-plane resolution of 0.94 mm2 attenuators run PA4, Tucker Davis Technologies) and head- (FE = 494 Ins, TR = 6000 ins, IT= 2100 ms, flip angle = 120). phone buffers (CDT HB6, Tucker Davis Technologies) before Selected parasagittal, corona', and horizontal MM sections presentation to the subject via HD580 headphones (Sennheiser). through superior temporal cortex are illustrated in Fig. 2. Abnormal HAIR signal involves all of the right TG, all of left Pure-tone Detection TG, all or almost all of right superior temporal gyms (STG), A two-interval, two-alternative, forced-choice (2I-2AFC) para- a portion of left STG posterior to TG, and underlying white digm with a 2-down, I -up adaptive procedure was used to matter, including the geniculo-temporal radiation. The right- measure the minimum intensity Case Al+ needed to detect the hemisphere lesion extends into adjacent frontal, temporal, and presence of a 1-kHz, 500-ms pure tone with a response accuracy of parietal areas; the smaller left-hemisphere lesion extends into 70.7% [I'll. Each interval's occurrence was indicated visually by adjacent temporal and parietal areas. Comparison with previous one of two boxes on the computer screen labeled "I" and "2"; box MRI sections through superior temporal cortex found no change 1 flashed during the first interval and box 2 during the second [4]. interval. The target tone (duration = 500 ms, 20-ms raised-cosine At the time of the present experiments, Case AI+ reported ramps) was randomly assigned to the first or second interval; no difficulty perceiving speech - especially in noisy environments and stimulus was present in the other interval. The threshold for each PLOS ONE I www.plosone.org 2 September 2012 I Volume 7 I Issue 9 I e44602 EFTA01100140  Auditory Cortex and Loudness Perception Figure 2. Case A1+ MRI FLAIR sequences. (A,B) Parasagittal sections through the left and right hemispheres. Leh TG is atrophic and right TG is replaced by encephalomalacia (low signal intensity). lschemic demyelination and retrograde degeneration within adjacent white matter regions appear as areas of high signal intensity. (C) Coronal section through the mid•portion of left and right TG and STG. (D) Horizontal section through left and right TG and SM. See text for image acquisition parameters. doi:l0.1371/joumal.pone.0044602.9002 not was defined as the mean dB SPI, of the last six turnaround tones was randomized on each trial. Listeners judged whether the points. Thresholds in llama's were measured with an Inter- second tone was "louder" or "softer" than the first tone. acoustics Diagnostics Audiometer (AD229e) and Telephonics Intensity difference thresholds were expressed as AL = I 0lo- headphones (I'DH-39P) using a modified Hughson-Westlake gl0[(1+AI)/IA 114 A 2I-2AFC, 2-down, I -up adaptive procedure procedure. tracked the 70.7% correct point on the psychometric function. In order to maximize the number of observations made near Loudness Discrimination threshold, step size was decreased serially (AL = 2A5, 1.48, On each trial, two 1-kHz pure tones were presented. Each tone 0.54 dB) over the course of the run. Threshold for each run was had a duration of 500 ms and was gated on and off with 20-ms defined as the mean AL of the last six turnaround points after the raised-cosine ramps. The two tones were separated by an inter- smallest step size had been reached. stimulus interval (ISI) of 200 ins. The same 2I-2AFC procedure Normal listeners participated in three left-ear runs and three used for pure-tone detection was used here. One tone was at the right-car runs. Contralateral noise at a level (per equivalent reference intensity (I =65 dB SPI, for normal controls, I =40 dB rectangular bandwidth) of 20 dB below the target was presented in SL for Case Ali). The intensity of the "test" tone (I+Al) differed order to prevent the use of the contralateral ear in performing the slightly in intensity from the reference by adding a -kHz, in-phase task [19]. The start car was pseudorandomized across subjects tone to the reference tone. 'Ile order of the reference and test such that an equal number of subjects started in each ear. Subjects PLOS ONE I www.plosone.org 3 September 2012 I Volume 7 I Issue 9 I e44602 EFTA01100141  Auditory Cortex and Loudness Perception performed three or more practice nuts until performance neurologically dissociable. In addition, the fact that Case Al+ was plateaued. able to perform louder-softer judgments, albeit at much higher AL Case Al+ participated in six runs for each ear. We did not thresholds, indicates that auditory structures spared by his strokes present contralateral masking noise. Blocks were counter-balanced specifically left anterior auditory association cortex and/or the by car using an ABBA paradigm: Right ear, left ear, kft ear, right auditory brainstem can mediate coarse loudness perception. car, with three nms per block. The start ear was randomly chosen. It should be noted here that the test conditions for Case Al+ Case Al+ performed three or more practice nuts until perfor- and normals were not identical (see Methods). However, based on mance plateaued. our review of relevant literature on the differences between one- and two-interval forced-choice tasks [20] as well as the effects of Results contralateral masking noise [21] and reference intensity level [7] on loudness discrimination thresholds, it is unlikely the differences Intensity Thresholds for Pure-tone Detection affect our conclusions. In fact, the fact that we used contralateral Fig. 3A shows pure-tone detection thresholds for Case Al+ and masking noise in our control population and not in Case Alt may the eleven normal controls. All were within normal clinical limits have underestimated his deficit. It is also unlikely that the observed [defined as 33 dB SM. at I kHz]. For Case Al+, the detection deficits in Case Al+ are attributable to non-modality specific threshold in the left ear, which is contralateral to the larger lesion, effects of his lesions. First, we did not observe signs of fatigue was IS dB SPL; the detection threshold in the right car was 9 dB during testing, and there was no significant order effect across SPL His kit-ear threshold was within one standard deviation (SD) blocks. Second, his intensity thresholds for pure-tone detection of the mean (NI) of the control population (NI ± were normal and were measured with an adaptive procedure that SD = 14.416.0 dB SPL). His right-ear threshold was within 2 was as demanding as the one used to measure loudness SDs of the control mean (NI ± SD = 19.815.6 dB SPI.), though discrimination. lastly, previous psychophysical measurements a Wilcoxian signed-rank test indicated that Case Alt's threshold demonstrated that both duration discrimination thresholds (for was lower than our normal control population (signed-rank= 1, long-duration pure tones) and vibrotactile intensity discrimination p =0.002). The absolute difference between the left and right ears thresholds were only slightly Unpaired [6]. in Case Al+ (9 dB) was within a half SD of the control mean (7.315.6 dB). Lesion-effect Studies in Humans While our single-case study establishes an existence proof for an Intensity Thresholds for Pure-tone Loudness auditory-rortex role in loudness perception, the generalizability of Discrimination our findings must be assessed in the broader context provided by Fig. 311 shows Case Al+ AL thresholds for individual nuts in previous rare caws with bilateral auditory cortex lesions as well as chronological order from the first run through the last. A Kruskal- cases with unilaterallesion cases studied with suitable psycho- Wallis test found no significant order effect across blocks for Case acoustic methods (summarized in Table l). Alt (e = 5.21, p=0.16). Most patients with unilateral lesions showed little or no deficit Fig. 3C shows AL thresholds (NI ± SD) for left- and right-ear for intensity-discrimination thresholds [22,23] (but see [24,25]), loudness discrimination. Fig. 3D shows the individual nut data; somewhat irrespective of whether the insult broached TG. box-and-whisker plots give the population median, interquanile Conversely, both patients with bilateral lesions to the superior range, and estimated 95% confidence interval. For Case Al+, AL temporal cortex had clear deficits [26,27], consistent with the thresholds averaged across the six runs for each ear were results front the present study. The single case in whom lesions 6.512.1 dB in the left and 6.511.9 dB in the right. For normal were localized precisely showed bilateral involvement of TO and controls, AL thresholds were 1.610.22 dB in the left ear and posterior STY: [27]. Given the conflicting results of unilateral 1.710.19 dB in the right car. In each car, Case Alt's median AL lesion studies in temporal lobectomy patients, and the conclusions was above - with only one Al. measurement within - the 95% from Baru and Karaseva's review of the Russian and German confidence interval of the control population. A Mann-Whitney literature [28], we conclude that unilateral Al and AA lesions have U-test using the AL for each run as the dependent variable little to no effect on either binaural or contralesional loudness confirmed that Case Al+ thresholds were significandy higher than perception. those of normals in each car [left and right ear: U=216, p<0.00001]. Inspection of Figs. 3B and 3C suggests no significant left-right Lesion-effect Studies in Non-human Primates car differences. A Mann-Whitney U Test using the threshold from We found only two Old-World monkey studies that examined each run confirmed this for Case Al+ (U = 34, p = 0.48, N = 6 per the effects of auditory cortex lesions on intensity processing [29,30] earl and for controls (U = 1031.5, p = 0.35, N=33 per ear). in Old World monkeys. In one [291, Rhesus macaques were trained to detect when a 1-kHz tone decreased in intensity• from 80 dB to 60 dB S1'1. before bilateral ablation of the superior Discussion temporal plane including primary auditory cortex. After ablation, The results support our first working hypothesis: pure-tone AL the subject did not reach the criterion level of performance of 90% thresholds for louder-softer loudness judgments were S dB greater correct in 25 sessions, after which the comparison intensity was in Case Al+ than nonnals. Contrary to our second a pion decreased to 40 dB, for which the subject achieved criterion after hypothesis, AL thresholds were not significantly greater in the kft 55 sessions. In the other [30]. Japanese macaques judged whether car despite his larger right hemisphere lesion. Finally, consistent a three-tone sequence was louder or softer than a three-tone with our third working hypothesis, intensity thresholds for tone standard sequence presented at 65 dB SPL in quasi-free field. The detection were within normal limits at all frequencies tested, monkey with near complete bilateral ablations of Al and AA had including the same frequency (1 kHz) used to test tone loudness elevated jnd's, while none of three monkeys with extensive discrimination. These findings support the claim that brain unilateral Al and AA lesions showed a deficit. mechanisms mediating auditory sensation and perception are PLOS ONE I www.plosone.org 4 September 2012 I Volume 7 I Issue 9 I e44602 EFTA01100142  Auditory Cortex and Loudness Perception A 1kHz detection thresholds B Case A1+ loudness discrimination thresholds 35 12 11 30 10 9 0 O CO 8 25 7 03 O O 6 2 20 m cn o O O O -o 5 15 < 4 p 10 X 3 0 o rn Right ear G- E 5 O Controls • Left ear x caseA1+ 2 0 0 5 10 15 20 25 30 35 1 2 3 4 5 6 7 8 9 10 11 12 Left-ear threshold (dB SPL) Run # C Loudness discrimination thresholds D Monaural loudness discrimination thresholds 1 2 3 4 5 6 789 Case A1+ Controls AL (dB) - Left ear Figure 3. Comarison of detection and discrimination thresholds for Case A1+ vs. controls. (A) Detection thresholds in dB SPL for I kHz pure tones measured in Case Al+ (x) and each normal control (circles, N = I I ). Left-ear thresholds are plotted on the x-axis, right-ear thresholds on the y-axis. The dashed lines at 33 dB SPL correspond to 25 d8 Hearing Level (HL), the upper limit of the clinically normal range. (B) Case A1+ monaural discrimination thresholds (AL) from individual runs in chronological order. Blocks of three runs were counterbalanced across ears (right ear = white; left ear = black). Error bars show ±1 SD of the last six turnaround points. (C) Monaural discrimination thresholds (AL) for louder-softer judgments of 1 kHz pure tones for Case A1+ (x) and each normal control (circles) averaged across runs. Left-ear thresholds are plotted on the x-axis, right-ear thresholds on the y-axis. Error bars show ±- 1 SD. (D) Monaural discrimination thresholds (AL) for Case Al+ (black, 4 and normal controls (gray, o). Each box shows the median and upper and lower quartiles of AL for each run; whiskers mark the 95% confidence intervals. doi:10.1371/joumal.pone.0044602.9003 Chronic vs. Acute Lesions or intensity discrimination, where long-term compensatory The aforementioned lesion-effect studies all examined the mechanisms are likely to have occurred. Indeed, Case Alt's impact of chronic lesions of auditory cortex on sound detection second infarct left him profoundly deaf for at least a month, after which he slowly recovered the ability to detect high- and PLOS ONE I www.plosone.org 5 September 2012 I Volume 71 Issue 9 I e44602 EFTA01100143  Auditory Cortex and Loudness Perception Table 1. Summary of human lesion effects on loudness strated that increases in intensity correlates with increased activity perception. in auditory cortex. The most relevant study for the present discussion measured sound-evoked BOLD activation as a function of intensity while subjects detected occasional changes in duration Monaural - Monaural - 181 Increases in sound level produced non-linear increases in both Left Right Binaural magnitude and spatial extent of activation, with stronger increases in TG (vs. STG) and contralateral (vs. ipsilateral) to the ear of Left 'ekes - Including TG stimulation. Other IMRI studies have also demonstrated high Milner (201 N =16 n/a n/a correlations between intensity and TG activation, particularly its Swisher DIL N=B 0 posterior-medial portion [10,381, the presumed core of human Hodgson (22), N=1 0 ++ n/a auditory cortex [12,13]. The one study which examined sub- Satan et al. (231, N=1 0 n/a cortical structures also found activation which increased with increasing intensity [10]. Left lesions - not including TG Swisher DIL N =10 0 Conclusions Right lesions - including TG Milner DOL N=11 n/a The present findings in Case Al+, in line with previous nta neuroimaging and neuophysiological studies not reviewed here Swisher (211. N = 18 0 [50-55], advance the claim that auditory cortex plays a critical Bilateral lesions role in basic auditory functions, particularly with respect to the Jerger et al. (24), N= I +++ n/a fine-grained analysis of spectral information [56]. Although Jager et aL (251, N=1 n/a auditory cortex plays a critical role in fine-grained loudness Case A1+ +++ +++ n/a discrimination, sensation per se and course loudness discrimination in the chronic state remain after complete bilateral lesions of Al O= no deficit +=mlldty Impaired moderately Impaired 4-t-s = severely and near-compete bilateral lesions of AA. We therefore hypoth- Impaired. The extent of damage to TG is unknown for Jerger et al. (24). The esize that intensity processing is organized hierarchically: the lesions in Jerger et al's case (25) extended Into TG bilaterally. 001.10.1371/J0utnal.p0ng.00446011001 auditory• cortex (most likely Al) is necessary for fine-grained loudness discrimination (though an explanation in terms of top- down effects due to loss of descending projections from the moderate-intensity sounds. In contrast, acute lesion studies (e.g., auditory• cortex to subcortical structures cannot be ruled out, see using inhibitor• agonists or reversible cooling) have the unique e.g. [57,58D, while the auditor• brainstem may be sufficient for ability to reveal the brain areas which normally support a given detection of sound after conical insult. It remains unclear whether function whilst ruling out compensatory reorganization. Such the auditory• brainstem, auditory• association cortex, or both are studies, mostly carried out in non-primate mammals, have sufficient for coarse loudness discrimination and subsequent produced mixed results regarding whether auditory cortex is response mapping after bilateral auditory• cortex lesions. normally involved in the detection and/or discrimination of sound As a consequence of his chronic bilateral Al and AA infarcts, [31-34], although it seems likely that acute inactivations of Case Al+ needed tones to be twice as loud to discriminate auditory cortex can produce disruption of both frequency increases from decreases in loudness. Given the importance of discriminaticomon and sound localization [35,36] as well as more musical and speech dynamics to aesthetics, prosody, and semantic complex functions [37]. In any case, the fact that Case Al+'s processing. these deficits in basic auditory functions would likely deficit in intensity discrimination persists years after his last infarct have profound effects at cognitive and emotional levels [59,60]. suggests that in healthy humans, fine-grained intensity processing is (i) supported by auditory cortex and (ii) cannot be completely restored by post-infarct compensatory mechanisms, although such Acknowledgments mechanisms could play a role in restoring sound detection and We thank Dr. Andrew J. Oxenham for technical assistance and helpful coarse loudness discrimination. on a previous version or the manuscript. COrilltlellts Neuroimaging Studies of Intensity Processing Author Contributions The coarse neural representation of sound level has been Conceived and designed the experiments: myr UM. Performed the investigated extensively using auditory-evoked potentials, PET, experiments: ARD CKK NUM Analyzed the data: ARID. 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