OPEN a.•

OPEN a.• ACCESS Reidy Vialliblit Online .OPL0S ONE Dissociation of Detection and Discrimination of Pure Tones following Bilateral Lesions of Auditory Cortex Andrew R. Dykstraw a, Christine K. Koh2'3, Louis D. Braidaw , 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 By the close of the 20th century, it seemed reasonably well- established on the basis of neuropsychology studies in patients and selective-ablation experiments in animals that auditory• cortex was devoted to higher functions such as pattern recognition but played little or no role in elementary functions invoking discrimination of a single acoustic feature and its corresponding percept (e.g., pure- tone intensity and loudness; for review see [1,2]). However, experiments with neurological patients employing rigorous psychoacoustic methods and in vivo lesion localization have since demonstrated that lesions of auditory• cortex impair pure-tone frequency processing and pitch discrimination, even when pure- tone audiograms are within normal limits [3-6]. These observa- tions suggest a dissociation between the effects of auditory cortex lesions on auditory sensation (i.e., detecting the presence of a sound) and auditory perception (i.e., determining whether and how two sounds differ in one or more attributes). The present study focuses on pure-tone intensity processing in relation to tone detection and loudness perception. The loudness of a sound source and its change over time conveys information about its size, location, movement, significance, and identity. Humans and animals modulate the loudness of vocal communi- cation sounds to convey meaning and emotion, and musical dynamics is a key ingredient of musical aesthetics. Normal adults demonstrate remarkably high perceptual acuity for loudness changes under optimal listening conditions: the just noticeable difference (jnd) for two-tone loudness discrimination is less than 1 dB at moderate and higher intensities throughout almost the entire audible spectmm (for review see [7]). Given recent evidence that auditory cortex supports high perceptual acuity for pure-tone pitch perception [3,6], we hypothesized that it also subserves fine- grained loudness perception. This idea is supported by recent studies utilizing functional neuroimaging which showed increased IMR1 activation in the auditory• cortex with increasing sound level (see, e.g., [8-11]), particularly in posteromeclial portion of the tranverse gyms of Heschl (TG) [8,11], the presumed core area of human auditory cortex [12-14]. However, such correlational studies cannot establish the necessity Ma given structure for a particular function, and psychoacoustic experiments with neurological patients who 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 auditory sensation and perception. While the rarity of cases with bilateral lesions limits the inferences one can draw about structure- function correlates in the general population, single-case studies 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 and a middle-aged, mixed-handed man, Case Al+, with chronic, bilateral middle cerebral artery (MCA) infarcts that include all of kft and right primary auditory cortex (Al) and much of auditory 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 Ethics Statement All procedures were approved by the Institutional Review Boards at the Massachusetts General Hospital (MGH) and the Massachusetts Institute of Technology (MIT), and mitten in- formed consent was obtained from all participants prior to their participation. Participants Case Al+. Case Al+ is a 46-year old mixed-handed man who suffered ischemic infarcts in the distribution of the right middle cerebral artery in 1980 and the left middle cerebral artery in 1981. He has twelve years of education and is not trained in music performance or theory. At the time of the present experiments, he was the primary caretaker of his and his wife's three young children and was on warfarin anti-thrombotic therapy and phenytoin anti-convuisant therapy. Details of the clinical history, neurological and audiological examinations, and radiographic findings have been reported previously [4,6,15,16]. In brief, the first cardioembolic stroke 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 within a month, but perception of speech, music, environmental sound, and sound source location remain impaired. At the time the current study was conducted, Case Al+ had thresholds which were within clinically-defined normal limits (Fig. I). Multi-planar MRI sections were acquired four months after the present psychoacoustic experiments using a Siemens TIM Trio Tr. Lesion localization was analyzed on fluid-attenuated in- version-recovery (FLAIR) sequences. Contiguous sections were 1.0 mm-thick with an in-plane resolution of 0.94 mm2 (FE = 494 Ins, TR = 6000 ins, IT= 2100 ms, flip angle = 120). Selected parasagittal, corona', and horizontal MM sections through superior temporal cortex are illustrated in Fig. 2. Abnormal HAIR signal involves all of the right TG, all of left TG, all or almost all of right superior temporal gyms (STG), a portion of left STG posterior to TG, and underlying white matter, including the geniculo-temporal radiation. The right- hemisphere lesion extends into adjacent frontal, temporal, and parietal areas; the smaller left-hemisphere lesion extends into adjacent temporal and parietal areas. Comparison with previous MRI sections through superior temporal cortex found no change [4]. At the time of the present experiments, Case AI+ reported difficulty perceiving speech - especially in noisy environments and 35 30 2 25 C- (r) 20 -C 5 0 • 125 250 500 1000 2000 4000 Frequency (Hz) - Right Ear - Left Ear - - ANSI 3.6-2004 Figure 1. Case AI+ pure-tone audiogram for left-ear (filled symbols) and right-ear (open symbols) presentation. Clinically. defined normal limits extend 25 dB above the dotted line, which indicates the average threshold from the ANSI standard. doi:10.1371/joumal.pone.0044602.9001 on the telephone as well as difficulty localizing sounds. He was alert, attentive, and without complaints throughout the psycho- acoustic experiments. Normal controls. Eleven age-matched right-handed adults (7 female, 4 male) participated as normal controls (median age = 41 years, range = 32 50 years). None reported a history of neurological disease or hearing impairment, and none were formally-trained musicians or actively performing music. Stimulus Delivery and Data Collection Participants sat in a double-walled sound-attenuated booth and faced a computer monitor on which instructions, visual cues, and feedback were given. Participants entered their responses using a computer keyboard. All stimuli, except for pure tone audiometry in normal control subjects, were generated digitally using MATLAB (The Mathwodcs) and converted to analog waveforms by a LynxOne (LynxStudio) 24-bit soundcard with a sampling frequency of 32 kHz. The stimuli passed through programmable attenuators run PA4, Tucker Davis Technologies) and head- phone buffers (CDT HB6, Tucker Davis Technologies) before presentation to the subject via HD580 headphones (Sennheiser). Pure-tone Detection A two-interval, two-alternative, forced-choice (2I-2AFC) para- digm with a 2-down, I -up adaptive procedure was used to measure the minimum intensity Case Al+ needed to detect the presence of a 1-kHz, 500-ms pure tone with a response accuracy of 70.7% [I'll. Each interval's occurrence was indicated visually by one of two boxes on the computer screen labeled "I" and "2"; box 1 flashed during the first interval and box 2 during the second interval. The target tone (duration = 500 ms, 20-ms raised-cosine ramps) was randomly assigned to the first or second interval; no 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 points. Thresholds in llama's were measured with an Inter- acoustics Diagnostics Audiometer (AD229e) and Telephonics headphones (I'DH-39P) using a modified Hughson-Westlake procedure. Loudness Discrimination On each trial, two 1-kHz pure tones were presented. Each tone had a duration of 500 ms and was gated on and off with 20-ms raised-cosine ramps. The two tones were separated by an inter- stimulus interval (ISI) of 200 ins. The same 2I-2AFC procedure used for pure-tone detection was used here. One tone was at the reference intensity (I =65 dB SPI, for normal controls, I =40 dB SL for Case Ali). The intensity of the "test" tone (I+Al) differed slightly in intensity from the reference by adding a -kHz, in-phase tone to the reference tone. 'Ile order of the reference and test tones was randomized on each trial. Listeners judged whether the second tone was "louder" or "softer" than the first tone. Intensity difference thresholds were expressed as AL = I 0lo- gl 0[(1+AI)/IA 114 A 2I-2AFC, 2-down, I -up adaptive procedure tracked the 70.7% correct point on the psychometric function. In order to maximize the number of observations made near threshold, step size was decreased serially (AL = 2A5, 1.48, 0.54 dB) over the course of the run. Threshold for each run was defined as the mean AL of the last six turnaround points after the smallest step size had been reached. Normal listeners participated in three left-ear runs and three right-car runs. Contralateral noise at a level (per equivalent rectangular bandwidth) of 20 dB below the target was presented in order to prevent the use of the contralateral ear in performing the task [19]. The start car was pseudorandomized across subjects 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 plateaued. Case Al+ participated in six runs for each ear. We did not present contralateral masking noise. Blocks were counter-balanced by car using an ABBA paradigm: Right ear, left ear, kft ear, right car, with three nms per block. The start ear was randomly chosen. Case Al+ performed three or more practice nuts until perfor- mance plateaued. Results Intensity Thresholds for Pure-tone Detection Fig. 3A shows pure-tone detection thresholds for Case Al+ and the eleven normal controls. All were within normal clinical limits [defined as 33 dB SM. at I kHz]. For Case Al+, the detection threshold in the left ear, which is contralateral to the larger lesion, was IS dB SPL; the detection threshold in the right car was 9 dB SPL His kit-ear threshold was within one standard deviation (SD) of the mean (NI) of the control population (NI ± SD = 14.416.0 dB SPL). His right-ear threshold was within 2 SDs of the control mean (NI ± SD = 19.815.6 dB SPI.), though a Wilcoxian signed-rank test indicated that Case Alt's threshold was lower than our normal control population (signed-rank= 1, p =0.002). The absolute difference between the left and right ears in Case Al+ (9 dB) was within a half SD of the control mean (7.315.6 dB). Intensity Thresholds for Pure-tone Loudness Discrimination Fig. 311 shows Case Al+ AL thresholds for individual nuts in chronological order from the first run through the last. A Kruskal- Wallis test found no significant order effect across blocks for Case Alt (e = 5.21, p=0.16). Fig. 3C shows AL thresholds (NI ± SD) for left- and right-ear loudness discrimination. Fig. 3D shows the individual nut data; box-and-whisker plots give the population median, interquanile range, and estimated 95% confidence interval. For Case Al+, AL thresholds averaged across the six runs for each ear were 6.512.1 dB in the left and 6.511.9 dB in the right. For normal controls, AL thresholds were 1.610.22 dB in the left ear and 1.710.19 dB in the right car. In each car, Case Alt's median AL was above - with only one Al. measurement within - the 95% confidence interval of the control population. A Mann-Whitney U-test using the AL for each run as the dependent variable confirmed that Case Al+ thresholds were significandy higher than 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 car differences. A Mann-Whitney U Test using the threshold from each run confirmed this for Case Al+ (U = 34, p = 0.48, N = 6 per earl and for controls (U = 1031.5, p = 0.35, N=33 per ear). Discussion The results support our first working hypothesis: pure-tone AL thresholds for louder-softer loudness judgments were S dB greater in Case Al+ than nonnals. Contrary to our second a pion hypothesis, AL thresholds were not significantly greater in the kft car despite his larger right hemisphere lesion. Finally, consistent with our third working hypothesis, intensity thresholds for tone detection were within normal limits at all frequencies tested, including the same frequency (1 kHz) used to test tone loudness discrimination. These findings support the claim that brain mechanisms mediating auditory sensation and perception are neurologically dissociable. In addition, the fact that Case Al+ was able to perform louder-softer judgments, albeit at much higher AL thresholds, indicates that auditory structures spared by his strokes specifically left anterior auditory association cortex and/or the auditory brainstem can mediate coarse loudness perception. It should be noted here that the test conditions for Case Al+ and normals were not identical (see Methods). However, based on our review of relevant literature on the differences between one- and two-interval forced-choice tasks [20] as well as the effects of contralateral masking noise [21] and reference intensity level [7] on loudness discrimination thresholds, it is unlikely the differences affect our conclusions. In fact, the fact that we used contralateral masking noise in our control population and not in Case Alt may have underestimated his deficit. It is also unlikely that the observed deficits in Case Al+ are attributable to non-modality specific effects of his lesions. First, we did not observe signs of fatigue during testing, and there was no significant order effect across blocks. Second, his intensity thresholds for pure-tone detection were normal and were measured with an adaptive procedure that was as demanding as the one used to measure loudness discrimination. lastly, previous psychophysical measurements demonstrated that both duration discrimination thresholds (for long-duration pure tones) and vibrotactile intensity discrimination thresholds were only slightly Unpaired [6]. Lesion-effect Studies in Humans While our single-case study establishes an existence proof for an auditory-rortex role in loudness perception, the generalizability of our findings must be assessed in the broader context provided by previous rare caws with bilateral auditory cortex lesions as well as cases with unilaterallesion cases studied with suitable psycho- acoustic methods (summarized in Table l). Most patients with unilateral lesions showed little or no deficit for intensity-discrimination thresholds [22,23] (but see [24,25]), somewhat irrespective of whether the insult broached TG. Conversely, both patients with bilateral lesions to the superior temporal cortex had clear deficits [26,27], consistent with the results front the present study. The single case in whom lesions were localized precisely showed bilateral involvement of TO and posterior STY: [27]. Given the conflicting results of unilateral lesion studies in temporal lobectomy patients, and the conclusions from Baru and Karaseva's review of the Russian and German literature [28], we conclude that unilateral Al and AA lesions have little to no effect on either binaural or contralesional loudness perception. Lesion-effect Studies in Non-human Primates We found only two Old-World monkey studies that examined the effects of auditory cortex lesions on intensity processing [29,30] 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 temporal plane including primary auditory cortex. After ablation, the subject did not reach the criterion level of performance of 90% correct in 25 sessions, after which the comparison intensity was decreased to 40 dB, for which the subject achieved criterion after 55 sessions. In the other [30]. Japanese macaques judged whether a three-tone sequence was louder or softer than a three-tone standard sequence presented at 65 dB SPL in quasi-free field. The monkey with near complete bilateral ablations of Al and AA had elevated jnd's, while none of three monkeys with extensive unilateral Al and AA lesions showed a deficit. PLOS ONE I www.plosone.org 4 September 2012 I Volume 7 I Issue 9 I e44602 EFTA01100142 Auditory Cortex and Loudness Perception A 0 35 30 O 12 11 10 9 8 CO 03 25 7 O O 6 2 20 cn o O O O m -o 5 15 < 4 p 10 rn 0 X 3 -GE 5 O Controls x caseA1+ 2 0 1 kHz detection thresholds B Case A1+ loudness discrimination thresholds C 0 5 10 15 20 25 30 35 Left-ear threshold (dB SPL) o Right ear • Left ear 1 2 3 4 5 6 7 8 9 10 11 12 Run # Loudness discrimination thresholds D Monaural loudness discrimination thresholds 1 2 3 4 5 6 789 AL (dB) - Left ear Case A1+ Controls 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 The aforementioned lesion-effect studies all examined the impact of chronic lesions of auditory cortex on sound detection or intensity discrimination, where long-term compensatory mechanisms are likely to have occurred. Indeed, Case Alt's 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 perception. Monaural - Left Monaural - Right Binaural Left 'ekes - Including TG Milner (201 N =16 n/a n/a Swisher DIL N=B 0 Hodgson (22), N=1 0 ++ n/a Satan et al. (231, N=1 0 n/a Left lesions - not including TG Swisher DIL N =10 0 Right lesions - including TG Milner DOL N=11 n/a nta Swisher (211. N = 18 0 Bilateral lesions Jerger et al. (24), N= I +++ n/a Jager et aL (251, N=1 n/a Case A1+ +++ +++ n/a O= no deficit +=mlldty Impaired moderately Impaired 4-t-s = severely Impaired. The extent of damage to TG is unknown for Jerger et al. (24). The lesions in Jerger et al's case (25) extended Into TG bilaterally. 001.10.1371/J0utnal.p0ng.00446011001 moderate-intensity sounds. In contrast, acute lesion studies (e.g., using inhibitor• agonists or reversible cooling) have the unique ability to reveal the brain areas which normally support a given function whilst ruling out compensatory reorganization. Such studies, mostly carried out in non-primate mammals, have produced mixed results regarding whether auditory cortex is normally involved in the detection and/or discrimination of sound [31-34], although it seems likely that acute inactivations of auditory cortex can produce disruption of both frequency discriminaticomon and sound localization [35,36] as well as more complex functions [37]. In any case, the fact that Case Al+'s deficit in intensity discrimination persists years after his last infarct 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 mechanisms could play a role in restoring sound detection and coarse loudness discrimination. Neuroimaging Studies of Intensity Processing The coarse neural representation of sound level has been investigated extensively using auditory-evoked potentials, PET, and IMRI [8-11,38-49]. These studies have consistently demon- References F Neff WI/. lhaniond I. Caeseday J (1975) Behavioral st tubes or atidnoty discrimination: central menials system. Handbook of Sensory Physiology. Andiron' System. New York, NY: Springer-Verlag. Vol. V. 307 .100. 2. Masterton RB, Berkley MA (1974) Brain ''unction: changing ideas on the role of sensory. motor, and AMOtiatilIal nines in behaiior. Annu Rev Psycho' 25: 277- 111 doi:10.1116/annorevis.25.020174.001425. 3. ,Johnsrude IS. Penhune VB. %atone RJ (1010,. Functional specificity in the right human auditmy cones Inc perceiving pitch direction. Blain 123 (Pt 1): 155-163. 4. Tramp MJ. IlhartichaJJ. Musiek (19!)ff Music Perception and Cognition Following Bilateral Lesions or Auditory Conn. Journal of Cognitive Neuroscience 1: 195-212. doi:10.1161/jmn.1990.2.1.195. 5. Tramo MJ. Grant A. firth& Ii) ,19941 Psychophysical measure-menu of eminency difference lindens for relative pitch discrimination reveal a tkficit following bilateral lesions of auditory cones Atlanta, GA. strated that increases in intensity correlates with increased activity 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 181 Increases in sound level produced non-linear increases in both magnitude and spatial extent of activation, with stronger increases in TG (vs. STG) and contralateral (vs. ipsilateral) to the ear of stimulation. Other IMRI studies have also demonstrated high correlations between intensity and TG activation, particularly its posterior-medial portion [10,381, the presumed core of human auditory cortex [12,13]. The one study which examined sub- cortical structures also found activation which increased with increasing intensity [10]. Conclusions The present findings in Case Al+, in line with previous neuroimaging and neuophysiological studies not reviewed here [50-55], advance the claim that auditory cortex plays a critical role in basic auditory functions, particularly with respect to the fine-grained analysis of spectral information [56]. Although auditory cortex plays a critical role in fine-grained loudness discrimination, sensation per se and course loudness discrimination in the chronic state remain after complete bilateral lesions of Al and near-compete bilateral lesions of AA. We therefore hypoth- esize that intensity processing is organized hierarchically: the 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 auditory• cortex to subcortical structures cannot be ruled out, see e.g. [57,58D, while the auditor• brainstem may be sufficient for detection of sound after conical insult. It remains unclear whether the auditory• brainstem, auditory• association cortex, or both are sufficient for coarse loudness discrimination and subsequent response mapping after bilateral auditory• cortex lesions. As a consequence of his chronic bilateral Al and AA infarcts, Case Al+ needed tones to be twice as loud to discriminate increases from decreases in loudness. 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