Frequency-Dependent Responses Exhibited by Multiple Regions in Human Auditory Cortex1

Hearing Research 150 (2000) 225^244 www.elsevier.com/locate/heares

Frequency-dependent responses exhibited by multiple regions in human auditory cortex1

Thomas M. Talavage a;b;*, Patrick J. Ledden b, Randall R. Benson b;2, Bruce R. Rosen b, Jennifer R. Melcher a;c;d;

a Speech and Hearing Sciences Program, MIT-Harvard Division of Health Sciences and Technology, Cambridge, MA, USA b MGH-NMR Center, Department of Radiology, Massachusetts General Hospital, Building 149, 13th Street (2301), Charlestown, Boston, MA 02129, USA c Department of Otology and Laryngology, Harvard Medical School, Boston, MA, USA d Department of Otolaryngology, Eaton-Peabody Laboratory, Massachusetts Eye and Ear In¢rmary, Boston, MA 02114, USA Received 3 July 1999; accepted 29 August 2000

Abstract

Recordings in experimental animals have detailed the tonotopic organization of auditory cortex, including the presence of multiple tonotopic maps. In contrast, relatively little is known about tonotopy within human auditory cortex, for which even the number and location of tonotopic maps remains unclear. The present study begins to develop a more complete picture of cortical tonotopic organization in humans using functional magnetic resonance imaging, a technique that enables the non-invasive localization of neural activity in the brain. Subjects were imaged while listening to lower- (below 660 Hz) and higher- (above 2490 Hz) frequency stimuli presented alternately and at moderate intensity. Multiple regions on the superior temporal lobe exhibited responses that depended upon stimulus spectral content. Eight of these `frequency-dependent response regions' (FDRRs) were identified repeatedly across subjects. Four of the FDRRs exhibited a greater response to higher frequencies, and four exhibited a greater response to lower frequencies. Based upon the location of the eight FDRRs, a correspondence is proposed between FDRRs and anatomically defined cortical areas on the human superior temporal lobe. Our findings suggest that a larger number of tonotopically organized areas exist (i.e., four or more) in the human auditory cortex than was previously recognized. ß 2000 Elsevier Science B.V. All rights reserved.

Key words: Auditory cortex; Functional magnetic resonance imaging; Tonotopy; Human

1. Introduction strated in structures throughout the auditory pathway, including auditory cortex (e.g., Rose et al., 1959; Wool- Tonotopy, an ordered mapping of neuronal fre- sey, 1971; Guinan et al., 1972; Merzenich and Reid, quency sensitivity to spatial location, has been demon- 1974). These demonstrations have typically involved recording from single or multiple units in non-human species and relating the acoustic frequency yielding the lowest response threshold (best frequency, BF) to * Corresponding author. Present address: School of Electrical and unit position (e.g., Hind, 1960; Merzenich and Brugge, Computer Engineering, Purdue University, West Lafayette, IN 47907, USA. Tel.: +1 (765) 494 5475; Fax: +1 (765) 494 6440; 1973; Merzenich et al., 1976; Reale and Imig, 1980; E-mail: [email protected] McMullen and Glaser, 1982; Sally and Kelly, 1988; Morel et al., 1993). Although neuronal responses in 1 Portions of this work were presented at the annual meeting of the International Society for Magnetic Resonance in Medicine (1996) and auditory cortex can depend on stimulus frequency in the annual meeting of the Association for Research in Otolaryngology complex ways, a single BF can usually be assigned to (1997). neurons in primary and certain non-primary areas (e.g., 2 Present address: University of Connecticut Health Center, Department of Neurology, 263 Farmington Ave., Farmington, CT Hind, 1960; Sutter and Schreiner, 1991; Rauschecker et 06030-1845, USA. al., 1995). Within cortical areas that are tonotopically

HEARES 3571 1-11-00 Cyaan Magenta Geel Zwart 226 T.M. Talavage et al. / Hearing Research 150 (2000) 225^244 organized, BF varies fairly systematically from low to tinen et al., 1993; Cansino et al., 1994; Huotilainen et high along the cortical surface, but is relatively constant al., 1995; Verkindt et al., 1995; Roberts and Poeppel, across cortical depth (e.g., Merzenich et al., 1975; Imig 1996; Diesch and Luce, 1997; Lu«tkenho«ner and et al., 1977; Rauschecker et al., 1995). The overall pic- Steinstra«ter, 1998; Mu«hlnickel et al., 1998). Studies tak- ture of cortical frequency organization from the animal ing this approach typically used moderate-intensity, literature is one of multiple tonotopic maps distributed narrow-band stimuli based on the hypothesis that (a) over the cortical surface. neurons responding to these stimuli would have a nar- In contrast with the extensive body of data docu- row range of BFs and therefore occupy a limited extent menting the tonotopic organization of the auditory of any underlying tonotopic map, and (b) the location pathway in animals, far less is known about this funda- of the responding neurons would move systematically mental organizing principle in humans. This is true even from one end of the map to the other with systematic for auditory cortical areas residing on the superior tem- increases or decreases in acoustic stimulus frequency. It poral lobe, perhaps the most studied part of the human has been reported that the position of brain activity central auditory system. Based on physiological record- generating several evoked response components ings, lesion studies and functional imaging, it is known changes systematically with frequency (Romani et al., that widespread areas on the human superior temporal 1982a,b; Elberling et al., 1982; Pelizzone et al., 1985; lobe respond to sound and play a critical role in the Pantev et al., 1988, 1990, 1991, 1994, 1995, 1996; Ya- perception of acoustic stimuli (e.g., Celesia, 1976; Tra- mamoto et al., 1988, 1992; Tiitinen et al., 1993; Can- mo et al., 1990; Zatorre et al., 1992; Binder et al., sino et al., 1994; Huotilainen et al., 1995; Diesch and 1994). The primary auditory cortex, which lies deep Luce, 1997; Lu«tkenho«ner and Steinstra«ter, 1998; Mu«hl- within the Sylvian ¢ssure on the medial two-thirds of nickel et al., 1998). In some studies examining more Heschl's gyrus, is an area exhibiting short-latency re- than one response component in the same individuals, sponses to transient acoustic stimuli (a de¢ning feature the generators of the various components were localized of primary cortex) as well as cytoarchitectonic and im- to di¡erent parts of the superior temporal lobe and munostaining properties typical of primary sensory cor- each showed a systematic relationship between position tical areas (e.g., Celesia, 1976; Galaburda and Sanides, and stimulus frequency (Pantev et al., 1994, 1995, 1996; 1980; Lie¨geois-Chauvel et al., 1991; Rademacher et al., Diesch and Luce, 1997; Lu«tkenho«ner and Steinstra«ter, 1993; Rivier and Clarke, 1997). The surrounding, 1998). These ¢ndings indicate that human auditory cor- acoustically responsive areas of the superior temporal tex includes more than one tonotopically organized lobe are anatomically and physiologically di¡erentiable area. from the primary area, and from each other (e.g., Gal- Several studies have examined human cortical fre- aburda and Sanides, 1980; Lie¨geois-Chauvel et al., quency organization using positron emission tomogra- 1994; Rivier and Clarke, 1997; Howard et al., 2000). phy (PET) or functional magnetic resonance imaging If, as in many animal species, the various di¡erentiable (fMRI), techniques that provide spatial maps of brain areas contain one or more frequency-to-place mappings activation (Lauter et al., 1985; Wessinger et al., 1997; (e.g., Imig and Reale, 1980; Morel et al., 1993; Kosaki Bilecen et al., 1998; Lockwood et al., 1999; Yang et al., et al., 1997; Rauschecker et al., 1997), one would expect 2000). These maps show changes in blood £ow (PET) there to be multiple tonotopic representations of the or blood oxygenation (fMRI) that re£ect changes in audible frequency range on the surface of the human neural activity (e.g., in response to a sensory stimulus; superior temporal lobe. Fox and Raichle, 1986; Fox et al., 1988; Bandettini et Evidence that parts of human auditory cortex are al., 1992; Kwong et al., 1992; Ogawa et al., 1992). The tonotopically organized has been provided by previous PET and fMRI studies examining cortical frequency studies using a variety of techniques. Some of this evi- organization employed essentially the same strategy as dence comes from single unit recordings from auditory the magnetic and electric recording studies: subjects cortex in humans (Howard et al., 1996). However, the were stimulated with band-limited sound with the idea majority derives from studies using non-invasive meth- that the resulting activity would occupy di¡erent parts ods and provides somewhat di¡erent information about of auditory cortex. Each of the studies examined the cortical activity. The most extensively used approach response to two or three stimulus frequencies and re- has involved recording sound-evoked magnetic or elec- ported either displacements in the volume of activation tric responses over the surface of the head and localiz- for di¡erent frequencies, or separable sites of maximal ing the brain activity generating these responses (Ro- activation ^ ¢ndings consistent with an underlying to- mani et al., 1982a,b; Arlinger et al., 1982; Elberling et notopic organization. al., 1982; Pelizzone et al., 1985; Pantev et al., 1988, While it is clear that human auditory cortex is tono- 1990, 1991, 1994, 1995, 1996; Yamamoto et al., 1988, topically organized, the number of tonotopically organ- 1992; Bertrand et al., 1991; Jacobson et al., 1992; Tii- ized areas, the spatial arrangement of these areas, and

HEARES 3571 1-11-00 Cyaan Magenta Geel Zwart T.M. Talavage et al. / Hearing Research 150 (2000) 225^244 227 their relationship to the cortical anatomy remains 2. Materials and methods largely unresolved. Although magnetic and electric recordings have indicated more than one tonotopically 2.1. Subjects organized area may be localized to the superior temporal lobe, the spatial relationship between these areas Six right-handed volunteers (four male, two female), and the relationship of these areas to cortical anatomy ages 22^35, were imaged in one (¢ve subjects) or three has, for the most part, been only roughly worked out sessions (one subject). All volunteers had normal hear- (however, see Lu«tkenho«ner and Steinstra«ter, 1998; Pan- ing (audiometric thresholds below 25 dB HL in the tev et al., 1990). PET and fMRI have thus far yielded a range from 250 to 8000 Hz). Informed consent was fairly gross picture of cortical frequency organization, obtained from all volunteers prior to imaging. The pro- even though these modalities are particularly well suited cedures were conducted in accordance with institutional to showing the spatial arrangement of tonotopically guidelines at the Massachusetts Institute of Technology, organized areas and, in the case of fMRI, localizing Massachusetts Eye and Ear In¢rmary and the Massa- the arrangement relative to anatomy. A retrospective chusetts General Hospital and with the guidelines of the examination of the previous PET and fMRI work sug- Declaration of Helsinki. gests several possible reasons for this situation. In some studies, the analyses localized only the maximum re- 2.2. Acoustic stimulation sponse to each stimulus frequency instead of seeking multiple local maxima as would be expected to occur In each session, subjects were stimulated binaurally with multiple tonotopically organized areas. In the case with a pair of narrow-bandwidth stimuli: one of `lower of the PET studies, spatial resolution was su¤ciently frequency' and one of `higher frequency'. The spectra of low that it is unlikely that the low- and high-frequency lower-frequency stimuli were restricted to frequencies areas within any single tonotopic map could have been below 660 Hz, while the spectra of higher-frequency resolved (based on the spatial extent of maps identi¢ed stimuli were restricted to frequencies above 2490 Hz. in magnetic and electric recordings). It is also notable Thus, approximately two octaves or more always sepa- that all of the previous PET and fMRI investigations rated the lower- and higher-frequency stimuli. We chose used tone burst stimuli, which may not be the most this minimum spectral separation based on evoked e¡ective stimuli for probing the frequency organization magnetic ¢eld data in humans indicating that acoustic of non-primary areas (e.g., Rauschecker et al., 1995). frequencies separated by two octaves can excite foci of Here, using insights drawn from previous investiga- cortical activity separated by approximately 6 mm (e.g., tions, we attempted to develop a more complete picture Romani et al., 1982a,b; Pantev et al., 1988) ^ a sepa- of human cortical frequency organization using fMRI. ration resolvable with the 3 mm resolution of our func- The present study examined the tonotopic organiza- tional imaging methodology (described below). The fre- tion of the human superior temporal lobe using an ap- quency bounds of our stimuli were also selected to proach designed to detect multiple frequency-organized avoid spectral overlap with the 1 kHz, 115 dB SPL areas and localize any identi¢ed areas relative to corti- fundamental of the acoustic noise generated during cal anatomy. We chose to use fMRI because (a) it can functional imaging (Ravicz et al., 2000). The reason be used to directly relate brain activation and anatomy for avoiding spectral overlap was to reduce interactions in individual subjects, and (b) it provides higher spatial between stimulus-induced brain activity and activity in- resolution than any other non-invasive imaging tech- duced by imager noise (Bandettini et al., 1998; Edmis- nique. The experimental design also included the fol- ter et al., 1999; Talavage et al., 1999)3. lowing considerations. (1) We used lower- and higher- Four pairs of lower- and higher-frequency stimuli frequency stimuli of moderate intensity and su¤cient were used, although only a single pair was presented spectral separation to produce spatially resolvable dif- in any given imaging session. The four stimulus pairs ferences in activation. The spectral content was also were: [session 1] instrumental music, low- and high- chosen to avoid the dominant frequency of the acoustic pass-¢ltered; [session 2] tone bursts, 650 and 2500 Hz background noise produced by the imaging equipment. (10 per second, 25 ms duration, 5 ms rise and fall (2) A variety of di¡erent stimulus types were used, with times); [sessions 3^5] amplitude-modulated (AM) white the idea that certain stimuli might be better than others noise, low- and high-pass ¢ltered (10 Hz modulation for probing di¡erent cortical areas. (3) An approach rate, 0.7 modulation index); [sessions 6^8] AM tones, was adopted that looked for multiple cortical regions showing di¡erential sensitivity to lower vs. higher frequencies (i.e., frequency-dependent response regions, 3 The present study was conducted prior to the implementation of `clustered' imaging techniques for reducing the impact of imager noise FDRRs). In the end, eight FDRRs were identi¢ed on on fMRI activation (e.g., Sche¥er et al., 1998; Edmister et al., 1999; the superior temporal lobe. Hall et al., 1999; Talavage et al., 1999).

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Table 1 Stimulus frequencies Session Stimulus Lower frequency (Hz)a Higher frequency (Hz)a 1 Instrumental music 20^100 7000^8000 2 Tone bursts 640^660 2490^2510 3 AM noise 75^125 3390^4610 4 AM noise 20^210 6990^8010 5 AM noise 20^210 3390^4610 6 AM tones 490^510 7990^8010 7 AM tones 490^510 7990^8010 8 AM tones 490^510 7990^8010 aThese are the bandlimits at 35 dB SL.

500 and 8000 Hz (10 Hz modulation rate, 0.7 modula- the ear canal. The earmu¡s reduced the intensity of tion index). The frequencies contained in each lower- imager acoustic noise at the subject's ears by approxi- and higher-frequency stimulus pair are listed in Table 1. mately 30 dB (Ravicz and Melcher, 1998). Multiple types of stimuli were utilized because it was not known a priori which stimuli would yield the stron- 2.3. Experimental paradigm gest responses. In deciding to use multiple types of stimuli, our operating assumption was that spectrum, Lower- and higher-frequency stimuli were presented rather than other stimulus characteristics, would be alternately in a standard fMRI `block paradigm'. One the dominant factor a¡ecting response location. `cycle' in this paradigm consisted of an òn' epoch of Stimulus levels were as follows. Stimuli in sessions 2^ lower-frequency stimulation, an ò¡' epoch of no stim- 8 were presented at 35 dB above behavioral threshold. ulation, an òn' epoch of higher-frequency stimulation, Behavioral thresholds for these sessions were measured and an ò¡' epoch (e.g., see Fig. 1d,e). Table 2 provides with the subject in the imager and under the same the duration of the epochs for each of the eight imaging acoustic conditions as during functional imaging. For sessions. Between three and eight cycles presented con- session 1, behavioral thresholds were measured with the secutively composed a functional imaging `run'. Be- subject in the imager, but in the absence of functional tween two and seven runs were conducted in each imag- imaging noise4. The lower-frequency stimulus for ses- ing session. sion 1 was presented 50 dB above threshold; the higher- Subjects were instructed to listen to the acoustic stim- frequency stimulus was matched in loudness (42 dB uli during each run and to keep their eyes closed or to above threshold). In all sessions, the subject could maintain ¢xation on an arbitrarily chosen point in their clearly hear the stimuli. direct line of sight. In sessions 2^8, subjects performed a All stimuli were played from a digital source and detection task to maintain their attention to the stimuli. presented via an air conduction system. Tone and noise The stimulus level was randomly adjusted by þ 4 dB for stimuli were digitally generated using LabVIEW on a 2 s, with a change in level occurring every 5^8 s. Sub- Macintosh Quadra computer out¢tted with a D/A jects responded to the level change by raising or low- board (National Instruments A2100). Bandpass-¢ltered ering a ¢nger, concordant with the direction of the level music was generated by passing the output of a CD change. Subject responses were monitored by the ex- player through a brickwall (115 dB per octave) band- perimenter who could see the subject's ¢nger from the pass ¢lter (Rockland Model 751A). The output of the imager control room. All subjects responded to the level ¢lter or D/A board was ampli¢ed and input to acoustic changes consistently and appropriately. transducers located in the room with the imager. The output of the transducers5passed through £exible plas- 2.4. Imaging tic tubing (3 m length) to and through earmu¡s. The sound emerged from the £exible tubing just lateral to Subjects were imaged using a 1.5 T Signa imager (General Electric, Milwaukee, WI), retro¢tted for high-speed imaging (i.e., echo-planar imaging) by Ad- 4 Even in the absence of functional imaging noise, there is on-going vanced NMR Systems, Inc. (Wilmington, MA). Subject low-frequency noise produced primarily by a pump for liquid helium (used to supercool the imager's permanent magnet). This noise motion was limited through use of a dental bite bar. reaches levels of V80 dB SPL in the frequency range of 100^500 Imaging sessions included ¢ve components: Hz (Ravicz et al., 2000).

5 The transducer frequency response was low-pass (6 kHz upper half- 1. Contiguous sagittal anatomical images were ac- power frequency). quired covering the entire brain (T1-weighted, in-

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Fig. 1. Three frequency-dependent response regions (FDRRs) on Heschl's gyrus for session 1. (a) A near-coronal slice (red line) that intersected the FDRRs is shown superimposed on a sagittal anatomical image through left Heschl's gyrus (at center of black ellipse). (b) Diagram of the near-coronal slice showing the area of the enlargement in (c) (delimited by box). (c) FDRRs 1^3 (blue and red regions) overlaid on an anatomical image (grayscale) of Heschl's gyrus. FDRR 1, on the superior aspect of Heschl's gyrus, exhibited signi¢cantly greater image signal levels when the lower- rather than higher-frequency stimulus was presented (unpaired t-test, P 6 0.05). FDRR 2 (inferomedial to FDRR 1) and FDRR 3 (inferolateral) exhibited signi¢cantly greater image signal levels when the higher-frequency stimulus was presented. (d, e) Image signal vs. time for FDRR 1 and for FDRRs 2 and 3. The blue and red vertical bands indicate periods of lower- and higher-frequency stimulation, respectively. The intervening white vertical bands indicate periods of no stimulation. The signal vs. time waveforms were smoothed using a 5 point mean ¢lter. The FDRR data are based on an average of two functional imaging runs each lasting approximately 6.5 min. Stimulus: instrumental music.

plane resolution = 0.78U0.78 mm, slice thick- surface of the temporal lobe. For the remaining ses- ness = 3.0 mm). sions, eight (sessions 2^6) or ¢ve (7, 8) slices of in- 2. The magnetic ¢elds over the superior temporal plane terest were imaged in a near-axial plane, parallel to were shimmed to improve ¢eld homogeneity (Reese the superior surface of the temporal lobe. et al., 1995). 4. Anatomical images were acquired of the slices of 3. The sagittal anatomical images were used to select interest (T1-weighted, in-plane resolution = 1.5U1.5 the `slices of interest' to be studied. These slices en- mm). compassed all or the majority of Heschl's gyrus. For 5. Functional images were acquired of the slices of in- session 1, ¢ve slices of interest were imaged in a terest (T2*-weighted, asymmetric spin echo, d = 325 near-coronal plane, perpendicular to the superior ms). During each functional imaging run, each slice

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Table 2 Imaging parameters Session TR (s) Number of runs Images per run Stimulus on duration (s) Stimulus o¡ duration (s) 1 4 2 100 40 20 2 2 2 190 30 30 3 2 6 256 16 16 4 2 2 256 16 16 5 2 7 128 16 16 6 2 4 128 24 8 7 2 4 128 24 8 8 2 3 128 24 8

was imaged every 2 or 4 s (i.e., the `repetition time', imaging session did not yield consistent results unless TR = 2 or 4 s) while acoustic stimuli were presented the SNR in auditory cortex was at least 35. Therefore, in the block paradigm described earlier. For session only those imaging sessions in which the SNR in the 1: TE = 77 ms, TR = 4 s, matrix size = 256U128, in- superior temporal plane for the ¢rst run was at least 35 plane resolution = 1.5U1.5 mm, slice thickness = (eight sessions) are described here. Seven of these ses- 4 mm, no gap between slices. For sessions 2^8: sions (sessions 2^8) used our specially designed surface TE = 70 ms, TR = 2 s, matrix of size = 128U64, coil (over the left or both hemispheres) and one session in-plane resolution = 3.1U3.1 mm, slice thickness = (session 1) utilized the 3Q diameter surface coil (over the 3 mm, gap between slices = 1 mm. left hemisphere). The few results that were obtained in sessions with lower SNR are generally consistent with the ¢ndings reported here. 2.5. Imaging coils 2.6. Data analysis The majority of our sessions used a surface coil designed speci¢cally for imaging the human auditory cor- The functional imaging data for each session were tex. The development of this coil was prompted by ¢rst processed using standard fMRI methods as fol- early experiments using a head coil in which there lows: was a general lack of fMRI response in auditory cortex. The lack of response was probably a consequence of the 1. The data (a time series of images of the slices of low signal-to-noise ratio6 (SNR) ^ typically 15 ^ in the interest) were corrected for subject motion (using superior temporal plane near the transverse temporal standard software, SPM95; Friston et al., 1995). gyrus (Heschl's gyrus). To improve the SNR we Speci¢cally, the functional images for a given session switched to 5Q and 3Q diameter surface coils, but it were aligned to `reference' images of the slices of was di¤cult to center these coils over the superior tem- interest (i.e., to the functional images acquired in poral plane and maintain them in a ¢xed position closest temporal proximity to the anatomical im- throughout the duration of an imaging session (approx- ages). imately 2 h). With the eventual goal of imaging both 2. For each run, the time series of image signal values hemispheres at the same time, we developed a set of for each voxel in the slices of interest was ratio-nor- bilateral imaging coils that were integrated into the ear- malized to a ¢xed mean level and was corrected for mu¡s. These consisted of square loop coils centered at any linear or quadratic drift in signal level (which the top of each earmu¡. The coils may be used individ- might otherwise be detected as an artifactual `re- ually or as a bilateral set. Sessions 2^7 utilized a single sponse' to our stimuli). coil over one hemisphere. The second coil was com- 3. To improve detection of responses to the stimuli, the pleted in time for session 8 to be conducted using functional image data for each session were com- both coils. Used individually or as a pair, this coil de- bined across runs. For sessions 1, 2, 4^8, the data sign consistently yields high SNR values ^ greater than were combined by averaging (i.e., image signal level 35 ^ in our region of interest, the superior temporal for each voxel and time point was averaged across lobe. runs). For session 3, the data from individual runs Single runs of the experimental paradigm within an were concatenated, rather than averaged, because the order of lower- and higher-frequency stimulation varied from run to run. The `combined' (i.e., aver- 6 The signal-to-noise ratio is de¢ned as the mean signal level (i.e., aged or concatenated) functional image data were signal averaged over time) divided by the standard deviation. used in all further analyses.

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2.6.1. Mapping to Talairach coordinate system To compare physiological responses across imaging To facilitate comparisons of results across sessions, sessions, the t-statistic values were normalized to ac- the image data were mapped into a common coordinate count for session-to-session di¡erences in the total num- system, the stereotaxic coordinate system of Talairach ber of functional images acquired. Normalization was (Talairach and Tournoux, 1988; sessions 2^8 only, ses- implemented by selecting a baseline t-statistic cuto¡ of sion 1 discussed below). First, a linear transformation t s 1.98 (P 6 0.05, uncorrected for multiple compari- was established between reference points in the Talair- sons) for the case in which 192 images were acquired ach system and corresponding landmarks in the sagittal in each of the higher- and lower-frequency stimulation anatomical images (e.g., the location of the anterior and conditions. The t-statistic cuto¡ was scaled up or down posterior commissures at the midline). This transforma- (assuming independent images) for use in the analysis tion was then applied to the functional image data of each session depending on the total number of im- (which were already automatically spatially registered ages obtained in the two stimulation conditions. The to the sagittal images). Once transformed, the sagittal normalization did not greatly change the observation anatomical images and the functional images were re- rates of regions exhibiting frequency-dependent resectioned in the coronal and axial planes of the Talair- sponses, but did make the spatial extent of these regions ach coordinate system (voxel size: 3U3U3 mm). Sub- more consistent across sessions. sequent analyses focussed on a volume centered mediolaterally and anteroposteriorly on Heschl's gyrus 2.7. Identi¢cation of frequency-dependent response and containing most of the superior temporal lobe (e.g., regions Penhune et al., 1996). In the left hemisphere (sessions 2^8), this volume was a rectangular box bounded by FDRRs were identi¢ed using the following proce- Talairach coordinates (x, y, z)=(372, 354, 0) and dure. First, we identi¢ed all voxels that (1) achieved a (312, 6, 15). In the right hemisphere (session 8 only), normalized threshold of P 6 0.05, (2) neighbored at the volume was the same, except re£ected across the least one other voxel meeting this threshold criterion midline. and exhibiting the same frequency dependence, and For session 1, the registration information required (3) were local statistical maxima. A voxel was a local to map the functional image data to the Talairach co- statistical maximum if its P value was lower (i.e., more ordinate system was not available. Therefore, the data signi¢cant) than that for the 26 neighboring voxels in a from this session were analyzed in the near-coronal 3U3U3 cube centered on the voxel. Each voxel meeting plane of the original images (voxel size: 1.5U1.5U4 the three criteria above was de¢ned as an `FDRR fo- mm) and in a reconstructed near-axial plane (voxel cus'. Around each focus, the remainder of the FDRR size: 1.5U4U1.5 mm; obtained as orthogonal slices was de¢ned as the set of contiguous voxels exhibiting through the original near-coronal images). the same frequency dependence, a P value less than or equal to 0.05, and a constant or increasing P value (i.e., 2.6.2. Statistical analysis constant or decreasing statistical signi¢cance) as a func- The functional image data were analyzed by statisti- tion of distance from the FDRR focus. The latter crite- cally comparing image signal levels during periods of rion allowed us to resolve two or more neighboring higher- vs. lower-frequency stimulation. These analyses FDRRs of the same frequency dependence even when were performed on the Talairach images for sessions 2^ the FDRRs merged into one another to create a single, 8 and the near-coronal images for session 1. For each large area of cortical activation. Note that an FDRR voxel, an unpaired t-test was used to compare mean focus is not necessarily at the center of the FDRR. image signal level during two conditions: higher-fre- Rather it is the voxel exhibiting the most statistically quency stimulation and lower-frequency stimulation. signi¢cant response (the `peak'). At this point, any An image was assigned to the higher-frequency (low- FDRRs containing non-cortical voxels were excluded er-frequency) condition if it was acquired 4 s or more from further analysis. Speci¢cally, an FDRR was ex- after the onset of the higher-frequency (lower-fre- cluded if, within two voxels of the FDRR focus, it quency) stimulus and at most 4 s after the o¡set of extended into the ventricles, out of the brain (identi¢ed the stimulus. This 4 s delay accounts for the onset as voxels showing a signal level greater than 100 in the and o¡set time of the blood oxygenation level-depen- anatomical images), or out of the temporal lobe (e.g., dent fMRI response (e.g., Buckner et al., 1996; Bandet- into parietal cortex). tini et al., 1993; Kwong et al., 1992). After these anal- The remaining FDRRs were assigned a number yses, each voxel was assigned a t-statistic (i.e., the result based on their frequency dependence, spatial relation- of the t-test), and a `frequency dependence' indicating ship to each other and position relative to anatomical whether image signal levels were greater during the landmarks, or they were left `unnumbered'. First, for higher- or the lower-frequency condition. each session, FDRRs were displayed in axial sections

HEARES 3571 1-11-00 Cyaan Magenta Geel Zwart 232 T.M. Talavage et al. / Hearing Research 150 (2000) 225^244 through the analyzed Talairach volume (sessions 2^8) or in near-axial sections (session 1). These displays were then examined for consistent trends across sessions ^ for instance, FDRRs with a particular frequency dependence that consistently occurred in conjunction with a particular anatomical landmark (e.g., the superior surface of Heschl's gyrus), or FDRRs that occurred repeatedly at a particular location relative to other FDRRs7. Initially, these examinations considered the full extent of the FDRRs. However, our ¢nal criteria for assigning a particular number to an FDRR were based on the locations of FDRR foci (see Section 3 and Fig. 3). At the outset of these analyses, it was decided that FDRRs would only be `numbered' if they occurred in over half the sessions and that all other FDRRs would be left `unnumbered'.

2.8. Data visualization

Two formats were used to show the spatial distribution of FDRRs. One (see Fig. 3) shows FDRR data in an axial plane ^ the plane used in assigning numbers to FDRRs. For three sessions (2, 5 and 8), FDRR foci from all six axial slices in the analyzed Talairach volume were overlaid upon axial anatomical images (i.e., the sagittal anatomical images mapped to Talairach coordinates and resectioned in the axial plane as 3 mm thick slices). So the foci could be readily visualized, the three lowest P value voxels within the FDRR immedi- Fig. 2. The relationship between FDRRs 1^3 and Heschl's gyrus for ately adjacent to each focus (and in the same axial each session shown diagrammatically in a coronal (sessions 2^8) or near-coronal (session 1) plane. The summary diagram for session 1 plane as the focus) were also identi¢ed. The FDRR (top, left) was obtained by outlining Heschl's gyrus and FDRRs 1^ foci (and adjacent voxels) in the axial slices centered 3 in Fig. 1c. The remaining summaries (for sessions 2^8) are projec- at Talairach z = +12, +6, and +0 mm were displayed tions of FDRRs 1^3 from three coronal slices onto the middle slice. on the corresponding axial anatomical images (i.e., at (For sessions 2^8, FDRRs 1^3 were displaced from each other ante- z = +12, +6, 0 mm). The foci (and adjacent voxels) for roposteriorly.) These projections compensated for the medial^lateral and superior^inferior displacement of Heschl's gyrus across coronal Talairach z = +15, +9 and +3 mm were projected onto locations (see Section 2.8). Summaries for sessions 1^7 show left the adjacent anatomical slices at z = +12, +6 and +0 Heschl's gyrus, and the summary for session 8 depicts right Heschl's mm, respectively. Thus, three-slice summaries were ob- gyrus. The variable anatomy of left Heschl's gyrus for subject 2 in tained showing the distribution of FDRR foci over the sessions 2 and 4 is a consequence of intersession di¡erences in the superior temporal lobe (see Fig. 3). imaging plane and variability in the identi¢cation of landmarks for the transformation to the Talairach coordinate system. The second format for visualizing FDRRs (see Fig. 2) showed the most reproducible FDRRs overlapping Heschl's gyrus (i.e., FDRRs 1^3) in a coronal (sessions Heschl's gyrus. A tracing was then made of anatomical 2^8) or a near-coronal (session 1) plane. For sessions 2^ landmarks in the middle slice (slice centered at y = 324 8, these FDRRs were usually spatially separated in the mm for sessions 2^5, 7 and 8; y = 321 mm for session anterior^posterior dimension. Therefore, to generate a 6). These landmarks included Heschl's gyrus, the ven- concise summary, the FDRRs were `collapsed' into a tricles, the edge of the brain and the midline. Next, the single coronal plane as follows. For each session, three outline of each FDRR in each coronal slice was super- coronal slices in the Talairach volume (i.e., covering a imposed on the tracing of the middle slice. When super- 9 mm anterior^posterior extent) were identi¢ed that in- imposing FDRR outlines, the anterior and posterior cluded portions of all three of the FDRRs overlapping slices were registered to the middle slice by ¢rst trans- lating them inferosuperiorly to align the superior edge of Heschl's gyrus. They were then translated mediolat- 7 For session 8, in which data were obtained for both right and left erally to achieve a best ¢t (by eye) of the medial^lateral hemispheres, the two hemispheres were examined separately. extent of the gyrus. This rigid body translation pre-

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Fig. 3. Distribution of FDRR foci in the axial plane for sessions 2 (top), 5 (middle), and 8 (bottom). The row for each session shows anatomical images (grayscale) and superimposed voxel clusters, each corresponding to an FDRR-either `numbered' (red or blue with diagonal lines) or `unnumbered' (grayshading with vertical or horizontal lines). The cluster for each FDRR includes the FDRR focus and up to three adjacent voxels. Adjacent voxels were displayed if they had P 6 0.05 and if they were among the three adjacent voxels with the lowest P values. The three anatomical images for each session correspond to slices centered at Talairach coordinates z = +12 mm (left), z = +6 (middle), and z =+0 (right). The superimposed FDRR foci (and adjacent voxels) correspond to slices centered at z = +15 and +12 mm (left), z = +9 and +6 mm (middle), and z = +3 and +0 mm (right). Left hemisphere data are shown for all three sessions. For session 8, FDRR foci (and adjacent voxels) from the right hemisphere were re£ected across the midline and also displayed. (Note that no adjustment was made for the fact that right Heschl's gyrus is, on average, displaced anteromedially relative to left Heschl's gyrus; Penhune et al., 1996.) The white outlines depict the maximal extent of Heschl's gyrus in each of the composite slices, identi¢ed by viewing the volumetric data simultaneously in the axial, coronal and sagittal planes. served the spatial relationship between FDRRs and the near-coronal plane of the original functional images Heschl's gyrus. The ¢nal result for sessions 2^8 was because the data could not be mapped into Talairach an `adjusted' projection of the FDRRs onto a single coordinates. All of the FDRRs of interest (1^3) ap- coronal slice that takes into account the displacement peared in a single slice (see Fig. 1c), so a `near-coronal of Heschl's gyrus across coronal locations in the Talair- summary' was generated by outlining Heschl's gyrus ach space. For session 1, the FDRRs were displayed in and the FDRRs for this slice.

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Table 3 Left (right) hemisphere volume of each numbered FDRR Session Volume (number of voxels)a Lower-frequency FDRR Higher-frequency FDRR 16782345 1 16 0 ^ 14 7 43 16 5 2 402732 16122713 3 99 53 48 124 26 10 23 5 4 19 3 21 35 2 6 11 0 5 3602119116 6 561319729320 7 7 872671317266 8 24 (25) 5 (23) 9 (7) 2 (0) 0 (3) 0 (12) 3 (0) 0 (0) aVoxel dimensions were (session 1) 1.5U1.5U4 mm or (sessions 2^8) 3U3U3 mm.

3. Experimental results ciated in axial slices. FDRR 1 (Fig. 3, middle slice for all sessions) was de¢ned as the lower-frequency FDRR Eight `numbered' FDRRs were identi¢ed on the having the medial-most focus on the superior half of superior temporal lobe. These FDRRs were `numbered' Heschl's gyrus. FDRR 1 was located on the anterior because they were observed in over half of the eight portion of the bifurcated gyrus for session 59 (Fig. 3, imaging sessions. FDRRs that were not observed as middle row). FDRR 2 (Fig. 3, middle slice) was de¢ned consistently were left `unnumbered' and will not be de- to be the higher-frequency FDRR with a focus on or scribed in detail. The description of `numbered' FDRRs near the anteromedial aspect of Heschl's gyrus, located will begin with those overlapping the medial two-thirds medial to the focus for FDRR 1. FDRR 3 (Fig. 3, of Heschl's gyrus, the location of primary auditory cor- superior slice) was de¢ned as the higher-frequency tex (e.g., Rademacher et al., 1993), and proceed to FDRR with a focus on or near the posterolateral aspect those in surrounding regions of cortex. of Heschl's gyrus, at least as lateral as the focus for Three of the eight `numbered' FDRRs overlapped FDRR 1. The focus for FDRR 3 was typically superior Heschl's gyrus and were seen in all sessions8. These to the focus for FDRR 1 even though the coronal sum- FDRRs, as imaged in a near-coronal plane for session maries give the opposite impression. This di¡erence is a 1, are depicted in Fig. 1. FDRR 1, located on the supe- consequence of the oblique angle between the superior rior aspect of Heschl's gyrus (Fig. 1c), exhibited signi¢- temporal plane and the anterior commissure^posterior cantly (P 6 0.05) greater image signal levels during pe- commissure line de¢ning the Talairach axial plane (Ta- riods of lower-frequency (low-pass-¢ltered music) lairach and Tournoux, 1988). Because of this angle, the stimulation than during periods of higher-frequency base of Heschl's gyrus posteriorly (where FDRR 3 is (high-pass-¢ltered music) stimulation (Fig. 1d). There- located) can be superior to the superior surface of Hes- fore, FDRR 1 is a `lower-frequency' FDRR. FDRRs 2 chl's gyrus anteriorly (where FDRR 1 is located) in and 3 (located inferomedial and inferolateral to FDRR Talairach space. 1 in Fig. 1c) exhibited signi¢cantly greater signal levels The remaining `numbered' FDRRs were observed in during periods of higher-frequency stimulation (Fig. 1e) six or more sessions and were de¢ned as follows (Figs. 3 and are therefore `higher-frequency' FDRRs. FDRRs and 4, 4). FDRR 4 was the higher-frequency FDRR 1^3 were also observed in the other seven imaging ses- having a focus on or near the most posteromedial sions. This is illustrated in Fig. 2 which shows, for each part of Heschl's gyrus, posterior to the focus for session, a projection of these FDRRs onto a coronal FDRR 2 (Fig. 3, superior slice). FDRR 5 (Fig. 3, in- slice through Heschl's gyrus (see Section 2.8). ferior slice of sessions 2 and 5) was de¢ned as the high- The identi¢cation and numbering of FDRRs (includ- er-frequency FDRR with a focus located in the inferior ing 1^3) was based on an analysis of FDRR foci in the third of the analyzed volume on or near the postero- axial plane (Fig. 3). Although the relationship between lateral aspect of Heschl's gyrus (where it begins to FDRRs 1^3 and Heschl's gyrus can be seen readily in merge with the superior temporal gyrus (STG) anteri- the coronal summaries of Fig. 2, the relationship be- orly). FDRR 6 was de¢ned to be the lower-frequency tween the full complement of FDRRs was best appre- FDRR with the most superior and lateral focus located

8 For session 8 (the one session in which both right and left hemisphere data were obtained), all three FDRRs (1^3) were seen on the 9 Subject 4 (session 5) was the only subject who exhibited a bifurcated right, but only FDRR 1 was seen on the left. Heschl's gyrus.

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Fig. 4. Criteria and Talairach coordinates of FDRR foci. The coordinates (mean þ S.E.M.) are an average across sessions 2^8 only because session 1 could not be mapped to the Talairach system. Only left hemisphere foci have been included in the average. An FDRR was deemed to be observed in session 8 if it was present in either the left or right hemisphere. on or immediately lateral to the anterior extreme of this variability, however, there was an apparent trend. Heschl's gyrus, superior and/or lateral to FDRR 1 FDRR 1 was typically the largest or second largest (Fig. 3, middle slice of all three sessions and superior FDRR. slice of session 8). FDRR 7 was de¢ned as the lower- frequency FDRR with a focus located anteriorly on or just anterior to the anterolateral extreme of Heschl's 4. Discussion gyrus. This anterior position also dictated that FDRR 7 was in the inferior half (z 9 +6 mm) of the analyzed Our experiments revealed eight repeatable FDRRs on volume (Fig. 3, inferior slice of sessions 2 and 8). Heschl's gyrus and surrounding areas of the superior FDRR 8 (Fig. 3, middle slice for sessions 2 and 8, temporal lobe (i.e., eight `numbered' FDRRs). Four superior slice for session 5) was de¢ned as the lower- of these FDRRs exhibited greater image signal levels frequency FDRR with a focus on the STG in the supe- in response to lower-frequency stimulation (lower-fre- rior half (z v +9 mm) of the analyzed volume, posterior quency FDRRs), while four exhibited greater signal to the foci for FDRRs 5 and 6 and posterolateral to the levels in response to higher-frequency stimulation (high- focus for FDRR 3. er-frequency FDRRs). Thus, each FDRR indicated a The full extent of each FDRR is quanti¢ed in Table site of frequency-sensitive physiological activity in audi- 3. Some FDRRs were little more than the FDRR focus tory cortex, as detected with fMRI. Each `numbered' (i.e., two voxels). However, in most instances FDRRs FDRR was identi¢ed repeatedly across subjects and were substantially larger. FDRR volume varied consid- had a fairly consistent position relative to other FDRRs erably across FDRRs and across sessions. In spite of and gross anatomical landmarks. We therefore propose

HEARES 3571 1-11-00 Cyaan Magenta Geel Zwart 236 T.M. Talavage et al. / Hearing Research 150 (2000) 225^244 that the eight `numbered' FDRRs together represent a Given the working hypothesis that FDRRs are local- signature pattern of cortical frequency sensitivity shared ized to tonotopically organized areas, the eight `num- by human subjects. As explained below, the FDRRs are bered' FDRRs suggest multiple tonotopically organized consistent with four or more tonotopically organized areas in human auditory cortex. One possibility is that areas in human auditory cortex. the FDRRs are divisible into lower- and higher-frequency pairs, with each pair localized to a particular 4.1. FDRRs and neural frequency sensitivity tonotopically organized area. The four lower- and four higher-frequency FDRRs could then correspond FDRRs can be interpreted in terms of neural fre- to four separate tonotopic maps. A somewhat di¡erent quency sensitivity by considering the relationship be- correspondence between FDRRs and tonotopic maps is tween neural activity and image signal changes during suggested by an organization commonly seen in ani- fMRI. It is known that an increase in neural activity mals, in which the low- or high-frequency ends of two (i.e., synaptic events, discharges) can lead to an increase adjacent maps abut and the progressions of neural fre- in local metabolic activity, including an increase in oxy- quency sensitivity in the two maps are mirror images of gen consumption (Phelps et al., 1981; Prichard et al., each other across the common boundary (e.g., Reale 1991). This increase drives an increase in blood delivery and Imig, 1980; Robertson and Irvine, 1989; Rau- that overcompensates for oxygen consumption (Fox schecker et al., 1995; Kosaki et al., 1997). If this mir- and Raichle, 1986; Mandeville et al., 1998; Hoppel et ror-image organization also occurs in human auditory al., 1993; Buxton et al., 1998). The result is excess oxy- cortex, a single FDRR could correspond to the abut- genated hemoglobin, and a corresponding reduction in ting low- or high-frequency ends of adjacent tonotopic the local concentration of deoxygenated hemoglobin maps. The eight `numbered' FDRRs could then corre- (Kwong et al., 1992; Ogawa et al., 1992). Because de- spond to more than four tonotopically organized areas. oxygenated hemoglobin is paramagnetic, a reduction in The hypothesis that FDRRs correspond to lower- its concentration results in an increase in local magnetic and higher-frequency regions within tonotopically or- ¢eld uniformity, and consequently an increase in image ganized areas is supported by our additional fMRI signal. In short, an increase (or decrease) in neural ac- work using a complementary stimulation paradigm to tivity leads to a concordant change in image signal. examine the tonotopic organization of human auditory Stimulus-induced changes in image signal occur over a cortex (Talavage et al., 1997). In this paradigm, the matter of seconds (e.g., Fig. 1) indicating that fMRI center frequency of a narrow-band noise was swept re£ects changes in the overall level of neural activity, from low to high (or high to low), and sites of peak rather than the detailed timing of activity. Given this image signal were tracked vs. time across the cortical relationship between fMRI signal changes and neural surface. The experiments using these frequency-swept activity, we interpret higher-frequency FDRRs as re- stimuli indicated progressions of frequency sensitivity gions where the overall level of neural activity is greater across the cortical surface, connecting seven of the during higher-, as compared to lower-frequency stimu- `numbered' FDRRs identi¢ed in the present study. lation; lower-frequency FDRRs are regions where the The progressions indicate that most of these FDRRs opposite is true. do indeed coincide with lower- and higher-frequency regions of tonotopically organized areas. In some cases, 4.2. Multiple FDRRs: implications for tonotopic progressions were seen from a single FDRR to multiple organization FDRRs, suggesting the presence of a mirror-image organization by which some FDRRs could represent One interpretation of lower- and higher-frequency the low- or high-frequency ends of abutting tonotopic FDRRs is that they are localized, respectively, to lower- maps. All of our work taken together indicates there and higher-frequency regions within tonotopically or- are seven tonotopically organized areas in human audi- ganized cortical areas. The idea is (a) within tonotopi- tory cortex, a number comparable to other species in- cally organized areas, neuronal BF varies systematically cluding cat and various non-human primates (e.g., with position, (b) the overall population of neurons in Reale and Imig, 1980; Morel et al., 1993; Rauschecker regions of lower- or higher-BF respond more vigorously et al., 1995, 1997; Kosaki et al., 1997). to lower- or higher-frequency stimuli, respectively, and (c) a region exhibiting di¡erential sensitivity to lower vs. 4.3. Relationship between FDRRs and anatomical areas higher frequencies is detected as an FDRR. An alter- in human auditory cortex native possibility is that at least some FDRRs correspond to cortical areas that are not tonotopically or- A correspondence may be proposed between the ganized, but nevertheless contain neurons that respond eight `numbered' FDRRs and anatomically de¢ned more to either lower- or higher-frequency stimuli. areas in auditory cortex. We will base this correspond-

HEARES 3571 1-11-00 Cyaan Magenta Geel Zwart T.M. Talavage et al. / Hearing Research 150 (2000) 225^244 237 ence on the proximity of our `numbered' FDRRs to the two-thirds of the length of Heschl's gyrus from the reported locations and extents of anatomical areas in medial-most end of the gyrus (Fig. 6), coinciding with human auditory cortex (e.g., Galaburda and Sanides, the lateral extent of koniocortex (Rademacher et al., 1980; Rivier and Clarke, 1997). Galaburda and Sanides 1993). The location of FDRR 1 roughly corresponds (1980) distinguished eight anatomical areas in auditory to the boundary between the medial (KAm) and lateral cortex based on cytoarchitectonic criteria, including two (KAlt) koniocortical areas of Galaburda and Sanides koniocortical divisions on Heschl's gyrus, two distinct (1980), a line that runs oblique to the long axis of areas anterior to Heschl's gyrus and four areas posteri- Heschl's gyrus, from the middle portion of the posterior or to the koniocortex (Fig. 5a). Rivier and Clarke boundary of koniocortex to its anterolateral end (Fig. (1997) identi¢ed six anatomical areas, one koniocortical 5a). No other auditory areas are proposed to contribute area on Heschl's gyrus, two areas anterior to Heschl's to FDRR 1 because the superior position of the FDRR gyrus, and three areas posterior to the koniocortex (Fig. on Heschl's gyrus is inconsistent with the described ex- 5b). Note that the distribution of the average Talairach tents of the nearest non-koniocortical areas ^ MA and positions of the foci of the eight `numbered' FDRRs AA of Rivier and Clarke (1997) or ProA and PaAr of (Fig. 6) covers approximately the same extent of the Galaburda and Sanides (1980). superior temporal lobe as the reported centers of the We propose that FDRR 2 corresponds to one or architectonically de¢ned auditory areas. both of two areas, the medial portion of A1 and the We will now consider the anatomical attribution of adjacent, inferior, medial auditory area, MA (Rivier each FDRR. and Clarke, 1997). With regard to the areas of Gala- We propose that FDRR 1 represents a response from burda and Sanides (1980), this amounts to a corre- the koniocortex, designated in its entirety as `primary spondence between FDRR 2 and KAm and/or the pro- auditory cortex' (A1) by Rivier and Clarke (1997), but koniocortex anteromedial to Heschl's gyrus (ProA). divided into medial (KAm) and lateral (KAlt) parts by This assignment is made for FDRR 2 due to the loca- Galaburda and Sanides (1980). FDRR 1 is located on tion of its focus on or near the anteromedial aspect of the superior aspect of Heschl's gyrus, 9 mm anterior Heschl's gyrus, equidistant from the centers of MA and and lateral of the average center of mass indicated for A1 ^ approximately 9 mm medial of both (Fig. 6) ^ and A1 (Rivier and Clarke, 1997). This position is roughly the observation that ProA is located immediately ante-

Fig. 5. Diagrams of architectonically de¢ned auditory areas in the superior temporal plane, depicted on an outline of the cortex based on the Talairach z = +4 mm plane (Talairach and Tournoux, 1988) to provide an indication of the relative positions of the areas to Heschl's gyrus. The anterior and posterior extent of Heschl's gyrus are based on the Talairach z = +8 mm plane. (a) An approximation of the spatial position and extent of the eight cytoarchitectonic areas of Galaburda and Sanides (1980), based upon their Fig. 1. (b) Schematic of the six architectonic areas in the superior temporal plane from Rivier and Clarke (1997), based upon their Fig. 10. The hexagonal labels of the architectonic areas indicate the average center of mass of the corresponding area, as computed from Table 5 of Rivier and Clarke (1997).

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areas are KAlt and the posteromedial extent of the in- ternal parakoniocortex (PaAi). The focus of FDRR 3 is, on average, located almost directly posterior to the focus for FDRR 1 (Fig. 6), on or just posterior to Heschl's gyrus, possibly in the sulcus just posterolateral to the gyrus. This location is consistent with the border between KAlt (lateral A1) and PaAi (LA). The assignment of FDRR 3 to either or both KAlt (lateral A1) and PaAi (LA) is further supported by the close proximity of FDRR 3 to the centers of mass of LA (6 mm) and A1 (9 mm) (Fig. 6). FDRR 4 corresponds most closely to the posterior auditory area, PA, of Rivier and Clarke. This may be said to correspond to the posterior portion of PaAc/d of Galaburda and Sanides (Figs. 5 and 6). The focus of FDRR 4 is, on average, located only 4.6 mm from the center of mass of PA, but more than 15 mm from the center of mass of any other architectonically de¢ned auditory area (Fig. 6). FDRR 5 is proposed to be a response from the external parakoniocortex of Galaburda and Sanides (Fig. 5a), which does not have a counterpart in the auditory areas described by Rivier and Clarke (1997). The focus of FDRR 5 is located anteriorly on or near the posterolateral aspect of Heschl's gyrus, more than 10 mm distant from the center of mass of either STA or LA. Its position is consistent with the extent of either the inter- nal (PaAi) or external (PaAe) parakoniocortex, both of Fig. 6. Average locations of the `numbered' FDRRs displayed with which extend anteriorly on the superior temporal gyrus, the six supratemporal anatomical areas of Rivier and Clarke (1997). The average Talairach locations of the four lower-frequency just lateral to Heschl's gyrus. The correspondence with (squares) and four higher-frequency (circles) FDRR foci (see Fig. 4) PaAe is more likely, due to the inferior (Talairach are superimposed on the same underlying outline (Talairach and z = +2.4 mm) position of FDRR 5. Tournoux, 1988) used in Fig. 5b. The average Talairach coordinates FDRR 6, by arguments similar to those used for of the centers of mass of the anatomical areas are indicated by the FDRR 5, is proposed to reside within PaAi of Gala- labeled hexagons, reproduced along with the approximate extent of each area from Fig. 5b. Overlapping symbols correspond to regions burda and Sanides (Fig. 5a). FDRR 6 does not corre- separated in the superior-inferior dimension. For example, area MA spond well with any of the areas described by Rivier is inferior to area A1 because it is located on the anteromedial face and Clarke (1997), its focus being located 11 mm ante- of Heschl's gyrus where it folds back under the crown of the gyrus rolateral of the center of mass of LA, 14 mm antero- on which A1 is located. medial (and superior) of the center of mass of STA and 16 mm anterolateral from the center of mass of A1. The rior to koniocortex. The assignment of FDRR 2 to average location for the focus of FDRR 6 on or imme- another anatomically de¢ned area is e¡ectively ruled diately lateral to the anterior extreme of Heschl's gyrus out by distance (e.g., 13 mm between the focus for is consistent with the described anterior extent of PaAi FDRR 2 and the center of mass of Rivier and Clarke's (Galaburda and Sanides, 1980). We do not attribute posterior auditory area, PA) and the anatomy (e.g., PA FDRR 6 to PaAe due to the more superior location is on or posterior to the posteromedial end of Heschl's of this FDRR. gyrus). It should be noted that Galaburda and Sanides We propose that FDRR 7 resides within the anterior (1980) did report that the caudal^dorsal parakoniocor- auditory area (AA) of Rivier and Clarke (1997), corre- tex (PaAc/d) sometimes extended anteriorly across sponding to the rostral parakoniocortex (PaAr) of Gal- Heschl's gyrus, but because this was not typical, we aburda and Sanides (1980). The focus for FDRR 7 is will not propose a correspondence with FDRR 2. centered 3 mm lateral of the center of mass for AA, We propose that FDRR 3 coincides with one or both strongly arguing for this correspondence (Fig. 6). The of two areas, the posterolateral portion of A1, and the focus of FDRR 7 is not within 10 mm of any other lateral auditory area, LA (Rivier and Clarke, 1997). In auditory areas, so no further correspondences are pro- the terminology of Galaburda and Sanides (1980), these posed.

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FDRR 8 is proposed to coincide to one or both of 4.5. Stimulus level two areas, STA and LA in the terminology of Rivier and Clarke (1997), and, alternately, PaAe and PaAi of Whether the pattern of cortical frequency sensitivity Galaburda and Sanides (1980). The focus of FDRR 8 revealed by fMRI depends on stimulus level remains an is, on average, located 5 mm posterolateral of the center open question because all of the stimuli used in this of mass of LA and 8 mm (4.8 mm posteromedial and study were similar in level and inferences concerning 6 mm superior) from the center of STA. Such close level e¡ects cannot be drawn con¢dently from the ani- proximity suggests that responses from both anatomical mal literature. Microelectrode recordings in animals areas may contribute to this FDRR. This is consistent have shown that the spatial pattern of auditory cortical with our knowledge that the posteromedial portion of activity evoked by narrowband sound can depend on PaAe abuts (posteriorly) the posterior portion of PaAi level in complex ways10 (Phillips et al., 1994; Heil et al., where both extend from the STG onto the superior 1994). However, it is not clear that fMRI activation temporal plane (Galaburda and Sanides, 1980). patterns would also show complex variations with level, because the animal ¢ndings are based on recordings of 4.3.1. Overview neuronal discharges whereas fMRI activation re£ects FDRRs 1^3 may best be explained as responses from both discharges and synaptic activity. In fact, it may the koniocortex. These three FDRRs are almost equi- be that fMRI activation patterns for narrowband stim- distant from the average center of Rivier and Clarke's uli are fairly insensitive to stimulus level given recent A1 and, along with FDRR 4, are the only `numbered' PET data (PET, like fMRI, re£ects both discharge and FDRRs in the immediate vicinity of the koniocortex ^ synaptic activity). Lockwood et al. (1999) found that the medial two-thirds of Heschl's gyrus (Rademacher et sites of maximal PET activation for tone burst stimuli al., 1993; Galaburda and Sanides, 1980; Rivier and showed little variation with stimulus level. Clarke, 1997). FDRRs 4^8 are proposed to be located in non-koniocortical areas (Figs. 5 and 6). 4.6. Imager-generated acoustic noise

4.4. Relationship between FDRRs, anatomical areas, and Whether or not imager-generated acoustic noise in- tonotopic maps on Heschl's gyrus £uenced our ¢ndings is also an open question. The present study attempted to reduce the e¡ects of im- The present study, combined with our work investi- ager-generated noise on fMRI activation by using stim- gating progressions in frequency sensitivity along the uli that avoided the frequency of the highest-level noise. cortical surface (Talavage et al., 1997), suggests that Nevertheless, we cannot exclude the possibility that the many of the anatomical areas in human auditory cortex number and pattern of FDRRs would be somewhat are tonotopically organized. Discussion of the relation- di¡erent under lower noise conditions. ship between anatomical areas and tonotopic maps will be largely deferred to a subsequent manuscript describ- 4.7. Possible interpretations of unnumbered FDRRs ing the frequency progression work. However, two re- lationships that follow straightforwardly from the There are several possible reasons for the inconsistent present study alone are proposed here. These pertain occurrence of some FDRRs (i.e., the FDRRs that were to the koniocortical areas of Heschl's gyrus. left `unnumbered'). For instance, the occurrence of The pattern of anatomical areas and FDRRs on FDRRs for some sessions and not others could re£ect Heschl's gyrus suggests that both KAm and KAlt con- the di¡erences in stimulus across sessions. A second tain a tonotopic map, and that the two maps abut at possibility is that the `unnumbered' FDRRs re£ect in- their low-frequency ends. Speci¢cally, we propose that ter-individual di¡erences in cortical tonotopic organiza- FDRR 1 is the result of responses from the lower- tion. For example, the locations of some tonotopically frequency ends of both maps, and that FDRRs 2 and organized areas may have been su¤ciently di¡erent be- 3 correspond to higher-frequency regions of KAm and tween subjects that the repeated occurrence of their KAlt, respectively. In terms of tonotopic maps, we pro- corresponding FDRRs went unrecognized. Thus, it is pose that there are two mirror-image maps on Heschl's possible that our identi¢cation of eight `numbered' gyrus, one corresponding to KAm and the other to FDRRs under-represents the number of repeatable fre- KAlt. This organization for KAm and KAlt ¢ts with quency-sensitive foci in human auditory cortex. the functional organization of potentially homologous regions in non-human primates ^ namely R and AI in the `core' region of auditory cortex (e.g., Kaas and 10 The complexities are at least partly attributable to an interplay between on-BF excitation and o¡-BF inhibition resulting in non-mon- Hackett, 1998). R and AI also exhibit a mirror-image otonic rate-level functions for many auditory cortical neurons (Phil- organization across a low-frequency border. lips et al., 1985, 1995; Phillips, 1988).

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4.8. Comparison with previous functional studies in (Bertrand et al., 1991; Verkindt et al., 1995), evoked humans magnetic ¢eld studies have repeatedly described an increase in N100 source depth with increasing stimulus Previous experiments examining the tonotopic orga- frequency (e.g., Pantev et al., 1988; Yamamoto et al., nization of human auditory cortex have been conducted 1988; Cansino et al., 1994; Huotilainen et al., 1995; using direct cortical recordings (Howard et al., 1996), Lu«tkenho«ner and Steinstra«ter, 1998; Mu«hlnickel et al., evoked magnetic ¢elds (e.g., Romani et al., 1982a), 1998). This relationship is typically such that a one evoked potentials (e.g., Bertrand et al., 1991), fMRI octave increase in frequency corresponds to a 2^3 mm (Wessinger et al., 1997; Bilecen et al., 1998; Yang et increase in source depth. al., 2000), and PET (Lauter et al., 1985; Lockwood et We examined whether some FDRRs might corre- al., 1999). Here, we compare our ¢ndings with this pre- spond to the tonotopically organized area generating vious work. N100 by comparing our data with the most repeatable trend for N100: the increase in source depth with in- 4.8.1. Single unit responses creasing stimulus frequency at a rate of 2^3 mm per Recordings of single unit BFs from the anteromedial octave. This trend suggests an underlying tonotopic half of Heschl's gyrus by Howard et al. (1996) can be map that would be compatible with (a) a lateral low- compared with the two FDRRs localized to this region, er-frequency FDRR and more medial higher-frequency namely FDRRs 1 and 2. The single unit recordings FDRR, and (b) a 10^15 mm separation between the were made from three locations along a posteromedial higher- and lower-frequency FDRR foci (estimated to anterolateral trajectory that turns out to approxi- based on the stimulus frequencies used in the present mate a line joining the foci of FDRRs 1 and 2 (see study and a representation of one octave per 2^3 mm). Fig. 6). The most posteromedial recording site was lo- In our data, two FDRR pairs best ¢t this description: cated approximately where FDRR 2 would be. Consis- FDRRs 3 (higher) and 8 (lower), and FDRRs 2 (high- tent with the observed higher-frequency sensitivity of er) and 1 (lower) (see Fig. 6). FDRRs 3 and 6 match the FDRR 2, the BFs at this site were in the frequency description, but also show a substantial anterior^poste- range of our higher-frequency stimuli. Across recording rior separation that does not ¢t with the most repeat- locations, BF progressively decreased from posterome- able ¢ndings for N100. We therefore propose that the dial to anterolateral. Because the recording sites fell tonotopically organized area generating N100 most approximately along a line joining FDRRs 2 and 1, likely corresponds to either FDRRs 3, 8 or FDRRs 2, the progression of BFs is consistent with a progressive 1. The location of both of these FDRR pairs relative to change from higher-frequency sensitivity near FDRR 2 superior temporal lobe anatomy is within the range of to lower-frequency sensitivity near FDRR 1. The single locations found for the source of N100 (Pantev et al., unit data therefore support the view that FDRRs 1 and 1990; Reite et al., 1994; Lu«tkenho«ner and Steinstra«ter, 2 correspond to lower and higher frequency regions of a 1998). single tonotopically organized area on Heschl's gyrus. Repeatable dependences on stimulus frequency have also been reported for the sources of two additional 4.8.2. Evoked magnetic and electric responses evoked response components: the sustained ¢eld (SF) Cortical tonotopic organization has been examined in and middle latency component Pa. Although the avail- the evoked magnetic ¢eld and evoked potential litera- able data are too sparse to propose de¢nitive corre- ture most commonly using transient stimuli (tone spondences between FDRRs and the tonotopically or- bursts). The strategy in these studies has been to model ganized areas generating SF and Pa, a tentative the source of a given evoked response component as a correspondence can be o¡ered if we adopt two working dipole and determine whether source location depends hypotheses: (a) SF, Pa, and N100 are each generated on stimulus frequency. In comparing our results with within a di¡erent tonotopically organized area, and (b) the evoked response literature, we focus on components FDRRs 3, 8 correspond to the tonotopically organized that have most repeatedly exhibited a relationship be- area generating N100. If we were instead to adopt the tween stimulus frequency and source location. view that FDRRs 2, 1 correspond to the tonotopic map By far the most studied component in the evoked of N100, a relationship between FDRRs and SF and Pa response tonotopy literature is N100, a component oc- is not obvious. curring approximately 100 ms after stimulus onset. The Our deductions regarding FDRRs and tonotopic primary source of N100 has been consistently localized maps underlying SF and Pa follow from spatial rela- to the superior temporal plane (e.g., Pantev et al., 1990; tionships between the sources of these components and Reite et al., 1994; Lu«tkenho«ner and Steinstra«ter, 1998). the source of N100. It has been reported that the source Although evoked potential studies have not reported a of the SF is approximately 5 mm anterior to the source frequency-dependent change in N100 source location of N100, is slightly more medial, and has a depth that

HEARES 3571 1-11-00 Cyaan Magenta Geel Zwart T.M. Talavage et al. / Hearing Research 150 (2000) 225^244 241 increases with increasing frequency (indicating that 4.8.4. PET higher frequencies were represented more medially; Two previous studies using PET found that low- and Pantev et al., 1994; Huotilainen et al., 1995; Diesch high-frequency monaural tone bursts produce di¡erent and Luce, 1997). Assuming that FDRRs 3, 8 corre- patterns of activation in the contralateral auditory cor- spond to N100, we suggest that FDRRs 2, 1 correspond tex. Lauter et al. (1985) reported that low-frequency to the tonotopically organized area generating the SF tone bursts (500 Hz) produced maximal activation lat- because (a) they are anterior and medial to FDRRs 3, 8 erally, while high-frequency bursts (4000 Hz) produced and (b) the higher-frequency FDRR (i.e., 2) is medial to maximal activation 27 mm more medially. Based on the the lower-frequency FDRR (1) (see Fig. 6). Deductions Talairach coordinates of these sites11 and the probabil- for Pa follow from similar reasoning. Pantev et al. istic map of Heschl's gyrus developed by Penhune et al. (1995, 1996) found that the source of Pa increases in (1996), the sites of high- and low-frequency sensitivity depth with decreasing stimulus frequency and is located were likely located on and lateral to Heschl's gyrus, V5 mm anterior to the source for N100. FDRRs 1, 5 respectively. Lockwood et al. (1999), also using 500 ¢t with this description because (a) they are anterior to and 4000 Hz tone bursts, did not con¢rm the lateral FDRRs 3, 8 and (b) the lower-frequency FDRR (i.e., 1) site of activation for low-frequency tone bursts. How- is medial to the higher-frequency FDRR (see Fig. 6). ever, they did con¢rm the medial high-frequency site. Thus, we propose the following correspondences be- Taken together, the PET data indicate two frequency- tween FDRRs and evoked response components: sensitive sites in human auditory cortex, a medial site FDRRs 3, 8 and N100, FDRRs 1, 2 and the SF, and more sensitive to high frequencies and a lateral site FDRRs 5,1 and Pa. Clearly, these proposed corre- more sensitive to low frequencies. spondences should be viewed as tentative hypotheses It is possible that the sites of low- and high-frequency to be tested. Nevertheless, it is notable that major as- sensitivity in the PET studies correspond to the low- pects of the previous evoked response tonotopy work and high-frequency regions of a single tonotopic map. can be reconciled with our FDRR data. However, this interpretation does not ¢t straightforwardly with evoked response data indicating that a 4.8.3. fMRI one octave separation in neuronal frequency sensitivity Two previous fMRI studies looked for gross di¡er- corresponds to a 2^3 mm spatial separation in at least ences in the activation produced by lower- vs. higher- some tonotopically organized cortical areas. Given a frequency stimuli but did not attempt more ¢ne-grained scaling factor of 2^3 mm per octave, the distance be- analyses required to test for multiple tonotopically or- tween the 500 and 4000 Hz regions of any underlying ganized areas. Wessinger et al. (1997) compared the tonotopic map would be roughly 6^9 mm. This distance sites of maximal activation produced by two binaural is substantially less than the 27 mm distance reported stimuli with frequencies below 1 kHz (55 Hz and 880 by Lauter et al. between the regions of low- and high- Hz). In the left hemisphere, they observed that the site frequency sensitivity. Therefore, our working hypothe- of maximal activation for the higher-frequency stimulus sis is that the low- and high-frequency-sensitive areas was usually posteromedial to the maximum for the low- identi¢ed with PET correspond to the low- and higher-frequency stimulus (no trend was seen in the right frequency areas of two separate tonotopic maps. hemisphere). Bilecen et al. (1998), using binaural 500 There are several points of comparison between the and 4000 Hz tone bursts, examined the overall extent FDRRs of the present study and the sites of frequency of activation on the superior temporal lobe. They re- sensitivity identi¢ed in the previous PET work. For in- ported that activation for the higher-frequency stimulus stance, of the `numbered' FDRRs, the focus for FDRR generally extended farther anteriorly and medially than 8 is located closest to the lateral low frequency site for the lower-frequency stimulus. Thus, these previous identi¢ed by Lauter et al. (i.e., within V7 mm)12. fMRI studies broadly support the view that human This location, coupled with the fact that FDRR 8 is auditory cortex is tonotopically organized. `lower-frequency', suggests that FDRR 8 corresponds A third fMRI study reported evidence for a single tonotopically organized area (Yang et al., 2000). For 11 We took into account the fact that Lauter et al. (1985) and Pen- tones at three frequencies, the authors found that the hune et al. (1996) referenced their anterior^posterior measurements to center of mass of activation shifted laterally with in- di¡erent locations. The reference for Lauter et al. was the `anterior^ creasing frequency. The region showing this shift most posterior midpoint' of the brain. The reference of Penhune et al. (1996) (and in our analyses) was located approximately 15 mm likely corresponds to FDRRs 1 and 5, based on loca- more anteriorly and corresponded to the plane of the anterior com- tion and the direction of the shift in frequency sensitiv- missure (Talairach and Tournoux, 1988). ity. 12 Some of the di¡erence in location between FDRR foci and frequency-sensitive areas in the PET work may be because of di¡erences in stimulus spectrum.

HEARES 3571 1-11-00 Cyaan Magenta Geel Zwart 242 T.M. Talavage et al. / Hearing Research 150 (2000) 225^244 to the lateral low-frequency site of Lauter et al. The organization of the auditory cortex observed with auditory evoked more medial focus of high-frequency sensitivity identi- potentials. Acta Otolaryngol. (Stockh.) 491 (Suppl.), 116^123. ¢ed by both Lauter et al. and Lockwood et al. is closest Bilecen, D., Sche¥er, K., Schmid, N., Tschopp, K., Seelig, J., 1998. Tonotopic organization of human auditory cortex as detected by to FDRRs 2 and 4 (and is approximately 5^12 mm BOLD-FMRI. Hear. Res. 126, 19^27. from the foci of these FDRRs). This close proximity, Binder, J.R., Rao, S.M., Hammeke, T.A., Yetkin, F.Z., Jesmanowicz, coupled with the fact that FDRRs 2 and 4 are `higher- A., Bandettini, P.A., Wong, E.C., Estkowski, L.D., Goldstein, frequency', suggests that either or both FDRRs 2 and 4 M.D., Haughton, V.M., Hyde, J.S., 1994. Functional magnetic resonance imaging of human auditory cortex. Ann. Neurol. 35, correspond to the medial high-frequency site identi¢ed 662^672. using PET. Thus, we propose that the frequency-sensi- Buckner, R.L., Bandettini, P.A., O'Craven, K.M., Savoy, R.L., Pe- tive sites identi¢ed with PET are a subset of the sites tersen, S.E., Raichle, M.E., Rosen, B.R., 1996. Detection of cor- identi¢ed in the present study. It is possible that the tical activation during averaged single trials of a cognitive task remaining FDRRs (1, 3, 5^7) were not resolved in the using functional magnetic resonance imaging. Proc. Natl. Acad. Sci. USA 93, 14878^14883. PET work because of the low spatial resolution of the Buxton, R.B., Wong, E.C., Frank, L.R., 1998. Dynamics of blood images (V15 mm; which is on the order of the spatial £ow and oxygenation changes during brain activation: the balloon separation between FDRRs). model. Magn. Reson. Med. 39, 855^864. Cansino, S., Williamson, S.J., Karron, D., 1994. Tonotopic organiza- 4.8.5. Overview tion of human auditory association cortex. Brain Res. 663, 38^50. The pattern of cortical frequency sensitivity in the Celesia, G.G., 1976. Organization of auditory cortical areas in man. Brain 99, 403^414. present study is consistent with previous single unit, Diesch, E., Luce, T., 1997. Magnetic ¢elds elicited by tones and vowel evoked response, fMRI and PET data concerning hu- formants reveal tonotopy and nonlinear summation of cortical man cortical tonotopic organization. However, the activation. Psychophysiology 34, 501^510. present work indicates that there are more tonotopi- Edmister, W.B., Talavage, T.M., Ledden, P.J., Weissko¡, R.M., 1999. Improved auditory cortex imaging using clustered volume acquis- cally organized areas in human auditory cortex than itions. Hum. Brain Map. 7, 88^97. previously recognized. Elberling, C., Bak, C., Kofoed, B., Lebech, J., Saermark, K., 1982. Auditory magnetic ¢elds. Scand. Audiol. 11, 61^65. Fox, P.T., Raichle, M.E., 1986. Focal physiological uncoupling of Acknowledgements cerebral blood £ow and oxidative metabolism during somatosen- sory stimulation in human subjects. Proc. Natl. Acad. Sci. USA 83, 1140^1144. The authors thank Dr. Albert Galaburda and Dr. M. Fox, P.T., Raichle, M.E., Mintun, M.A., Dence, D., 1988. Nonoxi- Christian Brown for their time and graciousness in their dative glucose consumption during focal physiologic neural activ- many insightful discussions, and Dr. John J. Guinan, ity. Science 241, 462^464. Jr., Dr. Barbara C. Fullerton, Dr. Donald Wong, Dr. Friston, K.J., Ashburner, J., Frith, C.D., Poline, J.B., Heather, J.D., Glenis Long, Dr. Monica Hawley, Irina S. Sigalovsky Frackowiak, R.S.J., 1995. Spatial registration and normalization of images. Hum. Brain Map. 2, 165^189. and Michael P. Harms for their many helpful comments Galaburda, A., Sanides, F., 1980. Cytoarchitectonic organization of and suggestions. We also thank Barbara Norris for her the human auditory cortex. J. Comp. Neurol. 190, 597^610. assistance with ¢gures. This research was partially Guinan, J.J., Jr., Norris, B.E., Guinan, S.S., 1972. Single auditory funded by NIH/NIDCD Grants P01DC00119 and units in the superior olivary complex. II: Locations of unit cate- gories and tonotopic organization. Int. J. Neurosci. 4, 147^166. T32DC00038-04, and a NSF Graduate Fellowship in Hall, D.A., Haggard, M.P., Akeroyd, M.A., Palmer, A.R., Summer- Electrical Engineering. ¢eld, A.Q., Elliott, M.R., Gurney, E.M., Bowtell, R.W., 1999. `Sparse' temporal sampling in auditory fMRI. Hum. Brain Map. 7, 213^223. References Heil, P., Rajan, R., Irvine, D.R.F., 1994. Topographic representation of tone intensity along the isofrequency axis of cat primary audi- Arlinger, S., Elberling, C., Bak, C., Kofoed, B., Lebech, J., Saermark, tory cortex. Hear. Res. 76, 188^202. K., 1982. 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