Frequency-dependent responses exhibited by multiple regions in human auditory cortex 1

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1 Hearing Research 150 (2000) 225^244 Frequency-dependent responses exhibited by multiple regions in human auditory cortex 1 Thomas M. Talavage a;b; *, Patrick J. Ledden b, Randall R. Benson b;2, Bruce R. Rosen b, Jennifer R. Melcher a;c;d; b a Speech and Hearing Sciences Program, MIT-Harvard Division of Health Sciences and Technology, Cambridge, MA, USA MGH-NMR Center, Department of Radiology, Massachusetts General Hospital, Building 149, 13 th 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 * Corresponding author. Present address: School of Electrical and Computer Engineering, Purdue University, West Lafayette, IN 47907, USA. Tel.: +1 (765) ; Fax: +1 (765) ; tmt@ecn.purdue.edu 1 Portions of this work were presented at the annual meeting of the International Society for Magnetic Resonance in Medicine (1996) and the annual meeting of the Association for Research in Otolaryngology (1997). 2 Present address: University of Connecticut Health Center, Department of Neurology, 263 Farmington Ave., Farmington, CT , USA. Tonotopy, an ordered mapping of neuronal frequency sensitivity to spatial location, has been demonstrated in structures throughout the auditory pathway, including auditory cortex (e.g., Rose et al., 1959; Woolsey, 1971; Guinan et al., 1972; Merzenich and Reid, 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 unit position (e.g., Hind, 1960; Merzenich and Brugge, 1973; Merzenich et al., 1976; Reale and Imig, 1980; McMullen and Glaser, 1982; Sally and Kelly, 1988; Morel et al., 1993). Although neuronal responses in auditory cortex can depend on stimulus frequency in complex ways, a single BF can usually be assigned to neurons in primary and certain non-primary areas (e.g., Hind, 1960; Sutter and Schreiner, 1991; Rauschecker et al., 1995). Within cortical areas that are tonotopically / 00 / $ ^ see front matter ß 2000 Elsevier Science B.V. All rights reserved. PII: S (00)

2 226 T.M. Talavage et al. / Hearing Research 150 (2000) 225^244 organized, BF varies fairly systematically from low to high along the cortical surface, but is relatively constant across cortical depth (e.g., Merzenich et al., 1975; Imig et al., 1977; Rauschecker et al., 1995). The overall picture of cortical frequency organization from the animal literature is one of multiple tonotopic maps distributed over the cortical surface. In contrast with the extensive body of data documenting the tonotopic organization of the auditory pathway in animals, far less is known about this fundamental organizing principle in humans. This is true even for auditory cortical areas residing on the superior temporal lobe, perhaps the most studied part of the human central auditory system. Based on physiological recordings, lesion studies and functional imaging, it is known that widespread areas on the human superior temporal lobe respond to sound and play a critical role in the perception of acoustic stimuli (e.g., Celesia, 1976; Tramo et al., 1990; Zatorre et al., 1992; Binder et al., 1994). The primary auditory cortex, which lies deep within the Sylvian ssure on the medial two-thirds of Heschl's gyrus, is an area exhibiting short-latency responses to transient acoustic stimuli (a de ning feature of primary cortex) as well as cytoarchitectonic and immunostaining properties typical of primary sensory cortical areas (e.g., Celesia, 1976; Galaburda and Sanides, 1980; Liëgeois-Chauvel et al., 1991; Rademacher et al., 1993; Rivier and Clarke, 1997). The surrounding, acoustically responsive areas of the superior temporal lobe are anatomically and physiologically di erentiable from the primary area, and from each other (e.g., Galaburda and Sanides, 1980; Liëgeois-Chauvel et al., 1994; Rivier and Clarke, 1997; Howard et al., 2000). If, as in many animal species, the various di erentiable areas contain one or more frequency-to-place mappings (e.g., Imig and Reale, 1980; Morel et al., 1993; Kosaki et al., 1997; Rauschecker et al., 1997), one would expect there to be multiple tonotopic representations of the audible frequency range on the surface of the human superior temporal lobe. Evidence that parts of human auditory cortex are tonotopically organized has been provided by previous studies using a variety of techniques. Some of this evidence comes from single unit recordings from auditory cortex in humans (Howard et al., 1996). However, the majority derives from studies using non-invasive methods and provides somewhat di erent information about cortical activity. The most extensively used approach has involved recording sound-evoked magnetic or electric responses over the surface of the head and localizing the brain activity generating these responses (Romani et al., 1982a,b; Arlinger et al., 1982; Elberling et al., 1982; Pelizzone et al., 1985; Pantev et al., 1988, 1990, 1991, 1994, 1995, 1996; Yamamoto et al., 1988, 1992; Bertrand et al., 1991; Jacobson et al., 1992; Tiitinen et al., 1993; Cansino et al., 1994; Huotilainen et al., 1995; Verkindt et al., 1995; Roberts and Poeppel, 1996; Diesch and Luce, 1997; Lu«tkenho«ner and Steinstra«ter, 1998; Mu«hlnickel et al., 1998). Studies taking this approach typically used moderate-intensity, narrow-band stimuli based on the hypothesis that (a) neurons responding to these stimuli would have a narrow range of BFs and therefore occupy a limited extent of any underlying tonotopic map, and (b) the location of the responding neurons would move systematically from one end of the map to the other with systematic increases or decreases in acoustic stimulus frequency. It has been reported that the position of brain activity generating several evoked response components changes systematically with frequency (Romani et al., 1982a,b; Elberling et al., 1982; Pelizzone et al., 1985; Pantev et al., 1988, 1990, 1991, 1994, 1995, 1996; Yamamoto et al., 1988, 1992; Tiitinen et al., 1993; Cansino et al., 1994; Huotilainen et al., 1995; Diesch and Luce, 1997; Lu«tkenho«ner and Steinstra«ter, 1998; Mu«hlnickel et al., 1998). In some studies examining more than one response component in the same individuals, the generators of the various components were localized to di erent parts of the superior temporal lobe and each showed a systematic relationship between position and stimulus frequency (Pantev et al., 1994, 1995, 1996; Diesch and Luce, 1997; Lu«tkenho«ner and Steinstra«ter, 1998). These ndings indicate that human auditory cortex includes more than one tonotopically organized area. Several studies have examined human cortical frequency organization using positron emission tomography (PET) or functional magnetic resonance imaging (fmri), techniques that provide spatial maps of brain activation (Lauter et al., 1985; Wessinger et al., 1997; Bilecen et al., 1998; Lockwood et al., 1999; Yang et al., 2000). These maps show changes in blood ow (PET) or blood oxygenation (fmri) that re ect changes in neural activity (e.g., in response to a sensory stimulus; Fox and Raichle, 1986; Fox et al., 1988; Bandettini et al., 1992; Kwong et al., 1992; Ogawa et al., 1992). The PET and fmri studies examining cortical frequency organization employed essentially the same strategy as the magnetic and electric recording studies: subjects were stimulated with band-limited sound with the idea that the resulting activity would occupy di erent parts of auditory cortex. Each of the studies examined the response to two or three stimulus frequencies and reported either displacements in the volume of activation for di erent frequencies, or separable sites of maximal activation ^ ndings consistent with an underlying tonotopic organization. While it is clear that human auditory cortex is tonotopically organized, the number of tonotopically organized areas, the spatial arrangement of these areas, and

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

4 228 T.M. Talavage et al. / Hearing Research 150 (2000) 225^244 Table 1 Stimulus frequencies Session Stimulus Lower frequency (Hz) a Higher frequency (Hz) a 1 Instrumental music 20^ ^ Tone bursts 640^ ^ AM noise 75^ ^ AM noise 20^ ^ AM noise 20^ ^ AM tones 490^ ^ AM tones 490^ ^ AM tones 490^ ^8010 a These are the bandlimits at 35 db SL. 500 and 8000 Hz (10 Hz modulation rate, 0.7 modulation index). The frequencies contained in each lowerand higher-frequency stimulus pair are listed in Table 1. Multiple types of stimuli were utilized because it was not known a priori which stimuli would yield the strongest responses. In deciding to use multiple types of stimuli, our operating assumption was that spectrum, rather than other stimulus characteristics, would be the dominant factor a ecting response location. Stimulus levels were as follows. Stimuli in sessions 2^ 8 were presented at 35 db above behavioral threshold. Behavioral thresholds for these sessions were measured with the subject in the imager and under the same acoustic conditions as during functional imaging. For session 1, behavioral thresholds were measured with the subject in the imager, but in the absence of functional imaging noise 4. The lower-frequency stimulus for session 1 was presented 50 db above threshold; the higherfrequency stimulus was matched in loudness (42 db above threshold). In all sessions, the subject could clearly hear the stimuli. All stimuli were played from a digital source and presented via an air conduction system. Tone and noise stimuli were digitally generated using LabVIEW on a Macintosh Quadra computer out tted with a D/A board (National Instruments A2100). Bandpass- ltered music was generated by passing the output of a CD player through a brickwall (115 db per octave) bandpass lter (Rockland Model 751A). The output of the lter or D/A board was ampli ed and input to acoustic transducers located in the room with the imager. The output of the transducers 5 passed through exible plastic tubing (3 m length) to and through earmu s. The sound emerged from the exible tubing just lateral to 4 Even in the absence of functional imaging noise, there is on-going low-frequency noise produced primarily by a pump for liquid helium (used to supercool the imager's permanent magnet). This noise reaches levels of V80 db SPL in the frequency range of 100^500 Hz (Ravicz et al., 2000). 5 The transducer frequency response was low-pass (6 khz upper halfpower frequency). the ear canal. The earmu s reduced the intensity of imager acoustic noise at the subject's ears by approximately 30 db (Ravicz and Melcher, 1998) Experimental paradigm Lower- and higher-frequency stimuli were presented alternately in a standard fmri `block paradigm'. One `cycle' in this paradigm consisted of an `on' epoch of lower-frequency stimulation, an `o ' epoch of no stimulation, an `on' epoch of higher-frequency stimulation, and an `o ' epoch (e.g., see Fig. 1d,e). Table 2 provides the duration of the epochs for each of the eight imaging sessions. Between three and eight cycles presented consecutively composed a functional imaging `run'. Between two and seven runs were conducted in each imaging session. Subjects were instructed to listen to the acoustic stimuli during each run and to keep their eyes closed or to maintain xation on an arbitrarily chosen point in their direct line of sight. In sessions 2^8, subjects performed a detection task to maintain their attention to the stimuli. The stimulus level was randomly adjusted by þ 4 db for 2 s, with a change in level occurring every 5^8 s. Subjects responded to the level change by raising or lowering a nger, concordant with the direction of the level change. Subject responses were monitored by the experimenter who could see the subject's nger from the imager control room. All subjects responded to the level changes consistently and appropriately Imaging 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 Advanced NMR Systems, Inc. (Wilmington, MA). Subject motion was limited through use of a dental bite bar. Imaging sessions included ve components: 1. Contiguous sagittal anatomical images were acquired covering the entire brain (T 1 -weighted, in-

5 T.M. Talavage et al. / Hearing Research 150 (2000) 225^ 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 ). 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 thickness = 3.0 mm). 2. The magnetic elds over the superior temporal plane were shimmed to improve eld homogeneity (Reese et al., 1995). 3. The sagittal anatomical images were used to select the `slices of interest' to be studied. These slices encompassed all or the majority of Heschl's gyrus. For session 1, ve slices of interest were imaged in a near-coronal plane, perpendicular to the superior surface of the temporal lobe. For the remaining sessions, eight (sessions 2^6) or ve (7, 8) slices of interest were imaged in a near-axial plane, parallel to the superior surface of the temporal lobe. 4. Anatomical images were acquired of the slices of interest (T 1 -weighted, in-plane resolution = 1.5U1.5 mm). 5. Functional images were acquired of the slices of interest (T 2 *-weighted, asymmetric spin echo, d = 325 ms). During each functional imaging run, each slice

6 230 T.M. Talavage et al. / Hearing Research 150 (2000) 225^244 Table 2 Imaging parameters Session TR (s) Number of runs Images per run Stimulus on duration (s) Stimulus o duration (s) was imaged every 2 or 4 s (i.e., the `repetition time', TR = 2 or 4 s) while acoustic stimuli were presented in the block paradigm described earlier. For session 1: TE = 77 ms, TR = 4 s, matrix size = 256U128, inplane resolution = 1.5U1.5 mm, slice thickness = 4 mm, no gap between slices. For sessions 2^8: TE = 70 ms, TR = 2 s, matrix of size = 128U64, in-plane resolution = 3.1U3.1 mm, slice thickness = 3 mm, gap between slices = 1 mm Imaging coils The majority of our sessions used a surface coil designed speci cally for imaging the human auditory cortex. The development of this coil was prompted by early experiments using a head coil in which there was a general lack of fmri response in auditory cortex. The lack of response was probably a consequence of the low signal-to-noise ratio 6 (SNR) ^ typically 15 ^ in the superior temporal plane near the transverse temporal gyrus (Heschl's gyrus). To improve the SNR we switched to 5Q and 3Q diameter surface coils, but it was di cult to center these coils over the superior temporal plane and maintain them in a xed position throughout the duration of an imaging session (approximately 2 h). With the eventual goal of imaging both hemispheres at the same time, we developed a set of bilateral imaging coils that were integrated into the earmu s. These consisted of square loop coils centered at the top of each earmu. The coils may be used individually or as a bilateral set. Sessions 2^7 utilized a single coil over one hemisphere. The second coil was completed in time for session 8 to be conducted using both coils. Used individually or as a pair, this coil design consistently yields high SNR values ^ greater than 35 ^ in our region of interest, the superior temporal lobe. Single runs of the experimental paradigm within an 6 The signal-to-noise ratio is de ned as the mean signal level (i.e., signal averaged over time) divided by the standard deviation. imaging session did not yield consistent results unless the SNR in auditory cortex was at least 35. Therefore, only those imaging sessions in which the SNR in the superior temporal plane for the rst run was at least 35 (eight sessions) are described here. Seven of these sessions (sessions 2^8) used our specially designed surface coil (over the left or both hemispheres) and one session (session 1) utilized the 3Q diameter surface coil (over the left hemisphere). The few results that were obtained in sessions with lower SNR are generally consistent with the ndings reported here Data analysis The functional imaging data for each session were rst processed using standard fmri methods as follows: 1. The data (a time series of images of the slices of interest) were corrected for subject motion (using standard software, SPM95; Friston et al., 1995). Speci cally, the functional images for a given session were aligned to `reference' images of the slices of interest (i.e., to the functional images acquired in closest temporal proximity to the anatomical images). 2. For each run, the time series of image signal values for each voxel in the slices of interest was ratio-normalized to a xed mean level and was corrected for any linear or quadratic drift in signal level (which might otherwise be detected as an artifactual `response' to our stimuli). 3. To improve detection of responses to the stimuli, the functional image data for each session were combined across runs. For sessions 1, 2, 4^8, the data were combined by averaging (i.e., image signal level for each voxel and time point was averaged across runs). For session 3, the data from individual runs were concatenated, rather than averaged, because the order of lower- and higher-frequency stimulation varied from run to run. The `combined' (i.e., averaged or concatenated) functional image data were used in all further analyses.

7 T.M. Talavage et al. / Hearing Research 150 (2000) 225^ Mapping to Talairach coordinate system To facilitate comparisons of results across sessions, the image data were mapped into a common coordinate system, the stereotaxic coordinate system of Talairach (Talairach and Tournoux, 1988; sessions 2^8 only, session 1 discussed below). First, a linear transformation was established between reference points in the Talairach system and corresponding landmarks in the sagittal anatomical images (e.g., the location of the anterior and posterior commissures at the midline). This transformation was then applied to the functional image data (which were already automatically spatially registered to the sagittal images). Once transformed, the sagittal anatomical images and the functional images were resectioned in the coronal and axial planes of the Talairach coordinate system (voxel size: 3U3U3 mm). Subsequent analyses focussed on a volume centered mediolaterally and anteroposteriorly on Heschl's gyrus and containing most of the superior temporal lobe (e.g., Penhune et al., 1996). In the left hemisphere (sessions 2^8), this volume was a rectangular box bounded by Talairach coordinates (x, y, z)=(372, 354, 0) and (312, 6, 15). In the right hemisphere (session 8 only), the volume was the same, except re ected across the midline. For session 1, the registration information required to map the functional image data to the Talairach coordinate system was not available. Therefore, the data from this session were analyzed in the near-coronal plane of the original images (voxel size: 1.5U1.5U4 mm) and in a reconstructed near-axial plane (voxel size: 1.5U4U1.5 mm; obtained as orthogonal slices through the original near-coronal images) Statistical analysis The functional image data were analyzed by statistically comparing image signal levels during periods of higher- vs. lower-frequency stimulation. These analyses were performed on the Talairach images for sessions 2^ 8 and the near-coronal images for session 1. For each voxel, an unpaired t-test was used to compare mean image signal level during two conditions: higher-frequency stimulation and lower-frequency stimulation. An image was assigned to the higher-frequency (lower-frequency) condition if it was acquired 4 s or more after the onset of the higher-frequency (lower-frequency) stimulus and at most 4 s after the o set of the stimulus. This 4 s delay accounts for the onset and o set time of the blood oxygenation level-dependent fmri response (e.g., Buckner et al., 1996; Bandettini et al., 1993; Kwong et al., 1992). After these analyses, each voxel was assigned a t-statistic (i.e., the result of the t-test), and a `frequency dependence' indicating whether image signal levels were greater during the higher- or the lower-frequency condition. To compare physiological responses across imaging sessions, the t-statistic values were normalized to account for session-to-session di erences in the total number of functional images acquired. Normalization was implemented by selecting a baseline t-statistic cuto of t s 1.98 (P , uncorrected for multiple comparisons) for the case in which 192 images were acquired in each of the higher- and lower-frequency stimulation conditions. The t-statistic cuto was scaled up or down (assuming independent images) for use in the analysis of each session depending on the total number of images obtained in the two stimulation conditions. The normalization did not greatly change the observation rates of regions exhibiting frequency-dependent responses, but did make the spatial extent of these regions more consistent across sessions Identi cation of frequency-dependent response regions FDRRs were identi ed using the following procedure. First, we identi ed all voxels that (1) achieved a normalized threshold of P , (2) neighbored at least one other voxel meeting this threshold criterion and exhibiting the same frequency dependence, and (3) were local statistical maxima. A voxel was a local statistical maximum if its P value was lower (i.e., more signi cant) than that for the 26 neighboring voxels in a 3U3U3 cube centered on the voxel. Each voxel meeting the three criteria above was de ned as an `FDRR focus'. Around each focus, the remainder of the FDRR was de ned as the set of contiguous voxels exhibiting the same frequency dependence, a P value less than or equal to 0.05, and a constant or increasing P value (i.e., constant or decreasing statistical signi cance) as a function of distance from the FDRR focus. The latter criterion allowed us to resolve two or more neighboring FDRRs of the same frequency dependence even when the FDRRs merged into one another to create a single, large area of cortical activation. Note that an FDRR focus is not necessarily at the center of the FDRR. Rather it is the voxel exhibiting the most statistically signi cant response (the `peak'). At this point, any FDRRs containing non-cortical voxels were excluded from further analysis. Speci cally, an FDRR was excluded if, within two voxels of the FDRR focus, it extended into the ventricles, out of the brain (identi ed as voxels showing a signal level greater than 100 in the anatomical images), or out of the temporal lobe (e.g., into parietal cortex). The remaining FDRRs were assigned a number based on their frequency dependence, spatial relationship to each other and position relative to anatomical landmarks, or they were left `unnumbered'. First, for each session, FDRRs were displayed in axial sections

8 232 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 FDRRs 7. 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' 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 immediately adjacent to each focus (and in the same axial plane as the focus) were also identi ed. The FDRR foci (and adjacent voxels) in the axial slices centered at Talairach z = +12, +6, and +0 mm were displayed on the corresponding axial anatomical images (i.e., at z = +12, +6, 0 mm). The foci (and adjacent voxels) for Talairach z = +15, +9 and +3 mm were projected onto the adjacent anatomical slices at z = +12, +6 and +0 mm, respectively. Thus, three-slice summaries were obtained showing the distribution of FDRR foci over the superior temporal lobe (see Fig. 3). 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 2^8) or a near-coronal (session 1) plane. For sessions 2^ 8, these FDRRs were usually spatially separated in the anterior^posterior dimension. Therefore, to generate a concise summary, the FDRRs were `collapsed' into a single coronal plane as follows. For each session, three coronal slices in the Talairach volume (i.e., covering a 9 mm anterior^posterior extent) were identi ed that included portions of all three of the FDRRs overlapping 7 For session 8, in which data were obtained for both right and left hemispheres, the two hemispheres were examined separately. Fig. 2. The relationship between FDRRs 1^3 and Heschl's gyrus for each session shown diagrammatically in a coronal (sessions 2^8) or near-coronal (session 1) plane. The summary diagram for session 1 (top, left) was obtained by outlining Heschl's gyrus and FDRRs 1^ 3 in Fig. 1c. The remaining summaries (for sessions 2^8) are projections of FDRRs 1^3 from three coronal slices onto the middle slice. (For sessions 2^8, FDRRs 1^3 were displaced from each other anteroposteriorly.) These projections compensated for the medial^lateral and superior^inferior displacement of Heschl's gyrus across coronal locations (see Section 2.8). Summaries for sessions 1^7 show left Heschl's gyrus, and the summary for session 8 depicts right Heschl's gyrus. The variable anatomy of left Heschl's gyrus for subject 2 in sessions 2 and 4 is a consequence of intersession di erences in the imaging plane and variability in the identi cation of landmarks for the transformation to the Talairach coordinate system. Heschl's gyrus. A tracing was then made of anatomical landmarks in the middle slice (slice centered at y = 324 mm for sessions 2^5, 7 and 8; y = 321 mm for session 6). These landmarks included Heschl's gyrus, the ventricles, the edge of the brain and the midline. Next, the outline of each FDRR in each coronal slice was superimposed on the tracing of the middle slice. When superimposing FDRR outlines, the anterior and posterior slices were registered to the middle slice by rst translating them inferosuperiorly to align the superior edge of Heschl's gyrus. They were then translated mediolaterally to achieve a best t (by eye) of the medial^lateral extent of the gyrus. This rigid body translation pre-

9 T.M. Talavage et al. / Hearing Research 150 (2000) 225^ 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 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 Heschl's gyrus. The nal result for sessions 2^8 was an `adjusted' projection of the FDRRs onto a single coronal slice that takes into account the displacement of Heschl's gyrus across coronal locations in the Talairach space. For session 1, the FDRRs were displayed in the near-coronal plane of the original functional images because the data could not be mapped into Talairach coordinates. All of the FDRRs of interest (1^3) appeared in a single slice (see Fig. 1c), so a `near-coronal summary' was generated by outlining Heschl's gyrus and the FDRRs for this slice.

10 234 T.M. Talavage et al. / Hearing Research 150 (2000) 225^244 Table 3 Left (right) hemisphere volume of each numbered FDRR Session Volume (number of voxels) a Lower-frequency FDRR Higher-frequency FDRR ^ (25) 5 (23) 9 (7) 2 (0) 0 (3) 0 (12) 3 (0) 0 (0) a Voxel dimensions were (session 1) 1.5U1.5U4 mm or (sessions 2^8) 3U3U3 mm. 3. Experimental results Eight `numbered' FDRRs were identi ed on the superior temporal lobe. These FDRRs were `numbered' because they were observed in over half of the eight imaging sessions. FDRRs that were not observed as consistently were left `unnumbered' and will not be described in detail. The description of `numbered' FDRRs will begin with those overlapping the medial two-thirds of Heschl's gyrus, the location of primary auditory cortex (e.g., Rademacher et al., 1993), and proceed to those in surrounding regions of cortex. Three of the eight `numbered' FDRRs overlapped Heschl's gyrus and were seen in all sessions 8. These FDRRs, as imaged in a near-coronal plane for session 1, are depicted in Fig. 1. FDRR 1, located on the superior aspect of Heschl's gyrus (Fig. 1c), exhibited signi cantly (P ) greater image signal levels during periods of lower-frequency (low-pass- ltered music) stimulation than during periods of higher-frequency (high-pass- ltered music) stimulation (Fig. 1d). Therefore, FDRR 1 is a `lower-frequency' FDRR. FDRRs 2 and 3 (located inferomedial and inferolateral to FDRR 1 in Fig. 1c) exhibited signi cantly greater signal levels during periods of higher-frequency stimulation (Fig. 1e) and are therefore `higher-frequency' FDRRs. FDRRs 1^3 were also observed in the other seven imaging sessions. This is illustrated in Fig. 2 which shows, for each session, a projection of these FDRRs onto a coronal slice through Heschl's gyrus (see Section 2.8). The identi cation and numbering of FDRRs (including 1^3) was based on an analysis of FDRR foci in the axial plane (Fig. 3). Although the relationship between FDRRs 1^3 and Heschl's gyrus can be seen readily in the coronal summaries of Fig. 2, the relationship between the full complement of FDRRs was best appreciated in axial slices. FDRR 1 (Fig. 3, middle slice for all sessions) was de ned as the lower-frequency FDRR having the medial-most focus on the superior half of Heschl's gyrus. FDRR 1 was located on the anterior portion of the bifurcated gyrus for session 5 9 (Fig. 3, middle row). FDRR 2 (Fig. 3, middle slice) was de ned to be the higher-frequency FDRR with a focus on or near the anteromedial aspect of Heschl's gyrus, located medial to the focus for FDRR 1. FDRR 3 (Fig. 3, superior slice) was de ned as the higher-frequency FDRR with a focus on or near the posterolateral aspect of Heschl's gyrus, at least as lateral as the focus for FDRR 1. The focus for FDRR 3 was typically superior to the focus for FDRR 1 even though the coronal summaries give the opposite impression. This di erence is a consequence of the oblique angle between the superior temporal plane and the anterior commissure^posterior commissure line de ning the Talairach axial plane (Talairach and Tournoux, 1988). Because of this angle, the base of Heschl's gyrus posteriorly (where FDRR 3 is located) can be superior to the superior surface of Heschl's gyrus anteriorly (where FDRR 1 is located) in Talairach space. The remaining `numbered' FDRRs were observed in six or more sessions and were de ned as follows (Figs. 3 and 4, 4). FDRR 4 was the higher-frequency FDRR having a focus on or near the most posteromedial part of Heschl's gyrus, posterior to the focus for FDRR 2 (Fig. 3, superior slice). FDRR 5 (Fig. 3, inferior slice of sessions 2 and 5) was de ned as the higher-frequency FDRR with a focus located in the inferior third of the analyzed volume on or near the posterolateral aspect of Heschl's gyrus (where it begins to merge with the superior temporal gyrus (STG) anteriorly). FDRR 6 was de ned to be the lower-frequency 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 right, but only FDRR 1 was seen on the left. 9 Subject 4 (session 5) was the only subject who exhibited a bifurcated Heschl's gyrus.

11 T.M. Talavage et al. / Hearing Research 150 (2000) 225^ 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 Heschl's gyrus, superior and/or lateral to FDRR 1 (Fig. 3, middle slice of all three sessions and superior slice of session 8). FDRR 7 was de ned as the lowerfrequency FDRR with a focus located anteriorly on or just anterior to the anterolateral extreme of Heschl's gyrus. This anterior position also dictated that FDRR 7 was in the inferior half (z 9 +6 mm) of the analyzed volume (Fig. 3, inferior slice of sessions 2 and 8). FDRR 8 (Fig. 3, middle slice for sessions 2 and 8, superior slice for session 5) was de ned as the lowerfrequency FDRR with a focus on the STG in the superior half (z v +9 mm) of the analyzed volume, posterior to the foci for FDRRs 5 and 6 and posterolateral to the focus for FDRR 3. The full extent of each FDRR is quanti ed in Table 3. Some FDRRs were little more than the FDRR focus (i.e., two voxels). However, in most instances FDRRs were substantially larger. FDRR volume varied considerably across FDRRs and across sessions. In spite of this variability, however, there was an apparent trend. FDRR 1 was typically the largest or second largest FDRR. 4. Discussion Our experiments revealed eight repeatable FDRRs on Heschl's gyrus and surrounding areas of the superior temporal lobe (i.e., eight `numbered' FDRRs). Four of these FDRRs exhibited greater image signal levels in response to lower-frequency stimulation (lower-frequency FDRRs), while four exhibited greater signal levels in response to higher-frequency stimulation (higher-frequency FDRRs). Thus, each FDRR indicated a site of frequency-sensitive physiological activity in auditory cortex, as detected with fmri. Each `numbered' FDRR was identi ed repeatedly across subjects and had a fairly consistent position relative to other FDRRs and gross anatomical landmarks. We therefore propose

12 236 T.M. Talavage et al. / Hearing Research 150 (2000) 225^244 that the eight `numbered' FDRRs together represent a signature pattern of cortical frequency sensitivity shared by human subjects. As explained below, the FDRRs are consistent with four or more tonotopically organized areas in human auditory cortex FDRRs and neural frequency sensitivity FDRRs can be interpreted in terms of neural frequency sensitivity by considering the relationship between neural activity and image signal changes during fmri. It is known that an increase in neural activity (i.e., synaptic events, discharges) can lead to an increase in local metabolic activity, including an increase in oxygen consumption (Phelps et al., 1981; Prichard et al., 1991). This increase drives an increase in blood delivery that overcompensates for oxygen consumption (Fox and Raichle, 1986; Mandeville et al., 1998; Hoppel et al., 1993; Buxton et al., 1998). The result is excess oxygenated hemoglobin, and a corresponding reduction in the local concentration of deoxygenated hemoglobin (Kwong et al., 1992; Ogawa et al., 1992). Because deoxygenated hemoglobin is paramagnetic, a reduction in its concentration results in an increase in local magnetic eld uniformity, and consequently an increase in image signal. In short, an increase (or decrease) in neural activity leads to a concordant change in image signal. Stimulus-induced changes in image signal occur over a matter of seconds (e.g., Fig. 1) indicating that fmri re ects changes in the overall level of neural activity, rather than the detailed timing of activity. Given this relationship between fmri signal changes and neural activity, we interpret higher-frequency FDRRs as regions where the overall level of neural activity is greater during higher-, as compared to lower-frequency stimulation; lower-frequency FDRRs are regions where the opposite is true Multiple FDRRs: implications for tonotopic organization One interpretation of lower- and higher-frequency FDRRs is that they are localized, respectively, to lowerand higher-frequency regions within tonotopically organized cortical areas. The idea is (a) within tonotopically organized areas, neuronal BF varies systematically with position, (b) the overall population of neurons in regions of lower- or higher-bf respond more vigorously to lower- or higher-frequency stimuli, respectively, and (c) a region exhibiting di erential sensitivity to lower vs. higher frequencies is detected as an FDRR. An alternative possibility is that at least some FDRRs correspond to cortical areas that are not tonotopically organized, but nevertheless contain neurons that respond more to either lower- or higher-frequency stimuli. Given the working hypothesis that FDRRs are localized to tonotopically organized areas, the eight `numbered' FDRRs suggest multiple tonotopically organized areas in human auditory cortex. One possibility is that the FDRRs are divisible into lower- and higher-frequency pairs, with each pair localized to a particular tonotopically organized area. The four lower- and four higher-frequency FDRRs could then correspond to four separate tonotopic maps. A somewhat di erent correspondence between FDRRs and tonotopic maps is suggested by an organization commonly seen in animals, in which the low- or high-frequency ends of two adjacent maps abut and the progressions of neural frequency sensitivity in the two maps are mirror images of each other across the common boundary (e.g., Reale and Imig, 1980; Robertson and Irvine, 1989; Rauschecker et al., 1995; Kosaki et al., 1997). If this mirror-image organization also occurs in human auditory cortex, a single FDRR could correspond to the abutting low- or high-frequency ends of adjacent tonotopic maps. The eight `numbered' FDRRs could then correspond to more than four tonotopically organized areas. The hypothesis that FDRRs correspond to lowerand higher-frequency regions within tonotopically organized areas is supported by our additional fmri work using a complementary stimulation paradigm to examine the tonotopic organization of human auditory cortex (Talavage et al., 1997). In this paradigm, the center frequency of a narrow-band noise was swept from low to high (or high to low), and sites of peak image signal were tracked vs. time across the cortical surface. The experiments using these frequency-swept stimuli indicated progressions of frequency sensitivity across the cortical surface, connecting seven of the `numbered' FDRRs identi ed in the present study. The progressions indicate that most of these FDRRs do indeed coincide with lower- and higher-frequency regions of tonotopically organized areas. In some cases, progressions were seen from a single FDRR to multiple FDRRs, suggesting the presence of a mirror-image organization by which some FDRRs could represent the low- or high-frequency ends of abutting tonotopic maps. All of our work taken together indicates there are seven tonotopically organized areas in human auditory cortex, a number comparable to other species including cat and various non-human primates (e.g., Reale and Imig, 1980; Morel et al., 1993; Rauschecker et al., 1995, 1997; Kosaki et al., 1997) Relationship between FDRRs and anatomical areas in human auditory cortex A correspondence may be proposed between the eight `numbered' FDRRs and anatomically de ned areas in auditory cortex. We will base this correspond-

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

14 238 T.M. Talavage et al. / Hearing Research 150 (2000) 225^244 Fig. 6. Average locations of the `numbered' FDRRs displayed with the six supratemporal anatomical areas of Rivier and Clarke (1997). The average Talairach locations of the four lower-frequency (squares) and four higher-frequency (circles) FDRR foci (see Fig. 4) are superimposed on the same underlying outline (Talairach and Tournoux, 1988) used in Fig. 5b. The average Talairach coordinates of the centers of mass of the anatomical areas are indicated by the labeled hexagons, reproduced along with the approximate extent of each area from Fig. 5b. Overlapping symbols correspond to regions separated in the superior-inferior dimension. For example, area MA is inferior to area A1 because it is located on the anteromedial face of Heschl's gyrus where it folds back under the crown of the gyrus on which A1 is located. rior to koniocortex. The assignment of FDRR 2 to another anatomically de ned area is e ectively ruled out by distance (e.g., 13 mm between the focus for FDRR 2 and the center of mass of Rivier and Clarke's posterior auditory area, PA) and the anatomy (e.g., PA is on or posterior to the posteromedial end of Heschl's gyrus). It should be noted that Galaburda and Sanides (1980) did report that the caudal^dorsal parakoniocortex (PaAc/d) sometimes extended anteriorly across Heschl's gyrus, but because this was not typical, we will not propose a correspondence with FDRR 2. We propose that FDRR 3 coincides with one or both of two areas, the posterolateral portion of A1, and the lateral auditory area, LA (Rivier and Clarke, 1997). In the terminology of Galaburda and Sanides (1980), these areas are KAlt and the posteromedial extent of the internal 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 internal (PaAi) or external (PaAe) parakoniocortex, both of which extend anteriorly on the superior temporal gyrus, just lateral to Heschl's gyrus. The correspondence with PaAe is more likely, due to the inferior (Talairach z = +2.4 mm) position of FDRR 5. FDRR 6, by arguments similar to those used for FDRR 5, is proposed to reside within PaAi of Galaburda and Sanides (Fig. 5a). FDRR 6 does not correspond well with any of the areas described by Rivier and Clarke (1997), its focus being located 11 mm anterolateral of the center of mass of LA, 14 mm anteromedial (and superior) of the center of mass of STA and 16 mm anterolateral from the center of mass of A1. The average location for the focus of FDRR 6 on or immediately lateral to the anterior extreme of Heschl's gyrus is consistent with the described anterior extent of PaAi (Galaburda and Sanides, 1980). We do not attribute FDRR 6 to PaAe due to the more superior location of this FDRR. We propose that FDRR 7 resides within the anterior auditory area (AA) of Rivier and Clarke (1997), corresponding to the rostral parakoniocortex (PaAr) of Galaburda and Sanides (1980). The focus for FDRR 7 is centered 3 mm lateral of the center of mass for AA, strongly arguing for this correspondence (Fig. 6). The focus of FDRR 7 is not within 10 mm of any other auditory areas, so no further correspondences are proposed.