subdivisions and connections of auditory cortex in owl monkeys

THE JOURNAL OF COMPARATIVE NEUROLOGY 3182743 (1992)

Subdivisions and Connections of Auditory Cortex in Owl Monkeys

ANNE MOREL AND JON H. KAAS Department of Psychology, Vanderbilt University, Nashville, Tennessee 37240

ABSTRACT The organization and connections of auditory cortex in owl monkeys, Aotus triuirgatus,

were investigated by combining microelectrode mapping methods with studies of architecture and connections in the same animals. In most experiments, portions of auditory cortex were first explored with microelectrodes, neurons were characterized as responsive or not to auditory stimuli, and best frequencies were determined whenever possible. Most recordings were in cortex previously designated as primary (A-I) and rostral (R) auditory fields (Imig et al. J Comp Neurol 171:111, '77) and in a newly defined rostrotemporal field (RT) located rostral to R. Injections of wheat germ agglutinin-horseradish peroxidase (WGA-HRP) and fluorescent tracers were placed in electrophysiologically identified locations of A-I, R, and RT; the posterolateral (PL) and anterolateral (AL) divisions of a narrow belt of auditory cortex lateral and adjacent to A-I and R; cortex of the superior temporal gyms lateral and rostrolateral to PL and AL; and regions of prefrontal cortex that receive inputs from auditory cortex.

There were several major findings: 1. Best frequencies were most clearly determined for neurons within a densely myelinated

strip of cortex on the lower bank and lip of the lateral sulcus. We divided this strip into three fields, A-I, R, and RT, although an alternative interpretation that A-I and Rare parts of a single field remains tenable. In some cases, isofrequency contours appeared to continue uninterrupted across fields A-I and R, with lower frequencies represented laterally and higher frequencies represented deeper in the sulcus. In other cases, there was a tendency for high frequencies to be represented caudally and medially, and low frequencies laterally in A-I and rostrally in R, with partial discontinuity in the isofrequency contours. A reversal of the tonotopic gradient appeared in RT with a common low-frequency representation at the caudal border with R, and progressively higher frequencies encountered rostrally. Of the three fields, A-I appears slightly more myelinated than R, and RT slightly less than R. The distinctiveness of the three fields is further demonstrated by the patterns of connections. In particular, A-I and RT are both interconnected with R, but not with each other. Connections between A-I and R are between tonotopically matched locations.

2. A narrow 2-3 mm wide band of cortex lateral to A-I, R, and RT was also responsive to auditory stimuli, but typically neurons were more difficult to activate, and best frequencies were more difficult to determine. No distinctions in myeloarchitecture or CO activity were obvious. Nevertheless, regions roughly corresponding to previously distinguished PL and AL divisions of the belt cortex (Imig et al. J Comp Neurol 171:111, '77) were interconnected. Both PL and AL were connected with R, but PL was connected with A-I while AL was connected with RT. We also denoted a lateral rostrotemporal zone lateral to RT, with inputs from R, RT, and cortex rostral to RT.

3. Another proposed subdivision is CM, a moderately myelinated area medial to A-I that is somewhat smaller than the CM of Imig et al. ('77). CM has connections with A-I, R, PL, and AL. Other parts of the caudal, medial, and rostral belt cortex have auditory connections either from the core areas or other parts of the belt, so that overall there appear to be seven or more fields, but the exact number and boundaries remain uncertain. 4. Patterns of connections also implicate cortex lateral and laterorostral to the belt in

auditory function. Cortex lateral to PL interconnects with PL and cortex lateral to AL, and this cortex and the cortex lateral and rostral to the belt have inputs from the auditory thalamus.

Accepted November 12,1991

o 1992 WILEY-LISS, INC.

28 A. MOREL AND J.H. KAAS

5. PL, AL and cortex lateral to these fields connect with cortex rostromedial to the frontal eye field. A-I, R, and RT do not directly connect with prefrontal cortex.

6. In the thalamus, the ventral division of the medial geniculate complex (MGV) projects to A-I, R, RT, and possibly weakly to PL and AL. The projections to different tonotopic locations in A-I and R suggest that low frequencies are represented caudoventrally and high frequencies rostrodorsally in MGV. The medial or magnocellular division (MGM) has more widespread projections to auditory cortex, including A-I, R, AL, and the lateral rostral temporal area (LRT). Although less precise than those of MGV, projections to A-I from MGM tend to be topographically organized with neurons projecting to high-frequency targets distributed dorsal to neurons projecting to low-frequency targets. The dorsal division, MGD, projects to R, RT, AL, and LRT, with more rostral fields receiving projections from the more caudal regions of MGD. The suprageniculate and limitans nuclei, as well as the medial pulvinar, also contribute to auditory fields outside the core areas A-I, R, and RT.

7. A-I, R, and RT project to the central nucleus of the inferior colliculus (CN), with A-I projections extending into the laminated portion of the CN. Other parts of the auditory cortex, including AL. and rostrolateral temporal cortex, project to the dorsal cortex (DC) and external nucleus (EN).

Key words: medial geniculate, inferior colliculus, frontal lobe, pulvinar

Much of what is known about the organization and connections of auditory cortex in primates comes from a series of landmark papers on owl monkeys. The first of these papers described aspects of the tonotopic organization of cortex responsive to auditory stimuli and related results to architectonic features (Imig et al., '77). Following the lead of an earlier report on macaque monkeys (Merzenich and Brugge, '73), Imig et al. ('77) presented evidence for the existence of two adjacent primary-like fields, the first auditory area (A-I) and the rostral field (R). Both fields had the cytoarchitectonic appearance of koniocortex, with the middle layers of cortex dominated by small densely packed cells, and while slight differences were noted, there was no

obvious boundary separating the two fields. A-I and R were further distinguished by different patterns of tonotopic organization, but considerable variability across animals was apparent. In some cases, A-I and R appeared as two serial representations of high to low frequencies, while in other cases, parallel isofrequency bands seemed to span the two fields without discontinuity. Since neurons in A-I and R responded to tones with similar vigor and latency, and the two areas were reportedly similar in cytoarchitecture, for some cases A-I and R could be construed as parts of a single, elongated area.

Cortex surrounding A-I and R was described as having less densely packed cells in layers IV and 111, and neurons

Abbreviations

A A-I, A1 AL C

CG CM CN co DC DI DL DLL DM EN FEF FV FST GC ils IT

cc

cs

IT, 1% IT, LGN Lim LL LRT Is M-I, M MGD

anterior field primary auditory area anterolateral area caudal area corpus callosum central gray caudomedial area central nucleus of the inferior colliculus nucleus collicular commissure central sulcus dorsal cortex of the inferior colliculus dorsointennediite area dorsolateral area dorsal nucleus of the lateral lernniscus dorsomedial area external nucleus of the inferior colliculus frontal eye field frontal ventral area fundal superior temporal area central gray inferior limiting sulcus inferotemporal cortex inferotemporal cortex, caudal division inferotemporal cortex, polar division inferotemporal cortex, rostral division lateral geniculate nucleus limitams nuclei lateral lemniscus lateral rostrotemporal area lateral sulcus primary motor cortex dorsal division of the medial geniculate complex

MGM

MGV MRT MT P PC P L PM Po PP Pul PUL PuM PV R RM RN RT SEF SG, Sg SMA ST sts SII V VI VII VP ZM 3a, 3b, 1,2

MGP medial division of the medial geniculate complex caudal pole of medial geniculate complex ventral division of the medial geniculate complex medial rostrotemporal area middle temporal area posterior field cerebral peduncle posterolateral area premotorcortex posterior group of thalamic nuclei posterior parietal cortex inferior pulvinar lateral pulvinar medial pulvinar parietal ventral area rostral area rostromedial area red nucleus rostrotemporal area supplementary eye field suprageniculate nucleus supplementary motor area superior temporal area superior temporal sulcus second somatosensory area ventral visual area primary visual area second visual area ventroposterior field marginal zone subdivisions of somatosensory cortex

AUDITORY CORTEX IN OWL MONKEYS 29

less responsive and more broadly tuned to tones. On the basis of minor cytoarchitectonic distinctions and limited electrophysiological evidence, Imig et al. ('77) suggested that the surrounding belt cortex may contain three or four separate auditory fields, and proposed, by location, caudomedial (CM), posterolateral (PL), anterolateral (AL), and rostromedial (RM) fields.

Two subsequent papers examined the projection patterns of A-I and R to cortical and subcortical targets (FitzPatrick and Imig, '78, '80). The results revealed that many connections of the two fields are similar, but with some distinctive differences, and that the two fields are interconnected. In addition, both fields projected to a number of foci in surrounding cortex, supporting the notion of a ring of several auditory fields.

More recent studies have concentrated on marmosets and tamarins, which constitute the family Callitrichidae of New World monkeys. These primates provide the advan- tage of having more of auditory cortex exposed on the lateral surface of the temporal lobe. Aitkin et al. ('86) recorded from A-I, and produced a detailed map of best frequencies in a pattern comparable to that of A-I in owl monkeys. Subsequently, the cortical and subcortical connections of A-I have been studied (Aitkin et al., '88; Luethke et al., '89), providing further evidence for R as an organized representation rostral to A-I, and for two or three additional bordering fields, including an elongated lateral field (Luethke et al., '89) encompassing parts of PL and AL of Imig et al. ('77).

Our interest in further exploring the organization and connections of auditory cortex in primates stems from the limited extent of present knowledge, and the ambiguous nature of some of the information. First, similarities in architecture, connections, and responsiveness of A-I and R, as well as individual variability in the continuity or discontinuity of isofrequeney bands across the two fields, suggest that R may be only a part of A-I rather than a separate area, or that R is a field that has gradually differentiated from A-I in the course of evolution. Descriptions of the response characteristics and tonotopic arrangement of R are limited to one study on owl monkeys (Imig et al., '77) and one study on macaque monkeys (RL of Merzenich and Brugge, '73). Both A-I and R have been portrayed as koniocellular in owl monkeys and macaque monkeys (Imig et al., '77; Merzenich and Brugge, '73), and densely myelinated in marmosets (Luethke et al., '891, although with R less myelinated than A-I. However, Aitkin et al. ('86) noted no rostral field with cytoarchitecture like R in common marmosets. Intemnnec- tions between A-I and R have been illustrated for both owl monkeys (FitzPatrick and Imig, '80) and marmosets (Ait- kin et al., '88; Luethke et al., '89), but other connections of R are known only from two studies with tritiated proline injections (FitzPatrick and Imig, '78, '80). Thus, there are uncertainties about the distinctiveness of the connections of A-I and R, and even the existence of R as a separate field.

Further uncertainties remain about the nature of the cortex surrounding A-I and R. Clearly this surrounding cortex is auditory, and several subdivisions appear to exist, but the number of areas is uncertain, and their boundaries and connections poorly understood (Merzenich and Brugge, '73; Imig et al., '77; Luethke et al., '89). While there have been a number of studies of the connections of cortex in the region of the auditory fields or of proposed architectonic subdivisions of auditory and adjoining cortex (e.g., Mesu- lam and Pandya, '73; Galaburda and Pandya, '83), there

have been no studies of the connections of the cortex of the auditory belt in which interpretations of injection sites and the resulting patterns of label were based on electrophysiological mapping.

In the present report, we used microelectrode recordings to characterize A-I, R, and surrounding cortex in owl monkeys, and related these results to cortical architecture and patterns of cortical and thalamic connections in the same cases. Injections of up to three different tracers in the same animal were placed in the following regions: A-I, R, and a field rostral to R that we termed the rostrotemporal area (RT); the lateral auditory belt; the cortex lateral to the auditory belt, and portions of the frontal lobe that are connected to the auditory belt; the results provided evidence for additional subdivisions of auditory cortex and a more complete understanding of the nature of the processing network for auditory information in primates. A brief report of some of the results was presented elsewhere (Morel et al., '89).

MATERIALS AND METHODS The protocol for surgical preparation, acoustical stimula-

tion, and recording is similar to that described previously (Luethke et al., '89). Adult owl monkeys (Aotus triuirgatus) were anesthetized for surgery and recording with ketamine hydrochloride (25-30 mglkg) supplemented by xylazine (2 mg/kg). Additional doses of anesthetic (5-10 mg) were given as required throughout the experiment. Surgery was performed under aseptic conditions and the body tempera- ture maintained around 38°C with a heating pad. An incision of the skin was made along the midline after subcutaneous infusion of a local anesthetic (lidocaine), The temporal muscle was then retracted and the skull opened to expose part of the temporal lobe. The dura was retracted and the cortex covered with liquid silicone to prevent desiccation. Photographs of the cortical surface were pre- pared for later use in marking the positions of electrode penetrations in relation to blood vessels.

During recordings, the animal head was held firmly by a rod cemented to the Occiput, leaving free access to the ears. Multiunit activity was recorded with low-impedance (1-1.5 M a ) tungsten microelectrodes advanced with a hydraulic micromanipulator and oriented parallel to the ventral bank of the lateral sulcus. The signal from the electrode was amplified, filtered, displayed on an oscilloscope, and also monitored through a loudspeaker. Small electrolytic lesions were made along the electrode tracks to mark locations of physiological significant changes by passing small cathodal currents (typically 10 pA,5 seconds) through the electrode.

Pure tones of varying frequencies and intensities were produced by a Krohn-Hite oscillator and shaped into 200 msec pulses (10 msec rise/fall time) with an electronic switch. The intensity of the tone bursts was preadjusted with an EXP-1 amplifier to provide a flat intensity response in the frequency range of 2-30 kHz. Stimuli were delivered to the contralateral ear at a rate of 1-2Jsec via a flexible hollow ear tube coupled to an audiometric driver. The output of the audiometric driver was calibrated with a one-half-inch condenser microphone coupled to a one-third- octave band filter and sound level meter. Broad band clicks and other test stimuli were also presented. Best frequencies (i.e., frequencies at which neurons or neuron clusters responded with lowest stimulus intensity) were determined in closely spaced penetrations on the superior temporal


gyrus, and at 200-400 pm intervals along penetrations parallel to the lateral sulcus. Recording sites where neurons were poorly responsive or unresponsive to pure tones were tested for responsiveness to broad-band auditory stimuli.

Injections of tracers After 3-5 hours of recording, injections of one to three

different tracers were placed in auditory cortex typically defined by recording. The tracers used were horseradish peroxidase conjugated to wheat germ agglutinin (WGA- HRP, 1% in saline), and the fluorescent dyes, fast blue (FB), diaminido-yellow (DY), and nuclear yellow (NY). WGA- HRP was injected with a glass micropipette sealed to the needle of a 1-p1 Hamilton microsyringe, and fluorescent dyes were either deposited in the cortex as dry crystals, or injected in 3% solution through a microsyringe.

Histological procedure Following injections, the skull opening was closed with

dental acrylic and the skin sutured. The animals were carefully monitored during recovery from anesthesia and maintained for survival periods of 3-6 days depending on the tracer or tracer combination used. The animals were then deeply anesthetized with a lethal dose of sodium thiopenthal, and, when areflexive, perfused through the heart with saline, followed by 2% paraformaldehyde in phosphate buffer, and the same fixative containing 10% sucrose.

Immediately after perfusion, the brain was removed and the cortex separated from the brainstem, unfolded, and flattened between glass plates. The flattened cortex was soaked overnight in 30% sucrose in phosphate buffer, and cut parallel to the cortical surface on a freezing microtome. Sets of serial sections were mounted for fluorescent micros- copy, processed for HRP following a low-artifact tetrameth- ylbenzidine (TMB) procedure (Gibson et al., '84), stained for myelin with the Gallyas ('79) method, or processed to reveal cytochrome oxidase activity (Wong-Riley, '79). The thalamus and brainstem were cut in the frontal plane and sections examined for fluorescence were later stained for Nissl substance with cresyl violet or thionin. In some cases, alternate sections were also treated for acetylcholinesterase activity (Geneser-Jensen and Blackstad, '71). Detailed en- larged drawings were made of brain sections, and reconstruc- tions of best frequency maps, histological boundaries, injection sites, and label were made by superimposing sections using blood vessels and marker lesions. Fluorescent label was analyzed using a computer-assisted X-Y plotter system (Bioquant System, R&M Biometrics, Inc.).

RESULTS Connections of auditory cortex were investigated in ten

owl monkeys by placing injections of up to three different tracers into A-I, R, auditory cortex immediately lateral and anterior to A-I and R, and cortex of the frontal lobe (Fig. 1). In all but one experiment, microelectrode mapping methods were used to characterize regions of auditory cortex and identify suitable sites for injections. Since a major goal was to determine areal patterns of cortical connections, cortex was separated from the brainstem, flattened, and cut parallel to the surface. Anatomical and physiological results were related to architectonic patterns seen in adjacent brain sections stained for myelin and reacted for cytochrome oxidase. These two stains have proved to be

particularly useful in identifying subdivisions of cortex in flattened preparations (e.g., Luethke et al., '89). In some experiments, the other hemisphere was processed in the same way for callosal connections. In the thalamus and brainstem, connection patterns were related to architectonic subdivisions revealed by Nissl and myelin stains, reactions for cytochrome oxidase activity, and sometimes reactions for acetylcholinesterase activity in sections cut in a standard coronal plane.

Neuron response characteristics and tonotopic patterns

Our observations based on microelectrode recordings are limited because our major goal was to obtain information to guide the placements of injections. Nevertheless, we were able to record extensively from A-I and R, and characterize the tonotopic organization of these fields. More limited observations were made on the response properties of neurons in cortex bordering A-I and R. Most of our recordings were in or near layer IV, where the most vigorous responses were obtained. Electrode penetrations were roughly perpendicular to the lateral surface of the temporal lobe just ventral to the lateral sulcus. Near the sulcus, such penetrations extended into the cortex of the lower bank of the lateral sulcus so that recordings could be obtained from buried parts of A-I, R, and adjoining cortex. Neurons and neuron clusters with short-latency, narrowly tuned responses to tones and a well-defined best frequency (as determined by the midpoint of the frequency range over which the response occurred near threshold stimulation) were found in a relatively small region of cortex partially buried in the ventral bank of the lateral sulcus. This region includes fields A-I and R as defined previously (Imig et al., '77), and an additional field rostral to R that we termed rostrotemporal (RT) for its location rostral to R in the temporal cortex. Neurons in other parts of the superior temporal gyrus were generally less responsive to tones, and responses were often to broader ranges of frequencies and more labile to repetitive stimulation, although best frequencies were obtained for some neurons outside of A-I, R, and RT.

Tonotopic organization of A-I and R. The best frequencies for neurons in and around A-I and R are illustrated for six hemispheres in Figure 2. Results are shown on surface views of the unfolded cortex of the lateral sulcus and adjacent surface of the superior temporal gyrus. The boundaries of A-I and R outline the region of dense myelination (see below) that contains neurons with response characteristics of A-I and R. Often, a clear boundary between A-I and R was not apparent architectonically or physiologically. Hence this border is either not indicated or is approximated (e.g., Fig. 2D; see also Figs. 4 and 5A).

Comparison of results across the six recorded hemispheres indicates that there are some basic similarities in the organization of A-I and R, as well as clear individual differences. In particular, it is sometimes difficult to separate A-I from R. This difficulty is apparent from Figure 2A, which illustrates how best frequencies are represented in A-I and R of case 89-58. Except for the most caudal penetration, where all recording sites revealed neurons responding to high frequencies, the four penetrations in the region designated as A-I produced similar sequences of best frequencies, starting from about 3 kHz laterally, to more than 30 kHz deeper in the sulcus. Gaps in the frequency sequences between closely spaced points occurred in several


Fig. 1. The locations of proposed auditory areas on a dorsolateral view of an owl monkey brain. Part of the parietal lobe has been removed to expose the lower bank of the lateral sulcus. Other brain areas are shown for reference. The view closely approximates that of Imig et al. ('77) of auditory cortex in owl monkeys to facilitate comparisons. Auditory areas A-I and R are from Imiget al. ('77). The rostrotemporal area is based on present findings described in the text. The subdivisions of the belt cortex surrounding A-I and R have been modified from Imig et al. ('77). Belt auditory fields include the caudal area, the caudomedial area, the rostromedial area, the medial rostrotemporal area, the lateral rostrotemporal area, the anterior lateral area, and the posterior lateral area. Somatosensory areas (3a, 3b, 1, and 2) are based on Merzenich et

penetrations, although these "missing" frequencies were sometimes detected in other parts of the map, as previously noted by Imig et al. ('77). In the most rostral rows, in the region designated as R, recordings were from neurons responding only in middle and low frequency ranges, with little variation of best frequencies along a given row. Overall from these data, there is no obvious junction between A-I and R, or even a reason to conclude that there are two auditory fields rather than one. Nevertheless, the existence of two parallel representations remains a possibility, with both A-I and R representing low frequencies near the lip of the lateral sulcus, and high frequencies deeper. If so, R would appear to have a very poor representation of high frequencies, at least in this particular experiment. This may reflect, however, a difficulty in recording from deeper parts of R near the fundus of the lateral sulcus and the inferior limiting sulcus, and in estimating the extent of R from myeloarchitecture, since the fundal region is difficult to flatten.

al. ('78). Visual areas include: areas VI (or 17) and VII (or 18); dorsolateral, dorsointermediate, and dorsomedial, middle temporal area, superior temporal area, and fundal superior temporal area; caudal, rostral, and polar divisions of inferotemporal cortex; the ventral area and posterior parietal cortex (see Kaas and Krubitzer, '91, for review). Motor and visuomotor fields include primary motor cortex, premotor cortex, supplementary motor area, supplementary eye field, frontal eye field, and frontal ventral area. These areas are based on Gould et al. ('86) and Preuss et al. ('91). Thicker lines mark fissures, including the short central sulcus in area 3b, the lateral sulcus, and the superior temporal sulcus.

Results from other cases are similar in that progressions of recording sites from the lateral to the medial margins of A-I and R encountered neurons with successively higher best frequencies. Maps of A-I are more complete than those of R, but sometimes the representations of low frequencies were missed in A-I (Fig. 2E,F, and to some extent D), often because recordings from parts of A-I on the lip of the sulcus or lateral surface were not obtained. Occasionally, recording sites on the lip of the sulcus encountered neurons that were clearly responsive to auditory stimuli, but as a result of poor responsiveness to tones, best frequencies could not be determined (Fig. 2E,F). Possibly local trauma due to the surgical exposure depressed these neurons.

While fewer recording sites were in the region of R, some sites corresponded to higher best frequencies, and, in some cases, gave the appearance of a partial reversal of tonotopic organization at the border between A-I and R, with a common representation of high best frequencies. Case 89-63 (Fig. 2C), for example, has sites in caudal R where

A

N

C

E

B

N-

D

F

Figure 2


Fig. 3. Flattened auditory cortex stained for myelin. A-I and R are densely myelinated, while RT and CM are slightly less densely stained for myelin. Boundaries, approximated by dashed lines, are best appreci-

ated by examining a series of sections. Cortex caudal to A-I is less myelinated in more superficial layers, while A-I remains densely myelinated. Caudal, left, medial, above. Scale bar = 1 mm.

neurons had best frequencies of 30 kHz or higher. Thus, R seems to share a border with A-I largely along a common representation of middle to high frequencies, with low frequencies represented more caudally in A-I and more rostrally in R. This type of organization most closely corresponds to that described by Imig et al. ('77), where A-I and R were seen as reversals of tonotopic order along a common representation of high best frequencies. Neverthe- less, in case 89-63 (Fig. 2 0 , the mapping is relatively incomplete, and it remains possible that isofrequency contours extend across A-I and R for low as well as high frequencies. In case 89-71 (Fig. 6), recordings were obtained in both hemispheres and revealed a lack of responsiveness to tones in the rostral region corresponding to R, although only few penetrations explored the region.

In summary, the physiological results indicate that A-I and R are tonotopically organized, and that some individual variability in tonotopic organization exists. However, the

Fig. 2. Best frequency maps of auditory cortex in owl monkeys. Auditory cortex is shown in its flattened extent with boundaries based on myeloarchitecture. Numbers mark recording sites projected to the cortical surface, and they indicate the best frequencies of recorded neurons at those sites in kHz. Some sites were auditory (A) but best frequencies were not determined, or nonresponsive (N). A-E: Separate cases (note case numbers), of the right hemisphere (caudal, left; medial, above). F: Left hemisphere (caudal is right) of the case in E. Dashed lines in D indicate estimated borders (see text). Dotted lines approxi- mate isofrequency contours. Scale bars = 1 mm.

physiological results seem compatible with interpretations of A-I and R as separate fields or as parts of a single field.

Field RT. A few recordings were made in the region rostral to field R in the lateral sulcus. In one mapped case (89-58, Fig. ZA), neurons in RT responded as vigorously as neurons in A-I and R to tones and had best frequencies in the range of 1-5 kHz. On the basis of this responsiveness, RT could be a rostral extension of R that is devoted to low frequencies. However, we favor the interpretation that RT is a separate field, with perhaps more rostral or deep parts representing higher frequencies (see Imig et al., '771, largely because RT is less myelinated than R (Fig. 3) and differs somewhat in connections (see below).

We made several attempts to record from cortex surrounding A-I and R, but in those attempts, fewer neurons could be activated by auditory stimuli. For some recording sites, best frequencies could be determined and these generally were in the range of best frequencies of neurons recorded in adjacent parts of A-I and R (see for example most caudal penetration in Fig. 2C and penetrations lateral to A-I and R, in Figs. 2A and E, and in Fig. 9A). Nevertheless, the neurons typically responded poorly to tones and they appeared to be broadly tuned.

The auditory belt.

Architecture of auditory cortex The architecture of auditory cortex was studied in flat-

tened sections stained for myelin or cytochrome oxidase. Previously, these two methods have been very useful, in conjunction with other methods, in identifying a number of cortical areas in New World as well as in Old World


useful example, because the injection was of the bidirectional tracer WGA-HRP, and thus both anterogradely and retrogradely labeled connections were revealed (Fig. 5A). In this and other WGA-HRP cases, foci of retrogradely labeled neurons closely overlapped regions of fine, scattered label that presumably reflect anterograde transport.

In case 89-65, the myeloarchitectonic extent of the A-I and R region was fairly clear, and much of A-I and part of R were physiologically mapped (Fig. 2D). The dense, uniform core of the injection site, corresponding to or exceeding the effective uptake zone (see Luethke et al., '891, was largely or exclusively confined to A-I. The injection was centered in a location where neurons responded best to frequencies near 30 kHz, although the uptake zone may have also extended to neurons with lower best frequencies in the range of 20 kHz. As a result of the injection in caudolateral A-I, several foci of transported label were in other parts of A-I or in R. While some uncertainty exists about the location of the border between A-I and R, the dotted line in Figure 5A (also see Fig. 2D) corresponds to a myeloarchitectonic border between a slightly darker A-I and a slightly ligher R. The focus of transported label on the caudal border of A-I was largely or completely caudal to A-I. The next more rostral focus was clearly centered in A-I, and was in part of A-I that was also responsive to high-frequency tones. Thus, the intrinsic connections of A-I sometimes extend over dis- tances of 2 mrn or more, and tend to be with tonotopically matched sites. A larger, more rostrolateral focus of label was located along the A-I/R border, apparently reflecting both intrinsic connections of A-I and extrinsic connections with R. Again, connections were with cortex responsive to high frequencies (25-32 kHz). A third, more rostral focus of label was solely in cortex judged to be R, in a region most responsive to tones of 20 kHz or more. Thus, interconnec- tions of A-I in the A-I/R area included regions estimated to be within A-I as well as regions within R, and in each instance, such connections were between tonotopically matched regions.

Comparable results on the connections of A-I with other parts of A-I and R were obtained in other cases. For example, in case 89-92 (Fig. 5B), an injection of WGA-HRP in a portion of A-I representing high frequencies (22-26 kHz) clearly labeled a portion of R devoted to the same range of high frequencies, as well as two distinct, separate foci in A-I. In case 89-71 (Fig. 6), a large injection of WGA-HRP was placed in lateral A-I. The injection zone covered much of lateral A-I and extended slightly into adjoining cortex. The injection core included cortex representing high frequencies (Fig. 2E), but it extended into unexplored cortex that may have represented middle and low frequencies. Intrinsic label was broadly distributed in A-I and near the A-I/R border, but only a small focus of anterograde label was clearly in the region of R. However, some of the foci near the border could have involved R.

Other ipsilateral cortical connections of A-I are with portions of the immediately adjoining auditory belt, as well as more distant locations in the superior temporal lobe. In case 89-65, the adjoining label included foci in cortex just lateral to A-I and along the caudal border of A-I (Fig. 5A). Similarly, two other injections of WGA-HRP in A-I, with slight involvements of the lateral border of A-I, labeled cortex caudal and especially lateral to A-I (Figs. 5B, 6). Label was seen in cortex medial to A-I in case 89-92 (Fig. 5B) and medial to R in case 89-71 (Fig. 6). More distant connections of A-I included cortex just lateral to caudal (C)

monkeys, including subdivisions of auditory cortex (e.g., Luethke et al., '89), While the use of sections from flattened cortex allowed the outlines of some subdivisions to be seen clearly in individual sections, it was difficult to cut sections SO that all parts were at the same depth in the region of the lateral sulcus. Thus it was necessary to reconstruct boundaries by &@hgborders from a series of sections. Neverthe- less, many aspects of the myeloarchitecture of auditory cortex and adjacent areas in owl monkeys can be appreci- ated in single sections (Fig. 3).

The region including physiologically defined A-I and R (see case 89-35, Fig. 2B) is characterized by a dense, relatively uniform myelination with no clear boundary between the two fields (Fig. 3). The extent and shape of the densely m y e h t e d area varied among different animals, but in most cases the rostral portion corresponding to field R appeared smaller and narrower than A-I and was mainly confined to the bank of the lateral sulcus (see outlines of myeloarchitectonic borders of A-I and R in the different maps shown in Fig. 2). Part of the variability in the extent of the densely myelinated region among animals may be due to difficulties in flattening the fundus of the lateral sulcus. The A-I and R region also exhibited high cytochrome oxidase (CO) activity, although the reaction pattern was not consistent enough from one case to the other to be as useful as the myelin stain.

Two regions adjacent to A-I and R were also distinguish- able by relatively dense myeloarchitecture (Fig. 3). One of these fields, RT, occupies a narrow band of cortex immediately rostral to field R. The dense myelination of RT is quite distinct from adjacent lateral cortex, which stains only lightly for myelin. RT corresponds to the more rostromedial part of field AL defined by Imig et al. ('77). The second densely myelinated area is medial to A-I in the depth of the lateral sulcus, and corresponds in location to the middle portion of caudomedial field of Imig et al. ('77). We retain the term CM, although architectonic evidence suggests that the field is narrower than that originally proposed. The medial limit of CM, though often difficult to determine with certainty, extends close to the fundus of the sulcus and in some cases also onto the dorsal bank of the lateral sulcus. While the CM region of belt cortex was always more densely myelinated than other aqjacent areas of the belt auditory cortex, the entire limits of CM were difficult to determine with certainty due to the uneveness of the plane of section in the fundus of the lateral sulcus. Most of the cortex caudal and lateral to A-I, R, and RT was relatively lightly stained for myelin, and we did not use myeloarchitecture to divide this cortex further, The denser myelination of cortex caudal to A-I in Figure 3 reflects the extension of the section into deeper layers in this location, rather than an overall increase in myelin staining.

Cortical connections The connections of subdivisions of auditory cortex were

evaluated by combining information from sections containing label, sections reacted for CO or stained for myelin, and physiological results, including partial maps of A-I and R, and data on the response characteristics of neurons at injection sites. In individual cases, typically several different tracers were injected (e.g., Fig. 4). This allowed comparisons within the same animal of connection patterns of several locations in auditory cortex.

Area A-Z. Seven injections were placed wholly or partially in A-I. Results from case 89-65 (Figs. 4,5A) provide a


Fig. 4. Injection sites in auditory cortex of owl monkey 89-65. Upper left, a dorsolateral view of the brain. Below, cortex that has been removed and flattened (see text). The lateral sulcus and superior temporal sulcus have been opened. Visual and somatosensory areas

have been identified architectonically and are indicated for reference. Injection sites (shaded or black ovals) are related to architectonically and physiologically defined auditory areas. Compare with Figure 5A.

area and to areas PL and AL, and cortex near or in the superior temporal visual area (ST). Case 89-65 (Fig. 5A) provides the clearest evidence for these connections, because the injection within A-I produced two foci in cortex caudal to the belt that were dense and obvious. However, other injections in A-I also labeled foci in the ST region and in cortex lateral to the belt. Results from case 89-71 (Fig. 6) also suggest that A-I connects with cortex lateral and medial to field R, but, alternatively, these two foci could be the result of the slight involvement of the injection in cortex bordering A-I.

Callosally transported label was studied in one case after an A-I injection (Fig. 6). Most of the interhemispheric connections of A-I were with A-I. The single injection in A-I produced a patchy distribution of labeled loci in A-I of the other hemisphere (Fig. 7).

The connections of R were best demonstrated in case 89-63 (Fig. 111, in which the core of the injection was completely confined to R. The iiection of WGA-HRP was centered in a portion of R representing frequencies near 5 kHz (Fig. 2C), but the effective uptake zone may have also included cortex representing slightly higher frequencies.

Area R.

A

B

C 89-65 2 m m

Y

Figure 5


Foci of labeled neurons and terminals were found in: 1) two locations well within A-I; 2) cortex along the medial border of A-I, possibly including A-I; 3) two sites lateral to A-I; 4) cortex lateral to R; and 5) rostral to R in RT. The foci of transported label in A-I were in locations where previous recordings indicated that the cortex was best activated by low-frequency frequency tones (Fig. 2C), thus demonstrat- ing the tonotopic matching of interconnected sites. The foci of label in RT could also be in a region responsive to lower frequencies, judging from recordings made in another case (Fig. 2A).

The connections of R were further demonstrated in cases 89-4 (Fig. 9B) and 89-35 (Fig. 8). In case 89-4, a large injection of NY centered in R labeled neurons throughout most of RT and most of A-I. Other labeled neurons were in CM, and a few were in PL and AL. In case 89-35, an injection of FB was placed in lateral R, near cortex responsive to lower frequencies (see Fig. 2B). Retrogradely labeled neurons were found more medially in R, caudally in parts of A-I also responsive to low frequencies, and rostrally in RT. In this case, an injection of WGA-HRP was also placed in caudal RT. The overlap of the zones of transported label from the R and RT injections with the injection sites provides compelling evidence for the existence of intercon- nections between the two fields. Again, other connections of R are with cortex lateral to R, and medial to A-I.

Related results were obtained in cases 89-65 (Fig. 5A) and 89-45 (Fig. 9A), in which injections in caudolateral R also involved cortex lateral to R and possibly A-I. In case 89-45, an injection near the A-I/R border labeled neurons in A-I, R, RT, and cortex medial to A-I and R, and cortex lateral to A-I. The connections with A-I, RT, and cortex medial to A-I, though more widespread through these areas, conform to those demonstrated for R in other cases. In case 89-65, labeled neurons were also in A-I, RT, cortex medial to A-I, and cortex lateral to A-I. Thus, injections confined to R or largely within R in five cases all reveal connections with A-I, RT, and lateral and medial parts of the auditory belt.

Only one injection directly involved the moderately myelinated oval of cortex that we designate as RT. In case 89-35, an injection of WGA-HRP was placed in the caudal pole of RT. The core of the injection site included RT and part of the adjoining cortex (Fig. 8; also see Fig. 2B). The injection densely labeled several foci in lateral R, a portion devoted to low-frequency tones. This result is consistent with our finding that injections in R labeled portions of RT. Other foci of label were in rostral RT, cortex lateral and medial to RT, and cortex lateral and medial to R and A-I. These connections could reflect targets of RT, as well as cortex along the lateral border of RT that was included in the injection core.

Auditory belt The patterns of label after injections in A-I, R, and RT

suggest that surrounding belt cortex is composed of several subdivisions but uncertainties remain about the number

Rostra1 temporal area RT.

Fig. 5. Distributions of transported label after injections of traeers into auditory cortex. Cortex has been flattened (see Fig. 4). A: Case 89-65 with injection extents and transported label for WGA-HRP (hrp), diamidino-yellow (dy), and fast blue (m). Light stippling indicates both anterograde and retrograde WGA-HRP label. B: Injection extents and transported label for case 89-92. Tracers as above. Conventions as in Figures 1 and 4.

and boundaries of these subdivisions. While area CM can be identified by its fairly distinct dense myelination, as dis- cussed above, the locations of four other subdivisions of belt cortex were suggested only by the topographical organization of connections with A-I and R, and no clear architectonic or physiological boundaries were identified. Neverthe- less, we investigated the cortical connections of three divisions of belt auditory cortex by placing injections in cortex in the PL region lateral to A-I, the AL region lateral to R, and the LRT region lateral to RT. In addition, some injections were placed further lateral and rostral in the superior temporal gyrus in order to examine the projections of auditory areas more distant from A-I and R.

Posterior and anterior divisions of the lateral belt. Several injections were in cortex immediately lateral to A-I and R, or included portions of lateral cortex as well as A-I and R. The results provide evidence for separate posterior and anterior divisions of the lateral belt, as well as another subdivision lateral to RT.

In one informative case, a relatively large injection of WGA-HRP was placed in the AL region just lateral to R (Fig. 9B). Several foci of label were distributed in A-I and R, an observation congruent with the evidence from injections in A-I and R that both fields are interconnected with AL. Other foci were in cortex medial to, and possibly overlap- ping with R and RT, the PL, cortex lateral to AL, and two locations in cortex lateral to RT. A similar pattern of label was obtained in case 89-65 (Fig. 5A), in which an injection of FB was in the AL region just lateral to R. Again, labeled neurons were found in A-I, R, RT, CM, PL, and cortex lateral to AL. The connections of the AL region with the PL region provide additional evidence for subdividing the lateral belt. An even more rostral injection in cortex just lateral to RT

(Fig. 5B) produced a quite different pattern that included labeled neurons either in the rostral extremity of RT or possibly in cortex rostral to RT, in cortex lateral to rostral RT, and in R, but not in cortex medial and lateral to A-I. Thus, cortex lateral to RT does not appear to be part of the AL belt.

Somewhat different results were produced by an injection in cortex more caudal in the lateral belt, just at the A-I/R junction (Fig. 5B). In particular, many labeled neurons were in cortex lateral and medial to A-I. Other labeled neurons were in RT, cortex rostrolateral to RT, along the caudal border of A-I, in ST, and parietal cortex ventral and rostral to the second somatosensory area (SII). The more extensive connections revealed by this more caudal injection in AL may also reflect the partial involvement of PL in the injection site, or the larger size of the injection.

While no injections exclusively involved the posterior lateral belt, an injection of FB in case 89-63 (Fig. 11) was largely in the PL region, but it also included A-I. The resulting distribution of labeled neurons over parts of A-I and R is consistent with evidence from injections in A-I or R that both fields are interconnected with PL. However, injections in A-I can produce similar patterns of intrinsic A-I and extrinsic R connections. Likewise, an injection of NY at the A-I/PL border (Fig. 8) labeled neurons in A-I and R. Finally, an injection more lateral to A-I, nearer the superior temporal sulcus (WGA-HRP, Fig. 9A), failed to produce detectable label in AI or R, suggesting that belt cortex extends only a few millimeters from the A-I/R border. WhiIe this more lateral injection produced a focus of

38

\ .. ... .+.::. 00 1 hrp .:.;

A. MOREL AND J.H. KAAS

89 -71

Fig. 6. Ipsilateral (above) and contralateral (below) patterns of transported label after injections of WGA-HRP (hrp) or fast blue (fb) into auditory cortex of the right hemisphere. Cortex has been flattened. Compare with Figure 4 for orientation. Open squares mark neurons

labeled with fb, while filled circles and fine dots mark hrp-labeled cells and terminals, respectively. Conventions as in Figures 1,4, and 5. Scale bar = 1 mm.


Fig. 7. An injection of WGA-HRP in A-I of the right hemisphere (above) of case 89-71 (see Fig. 6 for orientation) produced several dense foci in contralateral A-I (below). Scale bar = 1 mm.

label in PL, most of the label was in cortex rostral and caudal to the injection site.

Connections of the auditory belt and cortex of the superior temporal lobe with the frontal

lobe While A-I and R appear to have only local connections in

the temporal lobe, several subdivisions of auditory belt and superior temporal cortex are interconnected with the frontal lobe. More specifically, none of the injections confined to A-I and R produced label in the frontal lobe. Thus, we conclude that these fields do not directly relay to frontal cortex. However, injections in A-I that also involved PL cortex did label portions of frontal cortex. In case 89-35 (Fig. 8>, for example, a large injection of NY involving A-I and PL produced several foci of labeled neurons in cortex rostral or rostromedial to the architectonically defined frontal eye field (FEF; see Krubitzer and Kaas, '90a). In a similar manner, an injection of WGA-HRP that included both A-I and PL (case 89-71, Fig. 6) resulted in labeled neurons and foci over a more restricted zone of cortex just rostral to the FEF (not shown). Apatch of label also occured in the region of the parietal ventral area (PV) (not shown; see Fig. 8 for its location), a somatosensory area with neurons that also respond to auditory stimuli (Krubitzer and Kaas, '90b). Label was also found in rostromedial prefrontal cortex and in area PV after an injection of DY in

a more rostral portion of the auditory belt, largely in AL (case 89-92, Fig. 5B). These results provide evidence that PL has connections with cortex just rostral and medial to the FEF and that AL may have connections with cortex medial to the FEF. Both PL and AL appear to have connections with the somatosensory field PV.

Further support for the conclusion that the auditory belt interconnects with prefrontal cortex was obtained in case 89-58 (Fig. 101, in which an injection of WGA-HRP involved part of the FEF and cortex medial to the FEF. While most of the transported label was in other regions of the frontal lobe, in posterior parietal cortex, and in higher order visual areas (see also Fig. 11, several foci of label were located in the PL region and in adjacent parts of the superior temporal lobe. In another case in which an injection of NY was placed in cortex rostromedial to the frontal eye field (89-63, Fig. 111, large numbers of labeled neurons were observed in the superior temporal gyrus, including the PL and, to a lesser extent, the AL regions.

We have also investigated the connections of cortex more rostral in the superior temporal lobe to see if this cortex has connections with the auditory system. An injection of WGA-HRP placed in cortex just above the rostral tip of the superior temporal sulcus (case 89-6, Fig. 12) provided both scattered foci of label in the cortex of the superior temporal lobe, including cortex lateral to the belt, and several scattered foci in cortex rostromedial to the frontal eye field and in the orbitofrontal cortex. These connections do not necessarily identify the injected cortex of the superior temporal gyrus as auditory, but inputs from the medial geniculate complex (Fig. 12) suggest an auditory role. Thus, regions of cortex in the rostral superior temporal gyrus that are potentially higher auditory fields also project to prefrontal cortex.

Thalamic connections Injections in A-I, R, RT, the lateral belt, and the cortex

lateral to the belt labeled neurons and terminals in subdivisions of the medial geniculate complex and adjacent nuclei. The results suggest tonotopic organizations in subdivisions of the medial geniculate complex, and provide further connectional evidence for including the lateral belt in auditory cortex.

Architectonic subdivisions of the auditory thalamus. In the experimental material, subdivisions of the thalamus were identified in series of sections stained for Nissl substance, for myelin, or reacted for CO. The different types of preparations usefully complemented each other and allowed a reliable parcellation of the thalamus. The thalamic structures identified in the experimental brains correspond to nuclei previously described in owl monkeys (FitzPatrick and Imig, '78) and other monkeys (e.g., Jones, '85; Luethke et al., '89).

The medial geniculate complex includes ventral or princi- pal (MGV), medial or magnocellular (MGM), and dorsal (MGD) divisions or nuclei (Fig. 13). MGV occupies most of the caudorostral extent of the complex, except the caudal pole, and is characterized by densely packed, small to medium cells that often form radially oriented laminae. This laminar arrangement is more obvious in the middle and dorsal half of the nucleus that also reacts more densely for CO (see levels B/b and C/c in Fig. 13). The ventral division is capped dorsally and caudally by MGD, which has less densely stained, more scattered neurons of small to medium sizes. The dorsal division reacts only moderately

Figure 8

AUDITORY CORTEX IN OWL MONKEYS

for CO; thus a sharp border between MGD and MGV is usually apparent. The more rostral part of MGD appears less homogeneous, and it is not clear if the small goup of neurons often seen dorsolateral to MGV is part of the dorsal division, or, as suggested by the connections, part of the posterior complex (Po). MGM contains less densely packed medium and large neurons, and reacts moderately for CO. In myelin-stained sections, the caudal half of MGD is distinctly lighter than the adjacent part of MGV, and MGM is characterized by thick bundles of incoming fibers of the brachium of the inferior colliculus. More rostrally, the three divisions of the complex exhibit less distinct myeloarchitectonic features.

Other parts of the auditory thalamus include a previously defined (FitzPatrick and Imig, '78) marginal zone (ZM), which is a narrow band of small fusiform cells that reacts densely for CO along the dorsolateral border of the complex. ZM is separated from MGV and MGD by a thin, cell-poor, CO-light band. In addition, the suprageniculate nucleus (SG) and the limitans nuclei (Lim) have connections with auditory cortex. Neurons are somewhat more densely packed in SG than in adjoining dorsal and medial divisions of the medial geniculate complex. Rostrally, the SG extends dorsally to reach small groups of moderately packed neurons along the ventromedial border of the medial pulvinar that compose the limitans nuclei (not shown in Fig. 13, but their locations are indicated in Figs. 17 and 18). Finally, the medial pulvinar (PuM) has connections with subdivisions of cortex in the superior temporal gyrus-

The distribution of labeling in the thalamus after injections in A-I and R suggests that both fields receive inputs from MGV and MGM. However, field R receives an additional projection from MGD, and A-I appears to have some input from the caudolateral part of the posterior complex (Po).

Important aspects of the thalamic connections of A-I are illustrated by results from four cases. In case 89-65 (Fig. 151, an injection of WGA-HRP was placed in a caudolateral portion of A-I devoted to high frequencies (20-30 kHz; see also Fig. 2D). The injection labeled neurons and presump- tive axon terminals in the dorsal part of the rostral half of MGV. In MGM, the label was also dorsal, although there was also a small separate ventral focus. In addition, there was a restricted patch of label in what may be the rostral extremity of MGD (see Fig. 15, section 142), and more rostrally, in Po. No label was apparent in the SG, limitans nuclei, or the medial pulvinar. Very similar results were obtained in another case (89-92) with an injection of WGA-HRP into a portion of lateral A-I representing high frequencies, in the 22-26 kHz range (Fig. 18; see also Fig. 5B). The labeled neurons and terminals were in the dorsal cap of MGV, dorsal and ventral portions of MGM, and in Po. In another case (89-35, Fig. 17), an injection of NY involved a more rostral portion of lateral A-I where lower frequencies are represented (see also Fig. 2B). As expected, labeled neurons were found in both MGV and MGM. The labeled neurons were in the ventrocaudal portion of MGV. Other

Thalamic connections of A-I and R.

41

Fig. 8. Injection sites in flattened cortex (above) and the distributions of transported label in auditory cortex (below). Scattered dots in the frontal lobe indicate the locations of neurons labeled with nuclear yellow (ny), providing evidence that PL has frontal lobe connections. Scale bar in upper panel = 2 mm. Conventions as in previous figures.

labeled neurons in MGD, SG, and ZM presumably resulted from the injection extending from A-I into the auditory belt. Finally, in case 89-71 (not illustrated) where an injection of WGA-HRP included parts of A-I devoted to high frequencies and an injection of FB involved part of A-I related to middle frequency tones (see Fig. 2E), neurons and terminals labeled by the HRP injection in MGV were dorsal to the neurons labeled by the FB (the pattern of HRP label in a rostral section through MGV is illustrated on a photomicro- graph in Fig. 14). In a similar manner, HRP-labeled neurons were largely dorsal to FB-labeled neurons in MGM. However, there was partial overlap of the two populations of labeled neurons, suggesting that the cortical projections of MGM neurons are less precisely restricted to given frequency bands in A-I, Thus, evidence from these cases implies a dorsoventral progression of high to low frequencies in MGV, and a similar progression, although less ordered, in MGM.

The thalamic connections of R were clearly revealed in several cases. In case 89-4, where a large injection of NY was confined to the middle of R (Fig, 16), labeled neurons were found in MGV, MGM, and MGD. Similar results were obtained in case 89-63 (not illustrated) with an injection of WGA-HRP in R, and in case 89-35 (Fig. 171, with an injection of FB in R. Except for case 89-35, where few labeled neurons were present in SG and none in MGD, neurons were labeled in all three divisions of the medial geniculate complex after injections in R. Furthermore, as for A-I injections, the extent of label and its location in MGV reflected the extent and location of the injection in the frequency representation of R, thus providing evidence that the projections from MGV to R are tonotopically organized.

Thalamic connections of RT. One injection appeared to be located largely, although not exclusively, in RT. In case 89-35, an injection of WGA-HRP in caudolateral RT resulted in dense label in both MGV and MGD (Fig. 17). However, the label was in portions of the two nuclei that were caudal to locations labeled by injections in R and A-I in the same hemisphere.

Tha- lamic connections of cortex of the lateral belt were most effectively determined for cortex in the AL region, just lateral to field R. In case 89-4 (Fig. 16), an injection of WGA-HRP was placed in cortex just lateral to the rostral half of R. Dense zones of labeled cells and terminals were found in MGD and MGM. A few small foci of label also occurred along the medial and ventral borders of MGV and in SG.

Injections in cortex rostral to AL revealed strong connections of this part of the belt with MGM, SG, and PuM, and relatively minor connections with MGV (see for example the FB injection in case 89-92, Fig. 18). In the same hemisphere, an injection of DY located more caudally in belt cortex also densely labeled neurons in MGD, MGM, SG- Lim, and PuM. However, the label in MGD and MGM extended further rostrally than the label from the FB injection. Also a large population of neurons was labeled in MGV, suggesting that the injection in belt cortex may have included some of A-I representing low frequencies.

Two injections were made in cortex caudolateral and rostrolateral t o the auditory belt. In case 89-45 (Fig. 9A), a small WGA-HRP injection was placed in cortex lateral to PL and the label in the thalamus (not illustrated) was restricted to a small area in the medial pulvinar. In case 89-6, a relatively large injection of WGA-HRP in cortex lateral

Thalamic connections of the lateral auditory belt.


A

A.

N. 22.5 14. 7. - m . 5 2.5 .* N.

1. N.

B

Fig. 9. Distributions of transported label after injections in auditory cortex. A In case 89-45, WGA-HRP was placed in cortex just lateral to PL, and short, local connections were revealed. An injection of fast blue (fb) in R labeled neurons in both core and belt areas. Numbers indicate

best frequencies for recorded neurons (see Fig. 2). B: In case 89-4, injections were placed in R and AL. Conventions as in previous figures. Scale bars = 1 mm.

AUDITORY CORTEX IN OWL MONKEYS AUDITORY CORTEX IN OWL MONKEYS

5 mm

43

Fig. 10. Distribution of transported label in flattened cortex after a large injection of WGA-HRP in frontal cortex dorsal to and including the frontal eye field. Note foci of sparse label in belt and parabelt cortex caudal and lateral to A-I. Conventions as in previous figures.

and rostral to RT resulted in very dense anterograde and retrograde label in the most caudal pole of the MG complex (Fig. 12 and upper left panel of Fig. 14). Further rostrally, the label was confined to regions surrounding, but not including, MGV, i.e., in MGM, SG-Lim, and PuM. These connections, in particular with MGD and MGM, indicate that cortex on the rostrolateral surface of the superior temporal gyrus has auditory functions, though this cortex may have other functions as well.

Projections to the inferior colliculus The inferior colliculus was examined in those cases with

injections of the bidirectionally transported tracer WGA- HRP. Observations were limited to few cases involving injections in A-I, R, RT, AL, and cortex in the rostral and lateral parts of the superior temporal gyrus. Label was found in three architectonic subdivisions of the inferior colliculus that were identified in sections stained for Nissl

A

B .. . "Y

"," f b

. Figure 11


or myelin, or reacted for CO. These subdivisions consisted of a central (CN), dorsal cortical (DC), and external (EN) nuclei (Garey and Webster, '89; Morest and Oliver, '84). The central nucleus contains a dense population of small to medium cells that in most parts of the nucleus are arranged in columns oriented dorsomedial to ventrolateral. This orientation is similar to the orientation of isofrequency contours described in the inferior colliculus of squirrel monkeys (FitzPatrick, '75). The alignment of cells is not obvious in the dorsomedial portion of the CN, which also is less myelinated than the other part of the nucleus. The central nucleus is capped dorsally and caudally by the DC, which is composed of small cells that are more dense caudally than rostrally in the nucleus, in parallel with the progressive increase rostrally of the density of fibers run- ning in the intercollicular commissure ((20). The EN along the lateral surface of the CN reacts lightly for CO and is sparsely populated with cells. The external nucleus widens near the rostral pole of the IC. The border between EN and CN is particularly distinct in CO where the light EN is in sharp contrast with the darkly stained, lateral part of the CN. In some, but not all cases, the ventromedial portion of CN reacts less darkly for CO (Fig. 19). The significance of this variable CO light zone is not known.

Label was found bilaterally in the inferior colliculus after injections in A-I, R, RT, and AL. The contralateral lighter label was symmetrical in location to that of the denser ipsilateral label. After a WGA-HRP injection in A-I (case 89-71, Fig. 20A, see also Fig. 61, anterograde label was found in the dorsomedial part of the IC, largely within the medial part of the laminated portion of CN. The restriction of label suggests that the high frequencies (20-30 kHz) represented at the injection site in A-I are also represented along the medial margin of the central nucleus. The label also extends into the unlaminated dorsomedial part of the CN, but not into the more superficial, lightly myelinated DC nucleus. In a similar manner, a WGA-HRP injection placed in a portion of field R representing middle frequencies near 5 kHz resulted in a band of dense terminal label in the dorsal, unlaminated lightly myelinated part of CN. While the main focus of label was in CN, some label also extended into the more superficial DC (see photomicro- graph in Fig. 14). The label was more lateral than after the A-I injection, and this is consistent with the physiological evidence that middle and low frequencies are represented progressively more lateral in the IC (FitzPatrick, '75). These data suggest that projections from both A-I and R to the inferior colliculus involve the dorsal part of the central nucleus, but projections from A-I involve more of the laminated portion of CN than projections from R. Finally, an injection of WGA-HRP in field RT labeled the dorsal part of CN (not shown; see Fig. 17 for injection site), as did the injection in R, although the label was limited to the most caudal part of the IC.

Fig. 11. Distributions of transported label after injections of fast blue at the junction of PL with A-I, WGA-HRP in R, and nuclear yellow in frontal cortex rostromedial to the frontal eye field. A: Locations of transported label from the injection in frontal cortex. B Distribution of label in auditory cortex. Note that many cells in the C, PL, and AL regions and the parabelt cortex project to frontal cortex, and that R has major connections with RT. Scale bar = 2 mm in A. It corresponds to 0.5 mm in panel B. Conventions as in previous figures.

In contrast to A-I, R, and possibly RT, injections in the belt and cortex lateral to the belt selectively labeled DC and EN rather than CN. After a WGA-HRP injection in field AL of belt cortex, label in the IC was concentrated in the dorsal cortex. Other label was more rostrally located in EN (Fig. 2OC). Similarly, an injection in cortex lateral to the auditory belt in the rostrolateral part of the superior temporal gyrus (case 89-6) labeled dense terminals along the dorsal border of CN, in DC, and in the rostral part of EN. This injection also labeled cells in the locus coeruleus, dorsal raphe nucleus, and caudal reticular formation that were not labeled after injections placed in other regions of auditory cortex.

Although the cases in which corticocollicular connections could be examined are limited, they clearly show that A-I, R, and possibly also RT, project to the unlaminated dorsal portion of the IC, with various degrees of additional involvement of the laminated portion of the nucleus. In contrast, auditory belt cortex and cortex lateral and rostral to the belt, appear to project to the dorsocaudal and external nuclei of the IC, and not to the central nucleus.

DISCUSSION The present results lead to the following conclusions

regarding the organization and connections of auditory cortex in owl monkeys.

1. As previously reported (Imig et al., '77), a densely myelinated, koniocortical region of temporal cortex can be subdivided into two tonotopically organized, interconnected, primary-like fields, A-I and a rostral area R. A-I and R appear to differ only slightly in architecture and connections, so that the two fields are most clearly distinguished by having different patterns of tonotopic organization. Yet these patterns vary across owl monkeys, and, judging from other reports, across primate species in a manner suggesting that R may have evolved as a field that gradually differentiated from A-I.

2. A newly distinguished field, termed RT for its rostrotemporal location relative to R, is similar to A-I and R in its responsiveness to tones, myeloarchitecture, and connections, and yet clear differences in architecture and connections distinguish RT from R and A-I. Only the representation of low frequencies (up to 5 kHz) was found in RT, but it is likely that the field has been incompletely explored, since Imig et al. ('77) found a greater range of frequencies in this region.

3. As described by Imig et al. ('77)' the primary-like or core fields are surrounded by a narrow belt of cortex that is responsive to auditory stimuli, but less reliably driven by tones, and is generally less densely myelinated and less "sensory" in cytoarchitecture. This belt can be divided into a number of fields (six to eight), on the bases of patterns of cortical and thalamic connections, and myeloarchitectonic differences. We retain four of the subdivisions of Imig et al. ('77), but suggest somewhat different extents for these fields, and exclude the RT region from the belt. All areas of the belt appear to have inputs from the core, and thalamic connections, at least for part of the belt, include structures outside the medial geniculate complex.

4. Cortex lateral to the belt is interconnected with the belt, and thus presumably has a role in auditory function. Parts of the belt and lateral parabelt auditory cortex have connections with portions of the frontal lobe rostral and


A 89-6 c

1 mm

/ Fig. 12. Evidence that cortex of the rostral pole of the superior

temporal gyrus has auditory function. A. Location of the injection site of WGA-HRP in rostral superior temporal cortex on a dorsolateral view of the brain (left) and the flattened cortex (right). Note that cortical connections are both local in the temporal lobe and with an array of sites in frontal cortex, but do not include core or belt auditory cortex. B Labeled neurons (dots) and terminals (shading) in the auditory thala-

mus. Label included the caudal pole of the medial geniculate complex as well as parts of the medial pulvinar, the suprageniculate-limitans complex, and the marginal zone. Dorsal (D), medial (M), and ventral (V) divisions of the medial geniculate complex are indicated. The lateral geniculate nucleus and the inferior pulvinar are shown for reference. Frontal sections were cut at 40 p,m and numbered in caudorostral series.


medial to the frontal eye field and with the orbitofrontal cortex, while core regions do not appear to project to the frontal lobe. Thus, auditory information reaches prefrontal cortex after at least one step of cortical processing.

5. Connection patterns imply that both MGV and MGM are tonotopically organized, but the organization implied in MGV is more precise. The implied tonotopic order in MGV resembles that previously proposed for squirrel monkeys (Gross et al., '74) and marmosets (Aitkin et d., '88; Luethke et al., '89) as well as cats (Imig and Morel, '85), while the organization in MGM, though crude, is similar to that suggested in marmosets (Luethke et al., '89) and most completely described in cats (Imig and Morel, '85; Morel et al., '87; Rouiller et al., '89).

47

their description, they also illustrated eases with the tonotopic pattern of Figure 21B.

In other primates, A-I appears to have the caudomedial to rostrolateral tonotopic progression of high-to-low frequencies that is found in some owl monkeys (Fig. 21A, owl monkey; C , macaque; D, marmoset, and E, galago). A-I is described as somewhat larger in macaques (Merzenich and Brugge, '731, and also, surprisingly, in the much smaller brained marmosets (Aitkin et al., '86; Luethke et al., '89) than in owl monkeys. The reported orientation of the high-to-low tonotopic gradient from high to low across A-I varies across mammalian species (see Luethke et al., '88, for review), with the most common orientation being similar to those of owl monkeys (Fig. 21A,B). A-I seems to be most different in orientation in cats (Fig. 21F; Reale and Imig, '80), with the high to low progressions nearly opposite in orientation to that in monkeys. Comparison with another carnivore, the ferret (Kelly et al., '86), suggests that A-I has been rotated counterclockwise in cats from a more typical orientation. R. A rostral field has been described in owl monkeys

(Imig et al., '77; present study), macaque monkeys (Merzen- ich and Brugge, '731, marmosets (Luethke et al., '89), and galagos (Brugge, '82). The field is typically distinguished from A-I by a discontinuity or reversal of tonotopic organization at the A-I/R border, although slight differences in architecture (Merzenich and Brugge, '73; Imig et al., '77; Luethke et al., '89) and connections (Imig et al., '77; present study) have also been noted. What is surprising is that a number of different tonotopic organizations and border conjunctions have been reported for R, while the organization of A-I appears to be much more consistent across cases and species (Fig. 21).

The original description of R (termed RL) in macaque monkeys was of a reversal of the tonotopic pattern at a common low-frequency border so that neurons with successively higher best frequencies were recorded at successively more rostral sites in R (Merzenich and Brugge, '73). Neurons with high best frequencies were not encountered, suggesting an incomplete or reduced representation of high best frequencies, but we have recently recorded from R in macaque monkeys and found high frequencies represented medially in R, toward the fundus of the lateral sulcus (Morel et al., '91). Other tonotopic features of R corresponded to the description of Memenich and Brugge ('73). A common border related to low-frequency tones also appears to characterize A-I and R in marmosets (Luethke et al., '89), and to some extent in galagos (Brugge, '82), where another part of the border region of R is devoted to middle frequencies, but high frequencies have not been found (Fig. 21). Owl monkeys seem quite different from these other primates in that only in some cases is there a common low-frequency border between A-I and R, and even in these cases, the low-frequency border is limited to the lateral portion of the fields. In other cases, there is a distinction along the border so that middle and high best frequencies in R adjoin low and middle best frequencies, respectively, in A-I (Fig. 21). Thus, R appears to be much more variable than A-I in tonotopic organization.

The interesting pattern of tonotopic organization seen in A-I and R of some owl monkeys, in which isofrequency bands extend in a parallel fashion across both fields (Fig. 21B), raises several issues. Most notably, in such cases a border between the two fields is not apparent physiologically and there is no obvious way, other than by location, of

The core auditory fields, A-I, R, and RT A major conclusion of this study is that the "core" or

"primary-like" auditory cortex in owl monkeys consists of at least three tonotopic fields, A-I, R, and RT. This conclusion is derived from combined electrophysiological, architectonic, and connectional data. The distinction between A-I and R is consistent with previous evidence and conclusions for macaques (Merzenich and Brugge, '731, marmosets (Aitkin et al., '86; Luethke et al., '89), and galagos (Brugge, '82). Yet the response properties of neurons, the architecture, and the connections for each of these three fields are so similar that an alternative hypothesis (that they are all parts of a single field, A-I) remains tenable. However, even accepting the hypothesis that three separate fields exist, the similarities of the fields suggest that there may be practical problems in distinguishing and accurately determining borders between core fields.

A-I. Results from previous microelectrode mapping studies of A-I in primates indicate that A-I is characterized by: 1) strong, reliable, short-latency and narrowly tuned responses to tones; 2) a complete and orderly frequency (or tonotopic) representation, with high frequencies represented caudomedially, and low frequencies represented laterally and rostrally; and 3) cortex of koniocortical appearance, dense myelination, and CO staining (Merzenich and Brugge, '73; Aitkin et al., '86; Imig et al., '77; Luethke et al., '89). Our microelectrode maps of auditory cortex were incomplete, since our main goal was to identify locations within A-I and other fields for the injections of anatomical tracers. Nevertheless, a consistent general pattern of tonotopic organization was found in all cases, with high frequencies represented medially or caudomedially, and low frequencies represented laterally or rostrolaterally. However, individual monkeys varied in that the gradient of frequency change was largely mediolateral in some, and caudomedial to rostrolateral in others (Figs. 2, 21). A-I appeared to be coextensive with the caudal half of the densely myelinated region of cortex along the lateral sulcus. Borders with belt cortex correlated with reductions in responsiveness to tones and in myelination. More rostral in the koniocortical region, R sometimes appeared to be somewhat less densely myelinated than A-I, and a discontinuity in frequency representation was often noted across the border (Fig. 2), but it was difficult to ascertain a precise border between the two fields. The region we designate as A-I appears to correspond closely to A-I of Imig et al. ('77) in owl monkeys in location, size, and tonotopic organization. Likewise, the variability in tonotopic organization noted in A-I in the present cases was found in previous eases. Although Imig et al. ('77) stressed the tonotopic pattern of Figure 21A in


Fig. 14. A: Label in the caudal pole of the medial geniculate complex (MGp) after an injection of WGA-HRP in the rostroventral parabelt cortex (case 89-6). B: Labeled neurons in the dorsal and rostra1 part of the ventral (MGV) nucleus of the medial geniculate complex after an

injection of WGA-HRP in a high frequency portion of A-I (case 89-71). C: Band of labeled terminals in the central nucleus of the inferior colliculus after an injection of WGA-HRP into ipsilateral R in case 89-63 (see Fig. 20B for orientation). Scale bars = 0.5 mm.

identifying the two fields. This suggests that the distinction between A-I and R can be rather artificial. Perhaps A-I and R are parts of the Same field that, in some individual owl monkeys and in other primates, is complexly organized than A-1 in Other merits of isofrequencY bands Prevail. The Possibility that A-I and Rare both parts ofA-I is countered, however, by the

Fig. 13. The cytoarchitecture (A-D) and cytochrome oxidase (a-d) staining of the auditory thalamus. Frontal sections are from a caudorostral series with GO sections below matched with adjacent Nissl-stained sections above. Intervals between levels are 0.4 mm. Ventral (V), dorsal (D), and medial (M) divisions of the medial geniculate complex are indicated. Scale bar = 1 mm.

in which simp1e


/ 174

89-65

Fig. 15. Distributions of transported label in the auditory thalamus after injections of WGA-HRP in A-I, diaminido-yellow (dy) in R, and fast blue (fb) in AL. The lower box shows the location of the injection sites (also see Figs. 2D, 4, and 5B), and the upper box indicates the plane

evidence that the fields differ somewhat in connections and architecture (see below). Yet the overall similarities between A-I and R, and the finding that isofrequency bands extend in an uninterrupted fashion across both fields in some owl monkeys suggest that R could have evolved as a distinct auditory field by differentiating from A-I (see G a s , '89).

Because they are so similar, A-I and R may have been inadvertently combined in some studies as A-I and riot. distinguished as separate fields. This possibility seems especially likely in studies in which only architecture has been used to define A-I. For example, the koniocortical auditory field (KA) of Pandya and Sanides ('72) and Gala- burda and Pandya ('83) in macaque monkeys has been generally assumed to correspond to A-I, and yet KA roughly equals A-I and R in rostrocaudal extent. However, such misidentifications may occur even in studies in which detailed microelectrode maps of auditory cortex have been obtained, since such maps do not distinguish A-I and R in

of the frontal brain sections. The 40 wm sections are numbered in a caudorostral series, with most caudal section in lower left, and most rostral section in upper right. Other conventions as in previous figures. Scale bar = 1 mm.

some owl monkeys (Fig. 21B). For example, the organization of auditory cortex in marmosets may have been misinterpreted. In these primates, R has been described as notably less myelinated and granular than A-I (Aitkin et al., '86; Luethke et al., '891, in contrast to the great similarity in appearance noted for macaque and owl monkeys. The reduction in myelination is reminiscent of the distinction of RT from R in owl monkeys (Fig. 3). Thus, "A-I" in marmosets may actually be a combination of A-I and R, while R in marmosets may be RT. This may account for the description of A-I in marmosets (Aitkin et id., '86; Luethke et al., '89) as larger than A-I in owl monkeys (Imig et al., '77; present study) and nearly as large as in macaque monkeys (Merzenich and Brugge, '73).

A third issue raised by the variable border relationship of R with A-I in owl monkeys is the difficulty in establishing homologues across species. Did R evolve from A-I, and did this occur only in primates? Or is R an area common to a number of lines of mammalian evolution? In cats (Fig.


Fig. 16. Distributions of thalamic label after injections of nuclear yellow in R and WGA-HRP in AL. Scale bar = 1 mm. Conventions as in Figure 15.

21F), area P reverses along the low-frequency border of A-I, as R typically does in primates, but another field, area A, is similar to R in its rostral position and responsiveness to tones. Yet, unlike the usual relation of R to A-I, A borders A-I along a common representation of high best frequencies in cats (Fig. 21F). However, the finding that in some owl monkeys, R and A-I have a partial border that corresponds to high best frequencies indicates that different border conjunctions are possible.

The rostrotemporal area is a subdivision of auditory cortex that was included in the larger anterolateral field of Imig et al. ('77) and RT has not been previously delimited and defined as such. RT is characterized by moderately dense myelination, neurons sharply tuned and highly responsive to tones, and connections with major divisions of the medial geniculate complex. Because of these features, it seems reasonable to include RT with A-I and R as part of a core of areas with characteristics resembling those of primary auditory cortex. Clearly, however, RT is less primary-like in that myelination is reduced and tha-

RT.

lamic inputs include caudal parts of the medial geniculate complex (see below). Thus, RT may also be considered as intermediate between core areas and the less responsive, lightly myelinated belt areas.

Our recordings from RT have been from the region near the R border, where neurons have best frequencies in the 1-5 kHz range. While it is possible that RT is specialized for the processing of low-frequency information, the area has been incompletely explored, and it is possible that more rostral portions of RT lying deeper in the lateral fissure will be found to represent higher frequencies. Data reported by Imig et al. ('77) for cortex in the RT region provide evidence for a representation of frequencies of 10 kHz and higher.

While we have no direct evidence for RT in other primates, RT resembles the rostral parakoniocortical area of Pandya and Sanides ('72) in relative position and architecture. If the auditory koniocortical area of these authors includes both A-I and R, as we surmise from the illustrated size and position of the field, then the rostral parakoniocortical area is on the rostral border of R, is about the same


89-35 - I 97

Fig. 17. Distributions of thalamic label after injections of nuclear yellow (ny) at the A-I/PL border, fast blue (fD) in R, and WGA-HRP in RT. Scale bar = 1 mm. Conventions as in Figure 15. Also see Figure 8.

proportional size as RT, and has moderately dense myelination as does R. Furthermore, just as RT and Rare interconnected (Fig. 22), so too the rostral parakoniocortical area is interconnected with koniocortical region (Galaburda and Pandya, '83), possibly with R rather than A-I.

Auditory belt A narrow, 1-2 mm wide belt of cortex surrounding A-I, R,

and RT appears to be largely or completely auditory in function because neurons in the belt respond to auditory stimuli and most or all parts are densely interconnected with the core areas. We have tentatively divided the belt into seven regions or areas on the bases of connection patterns and architecture. Four of these fields (PL, AL, CM, and RM) correspond to fields previously described by Imig et al. ('77) in owl monkeys, but we have reduced the extent of PL laterally and CM medially to accommodate a caudal

area, C, just caudal to A-I, and reduced AL to allow for RT and separate belt areas lateral and medial to RT (Figs. 1,22).

1. Our caudomedial field (CM) is largely coextensive with CM of Imig et al. ('77). They described CM as a field on the medial border of A-I with generally less densely packed neurons in granular and supragranular layers than in A-I. Neurons in CM responded to tones, though less securely and with broader frequency tuning. Neurons with higher best frequencies tended to be caudal, and those with lower best frequencies tended to be rostral in CM. We find CM to be more densely myelinated than the adjoining portions of the belt, and because the region of denser myelination does not extend along the caudal border of A-I, we have restricted CM to cortex medial to A-I. A comparable area has been described in macaque monkeys (Merzenich and Brugge, '73).


Fig. 19. The cytoarchitecture (A) and cytochrome oxidase reaction (B ) of the inferior colliculus. The central nucleus, dorsal cortex, and external nucleus of the inferior colliculus are indicated. Dashed lines indicate limits between DC, the dorsomedial unlaminated and the ventral laminated CN. Frontal sections; medial, left. Scale bar = 1 mm.

2. Our caudal field (C) occupies cortex largely contained in a larger CM by Imig et al. ('771, and lateral C may overlap with part of their PL. C is clearly different from CM in having much less dense myelination, and C appears to have a separate projection from A-I as well (Fig. 22).

3. The rostromedial field (Fig. 1) corresponds closely to RM of Imig et al. ('77) where only a brief description was given. RM is the cortex along the medial border of R that is less myelinated than CM or R. Imig et al. ( '77) were uncertain about the extent of RM and whether it should be considered a separate area, but noted that the region was less packed with neurons in layers IV and I11 than R, and that neurons in RM could be driven by auditory stimuli. Connections with A-I and R (FitzPatrick and Imig, '80; present study) also characterize RM. 4 + 5. The PL and AL fields are lightly myelinated

regions bordering A-I and R, respectively. Our few recordings from neurons in these regions corresponded to those of Imig et al. ( '77) in that responsiveness was reduced and frequency tuning was broader than in core areas. Also, as Imig et al. ('77) noted, best frequencies, when they could be determined, tended to match those of neurons in adjacent parts of A-I and R. This limited evidence suggests that two crudely tonotopic patterns might distinguish PL and AL. Patterns of connections provide further evidence for two

areas, as injections in A-I produce separate patches of label in AL and PL. Thus, we retain the distinction between PL and AL, but do not extend PL caudal to A-I as in Imig et al. ( '77).

6 + 7. Cortical regions lateral and medial to RT may be extensions of the RM or AL fields, but they seem separable on the basis of connections (Fig. 22). Most notably, the LRT region is connected with AL and has denser connections with RT and less dense connections with R than AL. We are uncertain about the connections of the MRT region, partly because this region is near the fundus of the lateral sulcus and difficult to study, and partly because of limited number of cases. Both the LRT and MRT regions are lightly myelinated. We are reluctant to propose further subdivision of auditory belt cortex on such incomplete evidence, but introduce the tentative terms lateral rostral temporal (LRT) and medial rostral temporal (MRT) to facilitate further discussion and description.

Parabelt cortex. A strip of cortex lateral and caudal to the auditory belt has connections with the lateral belt and auditory thalamus (Fig. 22). It is not certain how far this parabelt region extends, but it at least includes cortex in the dorsal bank of the superior sulcus. Cortex in this region has been generally considered to be outside of the auditory


A

55

C Inj. AL (case 89-4) - Inj. A-I (case 89-71) -

B Inj. R (case 89-63) -

2 2 9 I

Fig. 20. Label in the inferior colliculus after injections in auditory cortex. Drawings are from frontal sections, cut at 40 pm, and numbered eaudorostrally. See Figures 6,11, and 9B for injection sites. Medial, left. Scale bar = 1 mm.

cortex, or multimodal in function in macaque monkeys (Bruce et al., '81; Baylis et al., '87; Hikosawa et al., '88).

Cortical connections of auditory cortex Our major conclusions regarding the connections of

auditory cortex in owl monkeys are summarized in Figure 22. Core areas connect most densely with each other and with immediately adjacent parts of the belt. Belt areas connect with adjacent belt areas and with parabelt cortex, and together, relay to frontal cortex.

Injections of tracers in A-I demonstrated major ipsilateral connections with CM, C, PL, and R, as well as sparse connections with RM and AL. Connections within A-I were patchy and tended to be between sites roughly matched for best frequencies. Callosal connections were studied only in one case, but connections with contralateral A-I were patchy and most dense in the locations corresponding to the

injection site. These results and conclusions are largely consistent with previous results reported for owl monkeys and other primates. Most notably, in the two owl monkey cases illustrated with an injection of 3H-proline confined to A-I, FitzPatrick and Imig ('80) also described projections from A-I to C, CM, RM, R, PL, and AL regions as presently defined. Thus, there is a good correspondence of proposed A-I targets in two studies of owl monkeys. After injections in A-I in New World monkeys of the marmoset family, Aitkin et al. ('88) and Luethke et al. ('89) noted labeling in cortex immediately rostra1 and caudal to A-I, presumably in R and C. Only the sparser connections of A-I to the RM and AL regions of owl monkeys were not detected in marmosets.

Connections of physiologically identified A-I have not been described for other primates, but Galaburda and Pandya ('83) illustrate results from two cases of injections within or including auditory KA in macaque monkeys. As


owl monkey

A

J

macaque

galago

E €I "F

MF lllD LF

Fig. 21. Proposed onotopic organization of auditory cortex in primates and cats. The frequency representations are simplified and divided into three domains (HF, high frequency, MF, middle frequency, and LF, low frequency) for illustration. All cases are represented as right hemispheres, with rostral, right, and medial, above. Owl monkey (A and B) types are based on the present study and Imig et al. ('77). C:

noted above, the proposed size of KA suggests that it includes both A-I and R. Nevertheless, results from the case with the most confined injection demonstrated connections with cortex immediately lateral, rostral, medial, and caudal to KA, as well as more distant sites in cortex along the superior temporal sulcus. Transported label was more widely spread in the second case, but together the cases

B

D

F

marmoset

cat

macaque, based on Merzenich and Brugge ('73). D marmoset, base on Aitkin et al. ('86) and Luethke et al. ('89). E: galago, based on Brugge ('82). F: cat, based on Reale and Imig ('80). Cat auditory areas include the primary area and posterior, ventroposterior, and anterior fields. The rostral field of primates has been called rostrolateral (RL) in macaques.

provide evidence that A-I of macaque monkeys for some or all of the short ipsilateral connections of owl monkeys, and perhaps even some longer ipsilateral connections.

In regard to the intrinsic connections and callosal connections of A-I, Luethke et al. ('89) noted in marmosets the tendency for label from injections in A-I to be in foci concentrated within, but not confined to, isofrequency


bands. Similar observations have been made for A-I of cats (Imig and Reale, '80; Matsubara and Phillips, '88). Callosal connections are scattered in contralateral A-I of owl monkeys and marmosets (Fig. 6; FitzPatrick and Imig, '80; Aitkin et al., '88; Luethke et al., '89). There is also evidence that auditory koniocortex in macaque monkeys projects interhemispherically to its counterpart and adjacent cortex (Pandya et al., '69; Cipolloni and Pandya, '89). In general, callosal connections of A-I are denser in portions of A-I that match the injection site (Fig. 6; Aitkin et al., '88; Luethke et al., '89). A-I apparently also has less dense callosal connections with R and with scattered regions in the belt areas (FitzPatrick and Imig, '80; Luethke et al., '89). In cats (Imig and Brugge, '78; Imig and Reale, '80) and squirrels (Luethke et al., '88), A-I has callosal connections with A-I that are most dense in parts matching the injection sites, and callosal connections of A-I include several regions of auditory cortex outside of A-I.

Present results indicate that the rostral area, R, connects with core areas A-I and RT, as well as belt areas RM and AL (Fig. 22). CM and PL are more sparsely connected with R. Likewise, FitzPatrick and Imig ('80) found that injections in R of owl monkeys labeled A-I and cortex in the AL, RM, and PL regions. In addition, some label attributed to the AL region appears to be in cortex we define as RT. Thus, there seems to be good agreement in results between the two studies. Connections of R have not been directly studied in other primates, but injections in A-I of marmosets (Aitkin et al., '88; Luethke et al., '89) demonstrate connections between A-I and the R region. In macaque monkeys, results from our preliminary studies of A-I injections indicate connections with R (Morel et al., '91). In addition, Gala- burda and Pandya ('83) reported that injections in auditory KA labeled cortex immediately rostral to KA, but our interpretation of KA is that it included both A-I and R. If so, injections that include A-I and R demonstrate connections to cortex lateral, medial, and rostral to A-I and R, suggesting that R in macaque monkeys has connections much like those in owl monkeys.

Connections of the rostrotemporal area, RT, have not been specifically studied before, but it seems intriguing that the major connections are with immediately adjoining areas (Fig. 22), as for A-I and R. We have classified RT as a core area because RT resembles A-I and R in myeloarchitecture and responsiveness to tones, and it seems that there are similarities in overall cortical connection patterns as well. It is also important to note that our proposal of a caudorostral sequence of three interconnected core areas has features in common with the schematic for macaque monkeys in the architectonic and connectional study of Galaburda and Pandya ('83). In their proposal, a caudorostral sequence of four core areas, bounded by belt cortex, are linked by connections much like A-I, R, and RT (Fig. 22). If their KA corresponds to A-I plus R, as we suggest, then their core area, PaAr, lies in the relative position of RT. Unfortu- nately, the connections of PaAr are not well established, since only one case with injection involving PaAr was illustrated by Galaburda and Pandya ('83) and the injection in that case includes other areas of cortex nearer the superior temporal sulcus.

Our results also indicate that the belt regions PL and AL project to more ventral cortex along the superior temporal sulcus that we term parabelt, and that belt and parabelt cortex relay auditory information to the frontal lobe (Fig. 22). These auditory connections are concentrated in cortex

just rostral and medial to the frontal eye field, suggesting that neurons activated or influenced by auditory stimuli should be found in this frontal region. While regions of responsiveness to auditory stimuli have not been described in the frontal lobe of owl monkeys, such regions have been noted rostral and medial to the frontal eye field in squirrel monkeys (Bignall, '70; Schechter and Murphy, '75; New- man and Lindsley, '76; Wollberg and Sela, '80) and in macaque monkeys (Azuma and Suzuki, '84; Suzuki, '85; Vaadia et al., '86).

In macaque monkeys, anatomical studies indicate that auditory information is relayed to frontal cortex from large portions of the superior temporal gyrus, with the clear exception of koniocortex (Jones and Powell, '70; Chavis and Pandya, '76; Barbas and Mesulam, '81, '85; Petrides and Pandya, '88). Some of these connections appear to involve belt and parabelt cortex just lateral to A-I and R as in owl monkeys.

Other connections of the lateral auditory belt are with the dorsal bank of the lateral sulcus, a region that includes the PV of somatosensory cortex. After an injection of fluorescent dye at the AL/PL border (Fig. 5B), many labeled neurons were found in the PV region. PV was first described as containing a systematic representation of the contralateral body surface in squirrels (Krubitzer et al., '86), and it has been subsequently described for rats (Li et al., '90; Fabri et al., 'go), bats (Krubitzer and Calford, '92) and monkeys (Krubitzer and Kaas, '90b). Thus, PV is likely to be an area common to a wide range of mammals. In squirrels, PV has some neurons that also respond to auditory stimuli, as well as connections with the auditory belt (Krubitzer et al., '86). The evidence for connections between the auditory belt and the PV region in owl monkeys suggests that PV may have some auditory function in monkeys as well.

Thalamie connections Injections in A-I, R, RT, PL, AL, and the parabelt region

were used to determine thalamocortical relations in owl monkeys. The results indicate that each of these areas has a different pattern of connections with the auditory thalamus, and provide evidence that both MGV and MGM are tonotopically organized (Figs. 22, 23). In addition, because some injections were of the bidirectional tracer, WGA-HRP, we have information on how different subdivisions of auditory cortex project to the inferior colliculus.

Our injections in A-I labeled neurons and terminals in MGV and MGM. In some cases, sparse amounts of label were found in MGD. Label in both MGV and MGM tended to be dorsal after injections in portions of A-I devoted t o high frequencies, and ventral after injections in portions activated by low frequencies (Fig. 23). These results, together with those from tonotopically organized areas R and RT, suggest the existence of predominantly dorsoventral progressions of high-to-low best frequencies for neurons in MGV and MGM, but with much greater tonotopic order in MGV than in MGM. Isofrequency bands, judging by connections, appear to be angled medioventrally to laterodorsally in MGV. Connections patterns did not reveal any clear pattern of tonotopic organization in MGD.

The present results are in basic agreement with those reported after 3H-proline injections in A-I of owl monkeys. FitzPatrick and Imig ('78) found that A-I projects to MGV and MGM, but not to MGD. Their injections were large and centered in A-I and thus revealed little about the tonotopic

A-I.


A

B

Belt

Core

Belt

Para be It

Frontal ‘I ~~

Thala mo -cortical connect ions

Figure 22

59 AUDITORY CORTEX IN OWL MONKEYS

Tonotopic organization in MGC

monkey cat

Fig. 23. The proposed tonotopic organizations of the medial (M) and ventral (V) nuclei of the medial geniculate complex of owl monkeys and domestic cats. Gradients of tonotopic changes are represented by two or three steps (high, middle, and low frequencies). The conclusion that a tonotopic organization exists in M but that the pattern is much cruder than in V is portrayed by the overlap between the two extremes (high and low) of the ftequency domain. Based on present results for owl monkeys, and Imig and Morel ('84) and Rouiller et al. ('89) for cats. Conventions as in Figure 21.

organization of MGV and MGM, but label tended to course ventrolaterally to dorsomedially, as in the present cases, suggesting that isorepresentation columns are oriented in this manner. In marmosets, both Aitkin et al. ('88) and Luethke et al. ('89) found progressively more ventral bands of labeled cells in MGV with injections in progressively lower frequency representations in A-I. As in the present study, isofrequency bands in MGV curved dorsally from medial to lateral in the nucleus. Aitkin et al. ('88) did not distinguish MGM, but some of the illustrated label appeared to be in the MGM region. Luethke et al. ('89) demonstrated connections of MGM with A-I, and provided evidence for a crude tonotopic organization with high frequencies represented dorsally. Finally, they described connections of A-I with MGD. Other studies of the thalamic connections of auditory cortex in primates have depended on architectonic definition of areas or refered to the general region of auditory responsive cortex. From these studies, it is clear that auditory koniocortex or cortex in that general region is interconnected with the medial geniculate complex in squirrel monkeys (Forbes and Moskowitz, '74;

Fig. 22. Connections of auditory cortex. A: Cortical connections. Major (thick arrows) and minor (thin arrows) projections are indicated, although all connections are likely to be reciprocal. Primary auditory, rostral area, and rostrotemporal area form a core of primary-like areas, surrounded by a belt with caudal, caudomedial, posterolateral, anterolateral, rostromedial, medial rostrotemporal, and lateral rostrotemporal subdivisions. Laterally adjoining parabelt cortex receives inputs from the belt, and both belt areas and parabelt cortex connect with prefrontal cortex. B Major thalamic connections of core and belt auditory areas. Letter size reflects the magnitude of the connections; parentheses denote connections indicated by equivocal evidence. Corti- cal areas are the same as above. Auditory nuclei are outlined on a drawing of a frontal section on the lower right. Ventral 0, medial (M), and dorsal (D) divisions of the medial geniculate complex are indicated. RT has major Connections with the caudal portion of the ventral (Vc) and dorsal (Dc) nuclei. Other nuclei are the suprageniculate, limitans, inferior pulvinar, superior or lateral pulvinar, and lateral geniculate (LGN) .

Burton and Jones, '76) and in macaque monkeys (Mesulam and Pandya, '73; Burton and Jones, '76). Overall, it seems reasonable to conclude that in owl monkeys, marmosets, and probably Old World macaques: 1) MGV is topographically connected with A-I; 2) lines of isofrequency representation extend mediolaterally with a dorsalward slant; and 3) low to high frequencies are represented from ventral to dorsal. Finally, evidence from the present study and from the report of Luethke et al. ('89) suggests that monkeys also have sparse connections between MG,D and A-I.

The conclusions about the tonotopic organization of MGV and MGM are consistent with results reported for the only published microelectrde mapping study of the tonotopic organization of auditory thalamus in primates. In lateromedial electrode penetrations through MGV in squirrel monkeys, Gross et al. ('74) found neurons to be most responsive to successively higher tones, as would occur with the angled isofrequency contours depicted for MGV of monkeys in Figure 23. Neurons medial to MGV, apparently in MGM, had well-defined best frequencies, and appeared to be tonotopically organized, but the nature of the organization was not clear. More recently, we have recorded from the MG complex with dorsoventral electrode penetrations in owl monkeys (Morel and Kaas, unpublished experiments). Penetrations through MGV encountered successively lower best frequencies, while in MGM limited recordings suggested a similar dorsoventral gradient from high to low best frequencies, although neurons were less selective and the nucleus had less precise tonotopy than MGV.

The above conclusions for monkeys probably apply more broadly to other mammals. Thalamocortical auditory connections are perhaps best known for cats, in which A-I clearly has connections with MGV and MGM, but the evidence for connections with MGD remains equivocal (Andersen et al., 1980a; Rouiller and de Ribaupierre, '85; Morel and Imig, '87; Rouiller et al., '89). While basically similar, the tonotopic pattern of the rostral portion of MGV is slightly rotated from that in monkeys, so that isofre- guency bands are nearly vertical in orientation (Fig. 23). More caudally in MGV of cats, the parallel arrangement of isofrequency contours is disrupted by an horizontal protru- sion of the low-frequency region (Imig and Morel, '84, '85). In cats, MGM appears to be tonotopically organized, although more crudely than MGV (Fig. 23; Imig and Morel, '85; Rouiller et al., '89), much as in monkeys.

R and RT. Present results indicate that like A-I, R receives major inputs from MGV and MGM, and that these connections are topological and congruent with the proposed tonotopic organization of MGV and MGM. Unlike A-I, R also receives a major input from MGD (Fig. 22). In the only other study of the thalamic connections of R, FitzPatrick and Imig ('78) reported that R projects to MGV, MGM, and MGD in owl monkeys. RT receives major inputs from caudal MGV, MGM, and caudal MGD. Thalamic connections of RT have not been previously described.

Other mammals have auditory fields in addition to A-I, and some of these fields resemble R and RT in responsiveness to tones, architecture, and relative position. Little comparative information is available about arrangements and variations across a range of mammalian species, and thus homologies remain uncertain. Yet, in cats, thalamocortical connections of fields P and A on the posterior and anterior borders of A-I, respectively, resemble those of R and RT in monkeys in that A and P also receive inputs from MGV. Thus, MGV projects to several cortical targets in


both carnivore and primate lines of evolution. In addition, the projection to P from MGV is from the caudal portion (Morel and Imig, '87), as is the projection of MGV to RT. Thus, in both carnivores and primates, the caudal portion of MGV may have different or more widely distributed cortical connections than the rostral portion. The finding of these similar features of thalamocortical organization in cats and monkeys suggests that such features are character- istic of a broad range of mammals.

Our information on the thalamic connections of the belt is based on a limited number of injections involving the AL and PL regions. The results provide evidence that AL receives inputs from the suprageniculate and limitans nuclei, and from the broadly connecting (see Kaas and Huerta, '88, for review) medial pulvinar (Fig. 22). The PL region appears to differ in that major inputs are from MGM and MGD, with perhaps some inputs from MGV. No other studies of the PL and AL regions as such have been reported, but Mesulam and Pandya ('73) studied thalamocortical relations in macaque monkeys after lesions in the auditory thalamus and concluded that MGV and possibly MGM project to cortex immediately lateral to auditory koniocortex. In addition, after injections of tritiated tracers in the thalamus, Burton and Jones ('76) reported that MGD projects to cortex lateral to auditory koniocortex in both squirrel and macaque monkeys. The results together suggest that parts of the lateral auditory belt in monkeys receive input from all three of the major divisions of the medial geniculate complex.

The cortical projections of suprageniculate and limitans nuclei in other mammals are not well known, and the suprageniculate is commonly included in the posterior complex (Jones, '85). Yet, there is evidence that the region of the suprageniculate nucleus and limitans nuclei in cats projects also to nonprimary auditory cortical areas (Andersen et al., '80a; Bowman and Olson, '88; Clarey and Irvine, '90; see also Winer, '85, for review). The medial pulvinar is known to project to portions of the superior temporal gyrus lateral to koniocortical areas, possibly including belt auditory cortex (Burton and Jones, '76) as well as large regions of the inferotemporal, parietal, and frontal cortex (see Kaas and Huerta, '88, for review). FitzPatrick and Imig ('78) indicated a small projection from field R to the medial pulvinar in owl monkeys.

Auditory belt.

Projections to the inferior colliculus Using Nissl stains and tissue reacted for CO, we have

divided the inferior colliculus into the traditional CN, DC (or pericentral nucleus), and EN (e.g., FitzPatrick, '75; FitzPatrick and Imig, '78; Morest and Oliver, '84; Garey and Webster, '89; Luethke et al., '89). A distinction between a larger ventral portion of CN with neurons aligned in mediodorsal to ventrolateral rows and a dorsal portion without distinct laminar organization can be made from Nissl material (FitzPatrick, '75; FitzPatrick and Imig, '78; Garey and Webster, '89) although the exact location of the transition from dorsal to ventral portions is not obvious.

We approximated the cytoarchitectonic border in CN of the present cases (Fig. 20) because dorsal and ventral portions of the nucleus differ in cortical inputs. In brief, we found bilateral projections from A-I, R, and AL to the dorsal part of the CN. The label was most dense ipsilaterally, and it was aligned in dorsomedial to ventrolateral columns. The label appeared to extend more ventrally in the CN for the

A-I injections. For at least the AL injection, the label also included some of the DC.

Bilateral projections from A-I to the inferior colliculus have been previously reported for owl monkeys (FitzPatrick and Imig, '78) and marmosets (Luethke et al., '89), as well as cats (e.g., Andersen et al., '80b). The label in all cases seems to involve the dorsal cortex and the dorsomedial portion of the central nucleus, and in owl monkeys also, part of the ventrolateral portion of the CN. The elongated bands of label from restricted injections extend in dorsomedial to ventrolateral columns that course along the upper parts of isofrequency bands, as judged from the arrangements of the aligned rows of neurons, as well as the microelectrode mapping studies of the inferior colliculus in squirrel monkeys (FitzPatrick, '75) and cats (Merzenich and Reid, '74; Semple and Aitkin, '79). Thus, it appears that neurons aligned along single isofrequency bands (or sheets) in the central nucleus of the inferior colliculus differ in that dorsomedial portion of the bands are directly influenced by inputs from several auditory cortical fields, while neurons in ventrolateral portion are not.

Information processing in auditory cortex of monkeys

Relative to the auditory system, much more is known about the processing of information in the visual and somatosensory systems of primates, for which somewhat detailed accounts of the hierarchical arrangements of areas, and the roles of the many parallel and distributed paths, have been achieved (see Kaas and Garraghty, '91, for a review). Nevertheless, the present results, together with those of related studies on the connections of auditory cortex in monkeys, allow a number of conclusions about the cortical processing of auditory inputs.

1. Auditory cortex has at least three primary-like areas (A-I, R, and RT) with the potential for independent activation by inputs from the major thalamic relay, MGV. In addition, PL and perhaps other belt areas may have significant inputs from MGV. It seems likely that these thalamic inputs account for the basic response properties of neurons in each of areas A-I, R, and RT, and thus lesions of any of the three areas would fail to deactivate neurons in the other two areas or alter their selective responsiveness to tones, while lesions of MGV would abolish selective responsiveness to tones and perhaps totally deactivate neurons.

2. Parallel thalamic inputs from MGM and MGD could potentially activate cortical neurons in A-I, R, RT in the absence of MGV, though one would expect selective responsiveness to specific tones to be highly degraded.

3. A-I, R, and RT appear to be sequential areas in a cortical processing hierarchy. Projections from A-I to R in owl monkeys (FitzPatrick and Imig, '80) are largely of the feedforward type (see Rockland and Pandya, '79; Maunsell and Van Essen, '83) that terminate most densely in layer IV and are expected to activate target neurons. The projections from R to A-I tend to resemble the feedback type that are expected to modulate target neurons. Our cases with flattened cortex and the greater use of tracers that label only neurons rather than neurons and terminals do not provide much information on the relationship of RT to R, but the possibility that RT receives feedforward inputs from R is consistent with the proposal of Galaburda and Pandya ('83) that auditory koniocortex, which may include


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4. Since anatomical substrates exist for both the independent thalamic activation and sequential cortical activation of A-I, R, and RT, lesion studies, such as those used to test assumptions about processing sequences in the visual system (e.g., Girard and Bullier, '89) and somatosensory system (e.g., Garraghty et al., '90) are needed. In the somatosensory system of monkeys, for example, area 1 appears from the connection patterns to be activated by feedforward inputs from area 3b, and yet both areas 3b and 1 receive thalamic projections from the ventroposterior nucleus, Lesion studies demonstrate that the activating input to area 1 is from area 3b rather than the thalamus, at least in New World monkeys (Garraghty et al., '90). We propose that A-I, R, and RT are highly dependent on MGV for activation, that inputs from MGM and MGD are largely modulatory, and that the MGV activation of R and RT may be indirect and depend on the intactness of A-I, or A-I and R.

5. Neurons in the belt cortex are less responsive to tones, and more broadly tuned than those in core areas, and this could reflect the relay and convergence of inputs from neurons in core areas. Patterns of connections suggest that belt areas are likely to be higher processing stations that are activated by the adjacent core areas that provide the bulk of their cortical input. However, the anatomical evidence on the relationship of specific belt areas to core areas is somewhat equivocal. Aitkin et al. ('88) commented little on the laminar patterns of ipsilateral connections of A-I in marmosets, but terminations extending across cortical layers, and thus of the intermediate type (Maunsell and Van Essen, '83) were illustrated for areas medial and lateral to A-I. In contrast, FitzPatrick and Imig ('80) illustrated variations of the feedforward type of terminations that were concentrated in layer IV for cortex lateral and medial to A-I and R after injections in A-I or R in owl monkeys. In addition, Galaburda and Pandya ('83) stressed the feedforward nature of projections from core to belt areas in their study of the connections of architectonic fields in macaque monkeys. Thus, lesions of core fields should have a pro- found impact on belt areas, perhaps deactivating them completely. Nevertheless, belt areas may also be activated by inputs from MGM and MGD.

6. Lateral belt areas connect with and may activate parabelt fields. Parabelt fields provide the bulk of the auditory information to frontal cortex. Little is known about other forward connections of most of the auditory belt, and thus it is not yet clear how auditory information reaches limbic structures related to memory (Mishkin, '82; Van Hoesen, '82). Interestingly, aspects of emotional responses to auditory stimuli may be mediated by direct inputs from the medial geniculate complex to the amygdala (LeDoux et al., '841, although direct projections from auditory cortex may be important as well (e.g., Amaral et al., '83; Tranel et al., '88).

ACKNOWLEDGMENTS We dedicate this paper to C.N. Woolsey in recognition of

his pioneering research on the organization of auditory cortex. We thank Leah Krubitzer for help during recordings, and Todd Preuss and Jeff Schall for comments on the manuscript. The work was funded by NIDCD-00922 and NS-16446.

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