auditory belt and parabelt projections to the prefrontal cortex in the rhesus monkey

Auditory Belt and Parabelt Projectionsto the Prefrontal Cortex

in the Rhesus Monkey

L.M. ROMANSKI,1* J.F. BATES,2 AND P.S. GOLDMAN-RAKIC1

1Section of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 065102Center for Morphometric Analysis, Massachusetts General Hospital East,

Charlestown, Massachusetts 02129

ABSTRACTRecent anatomical and electrophysiological studies have expanded our knowledge of the

auditory cortical system in primates and have described its organization as a series ofconcentric circles with a central or primary auditory core, surrounded by a lateral and medialbelt of secondary auditory cortex with a tertiary parabelt cortex just lateral to this belt.Because recent studies have shown that rostral and caudal belt and parabelt cortices havedistinct patterns of connections and acoustic responsivity, we hypothesized that thesedivergent auditory regions might have distinct targets in the frontal lobe. We, therefore,placed discrete injections of wheat germ agglutinin-horseradish peroxidase or fluorescentretrograde tracers into the prefrontal cortex of macaque monkeys and analyzed the antero-grade and retrograde labeling in the aforementioned auditory areas. Injections that includedrostral and orbital prefrontal areas (10, 46 rostral, 12) labeled the rostral belt and parabeltmost heavily, whereas injections including the caudal principal sulcus (area 46), periarcuatecortex (area 8a), and ventrolateral prefrontal cortex (area12vl) labeled the caudal belt andparabelt. Projections originating in the parabelt cortex were denser than those arising fromthe lateral or medial belt cortices in most cases. In addition, the anterior third of the superiortemporal gyrus and the dorsal bank of the superior temporal sulcus were also labeled afterprefrontal injections, confirming previous studies. The present topographical results suggestthat acoustic information diverges into separate streams that target distinct rostral andcaudal domains of the prefrontal cortex, which may serve different acoustic functions. J.Comp. Neurol. 403:141–157, 1999. r 1999 Wiley-Liss, Inc.

Indexing terms: auditory cortex; corticocortical; frontal lobe; association cortex; primate

Research in the visual system has pointed to the impor-tance of the prefrontal cortex (PFC) as a recipient ofsegregated visuospatial and visual object information bymeans of the dorsal and ventral visual streams (Wilson etal., 1993). In contrast to the visual pathways, the prefron-tal targets of central auditory pathways are much lessclear, despite the accepted role of the frontal lobe inlanguage and verbal working memory (Geschwind, 1970;Petrides et al., 1995; Demb et al., 1995; Smith et al., 1996;Gabrieli et al., 1998). Although historically, lesions ofBroca’s area have been associated with deficits in speechproduction (Geschwind, 1970; Damasio and Geschwind,1984), recent clinical and imaging findings have expandedthe role of areas on the inferior frontal gyrus to includecomprehension and memory for verbal stimuli (Caramazzaet al., 1981; Tramo et al., 1988; Schaffler et al., 1993;Swinney and Zurif, 1995; Cohen et al., 1997). In addition,lesion studies in nonhuman primates have implicated the

PFC in auditory mnemonic function (Gross and Weis-krantz, 1962; Goldman and Rosvold, 1970; Iversen andMishkin, 1970; Petrides, 1986).

Although a number of studies have described connec-tions of the superior temporal auditory areas with the PFCin primates (Pandya et al., 1969; Chavis and Pandya,1976; Jacobson and Trojanowski, 1977; Barbas and Mesu-lam, 1985; Petrides and Pandya, 1988; Barbas, 1988, 1992,1993; Seltzer and Pandya, 1989; Carmichael and Price,1995), recent physiological and anatomical refinements of

Grant Sponsor: NIMH; Grant number: MH-38546; Grant sponsor: JamesS. McDonnell Foundation; Grant number JSMF 93–28.

*Correspondence to: Dr. Lizabeth M. Romanski, Yale University School ofMedicine, Section of Neurobiology, B-413 SHM, 333 Cedar St. New Haven,CT 06510. E-mail: [email protected]

Received 20 April 1998; Revised 13 August 1998; Accepted 29 September1998

THE JOURNAL OF COMPARATIVE NEUROLOGY 403:141–157 (1999)

r 1999 WILEY-LISS, INC.

the primate auditory cortical system are cause for areexamination of this issue. These more recent studieshave revealed anatomical and electrophysiological differ-ences between anterior and posterior auditory cortex andbetween lateral and medial auditory zones of the superiortemporal gyrus (STG). It has been recently shown thatprimary and non–primary auditory cortex can be distin-guished on the basis of their differential staining for thecalcium binding protein parvalbumin (Jones et al., 1995;Kosaki et al., 1997; Hackett et al., 1998). Further cytoarchi-tectonic analysis of the auditory cortical system reveals aprimary, or core, region composed of two areas, AI and R,surrounded by and connected to, a medial and lateral beltof secondary auditory association cortex with a lowerdensity of parvalbumin staining (Morel et al., 1993; Joneset al., 1995; Kosaki et al., 1997; Hackett et al., 1998). Athird zone lying adjacent to the lateral belt is the parabeltauditory cortex. Further distinctions between the core andbelt, and the belt and parabelt have been based onmyeloarchitectonic, and connectional differences.

The recent anatomical parcellation of primary auditorycortex is consistent with prior physiological identificationof AI by Merzenich and Brugge (1973) and more recentelectrophysiological analysis (Morel et al., 1993; Raus-checker et al., 1995, 1997; Kosaki et al., 1997). Electrophysi-ological localization of the non–primary auditory cortexhas also recently been achieved (Rauschecker et al., 1995;Kosaki et al., 1997). Rauschecker et al. (1995) haveprovided the first electrophysiological evidence for threeseparate tonotopic regions (AL, ML, and CL) with frequencyreversals separating them, in the non–primary lateral beltassociation cortex. Compared with primary auditory corticalneurons, which readily respond to relatively simple acousticelements, such as pure tones, neurons of the lateral beltassociation cortex prefer complex stimuli including band-passed noise and vocalizations (Rauschecker et al., 1995,1997). The three lateral belt regions are physiologically disso-ciable by the frequency reversals between them and by theirdifferential responses to complex acoustic stimuli (Raus-checker et al., 1995, 1997; Tian and Rauschecker, 1995; Tian etal., 1997). The AL region exhibits a preference for low rates ofFM sweeps (25 Hz/msec), whereas the CL field has neuronsthat show a preference for high rates of FM sweeps (160Hz/msec) and broader frequency tuning. Together the electro-physiological and anatomical evidence support a view of theauditory cortical system as a series of concentric circles with acentral core, the primary auditory cortex, surrounded by anarrow belt of secondary association areas located laterallyand medially, and a parabelt auditory association cortexlocated on the ventral gyral surface of the STG just below thelateral belt (Fig. 1), with successively higher areas processingincreasingly complex stimuli. The anterior temporal lobe andthe dorsal bank of the superior temporal sulcus (STS) mayrepresent later stages of possible auditory processingbecause they receive afferents from the parabelt cortex(Hackett et al., 1998; Romanski et al., 1997b).

With this new organization and sequence of auditoryinformation processing, a reexamination of the connec-tions between the auditory cortical system and the frontallobes is warranted. We searched for auditory targets in thefrontal lobe by placing anterograde and retrograde tracersinto discrete frontal lobe regions and charting the connec-tions with the anatomically redefined areas of the superiortemporal region in rhesus macaques. We reasoned thatprojections from non–primary auditory cortical associa-

tion cortices to the frontal lobes may be part of theneuronal circuit for auditory working memory and, ulti-mately, for language in the human brain.

MATERIALS AND METHODS

Overview

Anterograde and retrograde tracers were placed intodistinct regions of the macaque frontal lobe to characterizethe connections of the PFC with the superior temporalregion, including the supratemporal plane, the STG, andthe cortex lining the dorsal bank of the STS. The retro-gradely labeled cells and anterogradely labeled terminalspresent in the superior temporal region were charted withcareful attention to location of this labeling within thecytoarchitectonically defined medial or lateral belt andparabelt auditory association regions. Some corticocortical(Bates and Goldman-Rakic, 1993) and thalamocortical(Romanski et al., 1997a) connections from some of thesecases have been reported previously.

Subjects and surgical procedures

Fourteen rhesus monkeys (Macaca mulatta) weighing2.5 to 7.0 kg were used in this study. All surgical proce-dures complied with policies and procedures prescribed inthe Guide for the Care and Use of Laboratory Animals, bythe National Institutes of Health and guidelines defined bythe Yale Animal Care and Use Committee. Sterile surgerywas conducted by using sodium pentobarbital (40 mg/kgi.v.) as an anesthetic and ketamine (10 mg/kg i.m.) plusatropine (0.02–0.10 mg/kg i.m.) as a preoperative agent.Heart rate and respiration were monitored continuouslyduring the surgical procedure. The animal was placed in aKopf stereotaxic apparatus, an incision was made in thescalp and the skull was trephined to remove the boneoverlying the target region(s). An incision was made in thedura and a sterile Hamilton syringe or glass pipette (tipdiameter, ,50 µm) was lowered to the target region. Smallinjections of either wheat germ agglutinin-horseradishperoxidase (WGA-HRP, 1.25%) or fluorescent dyes (FastBlue 5%, Diamidino Yellow 2% [Illing, Germany] andTetramethyl Rhodamine [Molecular Probes, Oregon]) weremade. Either one large or several small pressure injectionswere made with WGA-HRP (0.15- to 1.20-µl total volume)or fluorescent tracers (total volume, 1.0 µl spread overseveral injections). The cortical injections included areas8a, 8b, 9, 10, 11, 12, 13, 24, 45, and 46. In one animal (caseWI), the injection coordinates were obtained by usingmagnetic resonance imaging (MRI). The animal was anes-thetized and placed into a delran (nonmetallic), stereotaxicframe with earbars filled with an opaque oil. The frameand the animal were then imaged in a 1.5 Tesla MRImagnet. In this way, the earbars appeared opaque in thesubsequent images and marked the interaural line allow-ing for calculations of target regions by using earbar zeroas a reference. Injections into areas 32, 8B, and rostral 46,were made using this technique. After the injections, thesyringe or pipette remained in place for 15–30 minutes toprevent spread of the tracer and was then withdrawn. Thedura was sutured, and the incision was closed in layers.Upon recovery from anesthesia the animal was returned toits home cage and closely monitored.

A total of 16 prefrontal injections were made into 14rhesus monkeys (in case WI, three different prefrontal

142 L.M. ROMANSKI ET AL.

regions were injected) using WGA-HRP or fluorescenttracers as described in Table 1. Each case was examinedfor anterograde and retrograde labeling, but only those

cases that resulted in labeling of the auditory belt orparabelt were examined and plotted in greater detail.Eight prefrontal injections (Table 1, top; Fig. 2) all had

Abbreviations

AI primary auditory cortex, auditory area 1AL anterior lateral beltasd arcuate sulcus, dorsal limbasv arcuate sulcus, ventral limbcing s. cingulate sulcusCL caudal lateral beltCM caudal medial beltCP caudal auditory parabeltcs central sulcusIns insulals lateral sulcuslos lateral orbital sulcusmos medial orbital sulcusML middle lateral beltpaAlt lateral parakoniocortexPro proisocortexps principal sulcus

PFC prefrontal cortexR rostral area (core auditory cortex)RM rostromedial areaRP rostral auditory parabeltrs rostral sulcusRT rostrotemporal area (core auditory cortex)RTL lateral rostrotemporal auditory beltRTM medial rostrotemporal auditory beltSf sylvian fissure (lateral sulcus)STG superior temporal gyrusSTS, sts superior temporal sulcusTAa architectonic subdivision of the superior temporal sulcusTPO polysensory region of the superior temporal sulcusTpt temporoparietal areaTS1 superior temporal area 1TS2 superior temporal area 2TS3 superior temporal area 3

Fig. 1. Schematic diagrams of the cytoarchitecture of the prefron-tal cortex and the auditory cortical system in the macaque. A,B: Themedial and orbital cytoarchitectonic boundaries are shown accordingto Carmichael and Price (1994). C: The cytoarchitectonic boundaries ofthe dorsolateral prefrontal cortex according to Preuss and Goldman-Rakic (1991) is shown. The ps is divided into subregions, including arostral area (46r), the outer lips of the sulcus (46dr and 46vr), and thedepths and fundus of the sulcus (areas 46d and 46v). In C, primaryauditory cortex, AI, is labeled and the nomenclature of Galaburda and

Pandya (1983) has been superimposed over the shaded parabelt in thesuperior temporal gyrus. D: Enlarged view of the auditory corticalsystem is shown. The color coding shown in C is retained, and theterminology of Hackett et al. (1998) is portrayed. The core areas AI, R,and RT, are surrounded by the lateral (RTL, AL, ML, and CL) andmedial (RTM, RM, CM) belt cortices. The parabelt lies adjacent to thelateral belt and extends from rostral (RP) to caudal (CP). Forabbreviations, see list.

AUDITORY CONNECTIONS WITH PREFRONTAL CORTEX 143

labeling in the belt and/or parabelt auditory associationcortex and will be the focus of this study.

Perfusion and histochemistry

WGA-HRP. Approximately 48 hours after injection ofWGA-HRP, animals were given an overdose of sodiumpentobarbital and perfused with saline followed by amixture of 1% paraformaldehyde and 1.25% glutaralde-hyde followed by a gradient of increasing sucrose solutions(5–30%). The brain was removed, and stored in 30%sucrose at 4°C until sectioning (24–72 hours). The brainwas sectioned coronally at 40 µm and every tenth sectionwas processed, by using the tetramethylbenzidine (TMB)method (Mesulam, 1978). An adjacent series was pro-cessed with TMB and counterstained with cresyl violet,neutral red, or thionin. Sections were saved at 200-µmintervals through the injection site and were processedwith diaminobenzidine for enhanced visualization of theinjection site.

Fluorescent tracers. Animal WI in which three differ-ent fluorescent tracers were injected into the PFC wasperfused 14 days postoperatively with 0.9% saline, fol-lowed by 4% paraformaldehyde. The brain was removed,blocked in the coronal plane, and incubated for 48 hours inan increasing gradient of sucrose solutions (10–30%).Some blocks were snap frozen in isopentane at -40°C. Theblocks were sectioned on the cryostat at 40 µm, mountedimmediately onto gelatin-subbed slides, dried, cover-slipped with DPX, and stored refrigerated at 4°C. Anadjacent series was counterstained with cresyl violet.Additional series were processed for AChE, myelin, andparvalbumin to examine the cytoarchitecture of the supe-rior temporal region.

Cytoarchitecture

Cytoarchitecture of PFC. Cytoarchitectonic delinea-tion of the macaque PFC was based on Walker (1940), withmodifications by Preuss and Goldman-Rakic (1991) andCarmichael and Price (1994) for the purpose of definingthe injection sites (Fig. 1). Preuss and Goldman-Rakic(1991) subdivide the principal sulcus (ps) into severalsubdivisions including a rostral area termed 46r, theventral bank and fundus of the ps (46v), the dorsal bank ofthe ps (46d), the outer portion and ventral convexity of theps (46vr), and the dorsal rim and cortex just above the ps

(46dr). In addition, Preuss and Goldman-Rakic recognizesubdivisions within Walker’s area 12 as an orbital area,referred to here as 12o and a lateral region encompassingthe ventrolateral convexity, area 12vl (Fig. 1). In addition,Carmichael and Price (1994) have established criteria fordelineation of medial and orbital frontal regions whoseterminology we have adopted for these areas (Fig. 1A,B).The prefrontal areas examined include areas 8a, 8b, 9, 10,11, 12 vl, 12 o (orbital), 13, 14, 24, 25, 32, 45, 46d, 46dr, 46v,46vr, and 46r. These regions are noted in Figure 1.

Cytoarchitecture of STG. A number of studies havedescribed the cytoarchitecture of the STG. Early studiesdistinguished a central core of primary auditory cortexsurrounded by a belt of non–primary association corticesbased on cytoarchitectonic differences revealed by Nissland myelin stains (Pandya and Sanides, 1973; Galaburdaand Sanides, 1980; Galaburda and Pandya, 1983; Cipol-loni and Pandya, 1989). This core and belt organizationhas recently been updated by several groups (Morel et al.,1993; Jones et al., 1995; Kosaki et al., 1997) and mostrecently by Hackett et al. (1998). These studies haveestablished new criteria by which to view the primaryauditory cortex and its surrounding belt regions. AI iseasily distinguished by its intense parvalbumin stainingin layer IV and its appearance in Nissl stains where abroad layer IV, densely packed with small size granulecells, is apparent. A more rostral field R resembles AI inarchitecture and has been included as a primary auditorycortical field on the basis of its anatomical (Hackett et al.,1998) as well as electrophysiological (Rauschecker et al.,1997) characteristics. An additional core field, RT, hasbeen described lying just anterior to R (Hackett et al.,1998). The belt regions have a lighter pattern of parvalbu-min staining which is nonetheless distinct when comparedwith more lateral regions of the parabelt, which have faintparvalbumin staining. In Nissl sections of the lateral beltcortex, layer IV is smaller and less densely packed than AIand R, but more dense than adjacent parabelt regions.

It was not possible to distinguish among the physiologi-cal areas AL, ML, and CL on the lateral belt which havebeen physiologically identified by Rauschecker et al. (1995)by using cytoarchitectonic criteria. However, labeling inthe most rostral section of the lateral belt was attributed tothe AL region or the lateral rostrotemporal auditory belt(RTL) region, and labeling in the most caudal section wasattributed to CL. The ventral border of the parabelt wastaken as the beginning of the STS, area TAa. Labeling thatwas present in the dorsal bank of the STS was attributedto areas TAa and TPO (Seltzer and Pandya, 1989). Theseareas were charted because they may be possible sites ofauditory or multimodal input to the PFC (Bruce et al.,1981; Baylis et al., 1987) but were not distinguished on thebasis of cytoarchitecture. We used the cytoarchitectonicscheme of Hackett et al. (1998) for the core, belt, andparabelt regions. To describe the labeling in the anteriortemporal lobe, we relied on the terminology of Galaburdaand Pandya (1983) and have included the approximateboundaries for Pro, TS1, TS2, TS3, paAlt and Tpt on ourlateral brain schematic of the temporal lobe labeling(Fig. 1). Boundaries according to Hackett et al. (1998) aredelineated on the coronal sections, whereas the lateralbrain schematics are coded with shading to reveal core,belt, and parabelt regions according to Hackett et al.(1998) in the posterior two thirds of the STG (Figs. 3–9).

TABLE 1. Tracer Injections and Locations in the Prefrontal Cortex

Case Tracer AreaResulting

label

MR WGA-HRP Area 10 (dorsomedial) Belt and parabeltWI Diamidino yellow

Fluoro-rubyFast Blue

46dr, 46vr and 12 vlArea 328B

Belt and parabeltAnterior temporal lobeOther

HI WGA-HRP Areas 12, 13 orbital Belt and parabeltDF WGA-HRP Areas 24, 32 Belt and parabeltCA WGA-HRP Area 8a Belt and parabeltJA WGA-HRP 46v, 46vr, 46d and 46dr Belt and parabeltRO WGA-HRP Areas 12vl, 45, and 12

orbitalBelt and parabelt

MG WGA-HRP Area 10 Rostral parabeltOR WGA-HRP Area 9 Anterior temporal lobeKY WGA-HRP Area 9 Anterior temporal lobeTU WGA-HRP Area 45 OtherDH WGA-HRP Areas 11 and 13 (discon-

tinuous injection site)Other

SU WGA-HRP 46vr OtherDG WGA-HRP 46dr Other


Data analysis

Coronal sections though the temporal lobe were exam-ined for retrogradely labeled cells (WGA-HRP or fluores-cent tracers) and/or anterograde terminals (with WGA-HRP) under brightfield, darkfield, or fluorescenceillumination. For each case, anterograde terminals and/orretrogradely labeled cells from every tenth section (approxi-mately 400 µm apart), from the most rostral aspect of thetemporal pole to the end of the lateral sulcus were exam-ined. In these cases, sections with labeling in the STG werecharted every 800–1,200 microns and representative coro-nal sections are shown in Figures 3–10 along with compos-ite schematic drawings for each case.

In the WGA-HRP cases, the plotted TMB-reacted sec-tions were counterstained with thionin or cresyl violet toallow the identification of laminar borders. In the fluores-cent injection case, the laminar boundaries were plotted byusing the adjacent Nissl-, myelin-, and parvalbumin-stained sections. In all cases, the primary auditory corticalregion AI was identified by cytoarchitectonic criteria byusing Nissl or parvalbumin staining. Our identification of

AI included the additional primary field R. From thisboundary, the lateral and medial belt regions were identi-fied. The parabelt regions located on the ventral aspect ofthe STG were easiest to distinguish from the lateral beltregion by using parvalbumin-stained sections. The medialbelt, containing areas CM and RM, could easily be distin-guished from the primary cortical areas with Nissl orparvalbumin staining but was not subdivided. Recentanatomical studies have suggested the presence of arostral core area RT (Hackett et al., 1998), which was noteasily distinguished in our Nissl and parvalbumin sec-tions. It is included in our analysis along with the corre-sponding medial belt area RTM and the lateral belt region,RTL, proposed by Hackett et al. (1998) using geographiclocation. Because some cases used were taken from labora-tory archives that did not include a parvalbumin series ofthe superior temporal region, a standard lateral map of thesuperior temporal region (Fig. 1) based on parvalbuminand Nissl stains was used to portray the locations oflabeled cells in all cases. For each case, we identified AIand surrounding belt cortex by Nissl and/or parvalbu-

Fig. 2. Composite of injection sites (see also, Table 1). In the centerof the diagram, medial, lateral, and orbital schematics of the primateprefrontal cortex are shown with dark and light shaded injection siteson the cortical surface. Only the dark, striped, or stippled injectionsites resulted in labeling of the belt and parabelt auditory associationcortex and, therefore, are the focus of the present study. a–g: Surround-

ing the brain schematic are coronal sections through the rostral tocaudal extent of each corresponding darkly shaded injection site whichwas used in this study. The other injection sites that are shown in graywith case initials (see also Table 1) on the lateral, medial, and orbitalschematics did not result in extensive labeling of the auditory associa-tion cortex and are not shown in detail.


min stains, as described previously (Morel et al., 1993;Hackett et al., 1998) to normalize the data to this standardmap.

Injection sites in the PFC and the resultant labeling inthe temporal lobe were plotted by using the Neurolucidadigital plotting system with a Leitz Orthoplan or a ZeissAxioskop. Plotted coronal sections were imported fromNeurolucida into Canvas version 3.5 (graphics software byDeneba Systems, Inc.) in which the images could belabeled and oriented on the page. The locations of retro-gradely labeled cells in each coronal section were por-trayed on a drawing of the lateral surface of the brain togive a representative view of labeling in the entire superiortemporal region and the location of the injection sitewithin PFC for each case.

Photographic presentation

All figures with photomicrographs were prepared byscanning photographic negatives or color slides into AdobePhotoshop (Adobe Systems, Inc.) in which the image wascropped, enlarged, and oriented on the page. Image 10cand 10d were digitally captured directly from the coronalsection on a Zeiss Axiophot fitted with a Spot-2 camera. Allimages were imported into Adobe Illustrator or Canvasversion 5.0 in which they could be assembled as half- orfull-page plates and labeled appropriately. Gray scale andcolor prints were made on a Tektronics Phaser II. Cameralucida drawings, prepared with the Neurolucida digitalplotting system were imported into Canvas, labeled appro-priately, and printed in gray scale. As with normal photo-

Fig. 3. In case MR, an injection of WGA-HRP into the dorsomedialfrontal pole (area 10) was made. The injection site is portrayed at thetop left of the figure and is also shown in Figure 2f. In this case, theanterograde and retrograde labeling included the anterior temporallobe, the rostral parabelt, and the rostral edge of the rostral belt, areaRTL. On the lateral brain schematic at the top of each figure, theanterior temporal lobe is subdivided with boundary lines as in Figure1C, and the core and belt regions are color coded with shading toillustrate the boundaries of the core, belt, and parabelt regions as inFigure 1D. The location of retrogradely labeled cell clusters is por-trayed on the lateral brain schematic with small diamonds. Theresultant retrograde cell labeling (shown as small dots) and antero-

grade terminal labeling (shown as gray shading) has been charted oncoronal sections through the temporal lobe (A–F). The anteriortemporal lobe regions are labeled on the coronal sections by using theterminology of Galaburda and Pandya (1983), and the core and beltregions of the posterior two thirds of the superior temporal region arelabeled using the terminology of Hackett et al. (1998). Regions TAaand TPO on the dorsal bank of the sts (Seltzer and Pandya, 1989) arelabeled but were not distinguished on the basis of cytoarchitectureand, therefore, are not divided. In the coronal sections each dotrepresents one cell, whereas the gray shading covers the location of theanterograde columns and patches of terminals. For abbreviations, seelist.


graphic processing, uniform lighting, contrast, or bright-ness of the entire photograph could be modified but no datawere altered by using these electronic processes.

RESULTS

The resultant labeling in the STG attributable to injec-tions into prefrontal areas 8a, 8b, 9, 10, 11, 12 lateral, 12orbital, 13, 14, 24, 25, 32, 45, 46 dorsal, and 46 ventral wasexamined. A major finding in this study is the topographicnature of the connection between the PFC and the superiortemporal region. Our results indicate that injections thatincluded the rostral and orbital PFC (areas 10, 12, 13, and46 rostral) revealed connections with rostral belt andparabelt auditory cortex, whereas the caudal prefrontalregions (areas 8a, 12, and caudal 46) received projectionsfrom the caudal belt and parabelt. Some injections re-ceived afferents from both the anterior and posteriorauditory belt and parabelt. The results are presentedaccording to the region of the auditory association cortexthat was labeled as a result of the prefrontal injection. Theterminology of Hackett et al. (1998) has been used todescribe the belt and parabelt regions and is portrayed onthe coronal sections and is also portrayed as color coding

on the lateral brain schematics. The terminology of Gala-burda and Pandya (1983) will be used to describe theanterior temporal regions anterior to the belt and para-belt, which includes regions Pro, TS1, and TS2.

Rostral belt and parabelt

Frontal pole (area 10). Cases MR and MG (Table 1;Fig. 2f) had WGA-HRP injections localized to area 10. Bothcases resulted in labeled cells and terminals that werelocalized to the rostral two thirds of the STG, whichincluded portions of the rostral belt and parabelt. In caseMR, the injection included the dorsal-medial frontal poleand extended from the frontal pole caudally for about 2mm, remaining anterior to the rostral sulcus (Figs. 2f, 3).The injection site did intrude upon the white matter at themost rostral extent of the injection (Fig. 2f). In the superiortemporal region, retrogradely labeled cells were observedin the rostral belt, area RTL, and rostral parabelt regions(Figs. 3D, 10A). Retrogradely labeled cells were densest inthe rostral parabelt as well as area TS2 (Galaburda andPandya, 1983). Cells were confined to layers 3 and 5 withlayer 3 giving rise to most of the projections. Anterogradeterminals were heavy in TS2, and the rostral parabelt andappeared as columns which spanned all layers. Labeled

Fig. 4. In case WI, an injection of Diamidino Yellow into the rostralps (areas 46r, 46vr, 46dr) was made. The injection site is portrayed atthe top left of the figure and is also shown in Figure 2a. A–G: Theresultant retrograde cell labeling (shown as small dots) and antero-grade terminal labeling (shown as gray shading) has been charted oncoronal sections through the temporal lobe. The location of retro-gradely labeled cell clusters is summarized on the lateral brain

schematic of the temporal lobe with small diamonds. The anteriortemporal lobe areas TS1, TS2 (A,B) and the rostral parabelt (B–D)were lightly labeled in this case, whereas the dorsal bank of the STSwas more densely labeled (C–G). The terminology and labelingconventions are as described in Fig. 3 and 1D. For abbreviations, seelist.


cells and terminals were also sporadically noted in thecaudal half of the dorsal bank of the STS, area TPO (notshown).

Rostral principal sulcus. In case WI (Figs. 2a, 4), aninjection of Diamidino Yellow included the rostral half ofthe dorsal and ventral banks of the ps and resulted inlabeling that included the belt and parabelt auditoryassociation cortex. The injection covered the lips of theanterior ps, including areas 46r, 46dr, 46vr, and a smallportion of the rostral edge of area 12 vl (Fig. 2a) and did notpenetrate to the depths or fundus of the dorsal or ventralbank. The injection appeared to involve the white matterof the ventral bank of the ps (Fig. 2a) at the caudal edge ofthe injection site. Retrograde cellular labeling was presentsparsely in the anterior belt (area AL) and more densely inthe rostral parabelt regions (Fig. 4B–D). There were alsoclusters of labeled cells on the lateral surface of the rostralhalf of the STG in areas TS1, and TS2 as well as in thedorsal bank of the STS in areas TAa and TPO (Fig. 4E–G)

where dense retrograde cellular labeling was present inlayers 3 and 5 with some cells also in layer 6.

More caudal injections restricted to 46dr of the ps didnot label the belt and parabelt regions. In case DG (Table1; Fig.2, center), a small injection of the dorsal ps resultedin sparse labeling of the superior temporal region.

Lateral orbital cortex (areas 12 and 13). A WGA-HRP injection into the lateral orbital cortex (Figs. 2e, 5)labeled the rostral belt and parabelt regions (Fig. 5). Theinjection was focused on the lateral orbital cortex adjacentto the lateral orbital sulcus (Fig. 2e) and extended medi-ally at its caudal edge to involve area 13 but did notintrude upon the white matter. The retrograde labeling inthe temporal lobe appeared to involve the rostral beltregions RTL and AL (Fig. 5B–D). In addition, there wassome labeling medially within the inferior limiting sulcus,corresponding to anatomical regions Pro (Galaburda andPandya, 1983) and RTM (Hackett et al., 1998) (Fig. 4A,B)and some scattered cells located medially to R in the

Fig. 5. In case HI, an injection of WGA-HRP was made into thelateral orbital cortex (area 12o). The injection site is portrayed at thetop left of the figure and is also shown in Figure 2e. A–F: The resultantretrograde cell labeling (shown as small dots) and anterograde termi-nal labeling (shown as gray shading) has been charted on coronalsections through the temporal lobe. The location of retrogradely

labeled cell clusters is summarized on the lateral brain schematic ofthe temporal lobe with small diamonds. Labeling was largely confinedto the rostral belt and parabelt (B–E) as well as the anterior temporallobe (A,B). The terminology and labeling conventions are as describedin Figures 3 and 1D. For abbreviations, see list.


medial belt region RM. Labeling of the rostral parabeltwas more robust than the belt labeling. In addition to thebelt and parabelt, retrograde cellular labeling was alsointense in areas Pro, TS1, and TS2 (Galaburda andPandya, 1983) of the anterior temporal lobe. The retro-grade cells throughout the temporal lobe were, for themost part, confined to layers 3 and 5. Light anterogradelabeling was noted in all of the areas that had retrogradecells, including the rostral belt and parabelt regions aswell as Pro, TS1, and TS2 in the anterior temporal lobe(Galaburda and Pandya, 1983). The terminals were morecommonly found as patches in layers 1, 3, 4, and 6 ratherthan columns. Some cells and terminals were also presentin the dorsal bank of the STS at both rostral (Fig. 5B,C)and caudal (Fig. 5D–F) levels. These cells were localized tolayers 3, 5, and 6.

In contrast to the substantial labeling of the STG fromthis lateral orbital injection, a small injection of WGA-HRP placed more medially into areas 11 and 13 (shown onthe composite map in Fig. 2, case DH) produced very littleanterograde or retrograde labeling in the superior tempo-

ral region. Insular cortex and the fundus of the STS werelabeled by this more medially located injection but onlysparse labeling of the STG was observed.

Medial PFC. Both large and small injections (Table 1,cases DF and WI) were placed into the medial PFC. Theseinjections included areas 24 and 32, which had been shownin previous studies to label the STG (Barbas, 1992).However, our results indicate that this STG label isconfined to the rostral third of the STG and includes only asmall portion of the rostral parabelt and almost none of thebelt cortex of the auditory cortical system.

For example, an injection of WGA-HRP into areas 24and 32 (case DF) of the medial PFC just rostral to the genuof the corpus callosum (Figs. 2g, 6), resulted in densecellular labeling only in the rostral third of the STG. Theinjection site was quite dense through layers 1–6 but didnot appear to involve the white matter extensively. Theresultant temporal lobe labeling was heaviest in areas TS1and TS2 (Galaburda and Pandya, 1983) (Fig. 6A–E). Therostral edge of the rostral parabelt, as well as areas RTL,and the anterior medial belt region, RTM, were labeled.

Fig. 6. In case DF, an injection of WGA-HRP was made into areas24 and 32 of the medial prefrontal cortex. The injection site isportrayed at the top left of the figure and is also shown in figure 2g.A–G: The resultant retrograde cell labeling (shown as small dots) andanterograde terminal labeling (shown as gray shading) has beencharted on coronal sections through the temporal lobe. The location of

retrogradely labeled cell clusters is summarized on the lateral brainschematic of the temporal lobe with small diamonds. In this medialinjection, the labeling was restricted to the anterior temporal lobe(A–E) with only minimal involvement of the rostral belt and parabelt(D–F). The terminology and labeling conventions are as described inFigures 3 and 1D. For abbreviations, see list.


Labeled terminals were present in the same regions as theretrogradely labeled cells. In TS1, there was some sparsecolumnar terminal labeling; elsewhere the terminals wereconfined to layers 1 and 6. Area TAa on the dorsal bank ofthe STS also had several small patches of labeled cells inlayers 3, 5, and 6 (Fig. 6F,G).

Caudal belt and parabelt

Dorsal periarcuate cortex (area 8a). The WGA-HRP injection in case CA was placed caudal to the psbetween the dorsal and ventral limbs of the arcuate sulcus(Figs. 2c, 7, 10c), within the frontal eye fields. The injectionresulted in selective labeling of the STG of only the mostcaudal region, described by Galaburda and Pandya (1983),as Tpt and more recently as CL and CM (Rauschecker et

al., 1995, 1997; Hackett et al., 1998). The labeling includedcaudal parts of the lateral and medial belt and parabeltregions and the dorsal bank of the STS, which was heavilylabeled. There was a cluster of labeled cells on the supra-temporal plane in the caudal belt region CM (Figs. 7E,F,10B) behind primary auditory cortical region AI andscattered cells in the caudal parabelt (Fig. 7C–F). Theseretrogradely labeled cells were localized to layers 3, 5, and6, whereas the terminal labeling included both columnarand noncolumnar patches. A denser population of labeledcells and terminals were found in the caudal half of thedorsal bank of the STS, particularly in areas TAa, TPO,and in the fundus of the STS (Fig. 7C–F). Retrogradelylabeled cells were noted in layers 3, 5, and 6 and terminalsin layers 1 and 6 or as columns throughout all layers in theSTS.

Fig. 7. In case CA, area 8a was injected with WGA-HRP. Theinjection site is portrayed at the top left of the figure and is also shownin Figures 2c and 10c. A–F: The resultant retrograde cell labeling(shown as small dots) and anterograde terminal labeling (shown asgray shading) has been charted on coronal sections through thetemporal lobe. The location of retrogradely labeled cell clusters issummarized on the lateral brain schematic of the temporal lobe with

small diamonds. In this case, only the most caudal portion of the beltand parabelt had clusters of retrograde cells and anterograde termi-nals (C–F). Anterograde and retrograde labeling were denser in thecortex on the dorsal bank of the STS (B–F). The terminology andlabeling conventions are as described in Figures 3 and 1D. Forabbreviations, see list.


Both anterior and posterior belt and parabelt

Anterior and posterior principal sulcus (area 46).

A large WGA-HRP injection, case JA, included the lips anddepths of the dorsal and ventral banks of the ps, areas 46d,46 dr, 46v, and 46vr (Figs. 2b, 8). The dorsal bank was moreinvolved, especially at the rostral pole of the injection (Fig.2b). At the center of the injection site (Fig. 2b) the injectioninvolved the white matter in the dorsal bank of the ps,whereas in the ventral bank only the superficial layerswere consistently labeled. The anterior-posterior range ofthe injection extended through the entire middle third ofthe ps. The anterograde and retrograde labeling in the beltand parabelt regions resulting from this large injectionwas the most dense of any principalis injection. The areaslabeled included medial belt regions RTM, RM, CM,lateral belt regions RTL, AL, ML, CL, as well as anteriortemporal lobe regions TS1, TS2 (Galaburda and Pandya,1983), and the dorsal bank of the STS. The labeled cells

and terminals spanned the entire rostrocaudal length ofthe STG from dorsal to the ventral edge of the gyrus,bordered by the STS (Fig. 8). Labeling was densest in theparabelt but was significant in the middle and caudal halfof the lateral belt (Fig. 8C–E). The retrograde cells in thiscase were present in layers 3, 5, and 6. Anterogradeterminals were observed in layers 1 and 6 as patches or ascolumns that spanned all layers. Both types of termina-tions were found in all labeled regions. A small injection ofthe ventral bank of the caudal ps (Table 1; Fig. 2, center),case SU, did not result in labeling of the belt or parabeltauditory association cortex.

Inferior convexity (areas 12o and 12vl). The WGA-HRP injection in case RO (Figs. 2d, 9, 10D) included boththe cortex on the inferior convexity below the ps (area12 vl) and the lateral orbital cortex (area 12 orbital). Theinjection site was small in its anterior to posterior spreadbut did intrude on the white matter at its most caudal

Fig. 8. In case JA, a large injection of WGA-HRP was made into theps. The injection included not only the lips and cortex surrounding thesulcus (areas 46dr, 46vr) but the depths of the sulcus (areas 46d and46v) as well. The injection site is portrayed at the top left of the figureand is also shown in Figure 2b. A–F: The resultant retrograde celllabeling (shown as small dots) and anterograde terminal labeling(shown as gray shading) has been charted on coronal sections through

the temporal lobe. The location of retrogradely labeled cell clusters issummarized on the lateral brain schematic of the temporal lobe withsmall diamonds. There was dense labeling of the belt and parabeltespecially caudally (C–F). Additionally, the dorsal bank of the STS wasdensely labeled (A–F). The terminology and labeling conventions areas described in Figures 3, 1D. For abbreviations, see list.


aspect (Fig. 2d). This injection resulted in labeling of theSTG throughout its rostral to caudal extent and includedlateral and medial belt as well as parabelt regions. Thedensest retrograde cellular labeling of the STG occurred inthe rostral half of the STG (Fig. 9A,B) and spanned thedorsal to ventral aspect of the gyrus. The lateral belt(areas RTL, AL, ML, and CL) and the medial belt (areasRTM, RM, and CM) were labeled throughout their anteriorto posterior extent, although the parabelt labeling wasdenser, especially rostrally (Figs. 9B,C, 10E,F). The retro-gradely labeled cells were prominent in layers 3, 5, andoccasionally 6, of all areas labeled. Columns of anterogradeterminals which spanned all layers were common in theanterior temporal lobe and the rostral belt and parabelt.Medially, retrograde cells and terminals were present inthe infragranular layers of area pro (Galaburda andPandya, 1983), RTM, RM and CM (Fig. 9A–D). The dorsalbank of the STS, areas TAa and TPO, was densely labeled

from rostral to caudal extent (Fig. 9A–F), and labeled cellswere localized to layers 3, 5, and occasionally 6. Interest-ingly, there was a pattern to the terminal labeling suchthat the anterior temporal lobe regions displayed terminallabeling that was mostly columnar in appearance andaffected all layers, whereas caudally, near AI, the medialand lateral belt and parabelt, and the dorsal bank of theSTS had typical ‘‘feedback’’ terminal labeling (Fellemanand Van Essen, 1991), confined to layers 1 and 6.

Prefrontal injections which did not labelthe auditory belt and parabelt

Injections that were restricted to areas 8B (case WI), 9dorsomedial (cases OR and KY), and area 32 (case WI) aredescribed in Table 1 and shown in Figure 2 but did notlabel the auditory belt region. Most of these prefrontalinjections labeled only the most rostral edge of the rostral

Fig. 9. In case RO, a large injection of WGA-HRP included both theinferior convexity (area 12 vl) and the lateral orbital surface (12orbital). The injection site is portrayed at the top left of the figure andis also shown in Figures 2d, 10D. A–F: The resultant retrograde celllabeling (shown as small dots), and anterograde terminal labeling(shown as gray shading) has been charted on coronal sections throughthe temporal lobe. The location of retrogradely labeled cell clusters is

summarized on the lateral brain schematic of the temporal lobe withsmall diamonds. There was extensive labeling of the belt and parabeltas well as the anterior temporal lobe and the dorsal bank of the STS(A–F). The heaviest labeling is most apparent in the anterior temporallobe, rostral parabelt and rostral STS (A–C). The terminology andlabeling conventions are as described in Figures 3, 1D. For abbrevia-tions, see list.


Fig. 10. Photomicrographs of anterograde terminals and retro-gradely labeled cells in both anterior and posterior auditory associa-tion cortex and the corresponding WGA-HRP injection sites in theprefrontal cortex. A: Dense terminal and cellular labeling of the STG isshown in a coronal section (case MR) through the rostral parabelt as aresult of an injection of WGA-HRP into the frontal pole, area 10. Thelabeling was confined to the rostral belt and parabelt as well as theanterior temporal lobe. The cell and terminal clusters in A are presentin areas TS2 and RP. B: In contrast, the caudal belt and parabelt hadanterograde and retrograde labeling (arrowheads) in this coronalsection (case CA) as a result of a prefrontal injection (C) of WGA-HRPinto the periarcuate cortex, area 8a. C: A low-power photomicrographof the injection into area 8a. The dark injection site into the periarcu-

ate cortex is delimited by a dotted line. D: A low-power photomicro-graph of a coronal section in case RO where WGA-HRP has beeninjected into the inferior convexity of the frontal lobe. The darkinjection site is delimited by a dashed line and includes both 12 orbitaland 12 lateral. E: Parabelt and belt labeling in the temporal lobe as aresult of the injection into area 12 shown in D. A box is drawn aroundthe area shown in higher magnification in F. The arrow in E and Findicates a retrogradely labeled cell in the lateral belt auditoryassociation cortex. In this case, shown in detail in Figure 9, both theanterior and posterior belt and parabelt were labeled. The asterisksshown in E and F serve as a reference to depict the same region of Ethat has been magnified in F. For abbreviations, see list. Scale bar inA 5 800 µm in A–E, 200 µm in F.

parabelt but resulted in dense labeling anterior to theparabelt in areas Pro, TS1, and TS2 (Galaburda andPandya, 1983). Although previous results (Barbas, 1992;Carmichael and Price 1995) have shown that medialprefrontal regions are connected with the superior tempo-ral region, our results indicate that these regions do notextensively involve the auditory belt and parabelt associa-tion cortex. Although these frontal lobe areas did notreceive dense inputs from the earliest stages of auditoryassociation cortex, i.e., the belt and parabelt, they may stillplay a role in higher auditory function.

SUMMARY

Small injections into the rostral ps (Fig. 4) and thefrontal pole (Fig. 3) region both resulted in STG labelingthat included the rostral belt and parabelt. A largerinjection which was focused on the dorsal bank of the psand included the depths of the ps, areas 46d and 46v (Fig.8), resulted in extensive labeling of the rostral, medial, andlateral belt as well as the rostral parabelt region. Thisinjection also labeled the caudal belt and parabelt mostprobably due to inclusion of the caudal half of the ps withinthe injection site.

Two injections that included the lateral orbital cortexalso showed connections with the rostral belt and parabelt.One injection that was focused on area 12 orbital (Fig. 6)labeled the rostral and middle parabelt, lateral belt areasAL and RTL, and the rostral medial belt, whereas a largerinjection (Fig. 9) that included not only the lateral orbitalcortex but also the area 12 vl on the convexity resulted inmore extensive labeling of the belt and parabelt auditoryregions. In fact, the caudal belt and parabelt were lightlylabeled in addition to the dense rostral belt and parabeltlabeling possibly due to inclusion of area 12 vl. Thus, ourresults confirm Carmichael and Price’s (1995) delineationof the lateral orbital region as sensory/polymodal becauseof its connections with auditory association and superiortemporal polysensory cortex.

Injections of the caudal dosolateral PFC revealed connec-tions with the caudal belt and parabelt auditory cortex. Asmall injection of area 8a, which contains the frontal eyefields, resulted in dense labeling of the cortex of the STSbut selectively labeled the most caudal aspect of themedial and lateral belt (areas CM and CL) as well ascaudal parabelt. These results confirm prior reports (Bar-bas and Mesulam, 1981; Petrides and Pandya, 1988) thatshowed projections to the arcuate cortex from caudal STG.

Other areas of the frontal lobe including areas 24, 32,and areas 8B and 9 were reciprocally connected with theanterior third of the STG, including areas TS1, TS2, andsometimes, the rostral parabelt, however, the projectionsdid not include the medial or lateral belt cortex.

DISCUSSION

In this study, we searched for putative auditory process-ing regions in the frontal lobe by examining the innerva-tion of the PFC by auditory association cortex, as delin-eated by recent anatomical and physiological studies (Morelet al., 1993; Rauschecker et al., 1995, 1997; Kosaki et al.,1997; Hackett et al., 1998). We found several prefrontalloci that were reciprocally and topographically connectedto regions of the belt and parabelt auditory associationcortices. Specifically, the rostral and orbital areas of the

PFC are connected with rostral belt and parabelt, whereascaudal principalis and inferior convexity regions of thePFC are connected with the caudal belt and parabeltauditory association cortices (Fig. 11).

This rostrocaudal topography confirms the results ofearly connectional studies (Pandya and Kuypers, 1969;Jones and Powell, 1970; Chavis and Pandya, 1976; Petridesand Pandya, 1988; Barbas, 1992). In the earliest of theseconnectional studies, lesion/degeneration techniques re-vealed projections from the caudal STG to the periprinci-palis, periarcuate, and inferior convexity regions of thefrontal lobe and from the middle and rostral STG to rostralprincipalis and orbital regions (Pandya et al., 1969; Pan-dya and Kuypers, 1969; Jones and Powell, 1970; Chavisand Pandya, 1976). However, these studies focused on thegeneral connections of the STG with the frontal lobe andwere not able to provide detailed topographical connec-tions as can be done with tract tracing.

With the advent of tract tracing with HRP, more investi-gators turned toward the question of temporofrontal con-nections, supporting previous claims and revealing furtherspecificity. Studies of the periprincipalis and arcuate re-gion showed that the anterior and middle aspects of the ps,including areas 9, 10, and 46, were connected with themiddle and caudal STG (Barbas and Mesulam, 1985;Petrides and Pandya, 1988), whereas area 8 receivesprojections from mostly caudal STG (Barbas and Mesu-lam, 1981; Petrides and Pandya, 1988). Interestingly,denser retrograde labeling of the caudal and middle STGappeared to have occurred in the cases in which the depthsof the dorsal bank of the ps is included in the injection areaas opposed to only the lips of the ps. This was exactly thefinding in the present study as shown in Figures 4 and 8,where more labeling of the STG occurred when the depthof the ps (areas 46d and 46v) was injected as opposed toonly the lips (areas 46dr and 46vr). Further refinement oftemporofrontal connections was evident in later studies

Fig. 11. Summary of prefrontal connections with the belt andparabelt auditory association cortex. Caudal belt and parabelt audi-tory association cortex (shown with dark circles) are reciprocallyconnected to the caudal ps, dorsal periarcuate, and the inferiorconvexity in the frontal lobe (labeled with similar dark circles),whereas rostral belt and parabelt regions (gray squares) project to thefrontal pole, rostral principal sulcus, lateral orbital cortex, and theinferior convexity (shown with gray squares). The contribution fromthe parabelt (shown with larger circles and squares) is greater thanthat of the belt (shown with smaller symbols) for both rostral andcaudal auditory streams. In addition, the anterior temporal lobe(white triangles) has widespread connections with the rostral, orbital,and medial (not shown) prefrontal cortex.


that used the core and belt cytoarchitectural model of theSTG (Pandya and Sanides, 1973; Galaburda and Pandya,1983; Cipolloni and Pandya, 1989). Latter studies con-firmed the connection of the posterior STG with areas 46,dorsal area 8, and the middle STG with rostral-dorsal 46and 10, area 9, and area 12 (Petrides and Pandya, 1988;Barbas, 1992). Furthermore, the connections of the orbitaland medial prefrontal cortices with the anterior temporallobe and temporal polar regions were reinforced in thesetracing studies (Petrides and Pandya, 1988; Barbas, 1993;Carmichael and Price, 1995). Although cytoarchitectoniccriteria could distinguish between areas on the STG, littlewas known about the electrophysiological responses andthe sequential relationships of auditory association areas.Previous tracing studies did not rely on distinctions be-tween lateral and medial portions of the STG, now knownas the lateral and medial belt, or between dorsal andventral aspects of the STG that have been partitioned intothe belt and parabelt by recent electrophysiological andanatomical studies (Rauschecker et al., 1995; Hackett etal., 1998). It is this anatomical and electrophysiologicalmapping of relationships within the auditory corticalsystem that has allowed us to construct the hierarchicalsequence that auditory information may follow in highercognitive functions.

Cascades of hierarchical connections

Our present results have shown that prefrontal areasreceive projections from the lateral belt auditory region,which has been electrophysiologically characterized asacoustically responsive by several groups (Morel et al.,1993; Rauschecker et al., 1995, 1997; Kosaki et al., 1997)and the medial belt and parabelt cortex and that theseprojections obey a rostral-caudal topography. Moreover,our results, as well as those of others (Hackett et al., 1997),indicate that the PFC receives its strongest projectionsfrom the parabelt. In addition to the projections from thebelt and parabelt, the anterior third of the temporal lobe isalso connected with anterior, medial, and orbital prefron-tal areas, whereas the dorsal bank of the STS (Figs. 3–10)projects to dorso- and ventrolateral PFC. Both projectionsare among the heaviest observed in the present study.These results, together with previous studies suggest asequence of hierarchical auditory connections. Primaryregions, AI and R, project to the lateral and medial beltregions (Morel et al., 1993; Hackett et al., 1998). It is herewithin the auditory belt that two auditory streams diverge(Kosaki et al., 1997; Rauschecker et al., 1997) with therostral belt regions, RTL, AL, and ML, sending smallprojections to the anterior and orbital PFC and a denseprojection to the rostral auditory parabelt (area RP)(Romanski et al., 1997b; Hackett et al., 1998). The rostralparabelt sends a somewhat larger projection to the frontallobe and has further connections with the dorsal bank ofthe STS and the anterior temporal lobe (Romanski et al.,1997b; Hackett et al., 1997b, 1998). The STS and theanterior temporal lobe project to the frontal lobe and otherassociation cortices (Chavis and Pandya, 1976; Petridesand Pandya, 1988; Seltzer and Pandya, 1989). The otherauditory stream that begins in the middle and caudal belt(areas ML, CL, and CM) projects to the dorsal arcuateregion, caudal principalis, and the ventrolateral PFC butmay also have an intermediate relay in the posteriorparietal cortex, which is densely connected with the caudalPFC (Cavada and Goldman-Rakic, 1989).

Thus, a cascade of auditory afferents from two divergentstreams targets the PFC. Small streams enter the frontallobe from early auditory processing stations such as thelateral and medial belt and successively larger projectionsoriginating in the parabelt, anterior temporal lobe, and thedorsal bank of the STS join the flow of auditory informa-tion destined for the frontal lobe. The flow of visualinformation is known to follow a similar cascading patternwith area TEO, sending a restricted input to the frontallobe and to the more rostrally located area TE, whichprovides a more widespread input to the PFC than areaTEO (Webster et al., 1994).

The role of multiple streams of auditory projections tothe frontal lobe is unknown. A cascade of inputs fromincreasingly more complex auditory association cortexmay be necessary to represent all qualities of a complexauditory stimulus. First, crudely processed informationcomposed of mainly temporal- and frequency-related infor-mation from early unimodal belt association cortex mayarrive at specific prefrontal targets, whereas complexacoustic information from increasingly higher associativeauditory areas may follow. This process allows for a richrepresentation of complex auditory stimuli to reach thePFC in an efficient manner. Cascades of auditory afferentssuch as that suggested here, from increasingly higherregions of the auditory cortical hierarchy, have been shownto occur in the corticoamygdaloid pathway of the monkey(Turner et al., 1980) and rat (Romanski and LeDoux,1993).

Functional significance

As mentioned above, our data and previous studiessuggest a rostral-caudal topography to the temporofrontalprojections originating in the auditory belt and parabelt.The topography observed is not strict, and there are someareas that may receive convergent information from bothrostral and caudal auditory processing areas. For example,the lateral orbital and inferior convexity regions showedevidence of connections with anterior, middle, and poste-rior belt and parabelt regions. However, because theanterior and posterior auditory belt and parabelt regionsshow distinct local connections (Hackett et al., 1998) andelectrophysiological response profiles (Rauschecker et al.,1995; Tian and Rauschecker, 1995) and have some sepa-rate targets in the PFC, there is the suggestion of diver-gent auditory streams targeting the frontal lobe. Thepossibility of parallel auditory streams, derived from stud-ies of visual hierarchical processing (Ungerleider andMishkin, 1982), suggests a divergence in the function ofthese two auditory pathways and the prefrontal domainsthat they target.

Previous electrophysiological studies support a role forcaudal PFC in auditory spatial processing. For example,several studies have found neurons responsive to auditorystimuli in the periarcuate region (Ito, 1982; Azuma andSuzuki, 1984; Suzuki, 1985; Vaadia et al., 1986), andlesions of the periarcuate cortex have been shown toimpair auditory discrimination in primates (Gross andWeiskrantz, 1962; Petrides, 1986). Furthermore, it hasbeen demonstrated that neurons in the periarcuate regionthat respond to auditory stimuli are affected by thelocation of the sound source (Azuma and Suzuki, 1984;Russo and Bruce, 1989) and that the auditory responses ofthese neurons are affected by changes in gaze (Russo andBruce, 1989), which is to be expected in light of the role of


the frontal eye field in saccadic eye movements to salienttargets. Vaadia et al. (1986) has noted the increasedresponsivity of neurons in the periarcuate region whennonhuman primates were engaged in an auditory localiza-tion task compared with a passive listening task. Theseobservations of caudal prefrontal auditory spatial functionis complemented by the observation that neurons in thecaudal belt region that project to the dorsal periarcuateregion are sensitive to the location of auditory stimuli(Leinonen et al., 1980; Benson et al., 1981). In addition, theneurons of the caudal belt region display broad frequencytuning (Rauschecker et al., 1997), which is an advanta-geous characteristic for an area involved in localization ofsound (Makous and Middlebrooks, 1990). Thus, the caudalprincipalis and periarcuate region may be the targets of adorsal, auditory-spatial processing stream, originating inthe caudal belt and parabelt, to parallel the dorsal visuo-spatial stream which terminates in the periarcuate PFC(Wilson et al., 1993).

Although there have been few extensive studies ofauditory responses in rostral and orbital prefrontal re-gions in the macaque, responses to acoustic stimuli havebeen sporadically noted in the principalis, lateral orbital,and inferior convexity regions of Old and New Worldmonkeys (Newman and Lindsley, 1976; Benevento et al.,1977; Wolberg and Sela, 1980; Watanabe, 1992; Tanila etal., 1992, 1993; Bodner et al., 1996). Many of these studiesagree that salient environmental stimuli, and in particu-lar, vocalizations, are most effective in driving prefrontalneurons (Newman and Lindsley, 1976; Tanila et al., 1992).In accordance with this notion, the rostral belt region AL,which projects to rostral and orbital prefrontal corticalregions, has been shown to be selectively responsive tomonkey vocalizations and low FM sweeps, in the speechrange (Tian and Rauschecker, 1995; Tian et al., 1997).Hence, projections to the rostral and orbital PFC fromrostral belt and parabelt auditory cortex may be part of aventral auditory stream involved in some aspect of pho-netic processing in the macaque and in language process-ing in humans. Evidence for a prefrontal ventral stream orlanguage processing region located in the lateral PFC isabundant in human imaging and clinical neuropsychologi-cal studies. The inferior frontal gyrus is consistently activein studies of semantic encoding, word retrieval, and audi-tory attention, as studied with functional magnetic reso-nance imaging (Demb et al.,1995; Braver et al., 1997;Gabrieli et al., 1998) positron emission tomography(Petrides et al., 1995), and event-related potentials (Chaoand Knight, 1996).

Our evidence further supports the notion of domain-specific processing in the frontal lobe (Goldman-Rakic,1987, 1998). It has been shown previously that neuronswith object-related visual responses are found in theinferior convexity of the frontal lobe, whereas visuospatialprocesses can be localized to the caudal ps and frontal eyefields (Goldman-Rakic, 1987; Wilson et al., 1993). Theinferior convexity object region receives afferents fromventral stream, object/feature processing regions of theinferotemporal cortex (Webster et al., 1994), whereas thecaudal principalis and frontal eye fields receive a denseprojection from dorsal stream posterior parietal regions(Cavada and Goldman-Rakic, 1989) involved in visuospa-tial processing. Our evidence from the present studysuggests that divergent streams of auditory informationtarget separate prefrontal regions in the frontal lobe with

presumably different functions. Further studies are neededto decipher the distinct functions of these separate audi-tory targets in the frontal lobe.

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auditory belt and parabelt projections to the prefrontal cortex in the rhesus monkey

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