THEJOURNALOFCOMPARATIVENEUROLOGY441:197–222(2001)

ArchitectonicIdentificationoftheCore RegioninAuditoryCortexofMacaques, Chimpanzees,andHumans

TROYA.HACKETT,1,3* TODDM.PREUSS,2 ANDJONH.KAAS3 1DepartmentofHearingandSpeechSciences,VanderbiltUniversity, Nashville,Tennessee37203 2CognitiveEvolutionGroup,UniversityofLouisianaatLafayette, NewIberia,Louisiana70560 3DepartmentofPsychology,VanderbiltUniversity,Nashville,Tennessee37203

ABSTRACT Thegoalofthepresentstudywastodeterminewhetherthearchitectoniccriteriausedto identifythecoreregioninmacaquemonkeys(Macacamulatta,M.nemestrina)couldbeusedto identifyahomologousregioninchimpanzees(Pantroglodytes)andhumans(Homosapiens). Currentmodelsofauditorycorticalorganizationinprimatesdescribeacentrallylocatedcore regioncontainingtwoorthreesubdivisionsincludingtheprimaryauditoryarea(AI),asurround- ingbeltofcortexwithperhapssevendivisions,andalateralparabeltregioncomprisedofatleast twofields.Inmonkeysthecoreregioncanbeidentifiedonthebasisofspecificanatomicaland physiologicalfeatures.Inthisstudy,thecorewasidentifiedfromserialsetsofadjacentsections processedforcytoarchitecture,myeloarchitecture,acetylcholinesterase,andcytochromeoxidase. Qualitativeandquantitativecriteriawereusedtoidentifythebordersofthecoreregionin individualsections.Serialreconstructionsofeachbrainweremadeshowingthelocationofthe corewithrespecttogrossanatomicallandmarks.Thepositionofthecorewithrespecttomajor sulciandgyriinthesuperiortemporalregionvariedmostinthechimpanzeeandhuman specimens.Althoughthearchitectonicappearanceofthecoreareasdidvaryincertainrespects acrosstaxonomicgroups,thenumeroussimilaritiesmadeitpossibletoidentifyunambiguously ahomologouscorticalregioninmacaques,chimpanzees,andhumans.J.Comp.Neurol.441: 197–222,2001. ©2001Wiley-Liss,Inc.

Indexingterms:comparative;primate;neuroanatomy;neurolinguistics;;imaging; evolution;acetylcholinesterase;myelin

Thesearchforcorticalregionsthatarelargelyorwholly animalstohumansisespeciallyproblematicbecauseex- devotedtoauditoryprocessinghasbeenthesubjectof perimentalconstraintslimitdirectcomparisonsbetween numerousinvestigationsforover125years,leadingtothe species.Oneconsequenceisthatbothbodiesofknowledge identificationofmultipleauditorycorticalfieldsinmost expand,butlittleconnectionismadebetweenthem.As mammalsstudied.Thenumberoffieldsidentifiedranges from1(inmarsupials)toover12(inprimates).Incats,a singleprimaryauditoryfield(AI)issurroundedbyseveral nonprimaryauditoryfields.Inmonkeystwoorthreepri- GrantSponsor:NationalInstitutesofHealth,NIDCDgrantsDC00249 maryfields,includingAI,areenvelopedbyaneven andDC04318;Grantsponsor:theMcDonnell-PewPrograminCognitive greaternumberofnonprimaryfields(forreviews,see Neuroscience;Grantnumber:JSMF98-45;Grantsponsor:theJamesS. McDonnellFoundation;Grantnumber:JSMF20002029;Grantsponsor: WoolseyandWalzl,1982;BruggeandReale,1985;Aitkin, NINDS;Grantnumber:NS16446;Grantsponsor:theNationalInstituteon 1990;Schreiner,1992,1998;Ehret,1997;deRibaupierre, Aging;Grantnumber:NS1P30AG-13854-01. 1997;Rouiller,1997;Kaasetal.,1999;KaasandHackett, *Correspondenceto:TroyA.Hackett,Ph.D.,VanderbiltUniversity,301 st 2000).Currently,onlythehomologyofAIhasbeenwell WilsonHall,11121 AvenueSouth,Nashville,TN37203. E-mail:[email protected] establishedacrossmajortaxonomicgroups.Thus,theex- Received9March2001;Revised17July2001;Accepted17September tenttowhichfindingsinonespeciescanbegeneralizedto 2001 anotherisuncertain.Extendingfindingsfromresearch PublishedonlinetheweekofNovember12,2001

©2001WILEY-LISS,INC. DOI10.1002/cne.1407 198 T. HACKETT ET AL

Fig. 1. Schematic view of the macaque left hemisphere showing region (RP, CP; no shading) occupies the exposed surface of the the location and intrinsic connections of . The dorsal superior temporal (STG). The core fields project to surrounding bank of the lateral has been removed (cut) to expose the belt areas (arrows). Inputs to the parabelt arise from the lateral and superior temporal plane (LS ventral bank). The floor and outer bank medial belt subdivisions. Connections between the parabelt and me- of the circular sulcus (CiS) have been flattened to show the medial dial belt fields are not illustrated to improve clarity. Tonotopic gradi- auditory fields. The core region (dark shading) contains three subdi- ents in the core and lateral belt fields are indicated by the letters H visions (AI, R, RT). In the belt region (light shading) seven subdivi- (high frequency) and L (low frequency). For abbreviations, see list. sions are proposed (CM, CL, ML, AL, RTL, RTM, RM). The parabelt

this trend continues, the need for studies that attempt to link these findings also grows. Toward this end, we have initiated comparative architectonic studies of auditory Abbreviations cortex in macaque monkeys, chimpanzees, and . Our goal is to identify features of auditory cortical orga- AChE acetylcholinesterase AI auditory area I (core) nization that are common, and unique, to each taxonomic AL anterior lateral auditory belt group. AS arcuate sulcus In recent years we have developed a model of auditory ASC caudal CiS circular sulcus cortical organization in nonhuman primates based on a CL caudolateral auditory belt wide range of anatomical and physiological findings CM caudomedial auditory belt (Hackett et al., 1998a; Kaas et al., 1999; Kaas and Hack- CPB caudal parabelt ett, 2000). According to the model, primate auditory cortex CS circular sulcus CSHG Heschl’s gyrus consists of three major regions containing as many as 12 HG1 first (anterior) gyrus of Heschl different fields (Fig. 1). Two or three cochleotopically or- HG2 second (posterior) gyrus of Heschl ganized primary or primary-like auditory areas (AI, R, HSa Heschl’s sulcus (anterior) RT) with independent parallel inputs from the ventral HSp Heschl’s sulcus (posterior) IPS division of the medial geniculate complex (MGv) comprise LS the core region at a first level of processing. The core fields LuS are surrounded by a belt region of possibly seven fields LuSMF myelinated fibers (CL, CM, RM, RTM, RTL, AL, ML) at a second level of ML middle lateral auditory belt N Nissl substance processing, with major inputs from the core and the dorsal PS principal sulcus division of the medial geniculate complex (MGd). Co- R rostral area (core) chleotopic organization is preserved in at least some of the RM rostromedial auditory belt belt fields (Rauschecker et al., 1995; Kosaki et al., 1997). RMRPB rostral parabelt RT rostrotemporal area (core) The belt region is bordered laterally on the superior tem- RTL rostrotemporolateral auditory belt poral gyrus by a parabelt region of two or more divisions RTM rostrotemporomedial auditory belt (CP, RP) that are activated by inputs from the belt areas RTLRTMSI sulcus intermedius and the MGd, but not MGv or the core. Neurons in the belt STG STS and parabelt project to auditory-related fields in the tem- TTG transverse temporal gyrus (of Heschl) poral, parietal, and frontal lobes. Experimental evidence IDENTIFICATION OF THE AUDITORY CORE 199 supporting this model is derived from numerous studies of TABLE 1. Histologic Treatment of Macaque, Chimpanzee, and monkeys and chimpanzees (Campbell, 1905; Beck, 1929; Specimens1 Walker, 1937; von Bonin, 1938; Ades and Felder, 1942; Postmortem Plane of Bailey et al., 1943; Walzl and Woolsey, 1943; Walzl, 1947; Case Fixation procedure delay section von Bonin and Bailey, 1947; Bailey et al., 1950; Akert et M1–M4 P 4% PBPF 0 Off-coronal A al., 1959; Merzenich and Brugge, 1973; Jones and Burton, M5–M6 P 4% PBPF 0 Coronal Ch1 I 4% PBPF Ͻ12 hr Off-coronal A 1976; Imig et al., 1977; Fitzpatrick and Imig, 1980; Gala- Ch2 P 4% PBPF ϩ 0.1% GA 0 Off-coronal A burda and Pandya, 1983; Aitkin et al., 1988; Luethke et Ch3 P 10% formalin 20 min Off-coronal A Ch4 I 10% formalin 12 hr Off-coronal A al., 1989; Morel and Kaas, 1992; Morel et al., 1993; Jones Hu1 I 4% PBPF 6 hr Off-coronal A et al., 1995; Kosaki et al., 1997; Rauschecker et al., 1997; Hu2 I 2% PBPF Ͻ24 hr Off-coronal A Hackett et al., 1998a,b; Recanzone et al., 2000). Hu3 I 2% PBPF 23 hr Off-coronal B Extension of this model to human auditory cortex can be 1M, macaque; Ch, chimpanzee, Hu, human; P, perfusion; I, immersion; PBPF, done in a limited way by comparing anatomical features. phosphate-buffered paraformaldehyde; GA, glutaraldehyde; off-coronal A, perpendicu- lar to the superior temporal plane and midline; off-coronal B, perpendicular to the Detailed architectonic parcellations of the human audi- superior temporal plane and long axis of the first transverse temporal gyrus. All cortical tory cortex have appeared regularly for nearly a century blocks are left hemisphere. (Campbell, 1905; Brodmann, 1909; Vogt and Vogt, 1919; Flechsig, 1920; von Economo and Koskinas, 1925; Beck, 1928; von Economo, 1929; von Economo and Horn, 1930; Poljak, 1932; Hopf, 1954; Blinkov, 1955; Braak, 1978; tify the core region in monkeys could be used to identify a Galaburda and Sanides, 1980; Seldon 1981a,b, 1982; Ong homologous region in chimpanzees and humans. A prelim- and Garey, 1990; Rademacher et al., 1993; Rivier and inary report of these findings was previously published in Clarke, 1997; Clarke and Rivier, 1998; Morosan et al., abstract form (Hackett et al., 1998c). 2001). Although these parcellations differ from one an- other in many respects, including nomenclature, common MATERIALS AND METHODS features include a centrally located region with anatomi- cal features typical of primary sensory cortex (e.g., konio- Tissue specimens cortical cytoarchitecture, dense myelination) surrounded The of six macaque monkeys (three Macaca mu- by a variable number of nonprimary fields with distinctive latta and three M. nemestrina), four chimpanzees (Pan architectonic features. These findings suggest that the troglodytes), and three humans (Homo sapiens) were ob- basic organizational scheme proposed for monkeys (i.e., tained post mortem for use in these studies. Of the ma- core, belt) may also apply to humans. caque brains, four were included in previous experiments An important observation with relevance to the issue of of auditory cortex in which the auditory core had been homology is that the core, belt, and parabelt regions in identified by microelectrode mapping and/or tracer injec- macaques can be reliably identified on the basis of their tions (Morel et al., 1993; Hackett et al., 1998a); thus, structural architectonic features (e.g., cytoarchitecture, nonarchitectonic verification of the boundaries of the core myeloarchitecture). In addition, various molecules (e.g., region was available for these cases only. Chimpanzee cytochrome oxidase, acetylcholinesterase, parvalbumin) brains were obtained from the New Iberia Research Cen- are expressed at higher levels in the core than in the ter (New Iberia, LA) and the Yerkes Regional Primate surrounding belt areas (Wallace et al., 1991; Morel et al., Center (Atlanta, GA). All animals died of natural causes 1993; Jones et al., 1995; Hutsler and Gazzaniga, 1996; or were euthanized for veterinary reasons. Chimpanzees Rivier and Clarke, 1997; Hackett et al., 1998a; Clarke and were adult males, age range 20–33 years (estimated), and Rivier,1998). Cytochrome oxidase, involved in the oxida- presumed wild-caught. One (Hu1) was ob- tive metabolism of cells, exhibits patterned expression tained from the Vanderbilt University Medical Center reflecting the modular organization of primary sensory Department of Pathology from an adult male (45 years) cortices (Wong-Riley, 1989) and is also related to the neu- who died of non-Hodgkin’s type lymphoma. The other two rovascular events measured in functional imaging studies human brains were normal controls provided to the Uni- (Wobst et al., 2001). Acetylcholinesterase is linked to cho- versity of Louisiana at Lafayette by the Northwestern linergic activity in cortex (Mesulam and Geula, 1992) and Alzheimer’s Disease Center. The present analyses were is well known to modulate neuronal activity in primary limited to the left ; thus hemispheric differ- auditory cortex (Edeline, 1999). The role of the calcium ences were not addressed. binding protein parvalbumin is less clear, but it has been associated with distinct subpopulations of ␥-aminobutyric Histological processing acid (GABA)ergic neurons in sensory cortex (van Bred- All macaque monkey brains were perfused transcardi- erode et al., 1990) and is expressed at high levels in ally immediately after death. Perfusates consisted of the primary thalamocortical pathways to auditory cortex (Mo- following solutions delivered in succession: 500 ml linari et al., 1995; Hackett et al., 1998b). The coexpression phosphate-buffered saline (pH 7.4, room temperature); of these molecules at high levels in the core suggests they 500 ml 4% paraformaldehyde dissolved in 0.1 M phos- may be used as markers of this region and adds support to phate buffer (4°C, pH 7.4); and 500 ml 4% paraformalde- the theory that the core is a functionally distinct region of hyde ϩ 10% sucrose in 0.1 M phosphate buffer (4°C, pH auditory cortex. Furthermore, comparative studies of the 7.4; Table 1). Immediately after perfusion the brains were architecture could reveal similarities and differences removed, separated from the thalamus and brainstem, across taxonomic groups relevant to the organization and and cut into blocks. The blocks containing the temporal evolution of auditory cortex in primates. lobe were immersed in 30% sucrose in 0.1 M phosphate The purpose of the present study was to determine buffer (4°C, pH 7.4) overnight and then cut in a coronal or whether the architectonic criteria currently used to iden- semicoronal plane (Off-coronal type A, perpendicular to 200 T. HACKETT ET AL

Fig. 2. Dorsolateral views of the superior temporal plane. (second gyrus of Heschl). In human case Hu2 (F), only one HG is A,B: Macaque cases M1 and M3. C,D: Chimpanzee cases Ch1 and present. Solid white lines indicate plane of section. Dashed straight Ch4. E,F: Human cases Hu1 and Hu2. Single asterisks denote loca- white lines designate sulcal landmarks. a, anterior; m, medial. For tion of HG1 (first gyrus of Heschl). Double asterisk in E denotes HG2 other abbreviations, see list. Scale bars ϭ 5 mm. superior temporal plane and midline) at 40 or 50 ␮mona verse temporal gyrus of Heschl (Off-coronal B). Series of freezing microtome (Fig. 2). Chimpanzee brains were per- adjacent sections were processed for 1) anatomical tracers fused at variable postmortem delays ranging from zero (macaque experimental cases only); 2) acetylcholinester- minutes (Ch2) to 20 minutes (Ch3) or fixed by immersion ase (Geneser-Jensen and Blackstad, 1971); 3) myelin (Gal- after a postmortem delay of up to 12 hours (Table 1). lyas, 1979); or 4) staining for Nissl substance with thionin. Human brains were obtained at postmortem delays rang- In most brains, three additional series were reserved for ing from 6 to 23 hours and were not perfused. These additional reactions that were not included in the present specimens were fixed by immersion for 24–48 hours (4°C), analyses. Sections were mounted on glass slides and cov- as indicated in Table 1 and then cut into blocks. Temporal erslipped. lobe blocks were sunk in 30% sucrose (4°C) and then cut Architectonic analyses were conducted in sections on a freezing microtome. Chimpanzee and two human stained for Nissl substance (N), myelinated fibers (MF), cases (Hu1 and Hu2) were cut at 50 ␮m in a plane per- and acetylcholinesterase (AChE). The staining quality of pendicular to the superior temporal plane and long axis of the N, MF, and AChE was not noticeably degraded by the circular sulcus (Off-coronal A), as indicated in Figure postmortem delays to fixation of up to 23 hours. An excep- 2. One human case (Hu3) was cut perpendicular to the tion was case Hu2, which was immersed in formalin for an superior temporal plane and long axis of the first trans- unknown period of less than 24 hours (Table 1). Compared IDENTIFICATION OF THE AUDITORY CORE 201 with cases Hu1 and Hu3, which were fixed at 6 and 23 mean of profiles 7–11. This procedure was repeated until hours postmortem, respectively, Hu2 exhibited weakened the last profile was reached (e.g., Fig 3D, profile 41). The neuropil staining of AChE. AChE staining of cell soma two arithmetic differences with the greatest absolute was comparable in the three cases. The normal appear- value were considered to represent the lateral and medial ance of AChE expression in case Hu3 suggests that histo- boundaries of the most intensely stained region, corre- logical factors account for the weak neuropil staining in sponding to the core. In Figure 3D, this simple procedure case Hu2. identified borders between profiles 12 and 13 (lateral), and 29 and 30 (medial). The data were then imported into a Data analysis MATLAB routine (MathWorks, Natick, MA) for subse- Individual sections were studied at magnifications quent analyses. Relative gray level densities of each pro- ranging from 1.25 to 200ϫ on three microscopes: Nikon file were plotted as a function of percentage distance from E800S, Zeiss Axioscope 20, and Olympus BH-2. Borders the pial surface for inspection of laminar trends (Fig. between the core and belt were independently identified 3E–H). Compared with the actual distance (e.g., pixels or and marked on individual slides for matched sets of sec- micron-equivalents), plotting the density values as a func- tions stained for N, MF, and AChE. Sections in which a tion of percentage distance from the surface resulted in border(s) could not be identified were not marked. For better alignment of laminar peaks between samples be- stack reconstructions (Figs. 11–13), grayscale images of cause variability in cortical thickness altered absolute individual AChE sections (1.25ϫ, 300 dpi) were obtained laminar relationships. Individual profiles were detrended with a Leaf Systems Lumina scanning digital camera by a linear regression, and then a cross-correlation matrix (Southborough, MA) mounted on a Nikon E800M micro- was computed from these values among all profiles in the scope and Adobe Photoshop 5.0 software (Adobe Systems, section. Correlation coefficients were grouped into clusters San Jose, CA). The images were adjusted uniformly for of high and low coefficients by an arbitrary criterion (e.g., brightness (10%) and contrast (5%) and then printed. Bor- 0.65). Groups of profiles were related to predefined archi- ders in adjacent sections were marked on the printed tectonic borders (Fig. 3C, arrows). AChE sections with reference to blood vessels, lesions, and surface landmarks by using a drawing tube affixed to the microscope. In most sections, the deviations in border RESULTS location assessed independently using N, MF, and AChE were within 100 to 400 ␮m. Deviations exceeding 400 ␮m Gross anatomical features of the superior were uncommon, but in some sections ambiguous features temporal plane or histological imperfections prohibited precise border In each of our macaque, chimpanzee, and human cases identification. These sections were excluded from the the auditory core region was confined to the supratempo- analysis. The location of final borders represented a visual ral plane on the dorsal surface of the temporal lobe, hid- average of the three preparations. The marked AChE den from view by the overlying frontoparietal images were imported into Adobe Illustrator 7.0 and ar- (Fig. 2A,B). In macaques there was no transverse tempo- ranged in stacks, roughly perpendicular to the long axis of ral gyrus of Heschl (HG), and only gross anatomical fea- the core region. An outline of the core was made by a tures (e.g., vascular patterns, slight elevations or depres- dashed line connecting the border markers (Figs. 11–13). sion) sometimes coincided with the location of the core Densitometric measurements of region. The core was elongated along the rostrocaudal axis of the temporal lobe in both species of macaque monkeys AChE expression (M. mulatta, M. nemestrina). The core was at its widest Densitometric analyses were conducted on subgroups of caudally, narrowing rostrally as the supratemporal plane sections processed for AChE from each brain. Grayscale also diminished in width. One result of this narrowing was images of individual sections were adjusted uniformly for that the rostral portion of the core draped over the medial brightness (10%) and contrast (5%) and then imported edge of the supratemporal plane in some cases to occupy into NIH Image 1.61 for Macintosh for densitometric mea- the outer bank of the ventral circular sulcus. This feature surements and subsequent manipulations. Two analyses is not always obvious in flattened sections of cortex (e.g., were used to support qualitative judgments about border Hackett et al., 1998a). Among the four chimpanzee brains, locations. Both analyses were based on radial density three variants were noted. In one chimpanzee (Fig. 2C, profiles (Rivier and Clarke, 1997; Schleicher et al., 1999), case Ch1), the core region was located on a rudimentary obtained by measuring gray level density in rectangular transverse gyrus elongated rostrocaudally along the me- samples (3 pixels in width) aligned parallel to radial fiber dial edge of the supratemporal plane and outer bank of the columns spanning layers I–VI (Fig. 3C). When possible, circular sulcus, similar to that of M. fuscata (e.g., Jones et the open profiles of blood vessels, lesions, tissue tears, and al., 1995). The and planum polare were other imperfections were circumvented to avoid an arti- located posterior and anterior to the core, respectively. In factual modulation of optical density. The raw gray level a second chimpanzee (see Fig. 12A) there was no clear density values (0–255), averaged across the 3-pixel width, evidence of a transverse gyrus. Instead, the surface of the were converted to relative values by dividing by the mean supratemporal plane appeared relatively flat, as it does in gray level density of the white matter underlying the the macaque. In the two other animals there was a single region of interest (Fig. 3D). Based on these mean density prominent HG oriented from posteromedial to anterolat- values, the border between regions was estimated by the eral across the supratemporal plane (e.g., Fig. 2D, case following procedures. The mean of 5 adjacent profiles (e.g., Ch4; Fig. 12B). In these brains, HG was bounded antero- 1–5) was subtracted from the mean of the next 5 profiles medially by the anterior transverse sulcus of Heschl (HSa) (e.g., 6–10). The starting profile was then incremented by extending from the circular sulcus, and caudolaterally by 1 so that the mean of profiles 2–6 was subtracted from the the posterior transverse sulcus of Heschl (HSp). The ar- Figure 3 IDENTIFICATION OF THE AUDITORY CORE 203 chitectonic analyses detailed below indicated that the core the core derived from the predominance of small cells in region was roughly coextensive with the single HG. Pos- all layers. The dense concentration of small cells in layers terior to the HSp was a broad, mostly flat triangular II through IV and VI contrasted with lower cell density in region corresponding in location to the human planum layer V (Figs. 4A–6A). The inner and outer granular lay- temporale. Anterior to the HSa was a large region tenta- ers (IV and II) were prominent and densely populated by tively defined as the planum polare. In our human speci- very small cells. Layer III was populated by small to mens, the left hemisphere contained either one or two mid-sized pyramidal cells from IIIa to IIIc. Large pyrami- HGs, the long axes of which were oriented from postero- dal cells were rare in layer III but were found more often medial to anterolateral (Fig. 2E,F). The HG variants were at the border with the lateral belt region. In sections cut bounded by the HSa and HSp, as described above and by perpendicular to the radial orientation of the apical den- previous investigators (von Economo and Horn, 1930; drites in layer III, the small pyramidal cells were ar- Campaign and Minkler, 1976; Steinmetz et al., 1989; ranged in short radial columns, extending partially into Musiek and Reeves, 1990; Rademacher et al., 1993; Pen- layers II and IV. This feature appears to correspond to the hune et al., 1996; Leonard et al., 1998; Kim et al., 2000). “rainshower formation” described by von Economo and The double, or bifid, HG variant was bifurcated by the Koskinas (1925). sulcus intermedius (SI). The anteromedial HG was la- The core was not homogenous with respect to the cyto- beled HG1, and the posterolateral HG was labeled HG2 architectonic features described above. For example, the (Fig. 2E, case Hu1). The core was confined to HG when one granular construction and radial orientation of small py- gyrus was present. For the double HG variants, the core ramidal cells in layer III were more prominent features in occupied portions of HG1 and HG2. the medial and caudal (posterior) portions of the core. In Note that because there is currently no consensus on the the lateral and rostral (anterior) domains of the core, nomenclature for description of HG variants, we have especially near the core/belt border, pyramidal cells were adopted a nomenclature for labeling the HG based on slightly larger in IIIc, and the “rainshower formation” was anatomical location (i.e., HG1, most anterior; HG2, poste- a less dominant feature. Thus, a range of minor cytoarchi- rior to HG1; HG3, posterior to HG2, etc.). The sulci bound- tectonic variants was observed within the “koniocortical” ing single or multiple gyri of Heschl were named based on boundaries of the core. These variations were most obvi- anatomical location relative to the HG complex, regard- ous in the chimpanzee and human specimens. less of number; thus, HSa is always anterior to HG1, These structural variants sometimes contributed to am- separating it from the planum polare region, and HSp is biguity in border identification, although the cytoarchitec- always posterior to the most posterior HG, dividing it from ture of the core contrasted with the belt (Figs. 4B–6B) in the planum temporale region. key ways that served as the primary criteria for border In several locations throughout the remaining text, we identification. First, cell packing density and columnar refer to the parabelt region of auditory cortex. This region spacing was lower in the belt, a feature most noticeable in was previously defined in macaque monkeys on the bases layers II–IV. Second, pyramidal cells in layer III of the of architectonic features and connections (Hackett et al., belt areas were clearly larger and more numerous than in 1998a). In macaques, the parabelt region lies on the ex- the core. This feature was most obvious in layer IIIc, posed surface of the superior temporal gyrus, lateral to the where the largest layer III pyramidal cells were concen- lateral belt fields bordering the core. In this report, the trated. Such cells were rarely found within the core but term parabelt was used to denote that specific region only were sometimes found at the border between the core and in the macaque preparations. lateral belt areas. With respect to columnar organization in the belt, layer III pyramidal cells in belt areas lateral to Cytoarchitecture the core were arranged in well-organized vertical columns, We found the cytoarchitecture of the cortex correspond- referred to by von Economo and Koskinas (1925) as the ing to core and belt regions to be generally consistent with “organ pipe formation.” The thin radial lines formed by earlier descriptions in the literature. A centrally located strings of small pyramidal cells in the core were exagger- core region, with koniocortical cytoarchitecture, was sur- ated in the lateral belt where pyramidal cell size increased rounded by a number of belt fields with features typical of from layer IIIa to IIIc (Figs. 4B–6B). The columnar ar- para- or pro-koniocortex. The koniocortical appearance of rangement of pyramidal cells in layer III was less orderly in the belt fields medial and caudal (posterior) to the core. Myeloarchitecture

Fig. 3. Densitometric measurements of auditory cortex. A: Coro- In coronal sections stained for myelin, the auditory cor- nal section from macaque monkey stained for AChE. Arrows indicate tex of all three primates had a densely stained central core lateral (left) and medial (right) borders of the auditory core. B: Same (Figs. 4E–6E), flanked laterally and medially by belt re- image as in A after filtering and thresholding (see text). The dense gions of less dense myelination (Figs. 4F–6F) in which band in layer IIIc/IV corresponds to dense AChE staining in the core. prominent radial fiber bundles could be followed from the C: Same image as A showing placement of rectangular radial density samples used to obtain profiles in E–H. D: Mean relative gray level white matter to low/mid layer III. Following the typology density values for each radial profile in C. The white horizontal line at of Pandya and Sanides (1973), the characteristic pattern 4.25 represents the grand mean. Arrows indicate lateral (left) and of myelination in the core was astriate (i.e., no horizontal medial (right) borders of the core region. E–H: Radial density profiles stria visible in layers IV or Vb due to uniformly dense sorted by cortical region. Within a panel, each curve represents the fibrillarity from IV through VIb) to unistriate (i.e., only the gray level density of a single rectangular sample plotted as a function outer stria in layer IV was visible due to relatively weaker of the percentage distance from the pial surface. Profiles were grouped into core, lateral belt, medial belt, and parabelt regions on the basis of myelination in layer Va). The density of myelination in the architectonic criteria, as denoted by the arrows in A–C. For abbrevi- core was highest caudally, in presumptive AI, with a grad- ations, see list. Scale bar ϭ 1 mm in A–C. ual reduction rostrally. In all three primates, it was pos- Fig. 4. Architecture of macaque monkey core and lateral belt regions. A,B: Thionin stain for Nissl substance. C,D: Acetylcholinesterase histochemistry. E,F: Myelin stain. A,C,E are from the primary auditory core region. B,D,F are from the lateral belt. Scale bar ϭ 250 ␮m. IDENTIFICATION OF THE AUDITORY CORE 205

Fig. 5. Architecture of chimpanzee core and lateral belt regions. A,B: Thionin stain for Nissl sub- stance. C,D: Acetylcholinesterase histochemistry. E,F: Myelin stain. A,C,E are from the primary audi- tory core region. B,D,F are from the lateral belt. Scale bar ϭ 250 ␮m. 206 T. HACKETT ET AL

Fig. 6. Architecture of human core and lateral belt regions. A,B: Thionin stain for Nissl substance. C,D: Acetylcholinesterase histochemistry. E,F: Myelin stain. A,C,E are from the primary auditory core region. B,D,F are from the lateral belt. Scale bar ϭ 250 ␮m. IDENTIFICATION OF THE AUDITORY CORE 207 sible to distinguish between medial and lateral domains pyramidal cells, medium to large in size (Fig. 7C). This within the core on the basis of subtle differences in myeli- feature was found only in fields outside of the core. Thus, nation. The medial domain tended to be astriate, whereas with respect to the expression of AChE, CM shares fea- fibrillar density was weaker in layer Va of the lateral tures of core and belt cortex. In contrast, the cytoarchitec- domain, which was, therefore, unistriate. This distinction ture and myeloarchitecture of CM were more typical of the between medial and lateral domains of the core was main- belt. Thionin staining revealed that CM was highly gran- tained through most of the length of the core and was ular, but layers IIIb and IIIc were populated by numerous more apparent in sections stained for myelin than those medium and large pyramidal cells (Fig. 7B), and columnar stained for Nissl substance. In the belt areas myelin den- organization in layer IV was somewhat irregular. In my- sity was lower compared with the core, but particularly in elin, the staining pattern was bistriate, with a denser the interstriate layers, VIa and Va. The resulting bistriate inner stria (layer Vb) and visible Kaes-Bechterew strip in pattern of myelination resulted from prominent horizontal layer IIIa (Fig. 7D). The combined architectonic picture, fiber bands in layers Vb and IV. The transition to this therefore, places CM outside of the core in the caudal pattern was the principal criterion for identification of the (posterior) and medial domain of the belt region. This core/belt border in myelin preparations. conclusion is consistent with connection patterns and elec- trophysiological recordings in macaque monkeys (see Dis- Acetylcholinesterase expression cussion). Throughout most of the superior temporal cortex, AChE was distributed in laminar-specific bands that varied in Density measurements density between and within architectonic areas. AChE- In most sections, the location of the core in AChE prep- reactive elements included subpopulations of cell soma, arations could be estimated with great precision by proximal dendrites, and axons. The expression of AChE thresholding the Gaussian smoothed grayscale image at was greatest in layers I–IV and weaker in layers V and VI, one standard deviation above the mean density of the except for minor bands in Vb and VIb (Figs. 4C,D–6C,D). white matter (see Materials and Methods). Thresholding Reactivity in layer I was consistently high across archi- at this level preserved prominent suprathreshold regions tectonic subdivisions, whereas AChE expression in other corresponding to the dense bands of AChE expression in layers varied by region. These areal differences served as layers I and IIIc/IV of the core (Fig. 3A,B). In this example, the primary criteria for the localization of borders between only thin interrupted bands in layer IV extended from the fields. The borders identified in adjacent sections stained borders of the core (arrows) into lateral and medial belt for myelin and Nissl substance matched closely those de- fields. Except for layer I, AChE expression outside of the termined independently on the basis of AChE expression. core was strongly reduced or eliminated by the threshold- Reactivity for AChE was higher in the core than in ing procedure, revealing the position of the core. Thresh- surrounding cortex (Figs. 4C–6C). AChE expression in- olding was of limited usefulness for border estimation in creased markedly from layer IIIa to IIIc, reaching peak two conditions. First, in weakly stained sections, even density in a band involving layers IIIc and IV. The density mild thresholding degraded AChE-dense laminae in lay- and radial extent (thickness) of the IIIc/IV band dimin- ers I and IIIc/IV (i.e., human case 2). Second, in the CM ished abruptly at the borders with most of the belt areas. belt area, the layer IIIc/IV band was not degraded by This rapid transition was one of the primary criteria for thresholding; thus, the border between the core and CM localization of the borders between auditory cortical re- was not revealed. Higher thresholds (e.g., 1.5 or 2 stan- gions in AChE preparations. In layers V and VI, AChE dard deviations above the mean) tended to erode even the expression was much lower than in layer IV. A modest dense bands corresponding to layers I and the IIIc/IV band increase in the concentration of AChEϩ elements formed a in the core. minor band in layer Vb. A second criterion for border The border between the core and most belt fields could identification was based on the significant increase in the be objectively identified by the two analyses based on number of moderate and large AChEϩ pyramidal cells in radial density profiles (see Materials and Methods). In the layer IIIc in the belt (Figs. 4D–6D). In the medial belt example illustrated in Figure 3C,D, the lateral and medial areas, these cells were loosely arranged, often in clusters. borders of the core (arrows) were identified as profiles 13 In the lateral belt areas, cellular arrangement was more and 29 by the sliding window analysis of mean profile orderly, as columns of AChEϩ cells could be found extend- densities. Post hoc comparisons supported these findings, ing from IIIc into IIIb. Recall that the increase in the indicating that mean relative gray level densities for pro- number of moderate and large pyramidal cells in the belt files judged to be in the core (13–29) were significantly was also observed in thionin-stained sections, but our greater than profiles judged to be in the parabelt (1–7), present observations suggest that only a subpopulation of lateral belt (8–12), or medial belt (30–41), as determined these cells were AChEϩ in the lower part of layer III. by a two-tailed t-test (P Ͻ 0.001). Mean densities of para- One notable exception to the typical patterns of AChE belt and lateral belt profiles were not significantly differ- expression described above was found in an adjacent belt ent (P ϭ 0.33). field situated caudal (posterior) and medial to the core. In In Figure 3E–H, radial density profiles were plotted as macaques this field is known as the caudomedial area a function of the percentage distance from the pial surface. (CM; Fig. 1). For convenience, we will use the term CM to Profiles in this example, and the majority of other cases, denote the homologous field in chimpanzees and humans. were typically characterized by two prominent peaks cor- In all three species the density of AChE expression in the responding to dense AChE expression in layers I and IIIc/IV band of this field was high, comparable to that IIIc/IV, respectively (Figs. 3E–H). Across cortical regions, found in the core (Fig. 7A). Based on that criterion alone, layer I density was constant, whereas the density of the CM could be considered part of the core. However, layers IIIc/IV band was weaker in the belt regions outside of the IIIb and IIIc were also populated by numerous AChEϩ core. The reduction of the second peak in the belt and 208 T. HACKETT ET AL

parabelt contributed to lower mean relative gray level densities in these regions, as described above (Fig. 3D). Across cases, cross-correlation coefficients among profiles within a region tended to be high (range 0.70–0.96), whereas between regions (e.g., core vs. belt), they were much lower (range 0.1–0.55). These results indicate that profiles within an architectonic field were comparable, whereas profiles between regions were dissimilar. Border identification, achieved by grouping of correlation coeffi- cients according to an arbitrary fixed criterion (e.g., 0.65) was generally in good agreement with borders identified by qualitative criteria. As with the thresholding approach to border estimation, the radial profile analyses yielded variable results under two conditions: 1) at borders located in or near deep sulci; and 2) at the border of the core and CM, which exhibited dense AChE expression in the IIIc/IV band. The density-based analyses were not sensitive to subtle differences between fields under these conditions. In the present study, most of the errors involved the medial portion of the lateral sulcus. Oblique planes of section and complex cortical folding were frequent there, resulting in distortions of cortical thickness and laminar relationships. The morphology of radial density profiles reflected these distortions. The most common error was that the border between the core and medial belt was not identified. By comparison, the border between the core and lateral belt was usually located on the surface of the superior temporal plane or HG. Here, the border was rarely misidentified. Identification of borders between core and belt regions Ambiguity in border identification was reduced when adjacent sets of sections (i.e., Nissl, myelin, AChE) were studied and compared; thus, the use of multiple architec- tonic techniques enabled greater precision in border de- termination compared with reliance on a single approach. The images in Figures 8–10 are centered on the core/belt border (arrowheads) identified independently in thionin, AChE, and myelin stains. The panels in the top row are centered on the border between the medial belt and core. The panels in the bottom row are centered on the border between the lateral belt and core. In all panels the core is on the left. The borders between the core and adjacent belt fields were most easily identified in AChE preparations, but the architectonic details visible in the thionin- and myelin-stained sections are also sufficient to define the borders at this magnification. The transition from the core to the belt was abrupt in many sections but sometimes appeared to occur more gradually (over 300–500 ␮m), confounding identification of a precise border on this ba- sis. Gradual transitions were observed more often at the border of the core and lateral belt than at the border of the core and medial belt.

Fig. 7. Acetylcholinesterase (AchE) expression in the human cau- domedial belt area (CM). A: Off-coronal section (perpendicular to HG1) caudal and medial to the core. Note the dense AChE expression in the layer IIIc/IV band in CM compared with the adjacent lateral field. Arrowheads indicate medial (left) and lateral (right) borders of CM. B–D: Architecture of CM. A: Thionin stain for Nissl substance. B: Acetylcholinesterase histochemistry. C: Myelin stain. Note the pres- ence of AchEϩ pyramidal cells in the IIIc/IV band. Scale bar ϭ 1mm in A, 250 ␮m in B–D. IDENTIFICATION OF THE AUDITORY CORE 209

Fig. 8. Architecture of macaque auditory cortex showing borders (arrowheads) between the core and belt regions. Top row: Core is to the left of the arrowhead, and medial belt is to the right. Bottom row: Core is to the left of the arrowhead, and lateral belt is to the right. A,D: Thionin stain for Nissl substance. B,E: Acetylcholinesterase histochemistry. C,F: Myelin stain. Scale bar ϭ 1 mm.

Species differences auditory cortex in humans tend to be more variable (see Discussion). A second observation concerns myelination in In the cytoarchitecture and myeloarchitecture, laminar layer III. As Figures 4–6 and 8–10 reveal, the density and divisions and structural variants were easiest to resolve in the human tissue and most difficult in macaques. These complexity of fibrillar organization in layer III differed observations may be related to differences in the relative between primates. The network of small-diameter hori- concentration of the structural elements. In macaques, zontal and tangential fibers was most elaborate (or highly cellular and fibrillar density was relatively high, making developed) in humans, intermediate in chimpanzees, and laminar relationships more difficult to resolve. In the the least intricate in macaques. Similar differences may chimpanzee and human specimens, more generous spac- also characterize layers IV–VI, but these could not be ing improved the resolution of such details (see also Bux- resolved consistently due to heavy myelination in these layers. hoeveden et al., 1996). Consequently, differences between ϩ the medial and lateral domains of the core were more AChE pyramidal cells in layers III and V of the belt obvious in humans and chimpanzees than in macaques region were present in greater numbers in the chimpanzee (compare top and bottom panels in Figs. 8–10). This may and human than in the macaque material (refer to Figs. explain why subdivision of the core into lateral and medial 4–6). Cell somata in the human specimens were darkly zones is reported more often in studies of human tissue stained, and profiles were sharp. In the chimpanzee tis- than monkeys, and why published parcellations of the sue, cell staining was not quite as intense, and somatic 210 T. HACKETT ET AL

Fig. 9. Architecture of chimpanzee auditory cortex showing borders (arrowheads) between the core and belt regions. Top row: Core is to the left of the arrowhead, and and medial belt is to the right. Bottom row: Core is to the left of the arrowhead, and lateral belt is to the right. A,D: Thionin stain for Nissl substance. B,E: Acetylcholinesterase histochemistry. C,F: Myelin stain. Scale bar ϭ 1 mm.

profiles were somewhat less sharp, but were clearly more reconstructions. In Figures 11–13 we show reconstructions distinct than in macaques. In macaques, AChEϩ somatic for two cases of each species. Stacks of sections stained for profiles were typically indistinct or absent. In contrast, AChE were aligned approximately along the long axis of the the staining of fibers and dendritic processes did not seem core. Spacing between sections was somewhat arbitrary to to vary between species. Inspection of adjacent sections allow better visualization of architectonic details. Sections stained with thionin indicated that an increase in the were 50 ␮m thick, and every 12th section was illustrated, on number of middle- and large-size pyramidal cells charac- average (i.e., approximate distance of 600 ␮m between sec- terized the belt in all three taxa; thus the disparity ap- tions); thus, the shape of the core (black dashed outlines) was peared to be related to a phyletic difference in AChE slightly elongated compared with its shape in the whole expression by a particular class of cells. This issue awaits brain (Fig. 14). Some borders were not visible due to complex further investigation. folding of the cortex. The overlying parietal cortex was Reconstruction of serial sections and graphically deleted. localization of the core Macaque The identification of the borders between the core and There were few cues in the gross anatomy that would surrounding belt regions in individual sections allowed a contribute to postmortem localization of the core. The fairly precise outline of the core region to be made in serial superior temporal plane was relatively flat, and elevations IDENTIFICATION OF THE AUDITORY CORE 211

Fig. 10. Architecture of human auditory cortex showing borders (arrowheads) between the core and belt regions. Top row: Core is to the left of the arrowhead, and medial belt is to the right. Bottom row: Core is to the left of the arrowhead, and lateral belt is to the right. A,D: Thionin stain for Nissl substance. B,E: Acetylcholinesterase histochemistry. C,F: Myelin stain. Scale bar ϭ 1 mm. or depressions were not consistent markers of architec- trally in R. The boundaries of the core encompass the tonic boundaries. The position of the auditory fields in region of most intense AChE expression in layer IIIc/IV, macaque monkeys (Fig. 11) varied only slightly across except in CM, where density remained high in that band individual macaques. The core was positioned between the (e.g., Fig. 11A). Rostral to the core was a smaller region lateral and medial banks of the supratemporal plane; with core-like architecture that we tentatively identified thus, it was completely contained within the lower bank of as RT. This small field exhibited higher density AChE and the lateral sulcus. In rare instances, the core region was myelin staining than adjacent fields; however, these fea- shifted medially so that even the medial edge of AI tures were less robust than in AI and R. Furthermore, this dropped over the steep bank of the circular sulcus. In field had cytoarchitectonic properties of belt cortex (e.g., other cases, the width of the core relative to the width of reduced cell packing density, larger pyramidal cells in the superior temporal plane was either greater or ex- layer III). At present, RT remains the least certain mem- tended further laterally, shifting part of the lateral belt ber of the core in macaques. field over the edge of the lateral sulcus onto the exposed surface of the superior temporal gyrus. The magnitude of Chimpanzee this variability in the mediolateral dimension was on the Among the four chimpanzee cases, substantial differ- order of 1–2 mm. The shape of the core approximated an ences were found in the position of the core with respect to elongated oval, widest caudally in AI, and narrowing ros- the gross anatomy of the superior temporal plane. In case 212 T. HACKETT ET AL

Fig. 11. Reconstructions of AChE sections showing location of the fields. The images were aligned on the long axis of the elongated core core region (black dashed ovoid) on the dorsal surface of the superior region and lateral edge of the lateral sulcus. C, caudal; L, lateral. temporal plane for two macaque monkeys (A, case M1; B, case M3). Scale bar ϭ 4 mm. Small white dashed ovoid shows putative location of the CM and RT

Ch3 (Fig, 12A; not shown in Fig. 2), the planar surface was the rostral core region was positioned in the depths of the relatively flat and the bulk of the core region was found inferior limiting (circular) sulcus. Note also that the posi- medially on the surface of the lateral sulcus. Rostrally, the tion of the core was at a greater distance from the lateral medial edge of the core was shifted ventrally as a small edge of the superior temporal plane than in macaques. In rudimentary gyrus began to form. The medial border of case Ch1 (Figs. 2C, 12B), a transverse gyrus was more IDENTIFICATION OF THE AUDITORY CORE 213

Fig. 12. Reconstructions of AChE sections showing location of the putative RT. The images were aligned on the long axis of the elon- core region (black dashed ovoid) on the dorsal surface of the superior gated core region and lateral edge of the lateral sulcus. PM, postero- temporal plane for two chimpanzees (A, case Ch3; B, case Ch1). White medial; AM, anteromedial. For other abbreviations, see list. Scale dashed ovoid in A marks the estimated position of the caudomedial bar ϭ 4 mm. belt region (CM). The small white ovoid in B indicates location of Fig. 13. Reconstructions of AChE sections showing location of the region. The images were aligned on the long axis of the elongated core core region (black dashed ovoid) on the dorsal surface of the superior region and lateral edge of the lateral sulcus. PM, posteromedial; AM, temporal plane for two human cases (A, case Hu1; B, case Hu2). anteromedial. For other abbreviations, see list. Scale bar ϭ 4 mm. White dashes indicate estimated position of the caudomedial belt IDENTIFICATION OF THE AUDITORY CORE 215

Fig. 14. Dorsolateral views of the left superior temporal plane. in A–D denote location of putative RT. Dashed straight white lines A,B: Macaque cases M1 and M3. C,D: Chimpanzee cases Ch1 and designate sulcal landmarks. a, anterior, m, medial. For other abbre- Ch4. E,F: Human cases Hu1 and Hu2. Larger white dashed ovoids in viations, see list. Scale bars ϭ 5 mm. all panels indicate approximate boundaries of the core. Smaller ovoids evident but was still rudimentary compared with the This field was not obvious in case Ch3, but it may be prominent HG in case Ch4 (Fig. 2D). Except for its caudal included in the narrow anteromedial extension of the out- portion, the core region was confined to this transverse lined core region in Figure 12A. gyrus. In all four cases the general shape of the core region was similar to that found in macaques, but variability Human between the chimpanzee cases was higher. The patchy Similar variations in gross anatomy complicate descrip- staining in some sections (e.g., rostral to the core region in tions of the core in humans (Fig 13). In case Hu1 (Fig. case 2) was histological. 13A), there was a double/bifid HG, separated by an inter- In case Ch3 (Fig. 12A), the approximate location of mediate sulcus of Heschl. Along most of its length, the putative CM is outlined in white, as described above for elongated core region straddles the intermediate sulcus, macaques. The medial border of the field extended slightly while its borders lie laterally and medially near the dorsal onto the dorsal bank of the lateral sulcus, but in both cases surface of each gyrus (HG1, HG2). The lateral border of the remaining portion of the field was removed during the core shifted medially in more rostral sections, and dissection of the tissue into blocks; thus the size and eventually the entire core became confined to HG1 ros- extent of this field could not be determined. Note also the trally. Caudally, the intermediate sulcus became shallow, outline of a field resembling RT in case Ch1 (Fig. 12B). and then ended, but the core continued for a few sections. 216 T. HACKETT ET AL

The darkly stained CM region was most evident in this neuropil of layer IV. Major subcortical connections favor case. In case 2 (Fig. 13B), a single HG was present. In this the ventral (principal) division of the medial geniculate case, the core region was confined to the single HG along complex (MGv), and cortical projections are primarily di- most of its length. In a third case (Hu3, not illustrated), a rected to the belt fields surrounding the core (Akert et al., double HG was also present. Here, the core also straddled 1959; Mesulam and Pandya, 1973; Pandya and Sanides, the intermediate sulcus, but the bulk of the core was 1973; Forbes and Moskowitz, 1974; Burton and Jones, shifted medially, compared with case Hu1, so that the 1976; Casseday et al., 1976; Fitzpatrick and Imig, 1978; lateral border of the core was often in the depths of the Oliver and Hall, 1978; Galaburda and Pandya, 1983; Ait- intermediate sulcus instead of on the dorsal surface of the kin et al., 1988; Cipolloni and Pandya, 1989; Luethke et gyrus. Thus, in addition to variability in the gross anat- al., 1989; Morel and Kaas, 1992; Morel et al., 1993; Pan- omy of the superior temporal region, there was some vari- dya et al., 1994; Jones et al., 1995; Molinari et al., 1995; ability in the relative position of the core with respect to Rauschecker et al., 1997). these landmarks. Connections with the parabelt region and more distant AChE neuropil staining in case Hu2 was less intense cortical fields are at most minor (Hackett et al., 1998a), compared with case Hu1, so that the borders of the core and subdivisions within the core are thought to process region at low magnification were less obvious. It appears information in parallel (Rauschecker et al., 1997). Neu- that the longer postmortem period in this case may have rons in the core respond to a variable range of frequencies contributed to a reduction in the intensity of AChE neu- centered around a single characteristic frequency (CF). ropil staining. Interestingly, AChE expression in cells was Neurons with a similar CF are arranged in rows, known not affected, nor was staining for myelin or Nissl. Accord- as isofrequency contours. The organization of isofrequency ingly, density-based measurements of AChE neuropil ex- contours is cochleotopic (e.g., high CF caudomedial, low pression were not reliable for border identification for case CF rostrolateral) and roughly orthogonal to the isofre- Hu2. quency dimension (Licklider and Kryter, 1942; Walzl, 1947; Merzenich and Brugge, 1973; Imig et al., 1977; Pfingst and O’Connor, 1981; Aitkin et al., 1986; Luethke et DISCUSSION al., 1989; Morel and Kaas, 1992; Morel et al., 1993; Kosaki The core region of auditory cortex was identified in et al., 1997; Rauschecker et al., 1997; Recanzone et al., macaque monkeys, chimpanzees, and humans by a com- 1999, 2000). The topography of CF maps in adjacent core bined analysis of cytoarchitecture, myeloarchitecture, and fields (e.g., AI/R; R/RT) appears to be reversed in that AI expression of acetylcholinesterase (AChE). In all three and R share a common low-CF border. R and RT may primates, the core was found to occupy an elongated re- share a high-CF border, but physiological evidence of a gion of cortex on the superior temporal plane, hidden from reversal in the CF gradient in RT is inconclusive. Conse- view by the overlying parietal cortex (Fig. 14). In ma- quently, of the areas considered, the status of RT as a caques, the long axis of the core was oriented in the ros- member of the core is least certain (Morel et al., 1993; trocaudal plane. In chimpanzees and humans, the core Hackett et al., 1998a). was largely coextensive with the first transverse temporal In and humans, anatomical identification of the gyrus, although notable variants were found. The core core region primarily depends on the analysis of architec- exhibited primary-like architectonic features that distin- tonic features in postmortem tissue. Most of the parcella- guished it from the adjacent belt fields flanking it on all tions of auditory cortex were derived from analyses of sides. Systematic architectonic variations were also noted cytoarchitecture and/or myeloarchitecture (chimpanzee: within the core itself and appear to be present in all three Beck, 1929; human: Campbell, 1905; Brodmann, 1909; species. The combined architectonic approach using mul- Vogt and Vogt, 1919; Flechsig, 1920; von Economo and tiple markers was found to be more useful in border iden- Koskinas, 1925; Beck, 1928; von Economo, 1929; von tification than reliance on a single method. The results Economo and Horn, 1930; Poljak, 1932; Hopf, 1954; Pan- indicate that the core region can be identified in humans dya and Sanides, 1973; Galaburda and Sanides, 1980; and non-human primates by using the same anatomical Seldon 1981a,b, 1982; Morosan et al., 2001). A few studies criteria, suggesting that these criteria delineate homolo- in humans have also included additional markers (e.g., gous cortical regions in the taxa we examined. AChE, CO, NADPH-diaphorase) to identify or character- ize auditory related cortical fields (Ong and Garey, 1991; What is the auditory core? Hutsler and Gazzaniga, 1996; Rivier and Clarke, 1997; Most descriptions of the auditory cortex in mammals Clarke and Rivier, 1998). Despite substantial variations identify a single primary field known as AI. In the audi- in conclusions and nomenclature across studies, a com- tory cortex of monkeys more than one primary or primary- mon finding has been the identification of a central region like field can be identified, and the local aggregation of with primary, or primary-like, architectonic features sur- these fields is referred to as the core. Current models (e.g., rounded by several nonprimary fields. Fig. 1) include two or three distinct fields (AI, R, RT) Functional evidence of a core-like region in apes and arranged from caudal to rostral along the long axis of the humans can be derived from a number of studies. Surface core region at the initial stage of auditory cortical process- recordings in the chimpanzee have revealed the presence ing (Kaas and Hackett, 1998, 2000; Rauschecker, 1998, of an acoustically responsive region on the superior tem- Rauschecker and Tian, 2000). The identity of a core field poral plane with an orderly representation of stimulus depends on a profile derived from its architecture, connec- frequency similar to that found in monkeys (Bailey et al., tions, and neuron response properties. Architectonic fea- 1943; Woolsey, 1971). In humans, patterns of cochleotopic tures include koniocortical cytoarchitecture, dense organization resembling those found in macaques and astriate/unistriate myelination, and dense expression of chimpanzees have been found along the HG by using a AChE, cytochrome oxidase (CO), and parvalbumin in the variety of techniques (electrophysiology/evoked potentials: IDENTIFICATION OF THE AUDITORY CORE 217

Verkindt et al., 1995; Howard et al., 1996; magnetoen- often confined to the most anterior gyrus (HG1). In one cephalography: Elberling et al., 1982; Pantev et al., 1988, case, area 41 “continued for a short distance onto the 1995; Bertrand et al., 1991; Yamamoto et al., 1992; Ro- intrasulcal portion of the second, more caudal transverse mani et al., 1992; Tiitinen et al., 1993; Huotilainen et al., gyrus” (HG2). In the present study, the two cases present- 1995; Langner et al., 1997; Hoke et al., 1998; Lutkenhoner ing with a bifid HG were similar to this in that core and Steinstrater, 1998; Rosburg et al., 1998; positron extended posterolaterally across the intermediate trans- emission tomography: Lauter et al., 1985; de Rossi et al., verse sulcus and toward the crown of HG2. However, the 1996; Ottaviani et al., 1997; Lockwood et al., 1999; func- anteromedial boundary of the core was near the crown of tional magnetic resonance imaging: Strainer et al., 1997; HG1; thus, the core did not encompass HG1 and extend Wessinger et al., 1997; Bilecen et al., 1998; Talavage et al., onto HG2, but was shifted posterolaterally to involve 2000; Di Salle et al., 2001). about two-thirds of HG1 and one-third of HG2. The find- The anatomical and physiological findings reviewed ings of both studies illustrate the variable relationship of above, coupled with those of the present study, strongly the primary auditory fields to the surface landmarks. The support the existence of a core-like region in chimpanzees diversity in the morphology and location of the HG in and humans that should be considered homologous to the humans (Leonard et al., 1998) is especially problematic for auditory core identified in monkeys (Walker, 1937). De- functional studies in which the location of the auditory tailed anatomical studies and the refinement of noninva- core is in question. Although a small number of brains sive functional assays will allow us to evaluate this hy- have been sampled across studies, the best estimate of the pothesis further and extend our inquiries to fields position and areal extent of the core appears to be related surrounding the core, such as CM. to the boundaries of HG1, particularly when there is only one HG. For other configurations of HG, the position of Gross anatomical relationships of the core HG1 is a less reliable guide to the location of the core. One of the most impressive findings in this study was the high level of variability in the gross anatomical fea- Architectonic variation within the core tures of the auditory cortical region between individuals. Architectonic variations within a region commonly re- The greatest differences were found in chimpanzee and ferred to as primary auditory cortex are well known (e.g., human brains, where the number, size, shape, and extent Beck, 1928, 1929; von Economo and Horn, 1930; Pandya of the transverse temporal gyri varied between individu- and Sanides, 1973; Galaburda and Sanides, 1980; Moro- als. In all three species, the position of the core relative to san et al., 2001). In the cytoarchitectonic studies of von sulcal and gyral landmarks was also variable; thus, these Economo and Horn (1930), for example, up to 11 distinct gross anatomical features were used only to approximate “types” of granular cortex were identified within a region the location of the field. Precise localization depended on (TC) that corresponds closely to our conception of the core. the architectonic analyses. However, there is a relative uniformity with respect to the In macaques, we found that the shape and orientation of most consistent features that contributes to the profile of the core (Fig. 14A,B) was consistent with previous ana- the core as a distinct region (Brodmann, 1909; Vogt and tomical and/or physiological descriptions of this region (for Vogt, 1919). Similarly, the fields comprising the belt re- reviews, see Morel et al., 1993; Hackett et al., 1998a). gion surrounding the core are architectonically distinct Robust surface features marking the location of the core from those within the core, but within the belt region, were generally lacking in macaques, although a slight individual areas share a number of features typical of the elevation on the cortical surface seemed to correspond to belt. To the extent that these sets of architectonic features the location of the core in some species (Poljak, 1932; are unique to the core and belt, they can provide the basis Jones et al., 1995). In chimpanzees lacking a definitive HG for identification of the borders between regions. (Figs. 12A, 14C), the orientation of the core on the superior In the present study, the architectonic features within temporal plane was situated deep in the lateral sulcus and the region defined as the core were not uniform. Subtle elongated along the medial edge of the superior temporal and sometimes systematic variations were observed, par- plane. In chimpanzees with a prominent HG (Fig. 14D), ticularly in sections stained for Nissl substance and mye- the orientation and appearance of the core was more sim- lin. One of the more robust divided the core into medial ilar to that found in humans. The core in these cases was and lateral domains along the long axis of the region. confined to the HG regardless of its orientation. In hu- Myelination in the medial domain was more often astri- mans, the elongated shape of the core resembled that ate, whereas in the lateral portion, a reduction in fiber found in macaques and chimpanzees. The location of the density allowed better delineation of layer IV, contribut- core with respect to gross anatomical features, however, ing to a unistriate profile. This particular feature was was more variable (Fig. 14E,F). When a single HG was matched by trends in the cytoarchitecture. Granularity present, the core occupied most of its surface and was and columnar organization in layer III were more promi- constrained by its sulcal boundaries. When the HG was nent in the medial domain. The identification of two ko- divided by an intermediate transverse sulcus (bifid HG, niocortical domains, splitting the region lengthwise, has posterior duplication), the core region was found to occupy been suggested previously for humans (Hopf, 1954; variable portions of both (i.e., HG1 and HG2), spanning Sarkissow et al., 1955; Galaburda and Sanides, 1980). the intermediate sulcus of Heschl. This feature was also identified in macaque monkeys by In their evaluation of the relationship between topo- Pandya and Sanides (1973); however, it was not preserved graphic landmarks and cytoarchitectonic fields, Radema- in subsequent adaptations of their schema (e.g., Gala- cher et al. (1993) compared the areal extent of area 41 burda and Pandya, 1983). Pandya and Sanides (1973) (auditory koniocortex) with variations in the topography concluded that the denser myelination in Kam was related of the HG. When the HG was bifurcated by an intermedi- to a proposed greater concentration of callosal fibers me- ate transverse sulcus, they found that area 41 was most dially. As yet, additional support for a distinction between 218 T. HACKETT ET AL the medial and lateral domains has not been reported in macaques. The present findings also emphasize architec- either the connections or physiological profiles of neurons tonic similarities between macaque CM and a field caudal in the core. (posterior) and medial to the core in chimpanzees and Architectonic variations also distinguished the caudal humans. Based on architectonic descriptions in previous (posteromedial) and rostral (anterolateral) domains studies, the CM field in humans appears to correspond within the core. Myelination and AChE expression grad- most closely to the following areas: the medial portion of ually increased caudally, where the cytoarchitecture was the koniocortical TD sector of the Regio acustica (von more typical of koniocortex. Previous architectonic studies Economo and Koskinas, 1925; von Economo and Horn, in chimpanzees and humans have also identified regional 1930); ttrIin2 of the Pars intima of chimpanzees and hu- variations along this dimension of granular cortex (Beck, mans (Beck, 1928, 1929); medial PaAc (Galaburda and 1928, 1929; von Economo and Horn, 1930; Morosan et al., Sanides, 1980); and medial Te1.1 (Morosan et al., 2001). 2001). The transverse prima interna and externa of Beck Our preliminary results suggest that this field may be (1928, 1929), for example, mirror the relative positions of homologous in macaques, chimpanzees, and humans. AI and R in the macaque. Most recently, Morosan et al. Sources of variability in border (2001) identified three adjacent zones (Te1.1, Te1.0, Te1.2) distributed along the long axis of HG in humans. These identification anatomical gradients may relate to functional gradients Borders between adjacent cortical fields are not always (e.g., cochleotopy), as identified within the core region of characterized by an abrupt transition in the architecture. macaques (e.g., AI, R). There is no a priori reason why margins must be sharp, Based on comparison of the findings in the present but this is commonly reported in studies of sensory cortex. study with qualitative and quantitative descriptions of Indeed, conclusions sometimes depend on the identifica- temporal cortex in previous studies, we conclude that the tion of clean boundaries between fields. Transitional ar- core corresponds most closely to the following fields: area chitecture may, in fact, separate some fields in cortex, but 41 (Brodmann, 1909); TC (von Economo and Koskinas, the blurring of clean borders is often related to technical 1925); ttrIi/e (Beck, 1928, 1929); koniosus supratempora- variables. One important factor is the plane of section. lis (Bailey and von Bonin, 1951); Kam/Kalt (Pandya and Distortion results from cutting across and/or between the Sanides, 1973; Galaburda and Sanides, 1980; Galaburda radial axes of cell columns, thereby altering the three- and Pandya, 1983); temporal granulous core (Braak, dimensional relationships between the neural structures. 1978); AI (Rivier and Clarke, 1997); and Te1.0 (Morosan et An oblique plane of section alters the point of view, alter- al., 2001). ing the appearance of the architecture. Depending on the nature of the distortion, the distinction between the two Architectonic variation within the belt fields may be obvious only at some variable distance from Although we made no attempt to define subdivisions the border. In brains with greater gyrification, the cortex within the belt region in this study, our results indicate exhibits complex folding in several directions (e.g., the HG that the belt is not anatomically homogeneous in mon- in chimpanzees and humans). Thus, a coronal plane of keys, chimpanzees, or humans. Systematic differences section results in radially aligned sections through some were evident within and between the medial, lateral, and areas and oblique sections through others. In the present caudal domains of the belt. However, these fields also study, we found no single plane of section to be ideal for all share a basic architectonic profile that distinguishes them fields of interest. For macaques, a modified coronal plane, from the core and more distant regions, such as the para- perpendicular to the surface of the superior temporal belt in macaques (Hackett et al., 1998a). Additional sup- plane, resulted in minimal distortion and was roughly in port for these differences can be found in microelectrode line with the long axis of the elongated core. For chimpan- studies of macaque monkeys. Functional subdivisions of zees and humans with a HG, a modified parasagittal the belt correlate well with those identified anatomically plane, perpendicular to the long axis of the transverse (e.g., Rauschecker et al., 1995, 1997; Kosaki et al., 1997; gyrus (gyri) and its dorsal surface, resulted in minimal Romanski et al., 2000; Tian et al., 2001). distortion of fields on and immediately adjacent to the HG. In the present study, we briefly described the architec- A second variant is the relationship of borders to the tonic features of the belt field, CM, compared with the gross anatomy. The presence of deep sulci at and between adjacent part of the core (i.e., AI). In macaque monkeys architectonic borders substantially alters anatomical fea- CM is considered to be a belt field on the basis of its tures, particularly laminar relationships. In our macaque, architecture, connections, and neuron response proper- chimpanzee, and human specimens, for example, the bor- ties. Major inputs to CM originate in the dorsal (MGd) and der between the core and the medial belt was frequently magnocellular (MGm) divisions of the medial geniculate located at or near the sharp turn of the inferior limiting complex (Rauschecker et al., 1997), and AI in the core (circular) sulcus. Another troublesome location was the (Galaburda and Pandya, 1983; Morel et al., 1993). Cortical intermediate sulcus of Heschl in those human specimens projections of CM include the parabelt auditory cortex with a double, or bifid, HG. The compression of cortex in (Hackett et al., 1998a) and posterior parietal cortex (Lewis these sulci distorted laminar relationships, compromising and van Essen, 2000). Many neurons in CM are broadly the integrity of calculations based on radial density pro- tuned, are more responsive to temporally and spectrally files. In severely distorted sections, even the identity of complex acoustic stimuli, and appear to be dependent on the fields at a distance from the estimated border were in intact inputs from AI for responses to pure tones (Mer- question, so that judgements were based on modified cri- zenich and Brugge, 1973; Rauschecker et al., 1997; Recan- teria using identifiable features, as well as comparisons of zone et al., 2000). The results of the present study indicate the intact architecture on either side of the sulcus. that the architectonic profile of CM is most consistent with A third source of variability is histological. Aberrant its inclusion in the caudal portion of the belt region of staining patterns can result from variations in postmor- IDENTIFICATION OF THE AUDITORY CORE 219 tem delay, fixation, sectioning, buffer solutions, or minor be particularly useful in the validation of borders identi- details in the histological protocol. Although severe dis- fied by a strictly quantitative approach. tortions are obvious and easily excluded from analysis, subtle variations may not be detected. A gradual dissipa- Directions for future research tion of AChE expression at a border, for example, may be Functional studies in humans suggest that certain ele- an inherent property of the architecture, but this does not ments of the monkey model may be applicable to humans. explain why abrupt transitions are found in some sections, In addition to evidence of tonotopic organization in the but not others. In this study, staining quality for Nissl putative core region along the HG (see above), there is also substance and myelinated fibers was highly consistent evidence of hierarchical processing in human auditory across cases, regardless of species, perfusion, fixation, or cortex involving the core and surrounding regions. Nu- postmortem delay. Staining for AChE was more variable merous studies in humans indicate that auditory related (see Materials and Methods) but was not consistently activity in cortical fields outside of the core region can be related to any identifiable histological factor. As a partial dissociated from activity within by using stimuli of varied control, densitometric analyses in the present study were acoustic complexity or linguistic significance (Petersen et limited to measurements within individual sections. No al., 1988; Liegeois-Chauvel et al., 1991, 1994; Price et al., attempt was made to compare density measurements be- 1992; Demonet et al., 1992; Zatorre et al., 1992; Binder et tween cases or between sections. al., 1994, 2000; Berry et al., 1995; Hickock et al., 1997; Given the many factors that contribute to histological Scheich et al., 1998; Nishimura et al., 1999; Belin et al., variability, one of the merits of the multifaceted architec- 1999, 2000; Celsis et al., 1999; Jancke et al., 1999; Howard tonic analysis is that the redundancy increases confidence et al., 2000; Scott et al., 2000; Talavage et al., 2000; Di in border identification. The intense expression of AChE Salle et al., 2001). These results are consistent with find- in the core, for example, was an invaluable clue in approx- ings in monkeys that describe serial and parallel process- imating the position of the core, but the identification of ing among subdivisions of the core and belt regions (e.g., borders was most precise when direct comparisons were Rauschecker et al., 1997). Because the homology of the made with adjacent thionin- and myelin-stained sections. core in monkeys and humans appears to be well estab- When the borders were near or within sulci or when fields lished, and homologies among belt areas such as CM seem were sectioned tangential to the cortical surface (e.g., me- likely, further comparative studies will be needed to iden- dial belt region), important features of the cytoarchitec- tify other similarities and differences in the organization ture and myeloarchitecture were severely distorted, lim- of auditory cortex across taxonomic groups. For architec- iting border identification to differences in the density of tonic studies, progress will depend on the establishment of cellular or fibrillar elements. In such cases, the rapid anatomical profiles to distinguish cortical fields. The sen- change in layer IIIc/IV expression of AChE was often sitivity of observer-independent techniques could be im- visible and served as the most valid estimate of the border. proved by incorporating these features into the analyses. The combined architectonic approach was also useful in case Hu2, in which AChE neuropil expression was rela- tively weak. In this case, border identification was rein- CONCLUSIONS ϩ forced by cytoarchitecture, myeloarchitecture, and AChE In macaque monkeys the auditory core region repre- cell distribution. sents the first stage of processing in auditory cortex. A homologous region can be identified in chimpanzees and Observer-independent border identification humans by using architectonic criteria combining cytoar- One limitation of most architectonic studies is that de- chitecture, myeloarchitecture, and acetylcholinesterase cisions rely on the qualitative judgments of the observer. histochemistry. The combined architectonic approach us- As discussed above, the use of multiple architectonic ing multiple markers provides a more reliable estimate of markers greatly improves the consistency and precision of the boundaries of the core region than detailed analysis of border identification. The quantitative analyses employed a single preparation. In all three species, the core region is herein were accurate under certain conditions (e.g., well- surrounded by a belt of areas with distinctive architec- stained tissue, mild structural distortions imposed by cor- tonic features that vary by location. The position of the tical folding). The analyses did not, however, produce re- core with respect to surface landmarks is most variable in liable border identification when radial density profiles humans and chimpanzees, but it appears to be largely were distorted by cortical folding, an oblique plane of confined to the first transverse temporal gyrus of Heschl, section, low contrast staining, or gradual architectonic even when more than one such gyrus is present. Although transitions. Similar problems have been reported by oth- we consider the region identified as the core to be homol- ers using different techniques (Schleicher et al., 1999; ogous in macaques, chimpanzees, and humans, species Morosan et al., 2001). To account for such architectonic differences were noted in patterns of myelination and variability, the ideal reliable observer-independent acetylcholinesterase expression. These data establish a method must be sensitive only to relevant features. Oth- foundation for subsequent anatomical studies of auditory erwise, actual borders may be missed or false borders fields outside of the core and for functional studies of identified, depending on the criteria chosen. We are eval- auditory cortex in these species. uating ways of improving the sensitivity of such methods to key criteria, without introducing a bias toward the ACKNOWLEDGMENTS identification of false borders. The present findings sug- gest that the concurrent use of multiple histological mark- The authors thank the veterinary staff of the New Ibe- ers could be used to reduce qualitative and quantitative ria Research Center for their assistance in obtaining errors in border identification. A combined approach may chimpanzee material. We also thank Dr. William O. Whet- 220 T. HACKETT ET AL sell of the Vanderbilt University School of Medicine, Dr. Brodmann K. 1909. Vergleichende Lokalisationslehre der Grosshirnrinde. Bruce Quinn and Dr. John Smiley of the Northwestern Leipzig: Barth. University Alzheimer’s Disease Center, and the Clinical Brugge JF, Reale RA. 1985. Auditory cortex. In: Peters A, Jones EG, editors. , vol 4, Association and auditory cortices. New Core of the Northwestern University Alzheimer’s Disease York: Plenum Press. p 229–271. Center, Chicago for assistance in obtaining human mate- Burton H, Jones EG. 1976. The posterior thalamic region and its cortical rial. The authors also recognize Thomas Dinsenbacher for projection in New World and Old World monkeys. J Comp Neurol assistance with data analysis, as well as Judy Ives and 168:249–302. Laura Trice for histological assistance. T.A.H. was the Buxhoeveden D, Lefkowitz W, Loats P, Armstrong E. 1996. The linear recipient of grants DC00249 and DC04318 from the Na- organization of cell columns in human and nonhuman anthropoid Tpt tional Institutes of Health. T.M.P. was the recipient of cortex. Anat Embryol 194:23–36. 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