4.21 the evolution of neuron types and cortical histology...

4.21 The Evolution of Neuron Types and CorticalHistology in Apes and Humans

C C Sherwood, The George Washington University,Washington, DC, USAP R Hof, Mount Sinai School of Medicine,New York, NY, USA

ª 2007 Elsevier Inc. All rights reserved.

4.21.1 Introduction 3564.21.1.1 Evolutionary History of the Hominoids 3564.21.1.2 History of Studies Concerning Hominoid Cortical Histology 357

4.21.2 Comparative Anatomy of the Cerebral Cortex 3584.21.2.1 Topology of Cortical Maps 3584.21.2.2 Architecture of the Cortex 3584.21.2.3 Primary Visual Cortex 3594.21.2.4 Auditory Cortex 3624.21.2.5 Primary Motor Cortex 3644.21.2.6 Inferior Frontal Cortex 3664.21.2.7 Prefrontal Cortex 3674.21.2.8 Anterior Cingulate Cortex 368

4.21.3 Patterns of Cortical Organization in Hominoids 3694.21.3.1 The Emergence of Cell Types and Their Distribution 3694.21.3.2 The Evolution of Cortical Asymmetries 3704.21.3.3 How Much Variation in Cortical Architecture Can be Attributed to Scaling

versus Specialization? 3714.21.3.4 Genomic Data Provide Insights into Cortical Specializations 3724.21.3.5 On the Horizon 373

Glossary

allometry Many biological traits scale withoverall size in a nonlinear fashion.Such allometric scaling relation-ships can be expressed by thepower function: Y ¼ bXa. Thelogarithmic transformation of theallometric scaling equation yields:log Y ¼ log b þ a log X. Theexponent of the power functionbecomes the slope of the log-transformed function. The slopeof this line can then be interpretedin terms of a biological scalingrelationship between the indepen-dent and dependent variable.Positive allometry refers to a scal-ing relationship with an exponentthat is greater than 1, whichmeans that the structure in ques-tion grows disproportionatelylarger or more numerous withincreases in the size of the refer-ence variable. Negative allometryrefers to a scaling relationshipwith an exponent that is less

than 1, which means that thestructure in question becomes pro-portionally smaller or lessnumerous with increases in thesize of the reference variable.

chemoarchitecture The microanatomical organizationof the cerebral cortex revealed bystaining for biochemical substancesusing techniques such as immuno-histochemistry and enzyme orlectin histochemistry.

dysgranularcortex

A type of cortex that has a weaklydefined layer IV because it is vari-able in thickness. At points, layerIV seems to disappear becauseneurons from layers IIIc and Vaintermingle.

encephalization A relative measure of a species’brain size that represents the degreeto which it is larger or smaller thanexpected for a typical animal of itsbody size.

granular cortex A type of cortex that has a clearlyidentifiable layer IV.

gray level index(GLI)

The proportion of an area ofreference that is occupied bythe projected profiles of all

356 The Evolution of Neuron Types and Cortical Histology in Apes and Humans

Nissl-stained elements. This valueprovides an estimate of the frac-tion of tissue that containsneuronal somata, glial cell nuclei,and endothelial nuclei versus neu-ropil. GLI values are highlycorrelated with the volume den-sity occupied by neurons sinceglial and endothelial cell nucleicontribute only a very small pro-portion of the total volume.

hominoid A phylogenetic clade that includeslesser apes (gibbons and siamangs),great apes (orangutans, gorillas,chimpanzees, and bonobos), andhumans.

infragranularlayers

Cortical layers that are deep togranular layer IV, i.e., layers V andVI.

minicolumn Morphologically, minicolumnsappear as a single vertical row ofneurons with strong vertical inter-connections among layers, forminga fundamental structural and func-tional unit. The core region of thecolumn contains the majority of theneurons, their apical dendrites, andboth myelinated and unmyelinatedfibers. A cell-poor region, contain-ing dendritic arbors, unmyelinatedaxons, and synapses, surroundseach column.

neuropil The unstained portion ofNissl-stained tissue, which is com-prised of dendrites, axons, andsynapses.

supragranularlayers

Cortical layers that are superficialto granular layer IV, i.e., layers I,II, and III.

7 M

14 Mya

18 Mya

25 Mya

40 Mya

58 Mya

63 Mya

Figure 1 Cladogram showing the phylogenetic relationships of

are taken from Goodman et al. (2005).

4.21.1 Introduction

4.21.1.1 Evolutionary History of the Hominoids

Apes and humans are members of the primatesuperfamily Hominoidea (Figure 1). Molecularevidence indicates that the hominoid lineage splitfrom the Old World monkeys about 25 Mya(Wildman et al., 2003). The extant representatives ofthis phylogenetic group include two families. TheHylobatidae comprises gibbons and siamangs, andthe Hominidae includes great apes (i.e., orangutans,gorillas, chimpanzees, and bonobos) and humans(Groves, 2001). Living hominoids are distinguishedby a suite of shared derived traits that point to thekey adaptations of this clade. These characters includelack of an external tail, modifications of the shouldergirdle and wrist for greater mobility, and stabilizationof the lower back (Begun, 2003). These adaptationsallow hominoids to exploit resources in smallbranches of trees by developing suspensory posturesto distribute their body weight. This form of loco-motion may have been particularly important inallowing certain species to increase body size. In addi-tion, compared to other primates, hominoids haveextended periods of growth and development(Schultz, 1969), an increased complexity of socialinteractions (Potts, 2004), and larger brains thanwould be expected for a monkey of the same bodysize (Rilling and Insel, 1999). The increased encepha-lization and associated life history elongation of thesespecies suggest that cognitive flexibility and learningwere important aspects of the hominoid adaptivecomplex, which allowed them to deal with locatingephemeral resources from fruiting trees and to negoti-ate more complicated relationships in fission–fusionsocieties (Potts, 2004).

Humans

Bonobos

Chimpanzees

Gorillas

Orangutans

Gibbons and siamangs

Old World monkeys

New World monkeys

Tarsiers

Lemurs and lorises

ya

6 Mya

3 Mya

living hominoids and other primates. Estimated divergence dates

The Evolution of Neuron Types and Cortical Histology in Apes and Humans 357

Although only a small number of hominoid spe-cies persist today, the fossil record reveals a diversearray of successive adaptive radiations of hominoidsin the past. During the Miocene epoch, global cli-mates were warm and humid, supporting denseforests and lush woodlands extending throughoutthe tropics and into northern latitudes. These envir-onmental conditions were favorable for thediversification of arboreal specialists, such as thehominoids. In fact, hominoids were the most abun-dant type of anthropoid primate throughout theMiocene in Africa and Eurasia, occupying a rangeof different ecological niches (Begun, 2003). Theearliest apes in the fossil record are characterizedby hominoid-like dental morphology, but monkey-like postcranial anatomy. The best known of theseearly dental apes is the genus Proconsul fromthe Early Miocene (20–18 Mya) of East Africa.Proconsul africanus endocasts show a frontal lobemorphology that is similar to modern hominoids inbeing gyrified and lacking the simple V-shaped arc-uate sulcus that is characteristic of most Old Worldmonkeys (Radinsky, 1974). Furthermore, P. africa-nus had a relatively larger brain than extantmonkeys of comparable body size (Walker et al.,1983). Thus, increased encephalization and perhapsa greater degree of frontal lobe gyrification werepresent early in the evolution of the hominoids.

With the emergence of arid climates in the transi-tion to the Pliocene and the replacement of forestsby mosaic habitats, the arboreal specializations ofhominoids were less successful. The relatively slowreproductive rates of these taxa, moreover, made itdifficult for many to endure habitat loss resultingfrom climate change and human encroachment inrecent times (Jablonski et al., 2000). In the contextof these dramatic environmental changes, one line-age adopted a new form of locomotion, uprightbipedal walking, which would give rise to modernhumans. Other hominoids, however, fared less welland today apes are restricted to a small number ofendangered tropical forest species.

4.21.1.2 History of Studies ConcerningHominoid Cortical Histology

At the beginning of the twentieth century, neuro-anatomists applied new histological stainingtechniques to reveal the architecture of the cerebralcortex in numerous species, including apes andhumans (Campbell, 1905; Mauss, 1908, 1911;Brodmann, 1909; Beck, 1929; Filimonoff, 1933;Strasburger, 1937a, 1937b). In addition, with theadvent of various techniques for tracing neuronalconnectivity based on intracellular pathological

changes subsequent to ablation, some studies alsoexamined cortical projection systems in apes(Walker, 1938; Lassek and Wheatley, 1945;Kuypers, 1958; Jackson et al., 1969). After the1950s, however, the amount of research directedtoward understanding variation in the hominoidbrain declined. There are three main reasons forthis. First, the development of molecular biologicaltechniques caused neuroscientists to focus on asmall number of model species under the implicitassumption that many aspects of cortical structureare evolutionarily conserved. These ideas werefurther bolstered by claims of uniformity in thebasic columnar architecture of the cerebral cortex(Rockel et al., 1980). Second, findings from the firstsystematic studies of great ape behavior from thefield and laboratory were beginning to be appre-ciated (e.g., Kortlandt, 1962; Schaller, 1963;Yerkes and Learned, 1925; Yerkes and Yerkes,1929). These studies contributed to a more sophis-ticated understanding of cognitive and emotionalcomplexity in great apes and suggested that theydeserve special protected status with respect to theethics of invasive neurobiological experimentation.Third, the book Evolution of the Brain andIntelligence (Jerison, 1973) had an enormous influ-ence on the direction of later research incomparative neuroanatomy. This book argued forthe predictability of neuroanatomical structure frombrain size and encephalization, suggesting that thesemetrics form the most significant contribution tospecies diversity in brain organization. Combinedwith the ready availability of comparative brainregion volumetric data in primates and other mam-mals from the publications of Heinz Stephan, HeikoFrahm, George Baron, and colleagues (e.g., Stephanet al., 1981), a great deal of research effort has beenexpended in studies of allometric scaling and covar-iance of large regions of the brain (Finlay andDarlington, 1995; Barton and Harvey, 2000; deWinter and Oxnard, 2001). In contrast, much lessattention has been paid to the possibility of phylo-genetic variation in cortical histology (Preuss,2000). Fortunately, advances in quantitative neu-roanatomy and immunohistochemical stainingtechniques have opened new avenues of research toreveal interspecific diversity in the microstructure ofhominoid cerebral cortex.

The history of studies of hominoid cortical histol-ogy, therefore, has resulted in two eras of research.The early era comprises several qualitative com-parative mapping studies of the cerebral cortexbased on cyto- and myeloarchitecture, with theoccasional comment regarding species differencesin the microstructure of homologous cortical areas


(Campbell, 1905; Mauss, 1908, 1911; Brodmann,1909; Beck, 1929; Bailey et al., 1950). Later studiesfrom this era also contributed quantitative data con-cerning the surface area of particular cortical areas,as well as cellular sizes and densities in a few nonhu-man hominoid species (Mayer, 1912; Tilney andRiley, 1928; von Bonin, 1939; Lassek andWheatley, 1945; Shariff, 1953; Haug, 1956;Glezer, 1958; Blinkov and Glezer, 1968). Thesequantitative data, however, were rarely presentedin the context of a focused examination of variationamong hominoids.

The modern era is characterized by studies that usetechniques such as design-based stereology, compu-terized image analysis, and immunohistochemicaland histochemical staining to identify subpopula-tions of cortical cells. These new approaches areespecially appealing for investigations of phyloge-netic variation in cortical histology in species thatare not common to the laboratory because severalenzymatic, cytoskeletal, and other macromolecularconstituents that are well preserved in postmortemtissue can be used as reliable markers for subpopula-tions of distinct neuron types, thereby extendingcomparative studies of species for which anatomicaltracing, electrophysiological mapping, or otherexperimental procedures would be either unethicalor impractical (see The Evolution of Neuron Classesin the Neocortex of Mammals). Subsets of pyramidalneurons, for example, can be distinguished immuno-histochemically by staining with an antibody (e.g.,SMI-32) to nonphosphorylated epitopes on the med-ium- and high-molecular-weight subunits of theneurofilament triplet protein. These epitopes are par-ticularly enriched in subpopulations of large neuronsof the neocortex that have a specific laminar andregional distribution. Because nonphosphorylatedneurofilament protein (NPNFP) is involved in themaintenance and stabilization of the axonal cytoske-leton, its expression is associated with neurons thathave thick myelinated axons (Hoffman et al., 1987;Kirkcaldie et al., 2002). In addition, the calcium-binding proteins – calbindin D-28k (CB), calretinin(CR), and parvalbumin (PV) – are useful markers forunderstanding the cortical interneuron systembecause each of these molecules is typically co-loca-lized with GABA in morphologically andphysiologically distinct nonoverlapping populations(DeFelipe, 1997; Markram et al., 2004).

While the neuroanatomical structure of onehominoid species in particular has been studiedmost extensively, it is well beyond the scope of thisarticle to provide a comprehensive review of humancortical architecture. Here we focus explicitly oncomparative studies of the histology of hominoid

cerebral cortex, highlighting evidence concerningshared derived traits of hominoids in comparisonto other primates, as well as indicating possiblespecies-specific specializations. Hence, the studiesreviewed in this chapter provide the most directevidence currently available to delimit whichaspects of cortical histology are uniquely human,which are derived for all hominoids, and whichreflect the specializations of each species.

4.21.2 Comparative Anatomy ofthe Cerebral Cortex

4.21.2.1 Topology of Cortical Maps

Total brain weight in hominoids ranges fromapproximately 90 g in Kloss’s gibbons (Hylobatesklossii) to 1400 g in humans (Homo sapiens)(Table 1). While there is a large range of variationamong hominoids in total brain size, mapping studiesof the cortex (Figure 2) generally agree that the loca-tion of the primary sensory and motor areas aresimilar across species (Grunbaum and Sherrington,1903; Campbell, 1905; Mauss, 1908, 1911;Brodmann, 1909; Leyton and Sherrington, 1917;Beck, 1929; Bailey et al., 1950; Preuss et al., 1999;Hackett et al., 2001; Bush and Allman, 2004a,2004b; Sherwood et al., 2004b). In particular, theprimary visual cortex lies within the banks of thecalcarine sulcus. Primary auditory cortex is locatedon the posterior superior plane of the superior tem-poral gyrus, usually comprising the transverse gyrusof Heschl in great apes and humans. Primary soma-tosensory cortex is found within the posterior bankof the central sulcus and extends on to the postcentralgyrus. Primary motor cortex is located mostly on theanterior bank of the central sulcus. One notable dif-ference is the fact that primary visual cortex extendsto only a very small portion of the lateral convexity ofthe occipital lobe in humans, whereas a much largerpart of the lateral occipital lobe is comprised of stri-ate cortex in apes (Zilles and Rehkamper, 1988;Holloway et al., 2003). This is because the primaryvisual cortex in humans is 121% smaller thanexpected for a primate of the same brain size(Holloway, 1996). Other higher-order areas, particu-larly within the frontal cortex, have also been shownto occupy similar locations across these species(Strasburger, 1937a, 1937b; Semendeferi et al.,1998, 2001; Sherwood et al., 2003a).

4.21.2.2 Architecture of the Cortex

The general histological architecture of the neocor-tex in hominoids shares many features in common

Table 1 Endocranial volumes of hominoids (in cc)

Common name Species Sex Sample size Mean SD Range

White-handed gibbon Hylobates lar M 44 106.3 7.2 92–125

F 37 104.2 7.0 90–116

Siamang Symphalangus syndactylus M 8 127.7 8.2 99–140

F 12 125.9 12.7 102–143

Orangutan Pongo pygmaeus M 66 415.6 33.6 334–502

F 63 343.1 33.6 276–431

Gorilla Gorilla gorilla M 283 535.5 55.3 410–715

F 199 452.2 41.6 345–553

Chimpanzee Pan troglodytes M 159 397.2 39.4 322–503

F 204 365.7 31.9 270–450

Bonobo Pan paniscus M 28 351.8 30.6 295–440

F 30 349.0 37.7 265–420

Human Homo sapiens M 502 1457.2 119.8 1160–1850

F 165 1317.9 109.8 1040–1615

Endocranial volumes are shown, rather than brain volumes, because larger sample sizes are available for these species.

Reproduced from Holloway, R. L. 1996. Evolution of the human brain. In: Handbook of Human Symbolic Evolution (eds. A. Lock

and C. R. Peters), pp. 74–114. Oxford University Press.


with other primates and mammals in general, suchas a fundamental six-layered and columnar organi-zation (Mountcastle, 1998). Compared to othermammals of similar brain size, however, the cere-bral cortex of hominoids is reported to have arelatively low density of glial cells and a greatervariety of neuron soma sizes (Haug, 1987).Astroglia of the cerebral cortex in great apes, asrevealed by immunohistochemistry for glial fibril-lary acidic protein (GFAP), resemble other primatesin forming long, radially oriented interlaminar pro-cesses spanning supragranular cortical layers(Colombo et al., 2004). This configuration may beunique to primates, as GFAP staining in the cortexof other mammals appears distinctly different, com-prising a network of stellate astroglial somata withshort, branching processes (Colombo, 1996;Colombo et al., 2000; Colombo and Reisin, 2004).

Comparison of mammalian brains indicates thatthe surface area of the cortical sheet can vary by morethan five orders of magnitude, while the thickness ofthe cortex varies by less than one order of magnitude(Allman, 1990). Accordingly, evolutionary changesin the size of the cerebral cortex have occurred pri-marily in the tangential dimension, while the verticaldimension of the cortex may be more constrained bythe development of columnar units (Rakic, 1988,1995). Nonetheless, the cortical sheet does tend todisplay increased thickness in mammals with largerbrains (Hofman, 1988). Due to these scaling trends,hominoids have thicker cortices than other smaller-brained primates and homologous cortical areas inhumans tend to be thicker than in apes (Figure 3).

With the relative ease of establishing homologyamong the primary sensory and motor cortical areas

on the basis of cytoarchitecture and topology, severalstudies have compared the microstructure of theseareas among different hominoid species (reviewedbelow). On the whole, the cytoarchitecture of homo-logous cortical areas shows only subtle differencesacross hominoid species. Indeed, an early quantitativecomparative analysis of the cytoarchitecture of pri-mary cortical areas (areas 3, 4, 17, and 41/42), foundmarked similarities among species (orangutans, goril-las, chimpanzees, and humans) in terms of the relativethickness of different layers and the proportion ofneuropil in each layer (Zilles and Rehkamper, 1988).Only minor differences were noted, such as greaterrelative thickness of layer III in primary somatosensorycortex (area 3) in humans and gorillas, an increase inthe proportion of neuropil in layers V and VI of area 3in orangutans, and a relatively thicker layer IV ofprimary auditory cortex (area 41/42) in orangutans.These results were interpreted to corroborate the qua-litative observations of Campbell (1905) andBrodmann (1909), indicating that there are not anysubstantial differences between humans and apes inthe cytoarchitecture of these primary cortical areas.The study by Zilles and Rehkamper (1988), however,was based on small samples, which did not permitstatistical evaluation of species differences. Morerecent studies using larger samples, different stainingtechniques, and more refined quantitative methodshave revealed interesting phylogenetic differencesamong hominoids in cortical histological structure.

4.21.2.3 Primary Visual Cortex

Important modifications of primary visual cortex(Brodmann’s area 17) histology, particularly of the

(a)

(c) (d)

(b)

Figure 2 Parcellation maps of the cerebral cortex of apes. Chimpanzee (Pan troglodytes) cortical maps reproduced from

(a) Campbell, A. W. 1905. Histological Studies on the Localisation of Cerebral Function. Cambridge University Press. and (b) Bailey,

P., von Bonin, G., and McCulloch, W. S. 1950. The Isocortex of the Chimpanzee. University of Illinois Press. Orangutan (Pongo

pygmaeus) cortical maps reproduced from (c) Campbell (1905) and (d) Mauss (1908, 1911) compiled in Zilles and Rekamper (1988).

c and d, Reproduced from ‘‘figure 12-2’’, Orang-utan Biology, edited by Jeffrey H. Schwartz, copyright ª 1988 by Oxford University

Press, Inc., used by permission of Oxford University Press, Inc.


thalamic recipient layer IV, have taken place at severalpoints in the evolution of hominoids. Distinct parallelascending fiber systems arising from retinal ganglioncells project to the lateral geniculate nucleus (LGN) of

the thalamus. The M-type retinal ganglion cells giverise to the magnocellular channel, which is involved inthe analysis of motion and gross spatial properties ofstimuli. The P-type ganglion cells process visual

Chimpanzee HumanLong-tailed macaque

wmwm wm

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Figure 3 Cytoarchitecture of primary somatosensory cortex (area 3b) in long-tailed macaque (Macaca fascicularis), chimpanzee

(Pan troglodytes), and human (Homo sapiens), showing interspecific variation in the thickness of the cortex. Scale bar: 250 mm.

Saimiri

CO

CB

NPNF

Cat-301

Macaca Pan Homo

Figure 4 Comparative chemoarchitecture of layer IV in

primary visual cortex of squirrel monkeys (Saimiri ), macaques

(Macaca), chimpanzees (Pan), and humans (Homo).

Reproduced from Preuss, T. M. and Coleman, G., Human-

specific organization of primary visual cortex: Alternating com-

partments of dense Cat-301 and calbindin immunoreactivity in

layer 4A, Cereb. Cortex, 2002, 12, 671–691, Oxford University

Press.


information with high acuity and color sensitivity, andproject to parvocellular layers of the LGN. In thegeniculostriate component of these parallel pathways,different systems derive from distinct portions of theLGN and synapse within separate sublayers of layerIV in primary visual cortex. The complexity of segre-gated geniculostriate projects is reflected in thedevelopment of at least three subdivisions of layer IVin primates as demarcated by Brodmann (1909). Twocell-rich layers, IVA and IVC, are separated by a cell-poor layer, IVB, which contains a dense plexus ofmyelinated axons known as the stria of Gennari.Neurons in the magnocellular layers of the LGN

project to the upper half of layer IVC. Neurons inthe parvocellular layers of the LGN project to layerIVA.

The chemoarchitecture of layer IVA is markedlydifferent in hominoids compared to other primates(Figure 4). In most monkeys, except the nocturnalowl monkey, there is a dense band of cytochromeoxidase (CO)-rich staining in layer IVA (reviewed inPreuss et al., 1999), reflecting high levels of meta-bolic activity within this sublayer. However, in thehominoid species examined to date (orangutans,chimpanzees, and humans), intense CO staining inlayer IVA is absent, suggesting that the direct par-vocellular-geniculate projection to layer IVA waseither reduced or more dispersed to include bothlayers IVA and IVB in the last common ancestor ofthis phylogenetic group (Preuss et al., 1999; Preussand Coleman, 2002). Primary visual cortex of greatapes and humans is further distinguished frommonkeys in having increased staining of CB-immu-noreactive (-ir) interneurons and neuropil in layerIVA (Preuss and Coleman, 2002).

Layer IVA of primary visual cortex in humansexhibits additional modifications to the basic homi-noid plan described above. In humans, a meshworkpattern is observed in which compartments of neu-ropil that stain intensively for Cat-301 andnonpyramidal NPNFP-ir cells, and neurites alter-nate with bands of high densities of CB-irinterneurons (Preuss and Coleman, 2002). Thesechanges in human primary visual cortex have beeninterpreted to reflect a closer association of thislayer to M-pathway inputs than observed in anyother primates. The functional implications of


these histological changes are unclear; however, ithas been suggested that these alterations are relatedto specializations in humans for the visual percep-tion of rapid orofacial gestures in speech (Preuss andColeman, 2002).

Another distinctive feature of primary visualcortex organization in many primates is ocular dom-inance columns, which correspond to the horizontalsegregation of inputs from the two retinas to differ-ent compartments in layer IV of primary visualcortex. Ocular dominance columns have beenanatomically demonstrated in Old World monkeys,humans, and some other primates, such as the NewWorld spider monkey and the strepsirrhine galago(reviewed in Allman and McGuinness, 1988).A similar pattern of alternating patches of ocularrepresentation within primary visual cortex hasbeen described in a chimpanzee after monocularinjection of a transneuronal tritiated tracer sub-stance (Tigges and Tigges, 1979). It is worthnoting, however, that this study revealed geniculateprojections to layer IVC, but not to layer IVA, as isobserved in monkeys.

Large pyramidal neurons, which are found at theboundary between layers V and VI, called Meynertcells, are prominent in the primary visual cortex ofprimates, and their soma size displays interspecificvariation (Figure 5) (Sherwood et al., 2003c). Thesecells can be distinguished as a unique subtype on thebasis of their morphology and connectivity. Theirthick axon collaterals project to both area MT/V5and the superior colliculus, suggesting that thesecells are involved in processing visual motion (Frieset al., 1985; Movshon and Newsome, 1996;Livingstone, 1998). In a comparative study,Meynert cell somata were found to be on average2.8 times lager than other layer V pyramidal

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Figure 5 The location and morphology of Meynert cells in an

orangutan (Pongo pygmaeus). Meynert cells are located at the

boundary between layers V and VI, as indicated by the arrow in

the Nissl-stained section (a). The morphology of Meynert cells

as revealed by immunostaining for NPNFP with Nissl counter-

stain is shown (b). Scale bar: a, 250 mm; b, 50 mm.

neurons across a range of primates (Sherwoodet al., 2003c). Because the basal dendrites andaxon collaterals of Meynert cells extend horizon-tally in layers V and VI to integrate informationand facilitate responses across widespread areas ofvisual space, interspecific variation in Meynert cellsize appears to be largely constrained by their func-tion in the repetitive stereotyped local circuits thatrepresent the retinal sheet in primary visual cortex.In the context of the general scaling patterns ofMeynert cells, it is interesting that soma volumesof these neurons fit closely with predictions amonghumans (2.84 times larger than neighboring pyra-midal cells) and gorillas (2.98 times), whereas theyare relatively large in chimpanzees (3.78 times) andrelatively small in orangutans (1.94 times). Thesedifferences in neural organization for the processingof visual motion may relate to socioecological dif-ferences among these apes. Because wildchimpanzees engage in aggressive incursions intothe territory of neighboring groups (Watts andMitani, 2001) and hunt highly mobile prey such asred colobus monkeys (Watts and Mitani, 2002), wespeculate that relatively large Meynert cells evolvedin this species to enhance detection of visual motionduring boundary patrolling and hunting. In con-trast, relatively small Meynert cells in orangutansmay relate to the fact that these apes are solitary,large-bodied, committed frugivores (van Schaik andvan Hooff, 1996), which allows them to maintainlow levels of vigilance for motions of predators,competitors, and food items.

4.21.2.4 Auditory Cortex

There are two parallel thalamocortical projectionsfrom the medial geniculate nucleus (MGN) to thesuperior temporal cortex of primates. Neurons inthe ventral division of the MGN supply a tonotopicprojection to the core region of auditory cortex(Brodmann’s areas 41 and 42). Neurons in the dor-sal and medial divisions of the MGN project toareas surrounding the core. The core region of audi-tory cortex has been identified in macaques,chimpanzees, and humans as a discrete architecturalzone as compared to the surrounding belt cortex(Hackett et al., 2001). The core can be recognizedby a broad layer IV that receives a dense thalamicprojection, heavy myelination, and intense expres-sion of acetylcholinesterase (AChE), CO, and PV inthe neuropil of layer IV. In macaques, the relativelyhigh density of cells and fibers makes the auditorycortex core appear structurally homogeneous ascompared to the hominoids. In contrast, the medialand lateral domains of the core region of auditory


cortex are more clearly differentiated in humans andchimpanzees because of the lower packing density ofstructural elements. Additionally, the network ofsmall horizontal and tangential myelinated fibers inlayer III appears most complex in humans, intermedi-ate in chimpanzees, and least elaborate in macaques.

The auditory core region is enveloped by severalhigher-order belt and parabelt fields (Figure 6). Thebelt areas of auditory cortex, which are less precisein their tonotopic organization, receive major inputsfrom the core and diffuse input from the dorsaldivision of the MGN. The belt region is borderedlaterally on the superior temporal gyrus by a para-belt region of two or more divisions that areactivated by afferents from the belt areas and the

HG

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(c)(b)

Figure 6 Cytoarchitecture of auditory cortex of an orangutan

(Pongo pygmaeus). A parasagittal section of the superior tem-

poral gyrus shows the location of regions detailed below

(a). Higher-power micrographs show cytoarchitecture in (b) the

core of primary auditory cortex (Brodmann’s area 41 or von

Economo and Koskinas’ area TC) and (c) area Tpt (posterior

Brodmann’s area 22 or von Economo and Koskinas’ area TA1).

HG, Heschl’s gyrus; PT, planum temporale; S, superior;

P, posterior. Scale bar: 500 mm.

dorsal MGN, but not the ventral MGN or the core.Interestingly, AChE-stained pyramidal cells in layerIII and V of the belt region are more numerous inchimpanzees and humans compared to macaques(Hackett et al., 2001). Neurons in the belt and para-belt project to auditory-related fields in thetemporal, parietal, and frontal cortex. Other typesof processing that occur in the other divisions ofauditory cortex are not well understood, but theyare likely to be important for higher-order proces-sing of natural sounds, including those used incommunication. Neurons in the lateral belt cortexareas of rhesus macaques, for example, respond betterto species-specific vocalizations than to energy-matched pure tone stimuli (Rauschecker et al., 1995).

The comparative anatomy of one particularregion of auditory association cortex has been stu-died most extensively. In humans, Wernicke’s area,a region important for the comprehension of lan-guage and speech, is located in the posteriorsuperior temporal cortex. Gross anatomic observa-tions indicate that asymmetries similar to humansare present in the superior temporal lobe of non-human primates, such as leftward dominance of theplanum temporale in great apes (Gannon et al.,1998; Hopkins et al., 1998) and a longer left sylvianfissure in many anthropoid species (LeMay andGeschwind, 1975; Yeni-Komshian and Benson,1976; Heilbroner and Holloway, 1988; Hopkinset al., 2000).

Several investigations have examined the micro-structure of the cortical area most closely associatedwith Wernicke’s area. Area Tpt (Galaburda et al.,1978) or area TA1 (von Economo and Koskinas,1925) comprises a portion of posteriorBrodmann’s area 22 located on the upper bank ofthe superior temporal gyrus and sometimes extend-ing to part of the parietal operculum and theconvexities of the temporal and parietal lobes(Galaburda et al., 1978). This area represents atransition between auditory association cortex andcortex of the inferior parietal lobule (Shapleskeet al., 1999). Cortex with the cytoarchitectural char-acteristics of area Tpt has been described in galagos,macaques, chimpanzees, and humans (Galaburdaand Pandya, 1982; Preuss and Goldman-Rakic,1991; Buxhoeveden et al., 2001a, 2001b). Themicrostructure of area Tpt in these primates is dis-tinguished by a eulaminate appearance, with apoorly defined border of layer IV due to theencroachment of pyramidal cells in adjacent layersIIIc and Va, and an indistinct border between layersIV and V due to curvilinear columns of neurons thatbridge the two layers (Galaburda and Sanides,1980).

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Figure 7 Cytoarchitecture of primary motor cortex and

morphology of Betz cells in an orangutan (Pongo pygmaeus).

Betz cells can be seen in the bottom of layer V, as indicated by

the arrow in the Nissl-stained section (a). The morphology of

Betz cells as revealed by immunostaining for NPNFP with Nissl

counterstain is shown (b). Scale bar: a, 250 mm; b, 50 mm.


There are differences among rhesus monkeys,chimpanzees, and humans in the details of minicol-umn structure in area Tpt. In the left hemisphere,area Tpt of humans has wider minicolumns as com-pared to macaques or chimpanzees, whereas thewidth of minicolumns is similar in the nonhumanspecies (Buxhoeveden et al., 2001b). These findingssuggest that wider minicolumns in human area Tptmay be a species-specific specialization that allowsfor more extensive neuropil space containing inter-connections among neurons.

The microstructure of area Tpt has also beenshown to be asymmetric in humans, possibly as aneural substrate of hemispheric dominance in thecerebral representation of language. Long-rangeintrinsic connections within area Tpt labeled inpostmortem brains with lipophilic dyes haverevealed greater spacing between interconnectedpatches in the left hemisphere compared to theright (Galuske et al., 2000). Furthermore, leftarea Tpt has a greater number of the largest pyr-amidal cells in layer III, known asmagnopyramidal cells, that give rise to long corti-cocortical association projections (Hutsler, 2003).In addition, AChE-rich pyramidal cells displaygreater cell soma volumes in the left hemispheredespite lacking asymmetry in number (Hutsler andGazzaniga, 1996). In humans, left area Tpt hasalso been shown to contain a greater amount ofneuropil and axons with thicker myelin sheaths(Anderson et al., 1999). Of particular significance,a comparative analysis of area Tpt found thatonly humans, but not rhesus macaques or chim-panzees, exhibit left dominant asymmetry in areaTpt, with wider minicolumns and a greater pro-portion of neuropil (Buxhoeveden et al., 2001a).

4.21.2.5 Primary Motor Cortex

The primary motor cortex (Brodmann’s area 4) hasa distinctive cytoarchitectural appearance in pri-mates (Geyer et al., 2000; Sherwood et al., 2004b),containing giant Betz cells in the lower portion oflayer V, low cell density, large cellular sizes, anindistinct layer IV, and a diffuse border betweenlayer VI and the subjacent white matter(Figure 7a). In humans, the region of primarymotor cortex that corresponds to the representationof the hand exhibits interhemispheric asymmetry inits cytoarchitectural organization. Concomitantwith strong population-wide right handedness inhumans, most postmortem brains display a greaterproportion of neuropil volume in the left hemi-sphere of this part of primary motor cortex(Amunts et al., 1996). Interestingly, brains of

captive chimpanzees (Hopkins and Cantalupo,2004) and capuchin monkeys (Phillips andSherwood, 2005) show humanlike asymmetries ofthe hand region of the central sulcus that are corre-lated with the direction of individual handpreference. However, the histology of primarymotor cortex in nonhuman primates has not yetbeen examined for asymmetry (see The Evolutionof Hemispheric Specializations of the HumanBrain).

While the cytoarchitectural organization of pri-mary motor cortex is generally similar acrossspecies, interspecific differences have beendescribed. The cytoarchitecture of the region corre-sponding to orofacial representation of primarymotor cortex in several catarrhine species (long-tailed macaques, anubis baboon, orangutans, goril-las, chimpanzees, and humans) was analyzed usingthe gray level index (GLI) method (Sherwood et al.,2004b). Compared to Old World monkeys, greatapes and humans displayed an increased relativethickness of layer III and a greater proportion ofneuropil space. A stereologic investigation ofNPNFP and calcium-binding protein-ir neuronswas also conducted in this same comparative sample(Sherwood et al., 2004a). Primary motor cortex ingreat apes and humans was characterized by agreater percentage of neurons enriched in NPNFPand PV compared to the Old World monkeys

(a)

CBCB

(b)

CRCR

(c)

PVPV

Figure 8 Calcium-binding protein-immunoreactive neurons in layer III of primary motor cortex of a chimpanzee (Pan troglodytes).

Neurons stained for CB (a), CR (b), and PV (c) are shown. Morphologically, CR-ir interneurons correspond mostly to double-bouquet

cells. They are predominantly found in layers II and III, and have narrow vertically oriented axonal arbors that span several layers. CB-

ir neurons are morphologically more varied, including double-bouquet and bipolar types, with many showing a predominantly vertical

orientation of axons. In contrast, the morphology of PV-ir interneurons includes large multipolar types, such as large basket cells and

chandelier cells, which have horizontally spread axonal arbors spanning across cortical columns within the same layer as the parent

soma. Scale bar: 50 mm.


(Figure 8). Conversely, the percentage of CB- andCR-ir neuron subtypes did not significantly differamong these species. These modifications of parti-cular subsets of neuron types might contribute to thevoluntary dexterous control of orofacial musclesexhibited in the vocal and gestural communicationof great apes and humans. Enhancement of PV-irinterneuron-mediated lateral inhibition of cell col-umns may enhance specificity in the recruitment ofdifferent muscle groups for dynamic modulation offine orofacial movements. Increased proportions ofNPNFP-ir pyramidal cells, on the other hand, maybe a correlate of greater descending cortical innerva-tion of brainstem cranial motor nuclei by heavilymyelinated axons to allow for more voluntary con-trol (Kuypers, 1958).

The giant Betz cells are found in the lower half oflayer V of primary motor cortex and possess a largenumber of primary dendritic shafts that leave thesoma at several locations around its surface(Figure 7b) (Braak and Braak, 1976; Scheibel andScheibel, 1978; Meyer, 1987). They are largest andmost numerous in the cortical representation of theleg, where axons project farther along the cortico-spinal tract to reach large masses of muscles (Lassek,1948; Rivara et al., 2003). Betz cells are stronglyimmunoreactive for NPNFP among humans, greatapes, and Old World monkeys (Sherwood et al.,2004a). An analysis of scaling of Betz cell somatavolumes in the region of hand representation ofprimates revealed that these cell subtypes becomerelatively enlarged with increases in brain and bodysize (Sherwood et al., 2003c). At larger sizes, there isan increase in the distance to the spinal representa-tion of target muscles and a greater number of lessdensely distributed corticospinal neurons (Nudoet al., 1995). In larger brains and bodies, Betz cellaxons need to become thicker to maintain conduc-tion speed to reach more distant targets in the spinal

cord. Accordingly, Betz cells are scaled to globalconnectivity constraints and therefore increase insomatic volume in a manner that is correlated withbrain size. Due to these scaling trends, among homi-noids Betz cells are relatively largest in humans(10.96 times larger than neighboring pyramidalcells), then gorillas (8.37 times), chimpanzees (7.02times), and orangutans (6.51 times).

Specializations of biochemical phenotypes areknown for certain regionally restricted subsets ofpyramidal neurons. Although calcium-binding pro-teins are expressed transiently during prenatal andearly postnatal development (Moon et al., 2002;Ulfig, 2002), their expression in pyramidal neuronsof adult mammals is more limited. Neurons expres-sing the calcium-binding proteins – CB, CR, and PV –are thought to have relatively high metabolic ratesassociated with fast repolarization for multipleaction potentials (Baimbridge et al., 1992). Whilesuch calcium buffering mechanisms are most com-monly associated with GABAergic interneurons,the presence of calcium-binding proteins in pyra-midal cells might reflect a neurochemicalspecialization for higher rates of activity. In thiscontext, it is interesting that faint CR immunoreac-tivity is observed in isolated medium- and large-sizelayer V pyramidal neurons in primary motor cortexof great apes and humans, but not in macaques orbaboons (Hof et al., 1999; Sherwood et al., 2004a).PV-ir pyramidal neurons are also very rarelyobserved in the neocortex of mammals (see TheEvolution of Neuron Classes in the Neocortex ofMammals). However, large layer V pyramidal neu-rons, including Betz cells, have been reported toexpress PV immunoreactivity in primary motorcortex of humans (Nimchinsky et al., 1997;Sherwood et al., 2004a). Evidence concerning theexistence of PV-ir pyramidal neurons in othernonhuman primates is somewhat contradictory. In

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44-Nissl 44-NPNFP

45-NPNFP45-Nissl

(a)

(c) (d)

(b)

Figure 9 The architecture of areas 44 and 45 in a chimpanzee

(Pan troglodytes). Area 44 is shown stained for Nissl substance

(a) and NPNFP (b). Area 45 is shown stained for Nissl sub-

stance (c) and NPNFP (d). Scale bar: 500 mm.


one study, PV-ir pyramidal neurons were observedin primary motor and somatosensory cortices ofgalagos and macaques (Preuss and Kaas, 1996).Another study, however, failed to label PV-ir pyr-amidal cells in macaques (DeFelipe et al., 1989),probably due to methodological discrepanciesamong experiments. A comparative study of pri-mary motor cortex using the sameimmunohistochemical procedures across speciesfound that PV-ir pyramidal neurons were eithernot present or sparse in Old World monkeys,whereas they were considerably more numerousin great apes and humans (Sherwood et al., 2004a).

4.21.2.6 Inferior Frontal Cortex

The microstructure of the inferior frontal cortex, theregion that contains Broca’s area in humans, has beendescribed in hominoids on the basis on cyto-, myelo-,and NPNFP-architecture (von Economo, 1929;Bailey and von Bonin, 1951; Braak, 1980; Amuntset al., 1999; Hayes and Lewis, 1995; Sherwood et al.,2003a). Cytoarchitectural studies of chimpanzee andorangutan frontal cortex describe a dysgranularregion anterior to the inferior precentral sulcus com-prising a part of pars opercularis and designatedBrodmann’s area 44 (von Bonin, 1949; Sherwoodet al., 2003a), FCBm (Bailey et al., 1950), or areas56 and 57 (Kreht, 1936). In chimpanzees, this regionhas been shown to receive projections from the med-iodorsal nucleus of the thalamus (Walker, 1938). Inmacaques, a field with similar cytoarchitectural char-acteristics in the caudal bank of the inferior limb ofthe arcuate sulcus has been denoted area 44, witharea 45 located rostrally (Galaburda and Pandya,1982; Petrides and Pandya, 1994). The cytoarchitec-ture of area 44 is characterized by a columnarorganization similar to ventral premotor area 6, butit is distinguished by the development of a thin layerIV and clustered magnopyramidal neurons in thedeep part of layer III. Layer IV in area 44 has anundulating appearance due to the invasion of pyra-midal cells from layer III and layer V. NPNFPstaining in area 44 of chimpanzees and humans dis-plays clusters of large pyramidal neurons at thebottom of layer III and a lower band of immunoreac-tive layer V cells and neuropil (Figure 9) (Hayes andLewis, 1995; Sherwood et al., 2003a).

The cytoarchitecture of area 45 is distinguishedfrom area 44 by the presence of a more prominentlayer IV, a more homogeneous distribution ofpyramidal cells in the deep portion of layer III,and the absence of conspicuous cell columns.NPNFP staining in area 45 is characterized by aclearer separation of immunoreactive neurons into

upper (layer III) and lower (layer V) populations andby the absence of the intensely stained magnopyra-midal clusters, as seen in area 44.

Considering the preponderance of left hemispheredominant control of language in humans, severalstudies have examined the cortex of the inferior fron-tal gyrus in humans for microstructural asymmetries.Using GLI profile analysis methods to quantify regio-nal variation in cytoarchitecture, area 44 has beenshown to display left dominance in terms of volumeand an increased proportion of neuropil space,whereas area 45 does not show a consistent directionof asymmetry (Amunts et al., 1999). In addition, thetotal length of pyramidal cell dendrites is longer inthe left opercular region of the inferior frontal gyrusdue to a selective increase in the length of higher-order segments (Scheibel et al., 1985). Using differentmethods, another study examined asymmetries inonly magnopyramidal cells in layer III of area 45and found total dendritic length, dendritic complex-ity (numbers of branches and maximal branch order),and spine densities to be greater in the right (Hayesand Lewis, 1996). In area 45, AChE-positive layer IIImagnopyramidal cells have larger somata in the lefthemisphere, despite lacking asymmetry in their den-sity (Hayes and Lewis, 1995; Garcia et al., 2004).

While asymmetries of the inferior frontal cortex arewell established in humans, the condition of nonhu-man primates is less clear. Although population-level


leftward asymmetry of the fronto-orbital sulcus, aportion of the inferior frontal gyrus, has been reportedin great apes (Cantalupo and Hopkins, 2001), itremains to be known whether humanlike microstruc-tural asymmetries are present in the inferior frontalcortex of these species. In humans and chimpanzees,the borders of areas 44 and 45 have been shown tocorrespond poorly with external sulcal landmarks(Amunts et al., 1999; Sherwood et al., 2003a). Thus,determination of whether asymmetries are evident inregional volumes and intrinsic circuitry of areas 44and 45 of great apes will require histological studies.

4.21.2.7 Prefrontal Cortex

While it has been a popular notion that human cogni-tive abilities are associated with disproportionateenlargement of the frontal or prefrontal cortex, recentdata show that the human frontal cortex is no largerthan expected for a hominoid of the same brain size(Semendeferi et al., 1997, 2002). Furthermore, pro-gressive increase in the relative size of the frontalcortex accompanies enlarging brain size for primatesin general, with hominoids simply continuing thisscaling trend (Bush and Allman, 2004a; see Scalingthe Brain and Its Connections, Encephalization:Comparative Studies of Brain Size and StructureVolume in Mammals, Do All Mammals Have aPrefrontal Cortex?). At present, the comparativequantitative data available concerning the volume ofspecific prefrontal cortical areas in hominoids arescanty, representing only areas 10 and 13 in one indi-vidual per species (Semendeferi et al., 1998, 2001).Taken together, however, it does not seem that these

Bonobo ChimpanzeeHuman

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Figure 10 The cytoarchitecture of area 13 in hominoids. Scale

A comparative study of area 13, Am. J. Phys. Anthropol.; Semendefe

W.; Copyright ª 1998, Wiley-Liss. Reprinted with permission of W

prefrontal areas are disproportionately enlarged inhumans beyond what is expected for a hominoid ofthe same brain size (Holloway, 2002). Nonetheless,quantitative cytoarchitectural analyses have shownthat some prefrontal cortical areas differ in their his-tological organization among hominoid species.

Area 13 is a dysgranular field located in theposterior orbitofrontal cortex (Figure 10). Thiscortical area is remarkably integrative, receivinginputs from olfactory, gustatory, and visceral cen-ters, as well as premotor, somatosensory,auditory, visual, and parahippocampal cortices(Carmichael and Price, 1995; Cavada et al.,2000). Damage to this region disrupts perfor-mance on tasks that require behavioral inhibitionand causes impairments in emotional control(Fuster, 1998; Roberts and Wallis, 2000). In astudy of the cytoarchitecture of area 13 acrossmacaques and hominoids, several similaritieswere observed that suggest homology amongthese species (Semendeferi et al., 1998). This cor-tical area is distinguished by a poorly definedlayer IV, horizontal striations of cells in layers Vand VI, large pyramidal cells in layer V, relativelythick infragranular layers as compared with supra-granular layers, and greater neuropil space insupragranular layers as compared with deeperlayers. Among hominoids, area 13 is located inthe posterior portion of the medial orbital andposterior orbital gyri. This concords with the ear-lier description of an area labeled FF in theposterior orbitofrontal cortex of chimpanzeesthat seems to correspond to these cytoarchitec-tural features (Bailey et al., 1950).

OrangutanGorilla Gibbon

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bar: 500 mm. Modified from Limbic frontal cortex in hominoids:

ri, K., Armstrong, E., Schleicher, A., Zilles, K., and Van Hoesen, G.

iley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.

Human Bonobo Chimpanzee Gorilla Orangutan Gibbon

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Figure 11 The cytoarchitecture of area 10 in hominoids. Scale bar: 500 mm. Modified from Prefrontal cortex in humans and apes: A

comparative study of area 10, Am. J. Phys. Anthropol.; Semendeferi, K., Armstrong, E., Schleicher, A., Zilles, K., and Van Hoesen, G.

W.; Copyright ª 2001, Wiley-Liss. Reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.


While general similarities are found in thecytoarchitecture of area 13 of hominoids, quantita-tive analyses have identified some interspecificdifferences. For example, layer IV in orangutans isrelatively wide, making this cortex appear moresimilar to granular prefrontal cortex. Compared toother hominoids, area 13 in humans and bonobosoccupies a small proportion of total brain volumeand more cytoarchitectonic subdivisions occupy theorbitofrontal cortex adjacent to area 13. In contrast,area 13 of orangutans is relatively large and thusoccupies the majority of the orbitofrontal region.

Area 10 is a granular cortex that forms a part ofthe frontal pole in most hominoid species, includinghumans, chimpanzees, bonobos, orangutans, andgibbons (Figure 11) (Semendeferi et al., 2001). Thiscortical area is involved in planning and decisionmaking (Fuster, 1998). Area 10 receives highly pro-cessed sensory afferents from corticocorticalconnections in addition to inputs from the mediodor-sal nucleus of the thalamus, striatum, and manylimbic structures (Ongur and Price, 2000). In homi-noids, the cytoarchitecture of area 10 is characterizedby a distinct layer II, a wide layer III with largepyramidal cells in its deep portion, a clearly differ-entiated granular layer IV, large pyramidal cells inlayer Va, and a sharp boundary between layer VI andthe white matter. Quantitative analyses reveal a simi-lar pattern of relative laminar widths among humans,chimpanzees, and bonobos, such that the supragra-nular layers are relatively thick compared to theinfragranular layers (Semendeferi et al., 2001). Incontrast, the infragranular layers comprise a greaterproportion of cortical thickness in the other homi-noids. When GLI profile curves describing laminar

variation in neuron volume densities are comparedamong taxa, apes and macaques follow a similarpattern with roughly equal GLI throughout the cor-tical depth. The proportion of neuropil space inlayers II and III relative to infragranular layers, how-ever, is greater in humans. Notably, Semendeferiet al. (2001) raise uncertainty regarding whether ahomologue of area 10 is present in gorillas. In parti-cular, the cortex of the frontal pole in gorillas has aprominent layer II and Va, features that are not foundin macaques or other hominoids.

4.21.2.8 Anterior Cingulate Cortex

In layer Vb of anterior cingulate cortex (subareas24a, 24b, and 24c), large spindle-shaped cells arefound only in great apes and humans, to the exclu-sion of hylobatids and other primates (Nimchinskyet al., 1999). These neurons have a very elongate,gradually tapering, large soma that is symmetricalabout its vertical and horizontal axes (Figure 12).This distinctive somatic morphology arises from thepresence of a large apical dendrite that extendstoward the pial surface, as well as a single largebasal dendrite that extends toward the underlyingwhite matter, without any other dendrites branch-ing from the basal aspect of the cell. These uniqueneurons are also substantially larger in size thanother neighboring pyramidal cells. Interestingly,spindle neurons increase in soma size, density, andclustering from orangutans to gorillas, chimpanzees,bonobos, and humans. Furthermore, spindle-shapedneurons have been observed in layer Vb of area 24bin a fetal chimpanzee (E 224), indicating that thisspecialized projection cell type differentiates early in

(a) (b)

Figure 12 Morphology of spindle-shaped neurons in layer Vb

of anterior cingulate cortex in a bonobo (Pan paniscus) (a) and

gorilla (Gorilla gorilla) (b). Scale bar: 80 mm. Modified from

Nimchinsky, E. A., Gilissen, E., Allman, J. M., Perl, D. P.,

Erwin, J. M., and Hof, P. R. 1999. A neuronal morphologic type

unique to humans and great apes. Proc. Natl. Acad. Sci. USA

96, 5268–5273.


development (Hayashi et al., 2001). Notably, neu-rons with a spindle phenotype also have aphylogenetically restricted distribution withinanother region, the frontoinsular cortex. Spindlecells are found in layer V in the frontoinsular cortexonly in humans and African great apes (i.e., gorillas,chimpanzees, and bonobos), being far more numer-ous in humans compared to the apes (see Role ofSpindle Cells in the Social Cognition of Apes andHumans; Hakeem et al., 2004).

In addition to spindle-shaped neurons, the anteriorcingulate cortex of great apes and humans containsanother unique pyramidal cell phenotype. A survey ofthe anterior cingulate cortex of several primate speciesrevealed a small subpopulation of CR-containinglayer V pyramidal neurons that are only found ingreat apes and humans (Hof et al., 2001). These neu-rons are located in the superficial part of layer V inareas 24 and 25. In orangutans, they comprise 0.5%of all layer V pyramidal cells in the anterior cingulate,2% in gorillas, 4.1% in chimpanzees, and 5.3% inhumans. The occurrence of these cells decreases shar-ply at the boundary between anterior and posteriorcingulate cortex, suggesting that they are not directlyinvolved in the somatic motor functions associatedwith the posterior cingulate motor areas.

The restricted phylogenetic distribution of spin-dle-shaped cells and CR-ir pyramidal neurons inlayer V of anterior cingulate cortex may reflect spe-cializations of projection neurons in this region for arole in the control of vocalization, facial expression,attention, the expression and interpretation of emo-tions, and autonomic functions (Nimchinsky et al.,1999; Allman et al., 2001; Hof et al., 2001). Ofparticular interest, in humans, CR-immunoreactive

layer V pyramidal neurons are also present in theanterior paracingulate cortex (area 32) (Hof et al.,2001). The presence of this distinctive projectioncell type in area 32 of humans is intriguing, consid-ering that this cortical area has been found to berecruited in tasks that require theory of mind(Gallagher et al., 2000), which is the capacity toattribute mental states such as attention, intention,and beliefs to others and may be a cognitive capacitythat is exclusive to humans (Tomasello et al., 2003).

4.21.3 Patterns of CorticalOrganization in Hominoids

4.21.3.1 The Emergence of Cell Types andTheir Distribution

Particular cellular subtypes appear to have phylo-genetically restricted distributions. It is interestingthat among hominoids, the presence of these uniqueneuron phenotypes accords with the hierarchicalnested structure of monophyletic taxa, suggestingthat they are indicators of phylogenetic relation-ships (Table 2). For example, in all great apes andhumans, spindle-shaped neurons are found in layerV of anterior cingulate cortex. Also in these taxa,CR-ir pyramidal cells are found in layer V of ante-rior cingulate cortex and primary motor cortex. Injust African great apes and humans, layer V spindle-shaped neurons are found in frontoinsular cortex.And only in humans, CR-ir pyramidal neurons inlayer V are found in anterior paracingulate cortex.Thus, novel neuron phenotypes have appeared atseveral different times in hominoid evolution.

It is tempting to speculate that the evolution ofeach unique neuron type marks specializations ofthe cortical areas involved. In particular, the mor-phomolecular characteristics of these novel neurontypes suggest that there have been modifications ofspecific efferent projections to facilitate high levelsof activity or higher conduction velocity for outputs.The possibility that the great ape and human clade isdistinguished by such specializations of projectioncells is especially intriguing in light of recent hypoth-eses that intelligence among mammals is correlatedwith the rate of information processing capacity asrepresented by axonal conduction speed (Roth andDicke, 2005). The presence of unique neuron classesin great apes and humans extends this hypothesis tosuggest that specific cortical efferents located withinbehaviorally relevant circuits may be selectivelymodified. It is also significant that a common fea-ture of these novel projection cells is theirlocalization in layer V. This laminar distributionindicates that evolutionary modifications have

Table 2 Phylogenetic distribution of some cortical histological traits

Cortical area Layer Trait

Homo

sapiens

Pan

paniscus

Pan

troglodytes

Gorilla

gorilla

Pongo

pygmaeus

Hylobates

sp.

Macaca

sp.

Primary motor cortexa Layer V CR-ir pyramidal

neurons

þ ? þ þ þ ? �

Primary motor cortexa Layer V PV-ir pyramidal

neurons

þþ ? þþ ? þþ ? þ

Primary motor cortexa Layers

III and

V

NPNFP-ir

neurons

þþ ? þþ þþ þþ ? þ

Primary visual cortexb Layer

IVA

Loss of CO-

dense band

þ ? þ ? þ ? �


IVA

Dense CB-ir

neurons and

neuropil

þ ? þ ? þ ? �


IVA

Meshwork with

dense

NPNFP and

Cat-301

staining in

mesh bands

alternating

with dense

CB in

interstitial

zones

þ ? � ? � ? �

Auditory belt cortexc Layers

III and

V

AChE-stained

pyramidal

cells

þþ ? þþ ? ? ? þ

Anterior cingulate

cortexdLayer

Vb

Spindle-shaped

neurons

þþ þþ þþ þ þ � �

Anterior cingulate

cortexeLayer

Vb

CR-ir pyramidal

neurons

þþ ? þþ þ þ ? �

Anterior paracingulate

cortexeLayer

Vb

CR-ir pyramidal

neurons

þ ? � � � ? �

Frontoinsular cortexf Layer

Vb

Spindle-shaped

neurons

þþ þ þ þ � � �

aSherwood et al. (2004a).bPreuss and Coleman (2002).cHackett et al. (2001).dNimchinsky et al. (1999).eHof et al. (2001).fHakeem et al. (2004).

þ, present; þþ, present and abundant in comparison to other species; �, absent.


been focused upon descending cortical control overtargets in the brainstem and spinal cord.

4.21.3.2 The Evolution of Cortical Asymmetries

A substantial body of evidence shows that thehuman cerebral cortex expresses lateralization inthe control of language and fine motor actions ofthe hand (Toga and Thompson, 2003). Asymmetriesin histological structure have been demonstratedacross cortical areas implicated in these processesin humans, including Broca’s area (areas 44 and 45),Wernicke’s area (area Tpt), and the hand representa-tion of primary motor cortex (area 4). Some authorshave hypothesized that these anatomical asymmetries

are exclusive adaptations of the human brain that areencoded genetically and comprise the chief evolution-ary novelty in the speciation of modern humans(Crow, 2000; Annett, 2002).

An alternative view is that functional and anato-mical lateralization may be a byproduct ofincreases in overall brain size (Ringo et al., 1994;Hopkins and Rilling, 2000). One cost of increasingbrain size is that axons must propagate actionpotentials over a greater distance to communicatebetween the hemispheres (Harrison et al., 2002).While these delays in conduction can be overcometo some extent by increasing axon cross-sectionalarea and myelination (Changizi, 2001), the designproblems associated with large brains ultimately


may necessitate increased modularity of processingand more of an emphasis on local network connec-tivity (Kaas, 2000). In particular, as brains grow insize, the efficiency of interhemispheric transfer ofinformation by long connections diminishesbecause costs, in terms of wiring space, dictatethat axons cannot increase cross-sectional area suf-ficiently to keep pace with demands for processingspeed (Aboitiz and Montiel, 2003). Hence, it isexpected that cortical processes in large brains,especially those that depend on rapid computa-tions, will come to rely on specialized processingthat is dominant in one hemisphere. Indeed, it hasbeen shown that increasing brain size is accompa-nied by reduced hemispheric interconnectivity viathe corpus callosum (Ringo et al., 1994; Olivareset al., 2001) and the development of more pro-nounced gross cerebral asymmetries amonganthropoid primates (Hopkins and Rilling, 2000).

One consequence of lateralized hemispheric spe-cialization of function may be divergence in thehistological organization of homotopic corticalareas. Unfortunately, there is a surprising absence ofdata from nonhumans concerning microstructuralasymmetries in the homologues of Broca’s area,Wernicke’s area, and primary motor cortex. At pre-sent, the sole study of such histological asymmetryindicates that lateralization is not present in area Tptof chimpanzees or macaques, while asymmetry ofneuropil space and minicolumn widths are observedin humans (Buxhoeveden et al., 2001a). Althoughthis is an important finding, it should be kept inmind that there are many other aspects of microstruc-tural organization that have been demonstrated to beasymmetric in the human cortex, such as distribu-tions of cell volumes and dendritic geometry, whichhave yet to be investigated in other species. Thus, atthe present time, there are still insufficient data toadequately resolve whether many of the observedmicrostructural asymmetries of the human cerebralcortex are unique species-specific adaptations thatare related to language and handedness.

4.21.3.3 How Much Variation in CorticalArchitecture Can be Attributed to Scalingversus Specialization?

Interpretation of interspecific differences in the his-tological structure of the cortex in hominoidsrequires parsing the source of this variation.Certainly a portion of it can be attributed to specificalterations of circuitry that generate behavioral dif-ferences among species. Another cause, however,may be the effects of allometric scaling. That is, asoverall brain size changes, predictable changes

occur in cell sizes, cell packing density, dendriticgeometries, and other aspects of microstructure(Jerison, 1973; Striedter, 2005). Thus, with varia-tion in brain size among hominoids, some of theobserved interspecific differences may simply bethe result of scaling to maintain functional equiva-lence and may not indicate any significantdifferences in computational capacities. For exam-ple, how can we know whether greater densities ofAChE-stained neurons in the auditory belt of homi-noids (Hackett et al., 2001) is of functionalimportance until we have developed a clearer under-standing of the scaling principles that govern thedistribution of AChE-enriched neurons in general?Hence, whenever possible it is best to evaluate phy-logenetic variation in cortical histology from theperspective of allometric scaling. Accordingly, thecase for declaring that a trait is a phylogenetic spe-cialization is strengthened when it can bedemonstrated that individual species depart fromallometric expectations or that an entire clade scalesalong a different trajectory (i.e., grade shift).

It is well established that cortical neuron densityvaries among mammalian species. Across a largesample of mammals ranging from mouse to ele-phant, there is a negative correlation betweencortical neuron density and brain size that followsa �1/3 power law (Tower, 1954; Cragg, 1967;Haug, 1987; Prothero, 1997). Despite this broadtrend, however, some evidence suggests that neurondensities may be higher in hominoids (gorilla, chim-panzee, and human) than expected for their brainsize (Haug, 1987). It has also been shown that thefraction of the cortex that is comprised by neuropilspace versus cell somata increases in a negative allo-metric fashion with greater brain size (Shariff, 1953;Tower, 1954; Bok, 1959; Tower and Young, 1973;Zilles et al., 1982; Armstrong et al., 1986; Haug,1987). These empirical findings fit with a modelpredicting that a constant average percent intercon-nectedness among neurons cannot feasibly bemaintained in the face of increasing gray mattervolume, so the reach of processing networks cannotkeep pace with brain size variation (Changizi,2001).

Many of these theories concerning the scaling ofnetwork connectedness across brain size, however,were developed to explain variation in mouse-to-elephant comparisons. Are these predicted allo-metric relationships between neuron density,neuropil space, and brain size maintained whencomparisons are restricted to the hominoids?Table 3 shows the results of stereologic estimatesof neuron density and GLI from recent compara-tive studies of areas 4, 10, and 13 in hominoids.

Table 3 Neuron densities (in neurons per mm3) and gray level index (GLI) values for different cortical areas in hominoids and Old

World monkeys

Area 4a Area 10b Area 13c

Species GLI Neuron density GLI Neuron density GLI Neuron density

Homo sapiens 11.65 18 048 15.17 34 014 14.18 30 351

Pan troglodytes 13.19 22 177 17.52 60 468 18.63 50 686

Pan paniscus 18.17 55 690 16.98 44 111

Gorilla gorilla 8.76 24 733 15.87 47 300 14.62 54 783

Pongo pygmaeus 10.61 18 825 20.10 78 182 18.55 42 400

Hylobates lar 19.80 86 190 13.33 53 830

Macaca sp. 15.58 50 798 20.34 18.36

Papio anubis 14.85 33 661

aSherwood et al. (2003b); Sherwood et al. (2004b).bSemendeferi et al. (2001).cSemendeferi et al. (1998).

In all studies, neuron densities were estimated by the optical disector method.


In most of these cortical areas, there is not asignificant correlation between neuron densitiesor GLI and brain size. The one exception is pre-frontal area 10 neuron density, which scalesagainst brain weight with a reduced major axisslope of �0.42 based on log-transformed data(p¼ 0.03, n¼ 6). Therefore, the mammal-widerelationship between these parameters and brainsize may not explain interspecific variance ininterconnectedness within all cortical areas ofhominoids. This raises the interesting possibilitythat differences among hominoid species in thesevariables might instead correspond to functionallysignificant modifications in the organization ofcortical interconnections.

Other aspects of network scaling in the cerebralcortex are less well understood. For example, theredoes not appear to be a correlation between brainsize and the density of glial cells (Tower and Young,1973; Haug, 1987). However, phylogenetic differ-ences in glial cell densities have not yet beensystematically examined using modern immunohis-tochemical markers to identify astrocytes andoligodendrocytes separately. Furthermore, ques-tions regarding the scaling of subpopulations ofinterneurons and pyramidal cells have only begunto be addressed. Evidence suggests that the propor-tion of pyramidal neurons that are enriched inNPNFP may increase with brain size. In the oro-facial representation of primary motor cortex,there is a striking increase in the percentage of neu-rons stained for NPNFP in larger-brained great apesand humans in comparison to smaller-brained OldWorld monkeys (Sherwood et al., 2004a). Tsanget al. (2000) also found increasing NPNFP labelingin primary motor cortex across a sample including

rats, marmosets, rhesus macaques, and humans. Inaddition, Campbell and Morrison (1989) found alarger proportion of NPNFP-ir pyramidal neurons,particularly in supragranular layers, in humanscompared to macaque monkeys across several dif-ferent cortical areas.

Interneuron subtypes, as revealed by labeling forcalcium-binding proteins, appear to adhere to differ-ent scaling trends in anthropoid primates dependingon the cortical area. For example, when regressed ontotal neuron density, the density of PV-ir neuronsscales with negative allometry in the primary motorcortex and thus a greater proportion of PV-ir neuronsis observed in hominoids compared to Old Worldmonkeys (Sherwood et al., 2004a). In contrast, CB-ir neurons scale against total neuron density withpositive allometry in areas V1 and V2, resulting in asmaller percentage of CB-ir interneurons in apescompared to monkeys in these areas (Sherwoodet al., 2005). Further studies using allometricapproaches to examine the scaling of different neu-ron subtypes will be necessary to elucidatephylogenetic specializations of cortical circuitry.

4.21.3.4 Genomic Data Provide Insightsinto Cortical Specializations

Recent studies of phylogenetic variation in genesequences and expression provide additionalinsights into cortical specializations among homi-noids. While most of these studies have beendirected at determining the genetic basis for humanneural uniqueness (Enard et al., 2002a, 2002b;Caceres et al., 2003; Dorus et al., 2004; Uddinet al., 2004), some molecular data point to changesthat occurred at earlier times in the hominoid


radiation. For instance, all hominoids have evolveda novel biochemical mechanism to support highlevels of glutamate flux in neurotransmissionthrough the retroposition of the gene GLUD1(Burki and Kaessmann, 2004). This duplicatedgene, GLUD2, which is unique to hominoids,encodes an isotype of the enzyme glutamate dehy-drogenase that is expressed in astrocytes. Allhominoid GLUD2 sequences contain two keyamino acid substitutions that allow the GLUD2enzyme to be activated in astrocytes during condi-tions of high glutamatergic neurotransmitter flux.Concordant with this evidence for alterations in themolecular machinery necessary for enhanced neuro-nal activity in apes, it has been shown that the geneencoding the cytochrome c oxidase subunit 4-1underwent rapid nonsynonymous evolution in thehominoid stem, followed by purifying selection indescendent lineages (Wildman et al., 2002). Becausethese nucleotide substitutions have functional con-sequences for the manner and rate at whichelectrons are transferred from cytochrome c to oxy-gen, it is likely that these modifications wereselected to serve the needs of cells with high aerobicenergy demands, such as neurons.

Also of significance, an alternative splice variant ofneuropsin (type II) has originated in recent hominoidevolution (Li et al., 2004). Neuropsin is expressed inhippocampal pyramidal neurons and is involved inneuronal plasticity. The high incidence of poly-morphisms in the coding region of this protein ingibbons and orangutans, however, suggests that itmay not be functional in these species. In contrast,the coding region of the type II splice form of neu-ropsin shows relatively little variation in gorillas,chimpanzees, and humans, signifying that it is main-tained by functional constraint and that it might beinvolved in a molecular pathway important for learn-ing and memory in these hominoids.

With respect to brain size, several genes that areinvolved in controlling the development of cerebralcortex size have undergone accelerated rates ofsequence evolution in the hominoid lineage. Themicrocephalin gene shows an upsurge of nonsynon-ymous amino acid substitutions in a protein-codingdomain of the last common ancestor of great apesand humans (Wang and Su, 2004). Additionally, theASPM gene shows evidence of adaptive sequenceevolution in all African hominoids (i.e., gorillas,chimpanzees, bonobos, and humans) (Kouprinaet al., 2004).

These data put into phylogenetic context evidencethat, in the lineage leading to humans, several genesimportant in the development, physiology, and func-tion of the cerebral cortex show positive selection

(Enard et al., 2002b; Dorus et al., 2004; Evanset al., 2004). Furthermore, findings from studiesthat have compared human and chimpanzee tran-scriptomes indicate that the human cerebral cortexis distinguished by elevated expression levels of manygenes associated with energy metabolism (Cacereset al., 2003; Uddin et al., 2004), suggesting that levelsof neuronal activity might be higher in humans com-pared to chimpanzees (Preuss et al., 2004). While thephenotypic correlates of many of these geneticchanges await characterization by in situ hybridiza-tion and immunohistochemical studies, it is clear thatintensified efforts at analyzing variation in the histo-logical organization of the hominoid cerebral cortexwill be necessary if there is any hope of understand-ing how such molecular differences translate intomodifications of the computational capacities of cor-tical circuits.

4.21.3.5 On the Horizon

There remains an extraordinary amount to learnregarding the microstructure of the cerebral cortexof hominoids. Even the basic cytoarchitecture ofmany cortical areas, such as the posterior parietalcortex, inferior temporal cortex, posterior cingulatecortex, and premotor cortex, has not yet beenexplored using the methods of modern quantitativeneuroanatomy. Moreover, there is not a singlerecent study of parcellation for any part of the cere-bral cortex using chemoarchitectural stainingtechniques in apes. It will also be important toexamine the scaling patterns that govern the distri-bution of neurochemically identified subsets ofpyramidal neurons, interneurons, and glia acrossdifferent cortical areas from a broad phylogeneticperspective in order to clearly distinguish networkallometric scaling from phylogenetic specialization.Finally, determination of whether humanlike histo-logical asymmetries of cortical areas important inlanguage and control of the hand are present inother apes still requires systematic study. By takingseriously the task of understanding such species-specific neural adaptations, we stand to learn anextraordinary amount about the underlying sub-strates of the cognitive abilities of humans and ourclosest relatives.

Acknowledgments

This work was supported by the National ScienceFoundation (BCS-0515484 and BCS-0549117), theWenner-Gren Foundation for AnthropologicalResearch, and the James S. McDonnell Foundation(22002078). The great ape brain materials were


available from the Great Ape Aging Project,Cleveland Metroparks Zoo, and the Foundationfor Comparative and Conservation Biology.

References

Aboitiz, F. and Montiel, J. 2003. One hundred million years of

interhemispheric communication: The history of the corpus

callosum. Braz. J. Med. Biol. Res. 36, 409–420.Allman, J. 1990. Evolution of neocortex. In: Cerebral Cortex

(eds. E. G. Jones and A. Peters), pp. 269–283. Plenum Press.Allman, J. and McGuinness, E. 1988. Visual Cortex in primates.

In: Comparative Primate Biology, Neurosciences (eds. H.Steklis and J. Erwin), pp. 279–326. Alan, R. Liss.

Allman, J. M., Hakeem, A., Erwin, J. M., Nimchinsky, E., andHof, P. 2001. The anterior cingulate cortex. The evolution of

an interface between emotion and cognition. Ann. NY Acad.Sci. 935, 107–117.

Amunts, K., Schlaug, G., Schleicher, A., et al. 1996. Asymmetry

in the human motor cortex and handedness. Neuroimage 4,

216–222.Amunts, K., Schleicher, A., Burgel, U., Mohlberg, H.,

Uylings, H. B., and Zilles, K. 1999. Broca’s region revisited:Cytoarchitecture and intersubject variability. J. Comp.Neurol. 412, 319–341.

Anderson, B., Southern, B. D., and Powers, R. E. 1999. Anatomic

asymmetries of the posterior superior temporal lobes: A post-

mortem study. Neuropsychiat. Neuropsychol. Behav. Neurol.12, 247–254.

Annett, M. 2002. Handedness and Brain Asymmetry: The Right

Shift Theory. Psychology Press.Armstrong, E., Zilles, K., Schlaug, G., and Schleicher, A. 1986.

Comparative aspects of the primate posterior cingulate cor-tex. J. Comp. Neurol. 253, 539–548.

Bailey, P. and von Bonin, G. 1951. The Isocortex of Man.University of Illinois Press.

Bailey, P., von Bonin, G., and McCulloch, W. S. 1950. TheIsocortex of the Chimpanzee. University of Illinois Press.

Baimbridge, K. G., Celio, M. R., and Rogers, J. H. 1992.Calcium-binding proteins in the nervous system. TrendsNeurosci. 15, 303–308.

Barton, R. A. and Harvey, P. H. 2000. Mosaic evolution of brain

structure in mammals. Nature 405, 1055–1058.Beck, E. 1929. Die myeloarchitektonische Bau des in der

Sylvischen Furche gelegenen Teiles des Schlafenlappens beim

Schimpansen (Troglodytes niger). J. Psychol. Neurol. 38,

309–420.Begun, D. R. 2003. Planet of the apes. Sci. Am. 289, 74–83.Blinkov, S. M. and Glezer, I. I. 1968. The Human Brain in Figures

and Tables: A Quantitative Handbook. Plenum.Bok, S. T. 1959. Histonomy of the Cerebral Cortex. Van

Nostrand-Reinhold.Braak, H. 1980. Architectonics of the Human Telecephalic

Cortex. Springer.Braak, H. and Braak, E. 1976. The pyramidal cells of Betz within

the cingulate and precentral gigantopyramidal field in the

human brain. A Golgi and pigmentarchitectonic study. CellTissue Res. 172, 103–119.

Brodmann, K. 1909. Vergleichende Lokalisationslehre der

Grosshirnrinde in ihren Prinzipien dargestellt auf Grund desZellenbaues. Barth.

Burki, F. and Kaessmann, H. 2004. Birth and adaptive evolutionof a hominoid gene that supports high neurotransmitter flux.

Nat. Genet. 36, 1061–1063.

Bush, E. C. and Allman, J. M. 2004a. The scaling of frontal

cortex in primates and carnivores. Proc. Natl. Acad. Sci.USA 101, 3962–3966.

Bush, E. C. and Allman, J. M. 2004b. Three-dimensional struc-ture and evolution of primate primary visual cortex. Anat.Rec. 281A, 1088–1094.

Buxhoeveden, D. P., Switala, A. E., Litaker, M., Roy, E., and

Casanova, M. F. 2001a. Lateralization of minicolumns in

human planum temporale is absent in nonhuman primate

cortex. Brain Behav. Evol. 57, 349–358.Buxhoeveden, D. P., Switala, A. E., Roy, E., Litaker, M., and

Casanova, M. F. 2001b. Morphological differences betweenminicolumns in human and nonhuman primate cortex. Am. J.Phys. Anthropol. 115, 361–371.

Caceres, M., Lachuer, J., Zapala, M. A., et al. 2003. Elevated

gene expression levels distinguish human from non-human

primate brains. Proc. Natl. Acad. Sci. USA 100,

13030–13035.Campbell, A. W. 1905. Histological Studies on the Localisation

of Cerebral Function. Cambridge University Press.Campbell, M. J. and Morrison, J. H. 1989. Monoclonal antibody

to neurofilament protein (SMI-32) labels a subpopulation ofpyramidal neurons in the human and monkey neocortex.

J. Comp. Neurol. 282, 191–205.Cantalupo, C. and Hopkins, W. D. 2001. Asymmetric Broca’s

area in great apes. Nature 414, 505.Carmichael, S. T. and Price, C. J. 1995. Limbic connections of the

orbital and medial prefrontal cortex in macaque monkeys.

J. Comp. Neurol. 363, 615–641.Cavada, C., Company, T., Tejedor, J., Cruz-Rizzolo, R. J., and

Reinoso-Suarez, F. 2000. The anatomical connections of the

macaque monkey orbitofrontal cortex. A review. Cereb.Cortex 10, 220–242.

Changizi, M. A. 2001. Principles underlying mammalian neocor-tical scaling. Biol. Cybern. 84, 207–215.

Colombo, J. A. 1996. Interlaminar astroglial processes in thecerebral cortex of adult monkeys but not of adult rats. ActaAnat. (Basel) 155, 57–62.

Colombo, J. A. and Reisin, H. D. 2004. Interlaminar astroglia of

the cerebral cortex: A marker of the primate brain. Brain Res.1006, 126–131.

Colombo, J. A., Fuchs, E., Hartig, W., Marotte, L. R., and

Puissant, V. 2000. ‘Rodent-like’ and ‘primate-like’ types of

astroglial architecture in the adult cerebral cortex of mammals:A comparative study. Anat. Embryol. (Berl.) 201, 111–120.

Colombo, J. A., Sherwood, C. C., and Hof, P. R. 2004.Interlaminar astroglial processes in the cerebral cortex of

great apes. Anat. Embryol. (Berl.) 208, 215–218.Cragg, B. G. 1967. The density of synapses and neurones in the

motor and visual areas of the cerebral cortex. J. Anat. 101,

639–654.Crow, T. J. 2000. Schizophrenia as the price that Homo

sapiens pays for language: A resolution of the central

paradox in the origin of the species. Brain Res. Rev. 31,118–129.

de Winter, W. and Oxnard, C. E. 2001. Evolutionary radiationsand convergences in the structural organization of mamma-

lian brains. Nature 409, 710–714.DeFelipe, J. 1997. Types of neurons, synaptic connections and

chemical characteristics of cells immunoreactive for calbin-

din-D28k, parvalbumin and calretinin in the neocortex.

J. Chem. Neuroanat. 14, 1–19.DeFelipe, J., Hendry, S. H., and Jones, E. G. 1989. Visualization

of chandelier cell axons by parvalbumin immunoreactivity inmonkey cerebral cortex. Proc. Natl. Acad. Sci. USA 86,

2093–2097.


Dorus, S., Vallender, E. J., Evans, P. D., et al. 2004. Accelerated

evolution of nervous system genes in the origin of Homosapiens. Cell 119, 1027–1040.

Enard, W., Khaitovich, P., Klose, J., et al. 2002a. Intra- andinterspecific variation in primate gene expression patterns.

Science 296, 340–343.Enard, W., Przeworski, M., Fisher, S. E., et al. 2002b. Molecular

evolution of FOXP2, a gene involved in speech and language.

Nature 418, 869–872.Evans, P. D., Anderson, J. R., Vallender, E. J., et al. 2004.

Adaptive evolution of ASPM, a major determinant of cerebral

cortical size in humans. Hum. Mol. Genet. 13, 489–494.Filimonoff, I. N. 1933. Uber die Variabilitat der

Großhirnrindenstruktur. Mitteilung III. Regio occipitalis beiden hoheren und niederen Affen. J. Psychol. Neurol. 45, 69–137.

Finlay, B. L. and Darlington, R. B. 1995. Linked regularities inthe development and evolution of mammalian brains. Science268, 1578–1584.

Fries, W., Keizer, K., and Kuypers, H. G. 1985. Large layer VI

cells in macaque striate cortex (Meynert cells) project to both

superior colliculus and prestriate visual area V5. Exp. BrainRes. 58, 613–616.

Fuster, J. M. 1998. The Prefrontal Cortex. Raven Press.Galaburda, A. and Sanides, F. 1980. Cytoarchitectonic organiza-

tion of the human auditory cortex. J. Comp. Neurol. 190,

597–610.Galaburda, A. M. and Pandya, D. N. 1982. Role of architec-

tonics and connections in the study of primate brainevolution. In: Primate Brain Evolution: Methods and

Concepts (eds. E. Armstrong and D. Falk), pp. 203–216.

Plenum.Galaburda, A. M., Sanides, F., and Geschwind, N. 1978. Human

brain. Cytoarchitectonic left–right asymmetries in the tem-

poral speech region. Arch. Neurol. 35, 812–817.Gallagher, H. L., Happe, F., Brunswick, N., Fletcher, P. C.,

Frith, U., and Frith, C. D. 2000. Reading the mind in cartoonsand stories: An fMRI study of ‘theory of mind’ in verbal and

nonverbal tasks. Neuropsychologia 38, 11–21.Galuske, R. A., Schlote, W., Bratzke, H., and Singer, W. 2000.

Interhemispheric asymmetries of the modular structure in

human temporal cortex. Science 289, 1946–1949.Gannon, P. J., Holloway, R. L., Broadfield, D. C., and

Braun, A. R. 1998. Asymmetry of chimpanzee planum tem-

porale: Humanlike pattern of Wernicke’s brain language areahomolog. Science 279, 220–222.

Garcia, R. R., Montiel, J. F., Villalon, A. U., Gatica, M. A., andAboitiz, F. 2004. AChE-rich magnopyramidal neurons have a

left–right size asymmetry in Broca’s area. Brain Res. 1026,

313–316.Geyer, S., Matelli, M., Luppino, G., and Zilles, K. 2000.

Functional neuroanatomy of the primate isocortical motor

system. Anat. Embryol. (Berl.) 202, 443–474.Glezer, I. I. 1958. Area relationships in the precentral region in

a comparative-anatomical series of primates. Arkh. Anat.2, 26.

Goodman, M., Grossman, L. I., and Wildman, D. E. 2005.Moving primate genomics beyond the chimpanzee genome.

Trends Genet. 21, 511–517.Groves, C. 2001. Primate Taxonomy. Smithsonian Institute Press.

Grunbaum, A. S. F. and Sherrington, C. S. 1903. Observations onthe physiology of the cerebral cortex of the anthropoid apes.

Proc. R. Soc. 72, 152–155.Hackett, T. A., Preuss, T. M., and Kaas, J. H. 2001. Architectonic

identification of the core region in auditory cortex of maca-

ques, chimpanzees, and humans. J. Comp. Neurol. 441,

197–222.

Hakeem, A., Allman, J., Tetreault, N., and Semendeferi, K. 2004.

The spindle neurons of frontoinsular cortex (area FI) areunique to humans and African great apes. Am. J. Phys.Anthropol. 38, 106.

Harrison, K. H., Hof, P. R., and Wang, S. S. 2002. Scaling laws in

the mammalian neocortex: Does form provide clues to func-

tion? J. Neurocytol. 31, 289–298.Haug, H. 1956. Remarks on the determination and significance

of the gray cell coefficient. J. Comp. Neurol. 104, 473–493.Haug, R. 1987. Brain sizes, surfaces, and neuronal sizes of the

cortex cerebri: A stereological investigation of man and his

variability and a comparison with some mammals (primates,whales, marsupials, insectivores, and one elephant). Am.J. Anat. 180, 126–142.

Hayashi, M., Ito, M., and Shimizu, K. 2001. The spindle neurons

are present in the cingulate cortex of chimpanzee fetus.

Neurosci. Lett. 309, 97–100.Hayes, T. L. and Lewis, D. A. 1995. Anatomical specializations

of the anterior motor speech area: Hemispheric differences in

magnopyramidal neurons. Brain Lang. 49, 289–308.Hayes, T. L. and Lewis, D. A. 1996. Magnopyramidal neurons in

the anterior motor speech region. Dendritic features and inter-hemispheric comparisons. Arch. Neurol. 53, 1277–1283.

Heilbroner, P. L. and Holloway, R. L. 1988. Anatomical brainasymmetries in New World and Old World monkeys: Stages

of temporal lobe development in primate evolution. Am.J. Phys. Anthropol. 76, 39–48.

Hof, P. R., Glezer, II, Conde, F., et al. 1999. Cellular distribution

of the calcium-binding proteins parvalbumin, calbindin, and

calretinin in the neocortex of mammals: Phylogenetic anddevelopmental patterns. J. Chem. Neuroanat. 16, 77–116.

Hof, P. R., Nimchinsky, E. A., Perl, D. P., and Erwin, J. M. 2001.An unusual population of pyramidal neurons in the anterior

cingulate cortex of hominids contains the calcium-binding

protein calretinin. Neurosci. Lett. 307, 139–142.Hoffman, P. N., Cleveland, D. W., Griffin, J. W., Landes, P. W.,

Cowan, N. J., and Price, D. L. 1987. Neurofilament gene

expression: A major determinant of axonal caliber. Proc.Natl. Acad. Sci. USA 84, 3472–3476.

Hofman, M. A. 1988. Size and shape of the cerebral cortex inmammals. II: The cortical volume. Brain Behav. Evol. 32,

17–26.Holloway, R. L. 1996. Evolution of the human brain.

In: Handbook of Human Symbolic Evolution (eds. A. Lock

and C. R. Peters), pp. 74–114. Oxford University Press.Holloway, R. L. 2002. Brief communication: How much larger is

the relative volume of area 10 of the prefrontal cortex inhumans? Am. J. Phys. Anthropol. 118, 399–401.

Holloway, R. L., Broadfield, D. C., and Yuan, M. S. 2003.

Morphology and histology of chimpanzee primary visual stri-ate cortex indicate that brain reorganization predated brain

expansion in early hominid evolution. Anat. Rec. A Discov.Mol. Cell Evol. Biol. 273, 594–602.

Hopkins, W. D. and Cantalupo, C. 2004. Handedness in chim-

panzees (Pan troglodytes) is associated with asymmetries ofthe primary motor cortex but not with homologous language

areas. Behav. Neurosci. 118, 1176–1183.Hopkins, W. D. and Rilling, J. K. 2000. A comparative MRI

study of the relationship between neuroanatomical asymme-

try and interhemispheric connectivity in primates: Implication

for the evolution of functional asymmetries. Behav. Neurosci.114, 739–748.

Hopkins, W. D., Marino, L., Rilling, J. K., and MacGregor, L. A.

1998. Planum temporale asymmetries in great apes asrevealed by magnetic resonance imaging (MRI).

Neuroreport 9, 2913–2918.


Hopkins, W. D., Pilcher, D. L., and MacGregor, L. 2000.

Sylvian fissure asymmetreis in nonhuman primates revisited:A comparative MRI study. Brain Behav. Evol. 56,

293–299.Hutsler, J. J. 2003. The specialized structure of human language

cortex: Pyramidal cell size asymmetries within auditory and

language-associated regions of the temporal lobes. BrainLang. 86, 226–242.

Hutsler, J. J. and Gazzaniga, M. S. 1996. Acetylcholinesterase stain-

ing in human auditory and language cortices: Regional variationof structural features. Cereb. Cortex 6, 260–270.

Jablonski, N. G., Whitfort, M. J., Roberts-Smith, N., andQinqi, X. 2000. The influence of life history and diet on the

distribution of catarrhine primates during the Pleistocene in

eastern Asia. J. Hum. Evol. 39, 131–157.Jackson, W. J., Reite, M. L., and Buxton, D. F. 1969. The chim-

panzee central nervous system: A comparative review.

Primates Med. 4, 1–51.Jerison, H. J. 1973. Evolution of the Brain and Intelligence.

Academic Press.Kaas, J. H. 2000. Why is brain size so important: Design pro-

blems and solutions as neocortex gets bigger or smaller. BrainMind 1, 7–23.

Kirkcaldie, M. T., Dickson, T. C., King, C. E., Grasby, D.,Riederer, B. M., and Vickers, J. C. 2002. Neurofilament

triplet proteins are restricted to a subset of neurons in the rat

neocortex. J. Chem. Neuroanat. 24, 163–171.Kortlandt, A. 1962. Chimpanzees in the wild. Sci. Am. 206,

128–134.Kouprina, N., Pavlicek, A., Mochida, G. H., et al. 2004.

Accelerated evolution of the ASPM gene controlling brain size

begins prior to human brain expansion. PLoS Biol. 2, E126.Kreht, H. 1936. Architektonik der Brocaschen Region beim

Schimpansen und Orang-Utan. Z. Anat. Entwckl. Gech.105, 654–677.

Kuypers, H. G. J. M. 1958. Some projections from the peri-central cortex to the pons and lower brainstem in monkey

and chimpanzee. J. Comp. Neurol. 110, 221–251.Lassek, A. M. 1948. The pyramidal tract: Basic considerations of

corticospinal neurons. Assoc. Res. Nerv. Ment. Dis. 27,

106–128.Lassek, A. M. and Wheatley, W. D. 1945. An enumeration of the

large motor cells of area 4 and the axons in the pyramids of

the chimpanzee. J. Comp. Neurol. 82, 299–302.LeMay, M. and Geschwind, N. 1975. Hemispheric differences in

the brains of great apes. Brain Behav. Evol. 11, 48–52.Leyton, A. S. F. and Sherrington, C. S. 1917. Observations on the

excitable cortex of the chimpanzee, orang-utan, and gorilla.Q. J. Exp. Psychol. 11, 137–222.

Li, Y., Qian, Y. P., Yu, X. J., et al. 2004. Recent origin of ahominoid-specific splice form of neuropsin, a gene involved in

learning and memory. Mol. Biol. Evol. 21, 2111–2115.Livingstone, M. S. 1998. Mechanisms of direction selectivity in

macaque V1. Neuron 20, 509–526.Markram, H., Toledo-Rodriguez, M., Wang, Y., Gupta, A.,

Silberberg, G., and Wu, C. 2004. Interneurons of the neocor-

tical inhibitory system. Nat. Rev. Neurosci. 5, 793–807.Mauss, T. 1908. Die faserarchitektonische Gliederung der

Grosshirnrinde bei den niederen Affen. J. Psychol. Neurol.13, 263–325.

Mauss, T. 1911. Die faserarchitektonische Gliederung des Cortex

cerebri von den anthropomorphen Affen. J. Psychol. Neurol.18, 410–467.

Mayer, O. 1912. Mikrometrische Untersuchungen uberZelldichtigkeit der Grosshirnrinde bei den Affen. Jahrb.Pyschol. Neurol. 17.

Meyer, G. 1987. Forms and spatial arrangement of neurons in the

primary motor cortex of man. J. Comp. Neurol. 262,402–428.

Moon, J. S., Kim, J. J., Chang, I. Y., et al. 2002. Postnataldevelopment of parvalbumin and calbindin D-28k immunor-

eactivities in the canine anterior cingulate cortex: Transient

expression in layer V pyramidal cells. Int. J. Dev. Neurosci.20, 511.

Mountcastle, V. B. 1998. Perceptual Neuroscience: The Cerebral

Cortex. Harvard University Press.Movshon, J. A. and Newsome, W. T. 1996. Visual response

properties of striate cortical neurons projecting to area MTin macaque monkeys. J. Neurosci. 16, 7733–7741.

Nimchinsky, E. A., Vogt, B. A., Morrison, J. H., and Hof, P. R.1997. Neurofilament and calcium-binding proteins in the

human cingulate cortex. J. Comp. Neurol. 384, 597–620.Nimchinsky, E. A., Gilissen, E., Allman, J. M., Perl, D. P.,

Erwin, J. M., and Hof, P. R. 1999. A neuronal morphologic

type unique to humans and great apes. Proc. Natl. Acad. Sci.USA 96, 5268–5273.

Nudo, R. J., Sutherland, D. P., and Masterton, R. B. 1995. Variation

and evolution of mammalian corticospinal somata with specialreference to primates. J. Comp. Neurol. 358, 181–205.

Olivares, R., Montiel, J., and Aboitiz, F. 2001. Species differencesand similarities in the fine structure of the mammalian corpus

callosum. Brain Behav. Evol. 57, 98–105.Ongur, D. and Price, J. L. 2000. The organization of networks

within the orbital and medial prefrontal cortex of rats, mon-

keys and humans. Cereb. Cortex 10, 206–219.Petrides, M. and Pandya, D. N. 1994. Comparative architectonic

analysis of the human and macaque frontal cortex.

In: Handbook of Neuropsychology (eds. F. Boller andJ. Grafman), pp. 17–58. Elsevier.

Phillips, K. A. and Sherwood, C. C. 2005. Primary motorcortex asymmetry is correlated with handedness in

capuchin monkeys (Cebus apella). Behav. Neurosci. 119,

1701–1704.Potts, R. 2004. Paleoenvironmental basis of cognitive evolution

in great apes. Am. J. Primatol. 62, 209–228.Preuss, T. M. 2000. Taking the measure of diversity:

Comparative alternatives to the model-animal paradigm in

cortical neuroscience. Brain Behav. Evol. 55, 287–299.Preuss, T. M. and Coleman, G. Q. 2002. Human-specific organi-

zation of primary visual cortex: Alternating compartments ofdense Cat-301 and calbindin immunoreactivity in layer 4A.

Cereb. Cortex 12, 671–691.Preuss, T. M. and Goldman-Rakic, P. S. 1991. Architectonics of

the parietal and temporal association cortex in the strepsir-

hine primate Galago compared to the anthropoid primate

Macaca. J. Comp. Neurol. 310, 475–506.Preuss, T. M. and Kaas, J. H. 1996. Parvalbumin-like immunor-

eactivity of layer V pyramidal cells in the motor andsomatosensory cortex of adult primates. Brain Res. 712,

353–357.Preuss, T. M., Qi, H., and Kaas, J. H. 1999. Distinctive compart-

mental organization of human primary visual cortex. Proc.Natl. Acad. Sci. USA 96, 11601–11606.

Preuss, T. M., Caceres, M., Oldham, M. C., and

Geschwind, D. H. 2004. Human brain evolution: Insightsfrom microarrays. Nat. Rev. Genet. 5, 850–860.

Prothero, J. 1997. Scaling of cortical neuron density and white

matter volume in mammals. J. Hirnforsch. 38, 513–524.Radinsky, L. 1974. The fossil evidence of anthropoid brain evo-

lution. Am. J. Phys. Anthropol. 41, 15–28.Rakic, P. 1988. Specification of cerebral cortical areas. Science

241, 170–176.


Rakic, P. 1995. A small step for the cell, a giant leap for mankind:

A hypothesis of neocortical expansion during evolution.Trends Neurosci. 18, 383–388.

Rauschecker, J. P., Tian, B., and Hauser, M. 1995. Processing ofcomplex sounds in macaque nonprimary auditory cortex.

Science 267, 111–114.Rilling, J. K. and Insel, T. R. 1999. The primate neocortex in

comparative perspective using magnetic resonance imaging.

J. Hum. Evol. 37, 191–223.Ringo, J. L., Doty, R. W., Demeter, S., and Simard, P. Y. 1994.

Time is of the essence: A conjecture that hemispheric specia-

lization arises from interhemispheric conduction delay. Cereb.Cortex 4, 331–343.

Rivara, C.-B., Sherwood, C. C., Bouras, C., and Hof, P. R. 2003.Stereologic characterization and spatial distribution patterns

of Betz cells in human primary motor cortex. Anat. Rec.270A, 137–151.

Roberts, A. C. and Wallis, J. D. 2000. Inhibitory control and

affective processing in the prefrontal cortex:

Neuropsychological studies in the common marmoset.Cereb. Cortex 10, 252–262.

Rockel, A. J., Hiorns, R. W., and Powell, T. P. S. 1980. The basicuniformity in structure of the neocortex. Brain 103, 221–244.

Roth, G. and Dicke, U. 2005. Evolution of the brain and intelli-gence. Trends Cogn. Sci. 9, 250–257.

Schaller, G. B. 1963. The Mountain Gorilla: Ecology andBehavior. University of Chicago Press.

Scheibel, A. B., Paul, L. A., Fried, I., et al. 1985. Dendritic organi-zation of the anterior speech area. Exp. Neurol. 87, 109–117.

Scheibel, M. E. and Scheibel, A. B. 1978. The dendritic structure ofthe human Betz cell. In: Architectonics of the Cerebral Cortex

(eds. M. A. B. Brazier and H. Pets), pp. 43–57. Raven Press.Schultz, A. 1969. The Life of Primates. Weidenfeld and

Nicholson.Semendeferi, K., Damasio, H., Frank, R., and Van Hoesen, G. W.

1997. The evolution of the frontal lobes: A volumetric analy-

sis based on three-dimensional reconstructions of magnetic

resonance scans of human and ape brains. J. Hum. Evol. 32,375–388.

Semendeferi, K., Armstrong, E., Schleicher, A., Zilles, K., andVan Hoesen, G. W. 1998. Limbic frontal cortex in hominoids:

A comparative study of area 13. Am. J. Phys. Anthropol. 106,

129–155.Semendeferi, K., Armstrong, E., Schleicher, A., Zilles, K., and

Van Hoesen, G. W. 2001. Prefrontal cortex in humans and

apes: A comparative study of area 10. Am. J. Phys. Anthropol.114, 224–241.

Semendeferi, K., Lu, A., Schenker, N., and Damasio, H. 2002.Humans and great apes share a large frontal cortex. Nat.Neurosci. 5, 272–276.

Shapleske, J., Rossell, S. L., Woodruff, P. W., and David, A. S.

1999. The planum temporale: A systematic, quantitative

review of its structural, functional and clinical significance.

Brain Res. Rev. 29, 26–49.Shariff, G. A. 1953. Cell counts in the primate cerebral cortex.

J. Comp. Neurol. 98, 381–400.Sherwood, C. C., Broadfield, D. C., Holloway, R. L.,

Gannon, P. J., and Hof, P. R. 2003a. Variability of Broca’sarea homologue in African great apes: Implications for lan-

guage evolution. Anat. Rec. 271A, 276–285.Sherwood, C. C., Holloway, R. L., Gannon, P. J., et al. 2003b.

Neuroanatomical basis of facial expression in monkeys, apes,

and humans. Ann. NY Acad. Sci. 1000, 99–103.Sherwood, C. C., Lee, P. H., Rivara, C.-B., et al. 2003c. Evolution

of specialized pyramidal neurons in primate visual and motor

cortex. Brain Behav. Evol. 61, 28–44.

Sherwood, C. C., Holloway, R. L., Erwin, J. M., and Hof, P. R.

2004a. Cortical orofacial motor representation in Old Worldmonkeys, great apes, and humans. II: Stereologic analysis of

chemoarchitecture. Brain Behav. Evol. 63, 82–106.Sherwood, C. C., Holloway, R. L., Erwin, J. M., Schleicher, A.,

Zilles, K., and Hof, P. R. 2004b. Cortical orofacial motor

representation in Old World monkeys, great apes, and

humans. I: Quantitative analysis of cytoarchitecture. BrainBehav. Evol. 63, 61–81.

Sherwood, C. C., Raghanti, M. A., Wahl, E., de Sousa, A., Erwin,J. M., and Hof, P. R. 2005. Scaling of inhibitory microcircui-

try in areas V1 and V2 of anthropoid primates as revealed by

calcium-binding protein immunohistochemistry. Soc.Neurosci. Abst., Program No. 182. 119.

Stephan, H., Frahm, H. D., and Baron, G. 1981. New and revised

data on volumes of brain structures in insectivores and pri-mates. Folia Primatol. 35, 1–29.

Strasburger, E. H. 1937a. Die myeloarchitektonische Gliederungdes Stirnhirns beim Menschen und Schimpansen. I: Teil.

Myeloarchitektonische Gliederung des menschlichen

Stirnhirns. J. Psychol. Neurol. 47, 461–491.Strasburger, E. H. 1937b. Die myeloarchitektonische Gliederung

des Stirnhirns beim Menschen und Schimpansen. II: Teil. DerFaserbau des Stirnhirns beim Schimpansen. J. Psychol.Neurol. 47, 461–491.

Striedter, G. F. 2005. Principles of Brain Evolution. SinauerAssociates.

Tigges, J. and Tigges, M. 1979. Ocular dominance columns in thestriate cortex of chimpanzee (Pan troglodytes). Brain Res.166, 386–390.

Tilney, F. and Riley, H. A. 1928. The Brain from Ape to Man.

Paul, B. Hoeber.Toga, A. W. and Thompson, P. M. 2003. Mapping brain asym-

metry. Nat. Rev. Neurosci. 4, 37–48.Tomasello, M., Call, J., and Hare, B. 2003. Chimpanzees under-

stand psychological states – the question is which ones and to

what extent. Trends Cogn. Sci. 7, 153–156.Tower, D. B. 1954. Structural and functional organization of

mammalian cerebral cortex: The correlation of neurone den-

sity with brain size. J. Comp. Neurol. 101, 19–52.Tower, D. B. and Young, O. M. 1973. The activities of butyr-

ylcholinesterase and carbonic anhydrase, the rate of anaerobicglycolysis and the question of constant density of glial cells in

cerebral cortices of mammalian species from mouse to whale.

J. Neurochem. 20, 269–278.Tsang, Y. M., Chiong, F., Kuznetsov, D., Kasarskis, E., and

Geula, C. 2000. Motor neurons are rich in non-phosphory-lated neurofilaments: Cross-species comparison and

alterations in ALS. Brain Res. 861, 45–58.

Uddin, M., Wildman, D. E., Liu, G., et al. 2004. Sister groupingof chimpanzees and humans as revealed by genome-wide

phylogenetic analysis of brain gene expression profiles. Proc.Natl. Acad. Sci. USA 101, 2957–2962.

Ulfig, N. 2002. Calcium-binding proteins in the human devel-

oping brain. Adv. Anat. Embryol. Cell Biol. 165, III–IX,1–92.

van Schaik, C. P. and van Hooff, J. A. R. A. M. 1996. Toward anunderstanding of the orangutan’s social system. In: Great Ape

Societies (eds. W. C. McGrew, L. F. Marchant, and T.

Nishida), pp. 3–15. Cambridge University Press.von Bonin, G. 1939. Studies of the size of the cells in the cerebral

cortex. III: The striate area of man, orang and cebus. J. Comp.Neurol. 70, 395–412.

von Bonin, G. 1949. Architecture of the precentral motor cortex

and some adjacent areas. In: The Precentral Motor Cortex(ed. P. C. Bucy), pp. 7–82. University of Illinois Press.


von Economo, C. 1929. The Cytoarchitectonics of the Human

Cerebral Cortex. Oxford University Press.von Economo, C. and Koskinas, G. N. 1925. Die

Cytoarchitektonik der Hirnrinde des erwachsenenMenschen. J. Springer.

Walker, A., Falk, D., Smith, R., and Pickford, M. 1983. The skullof Proconsul africanus: Reconstruction and cranial capacity.

Nature 305, 525–527.Walker, A. E. 1938. Thalamus of the chimpanzee. IV: Thalamic

projections to the cerebral cortex. J. Anat. 73, 37–93.Wang, Y. Q. and Su, B. 2004. Molecular evolution of microce-

phalin, a gene determining human brain size. Hum. Mol.Genet. 13, 1131–1137.

Watts, D. P. and Mitani, J. C. 2001. Boundary patrols and intergroup

encounters in wild chimpanzees. Behaviour 138, 299–327.Watts, D. P. and Mitani, J. C. 2002. Hunting behavior of chim-

panzees at Ngogo, Kibale National Park, Uganda. Int.J. Primatol. 23, 1–28.

Wildman, D. E., Wu, W., Goodman, M., and Grossman, L. I.

2002. Episodic positive selection in ape cytochrome c oxidasesubunit IV. Mol. Biol. Evol. 19, 1812–1815.

Wildman, D. E., Uddin, M., Liu, G., Grossman, L. I., andGoodman, M. 2003. Implications of natural selection in shap-

ing 99.4% nonsynonymous DNA identity between humans

and chimpanzees: Enlarging genus Homo. Proc. Natl. Acad.Sci. USA 100, 7181–7188.

Yeni-Komshian, G. H. and Benson, D. A. 1976. Anatomical

study of cerebral asymmetry in the temporal lobe of humans,chimpanzees, and rhesus monkeys. Science 192, 387–389.

Yerkes, R. M. and Learned, B. W. 1925. Chimpanzee Intelligence

and Its Vocal Expressions. Williams and Wilkins.Yerkes, R. M. and Yerkes, A. W. 1929. The Great Apes. Yale

University Press.Zilles, K. and Rehkamper, G. 1988. The brain, with special

reference to the telencephalon. In: Orang-utan Biology(ed. J. H. Schwartz), pp. 157–176. Oxford University Press.

Zilles, K., Stephan, H., and Schleicher, A. 1982. Quantitativecytoarchitectonics of the cerebral cortices of several prosi-

mian species. In: Primate Brain Evolution: Methods and

Concepts (eds. E. Armstrong and D. Falk), pp. 177–202.

Plenum.

Further Reading

Bailey, P., von Bonin, G., and McCulloch, W. S. 1950. TheIsocortex of the Chimpanzee. University of Illinois Press.

Holloway, R. L. 1996. Evolution of the human brain.

In: Handbook of Human Symbolic Evolution (eds. A. Lockand C. R. Peters), pp. 74–114. Oxford University Press.

Preuss, T. M. 2004. What is it like to be a human? In: The

Cognitive Neurosciences III (ed. M. S. Gazzaniga), pp. 5–22.

MIT Press.Zilles, K. 2005. Evolution of the human brain and comparative

cyto- and receptor architecture. In: From Monkey

Brain to Human Brain: A Fyssen Foundation Symposium

(eds. S. Dehaene, J. R. Duhamel, M. D. Hauser, and G.Rizzolatti), pp. 41–56. MIT Press.

4.21 the evolution of neuron types and cortical histology...

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