The Von Economo Neurons in Apes and Humans 2010-1

Raymond Pearl Memorial Lecture

The von Economo Neurons in Apes and HumansJOHN M. ALLMAN,* NICOLE A. TETREAULT, ATIYAY. HAKEEM, AND SOYOUNG PARKDivision of Biology, 216-76, California Institute of Technology, Pasadena, California 91125

ABSTRACT The von Economo neurons (VENs) are large bipolar neurons located in frontoinsular (FI) and anteriorcingulate cortex (ACC) in great apes and humans but not other primates. We stereologically counted the VENs in FIand the limbic anterior (LA) area of ACC and found them to be more numerous in humans than in apes. In humans,VENs first appear in small numbers in the 36th week postconception are rare at birth and increase in number duringthe first 8 months after birth. There are significantly more VENs in the right hemisphere than the left in FI and LA inpostnatal brains; this may be related to asymmetries in the autonomic nervous system. The activity of the inferior ante-rior insula, containing FI, is related to physiological changes in the body, decision-making, error recognition, and aware-ness. In a preliminary diffusion tensor imaging study of the connections of FI, we found that the VEN-containingregions connect with the frontal pole as well as with other parts of frontal and insular cortex, the septum, and the amyg-dala. The VENs and a related cell population, the fork cells, selectively express the bombesin peptides neuromedin B(NMB) and gastrin releasing pepide, which signal satiety. The loss of VENs and fork cells may be related to the loss ofsatiety signaling in patients with frontotemporal dementia who have damage to FI. These cells may be morphologicalspecializations of an ancient population of neurons involved in the control of appetite present in the insular cortex in allmammals. Am. J. Hum. Biol. 23:5–21, 2011. ' 2010 Wiley-Liss, Inc.

In their comprehensive study of the cytoarchitecture ofthe human cerebral cortex, von Economo and Koskinas(1925) and von Economo (2009) described large bipolarneurons in frontoinsular (FI) cortex and in the limbic an-terior (LA) area of anterior cingulate cortex. von Economo(1926) called these specialized neurons the rod and cork-screw cells, referring to the straight and twisted variantsof this distinct class of neurons. These unusual cells hadpreviously been observed by many classical neuroanato-mists including Betz (1881), Hammarberg (1895), andRamon y Cajal (1899), but von Economo (1926) made amore complete description of their morphology andmapped their specific locations in human cortex. Rose(1927) additionally described cells of this type in anteriorcingulate cortex of a chimpanzee brain. They have oftenbeen termed ‘‘spindle cells,’’ (Nimchinsky et al., 1995,1999) but because of possible confusion with other uses ofthis term, we have opted to call then von Economo neu-rons (VENs).

The VENs are projection neurons and are substantiallylarger than their pyramidal cell neighbors (Allman et al.,2001; Nimchinsky et al., 1999). They possess a single largebasal dendrite, distinguishing them from pyramidal neu-rons, which have an array of smaller basal dendrites(Watson et al., 2006). This single large basal dendrite mayhave resulted from a transformation during evolution ofthe genetic programs for pyramidal neuron developmentto modify the basal dendrite so as to concentrate itsgrowth in the primary component and suppress the sec-ondary and tertiary branching. The VENs have a narrowdendritic arborization that spans the layers of the cortexand may be able to sample and rapidly relay the outputfrom a columnar array of neurons (Watson et al., 2006).The apical and basal dendrites of the VENs are remark-ably symmetric, and this architecture suggests that theymay be comparing inputs to these two symmetric den-drites (Watson et al., 2006). The VENs in LA filled retro-gradely with the carbocyanin tracer DiI after it was depos-ited in the cingulum bundle, and thus the VENS are likely

to be projection neurons with axonal connections extend-ing through the underlying white mater to other parts ofthe brain (Nimchinsky et al., 1995). The VENs’ large sizeand preferential staining with the antibody for nonphos-phorylated neurofilament are also characteristic featuresof cortical projection neurons (Allman et al., 2002; Nim-chinsky et al., 1995).The posterior insula and anterior cingulate cortex in

anthropoid primates receive differentiated inputs sub-serving pain, itch, warmth, cooling, and sensual touch,which are central components of highly evolved mecha-nisms for physiological homeostasis (Craig, 2003, 2009).The VEN containing areas, FI, which is located in inferioranterior insula and LA, which is a component of anteriorcingulate cortex, may be considered as a further elabora-tion of these homeostatic mechanisms, which while retain-ing some aspects of their basic physiological functionssuch as appetite regulation, have extended to the regula-tion of social interactions and the homeostasis of interper-sonal relationships. The inferior anterior insula has beenfound to be consistently activated by peripheral autonomicchanges in an exhaustive meta-analysis of the imagingdata (Mutschler et al., 2009). One such connectionbetween autonomic arousal and decision-making is sug-gested by the findings of Critchley and colleagues (2000)who found that anterior insula was activated when thesubjects had increased galvanic skin responses. The activ-ity of anterior insula was also as a function of uncertaintyduring the anticipatory period in a gambling task

Contract grant sponsors: James S. McDonnell Foundation, David andLucille Packard Foundation, Simons Foundation, ‘‘Comparative Neurobiol-ogy of Aging Resource’’ NIH/NIA; Contract grant number: AG14308.

*Correspondence to: John Allman, 1200 E. California Blvd., Caltech, M.C. 216-76, Pasadena, CA 91125, USA. E-mail: [email protected]

Received 17 September 2010; Revision received 15 October 2010;Accepted 18 October 2010

DOI 10.1002/ajhb.21136

Published online 7 December 2010 in Wiley Online Library(wileyonlinelibrary.com).

AMERICAN JOURNAL OF HUMAN BIOLOGY 23:5–21 (2011)

VVC 2010 Wiley-Liss, Inc.

(Critchley et al., 2001a). Preuschoff et al. (2008) foundthat the region of anterior insula closely matching thelocation of FI was specifically activated during ‘‘risk pre-diction error’’ when the subject sustained a loss after theconsequences of gambling decision were revealed to thesubject. The anterior inferior insula, also in a locationclosely corresponding to FI, is strongly activated by nega-tive feedback in the form of frowning faces in a decisiontask involving a high degree of uncertainty (Ullspergerand von Cramon, 2004). The region corresponding to FI onthe right side is also activated when subjects scrutinize fa-cial expressions to discern intentions (Baron-Cohen et al.,1999. The integrative functioning of lateral part of FI inresponse to negative feedback is illustrated in a series ofexperiments by Jabbi et al. (2008) who elicited activity inthis VEN-rich region through the experience involvingdisgust mediated by taste by the observation of someoneelse responding to a disgusting taste and by imagining adisgusting taste. (Note, however, that the activityobserved in these experiments could also have arisen fromthe adjacent inferior frontal region.) These data togetherwith many other experiments suggest that anterior insulaand cingulate cortex are involved in the recognition oferror and the initiation of adaptive responses to error andnegative feedback (Dehaene et al., 1994; Gehring et al.,1993; Klein et al., 2007; Lamm and Singer, 2010). Anteriorinsula and anterior cingulate cortex are major compo-nents of the system for the flexible control of goal-directedbehavior (Dosenbach et al., 2007).

ANTERIOR INSULA AND ANTERIOR CINGULATE CORTEXARE ACTIVATED BY SOCIAL ERROR SIGNALS

Anterior insula and anterior cingulate cortex are acti-vated by situations that involve social error, a defect inthe social network in which the individual is participat-ing, or a change in state of one of the participants. Forexample, these structures are activated by resentment(Sanfey et al., 2003), deception (Spence et al., 2001),embarrassment (Berthoz et al., 2002), and guilt (Shinet al., 2000). They are also activated by feelings of empa-thy for the suffering of others, another type of social errorsignal (Singer et al., 2004b). In mothers, FI in the righthemisphere responds to the cries of distressed infants(Lorberbaum et al., 2002), which are a powerful socialerror signal. The anterior insula (including both superiorand inferior components) was activated when partners inthe prisoner’s dilemma game failed to reciprocate co-oper-ation moves made by the subject, which is a type of socialerror signal (Rilling et al., 2008). Anterior insula and an-terior cingulate cortex are activated by prosocial signalssuch as love and trust (Bartels and Zeki 2004; Singeret al., 2004a), which suggests that these structures regis-ter both negative and positive aspects of the states ofsocial networks. The responses of FI and LA are paramet-rically related to how humorous subjects judge cartoons tobe; the humorous content of the cartoons typicallyinvolved social errors (Watson et al., 2007).

VENS IN NEUROPSYCHIATRIC DISORDERS

The VENs are implicated in several neuropsychiatricillnesses. Seeley et al. (2006, 2007, 2008) found in a stereo-logical study that the VENs are specifically and selectivelyattacked in the early stages of the behavioral variant of

frontotemporal dementia (FTD), in which empathy, socialawareness, and self-control are severely diminished. TheVEN population of ACC is reduced by an average of 74%in these patients, and many of the surviving VENs areseverely dysmorphic. The destruction of the VENs in FTDresults from two distinct molecular mechanisms in differ-ent patients, which are related to abnormal isoforms ofthe tau protein and to abnormal cytoplasmic expression inthe cytoplasm of VENs of the DNA-binding protein, TDP-43 (Seeley, 2008; Seeley et al., 2006). The VENs are alsoreduced in FI (Seeley et al., 2007). By contrast, Seeleyet al. (2006, 2007) found that the VENs were not signifi-cantly reduced in Alzheimer’s dementia although a reduc-tion had been reported in an earlier study, which did notuse stereological methods (Nimchinsky et al., 1995). Ran-kin and colleagues (2006) systematically investigated thecapacity for empathic concern in a large population of neu-rological patients and found that this capacity was greatlyreduced in FTD patients; while this capacity was variablyexpressed in Alzheimer’s patients, it was not significantlyreduced relative to neurological normal controls.Agenesis of the corpus callosum is another condition in

which abnormal social behavior may be linked to reducedVEN populations. Patients with agenesis of the corpus cal-losum often have impoverished and superficial relation-ships, suffer from social isolation, and have interpersonalconflicts both at home and at work due to misinterpreta-tion of social cues (Paul et al., 2007). Kaufman et al.(2008) found that the VENs were reduced by 50% in a sub-ject with partial agenesis of the corpus callosum and 90%in a subject with complete agenesis compared to adult con-trols. The VEN loss could not be attributed to the reduc-tion or absence of the corpus callosum itself, because theVEN concentration in FI was normal in another subjectwhose corpus callosum was destroyed as the result of astroke 15 years before her death. Because the surgical sec-tioning of the corpus callosum does not disrupt socialbehavior (Shorvon, 2005), the social deficit in agenesis ofthe corpus callosum may be related to VEN loss. There isevidence from our diffusion tensor-imaging studies (seebelow) that FI sends fibers into the corpus callosum, butapparently the severing of this connection does not resultin a significant loss in the number of VENs in FI.There are many features of autism that suggest that the

VENs may be involved in this disorder (Allman et al.,2005; van Kooten, 2008). An initial stereological study ofthe numbers of VENs in area FI involving four autisticsubjects plus controls did not confirm this conjecture(Kennedy et al., 2007). However, a second stereologicalstudy of VENs in dorsal ACC, involving nine autistic sub-jects plus controls, found that the autistic subjects fell intotwo groups, one with significantly higher numbers ofVENs than controls, and the other which had significantlyfewer than controls VENs (Simms et al., 2009). Thus, thecontrols occupied a middle zone with little overlap withthe high or low-VEN autism groups. The Simms et al.(2009) results suggest that two different mechanismsinfluence the number of VENs in autism, possibly throughdifferent effects on migration and survival. As in FTD, inautism, the VENs may be vulnerable to more than onepathological process that may contribute to the disorderas it manifests in different individuals. A strong linkagebetween reduced activity in the right anterior insula inautistic subjects versus controls in social tasks contrastedwith nonsocial tasks was revealed in a meta-analysis of 39

6 J.M. ALLMAN ET AL.

American Journal of Human Biology

functional imaging studies (Di Martino et al., 2009). Thesestudies suggest a possible role for the VENs in autism.

VEN LOCATIONS AND STEREOLOGICAL COUNTS

The locations of the VEN-containing areas FI and LAare illustrated in three-dimensional transparent recon-structions of the right hemispheres of a chimpanzee and ahuman brain in Figures 1 and 2. These figures also showthe location of FI and LA in frontal, horizontal, and para-sagittal MRI sections that intersect on FI. In Figure 3, ev-ery VEN is plotted for a section through FI and adjacentcortex from a chimpanzee, a gorilla, and a human. To theleft of each section is a corresponding low-power photomi-crograph of the section. The section illustrated from thechimpanzee brain in Figure 3 corresponds approximatelyto frontal MRI section for this same individual illustratedin Figure 1. The VEN containing area is largely confinedto the region of high flexure in the chimpanzee, butextends medially in the gorilla and even further in the

medial direction in the human. The transition between FIand superior anterior insula (SAI) corresponds to gradientin VENs density rather than a sharp border. There are asmall number of VENs in layer 6 in the adjacent SAI in allthree species; these layer 6 neurons have the distinctiveVEN morphology but are oriented parallel to the white-gray matter interface and are orthogonal to the typical ra-dial VEN orientation. These horizontally oriented cellsmay thus have a different functional role than the VENsin FI. In Figure 4, the medium power photomicrographsfrom layer 5 from the same chimpanzee, gorilla, andhuman illustrate the strong radial (columnar) patterningof layer 5 in FI with the presence of many VENs, and therelative absence of these features in the SAI. The locationsof the medium power sections are indicated by the arrow-heads superimposed on the low-power photomicrographsin Figure 3. SAI appears to correspond to Rose (1928)granular insular areas (i7, i8, and i9). The cytoarchitec-ture of area LA and the location of the VENs in this areaof anterior cingulate cortex are illustrated in von Economo(2009) and Nimchinsky et al. (1995, 1999).

Fig. 1. The location of the VEN-containing FI and LA areas in MRIs of the right hemisphere of a 39-year-old male chimpanzee based onnissl-stained histological sections. LA and FI are red in these images. MRI sections A, B, and C are frontal, horizontal, and parasagittal sectionsthat intersect in FI. Section A corresponds to approximately the same level as the partial section illustrated for this individual in Figure 3. Onthe right are three-dimensional reconstructions of the left hemisphere. D is an anterolateral view: E is a lateral view and F is a medial view.[Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

7VENs IN APES AND HUMANS


The VENs are illustrated at higher magnification inFigure 5, which shows very similar morphology in thegreat apes and humans. In primates, the VENs are pres-ent in FI only in great apes and humans (see Table 1).This is the same taxonomic distribution as was found forthe VENs in LA (Nimchinsky et al., 1999), which suggeststhat the VENs emerged as a specialized neuron type inthe common ancestor of great apes and humans, a primi-tive ape living in the Miocene period (Kunimatsu et al.,2007). However, in orangutans, we found only one out ofseven individuals examined to have a substantial VENpopulation in FI and LA. The VEN distribution in thisindividual, a 25-year-old Sumatran female (Pongo abelii),closely resembled the pattern seen in the African apes. Intwo of the others (adult male Bornean orangutans, Pongo

pygmaeus), the VENs were not present in the FI regionbut were abnormally located in the gyrus rectus, which isin the medial orbitofrontal cortex where VENs are usuallynot present. In the other four orangutans examined (anadult male Sumatran, an adult male and a femaleBornean, and an infant Bornean), VENs were rare in FIand LA.The occurrence of VENs is not related to relative brain

size or encephalization (see Fig. 6). Some of the NewWorld monkeys and lesser apes (gibbons) are much moreencephalized than the great apes, but lack VENs. Thepresence of VENs may be related to absolute brain size,because the brain weights for the group on the left in Fig-ure 6 are much smaller than for the primates who haveVENs (see figure legend).

Fig. 2. The location of the VEN-containing FI and LA areas in MRIs the right hemisphere of a young adult human female. LA and FI are redin these images. MRI sections A, B, and C are frontal, horizontal, and parasagittal sections that intersect in FI. On the right are three-dimen-sional reconstructions of the left hemisphere. D is an anterolateral view: E is a lateral view and F is a medial view. [Color figure can be viewedin the online issue, which is available at wileyonlinelibrary.com.]



Our key stereological findings are represented in theform of graphs (Figs. 7–9); a more extensive account of thestereological findings together with the methods employedis given in Allman et al. (2010). Figure 7 shows that theVENs are more numerous in humans than in apes, butthat the VENs constitute a higher percentage of the totalneurons in the regions of interest in the apes than inhumans. In LA, one of the individual apes (a gorilla)stands out as having considerably more VENs than theothers, approaching the lower end of the human range.The VEN count was similarly elevated relative to theother apes in this same gorilla in FI on the left side andalso approached the lower end of the human range for thisstructure (see Table 2); unfortunately, postmortem dam-age to the right FI in this individual made it impossible tomake a stereological count for this structure in the righthemisphere. The relative abundance of VENs for this go-rilla is also illustrated in comparison with a chimpanzee

in Figure 3. This individual gorilla had an exceptionallyenriched environment (Patterson and Gordon, 2002).Although we can conclude nothing definitive from this iso-lated observation, it does raise the possibility that VENabundance may be related to environmental influences.

THE VENS EMERGE MOSTLY POSTNATALLYAND AREMORE ABUNDANT IN THE RIGHT HEMISPHERE

We examined FI and LA in fetal brains at postconcep-tion ages of 32 weeks (n 5 1, 33 weeks (n 5 1), 34 weeks (n5 3), and 35 weeks (n 5 2) and found no VENs. In one 36week postconception brain, small numbers of VENs werepresent in FI and LA. Figure 7 shows that the VENs existin relatively low numbers in FI at birth; in LA, the VENswere so rare that we were not able to make stereologicalestimates in the brains of neonates. In the late term neo-nate (42 weeks postconception), the number of VENs in FI

Fig. 3. Photomicrographs of frontal sections through area FI in a 39-year-old male chimpanzee, a 27-year-old male gorilla, and a 1.6-year-oldmale human. On the right side are outlines of the corresponding sections in which the location of each VEN has been plotted. There are 354VENs plotted in the chimpanzee; 919 in the gorilla; 2415 in the human plotted by scanning through the different depth planes with a 403 oilimmersion lens with the aid of Stereoinvestigator software. The sections were 100 micra thick. All images are represented at the same scale.The sections are from FI on the right side except for the gorilla in which FI was damaged during histological processing, and instead the left FIhas been used and the image reversed for ease of comparison with the other cases. The locations of the higher magnification photomicrographsshown in Figure 4 are indicated by arrows in the low-power photomicrographs. The section illustrated for the gorilla corresponds approximatelyto Figure 12B, which shows the location of the seed voxels for the tractography done in the same individual. FI, frontoinsular cortex; SAI, supe-rior insular cortex. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]



was considerably higher that the normal term neonates(38–40-week postconception), suggesting that the numberof VENs in FI increases immediately after the normaltime of birth. The number of VENs is significantly greaterin the postnatal brains relative to the neonatal brains.The percentage of total neurons that are VENs is rela-

tively stable in adulthood (see Tables 2 and 3) and is simi-lar to the percentages observed by Seeley et al. (2006).Figure 9 illustrates the ratio between the number of

VENs in the right hemisphere and that in the left. In new-borns, there is no clear hemispheric preference, but nearlyall of the postnatal humans and all of the apes show aclear predominance of VENs in the right hemisphere inboth FI and LA. The predominance is greatest in the 7and 8-month-old infants, which correspond to the peak inabsolute numbers of VENs seen during the course of lifein our samples. These data also suggest that the VENs de-velop in the right hemisphere before the left, which is con-sistent with the general pattern of the right hemispheredeveloping earlier than the left in embryogenesis (Gilleset al., 1983). In a large MRI study of adult humans, thecortex in the regions of FI and ACC was significantlylarger on the right side than the left (Watkins et al.,2001).The VENs mostly emerge postnatally, which can be

seen in their numbers, concentrations, and the formation

Fig. 4. The cytoarchitecture of FI and SAI in a chimpanzee, gorilla,and human corresponding to the regions indicated in Figure 3. Notethe presence of the VENs and columnar architecture in the FI sec-tions and the paucity of VENs and reduced columnar architecture inSAI (superior anterior insula). The pial surface lies above each sec-tion. Note that these images only represent one depth plane thoughthe section; the VENs are more abundant throughout the total thick-ness of FI sections.

Fig. 5. VENs in area FI of humans and great apes. Photomicro-graphs are of Nissl-stained sections. All panels share the scale indi-cated in the central panel.

TABLE 1. Primate species examined for VENs in FI

Taxonomy Common name VENs N

ProsimiiLemuroideaLemuridaeHapalemur griseus Lesser bamboo lemur No 1Lemur catta Ring-tailed lemur No 1

IndridaePropithecus verreauxi Verreaux’s sifaka No 1

CheirogaleidaeMicrocebus murinus Gray mouse lemur No 1

LoroideaGalagonidaeGalago senegalensis Lesser galago No 1

LorisidaeLoris tardigradus Slender loris No 1Nycticebus coucang Slow loris No 1Perodicticus potto Potto No 1

TarsioideaTarsiidaeTarsius syrichta Philippine tarsier No 1

AnthropoideaCeboideaCallithricidaeSaguinus sp. Tamarin No 1

CebidaeAlouatta palliata Mantled howler monkey No 1Aotus trivirgatus Owl monkey No 1Ateles fusciceps Black spider monkey No 1Callicebus moloch Dusky titi monkey No 1

CercopithecoideaCercopithecidaeCercocebus atys Sooty mangabey No 1Macaca mulatta Rhesus macaque No 1Mandrillus sphinx Mandrill No 1Papio papio Guinea baboon No 1Presbytis entellus Hanuman langur No 1

HominoideaHylobatidaeHylobates lar White-handed gibbon No 4Hylobates syndactylus Siamang No 1

HominidaePongo pygmaeus Bornean orangutan Yes* 4Pongo abelii Sumatran orangutan Yes* 3Gorilla gorilla gorilla Western lowland gorilla Yes 3Pan troglodytes Chimpanzee Yes 4Pan paniscus Bonobo Yes 4Homo sapiens Human Yes 161

*See text.



of the hemispheric predominance of VENs on the rightside in the first few months after birth. This emergencecould come about by the transformation of another celltype into the VENs or by postnatal neurogenesis. The longthin spindle shape of the VENs with sometimes undulat-ing apical and basal dendrites closely resembles that ofmigrating neurons with undulating leading and trailingprocesses, and this is particularly evident in infant brains(Allman et al., 2002). Although there are many technicaldifficulties in experimentally resolving whether the VENsarise by transformation or postnatal neurogenesis, futureresearch should reveal whether either of these possibil-ities is correct. Hayashi et al. (2001) observed VENs in theanterior cingulate cortex of a 224-day postconception fetalchimpanzee. This is about 2 weeks before full term (237days) in the chimpanzee and is consistent with our obser-vation that the VENs are present at this late stage of fetaldevelopment in humans. However, they also reported that5.3% of the neurons in layer 5b are VENs in this fetalchimpanzee, while, in humans, the VENs are rare at thisstage, suggesting that the VEN population develops ear-lier in chimpanzees than in humans.

An important finding in our study is the larger numberof VENs in the right hemisphere than the left except invery young subjects and thus that the rightward asymme-

try emerges during the first few months of postnatal life.Stereological evidence for hemispheric differences in neu-ron number in primates (including humans) is very lim-ited. Uylings et al. (2006) found a trend toward a largernumber of total neurons in Broca’s area for a population offive female brains. Sherwood et al. (2007) found thatright–left differences in the density of parvalbumin-posi-tive interneurons in layers 2 and 3 of primary motorcortex in chimpanzees are linked to hand preference.However, there is excellent evidence that the anterior cin-gulate cortex is larger on the right side from a structuralMRI study of 100 young adult subjects. This study foundthat ACC is 13% larger on the right side, while the size ofposterior cingulate cortex is the same in both hemispheres(Gundel et al., 2004). There is also structural MRI data for142 young adults, which suggest that FI is enlarged byabout the same amount on the right side (Watkins et al.,2001). The significantly increased number of VENs in theright hemisphere in FI and ACC are among the few dem-onstrations of hemispheric differences in neuron numberbased on stereological techniques, and these rightwardpredominances correspond to size differences in FI and

Fig. 6. Encephalization is not correlated with the presence or ab-sence of VENs. Brain weight residuals were calculated by fitting aleast-squares regression line to a plot of brain weight versus bodyweight for a large sample of haplorhine primate species. The residualfor a given species is the distance that species’ brain weight fallsabove or below the regression line. Thus, a highly encephalized spe-cies, having an unusually large brain for its body size, will have a pos-itive brain weight residual, while one with an unusually small brainfor its body size will have a negative residual. The species at left (graydots) do not have VENs (see Table 1) but are more highly encephal-ized than the great apes (unfilled dots), which do have VENs. Thebars indicate the average value of the data points in each column. Theaverage brain weights are ateles 108.8 g, cebus 67.6 g, hylobates 94.4g, siamang 131.3 g, orangutan 344.4 g, gorilla 493.8 g, chimpanzee402.3 g, and human 1295 g. Note that all the individuals to the left ofthe graph have brain weights below 150 g, suggesting that the posses-sion of VENs may be related to an absolute brain size threshold. Brainand body weight data are from Stephan et al. (1981) and Brauerand Schober (1970). Also, see Allman et al. (1993). [Color figure can beviewed in the online issue, which is available at wileyonlinelibrary.com.]

Fig. 7. A comparison of the number and proportion of VENs in areaFI and ACC of adult humans and great apes (see Tables 2 and 3 fordata.) Bars indicate the average of all data points in a given column.A: The number of VENs in area FI (both hemispheres combined). FIcontains many more VENs in humans than in great apes (P 5 0.001).B: The percentage of neurons in area FI that are VENs. Although thegreat apes have a smaller total number of VENs in FI, the have ahigher proportion of VENs to non-VEN neurons in FI (P 5 0.029). C:The number of VENs in ACC (both hemispheres combined). As inarea FI, humans have more VENs than the great apes (P 5 0.016),although this difference is less great in ACC. D: The percentage ofneurons in ACC that are VENs. Again, as in FI, the great apes have ahigher percentage of neurons that are VENs (P 5 0.016). All compari-sons are Mann–Whitney tests. [Color figure can be viewed in theonline issue, which is available at wileyonlinelibrary.com.]



ACC observed in structural MRI studies done in largepopulations of adult human subjects. The fact that thesehemispheric differences are present in both humans andgreat apes suggests that they may have existed in thecommon ancestor of both groups. There is recent evidencefrom a developmental MRI study based on 358 subjectsthat the anterior insular and posterior orbitofrontal cortexis thinner on the right side than the left at age 4 in normalsubjects but progresses by age 20 to be significantlythicker by about 0.3 mm on the right side than the left(Shaw et al., 2009). The rightward asymmetry in corticalthickness for the region containing FI in the adult brain isconsistent with previous MRI studies done in adults andwith the rightward asymmetry in VEN numbers in ourstudy; however, in our study, we found a rightward asym-metry in VEN numbers throughout postnatal life. Thus,the rightward predominance of VEN numbers developsbefore the predominance in cortical thickness in this corti-cal regions. In our preliminary study of tractographybased on diffusion tensor imaging, we found that area FIin a gorilla is connected via the uncinate fasciculus withthe temporal pole, amygdala, and inferotemporal cortex.Diffusion tensor imaging provides a strong measure of thedegree of coherence of axonal pathways in the brain (frac-tional anisotropy) and, recently, James Rilling and hiscolleagues (personal communication) have found that theuncinate fasciculus has a significantly higher fractionalanisotropy on the right side than the left in humans,which is another measure of the rightward predominanceof this system and its connections. The uncinate fasciculusis unusual in this respect, because leftward asymmetriespredominate in their fractional anisotropy data for thehuman brains.

What is the biological significance of the rightwardhemispheric asymmetry of the VENs in FI and ACC? TheVEN asymmetry may be related to asymmetry in the au-tonomic nervous system in which the right hemisphere ispreferentially involved in sympathetic activation, aswould result from negative feedback and subsequent errorcorrecting behavior; the left hemisphere is preferentiallyinvolved in parasympathetic activity associated withreduced tension or calming responses (Craig, 2005). Fol-lowing on from this reasoning, there may be more VENson the right side, because the responses to negative feed-back require more complex and more urgent behavioralresponses than do situations that are calming and involvereduced tension. Many of these experiments probably

Fig. 8. The number of VENs increases after birth. The number ofVENs in right hemisphere FI in humans of different ages. VEN num-bers are low in neonates and increase after birth. The 8-month-oldindividual examined had markedly more VENs in the right hemi-sphere than any other subject in this study; this might possibly bedue to individual variation. The right hemisphere VEN measurementin this individual was repeated with similar results (see Table 2). Thedifference between the number of VENs in right FI for pre- and post-natal subjects was statistically significant (P 5 0.0029), and this sig-nificance remained when the 8-month-old individual was removedfrom the comparison (P 5 0.0040). The number of VENS in left FI andin both hemispheres together was also significantly different for pre-and postnatal individuals (P 5 0.0056 for both). Significance wasdetermined using the Mann–Whitney test. [Color figure can beviewed in the online issue, which is available at wileyonlinelibrary.com.]

Fig. 9. The ratio of the number of VENs in the right hemisphere tothe number of VENs in the left hemisphere. A: In postnatal humansand great apes, there are consistently more VENs in FI on the rightside. This ratio develops after birth. In neonates, the numbers in eachhemisphere are almost even, while in infants, juveniles, and adults,there are many more VENs in the right hemisphere. When the num-bers of VENs in the right and left hemispheres were compared for FIin the postnatal cases, the difference was statistically significant bothwith and without the 8-month-old outlier (P 5 0.0039 for all postnatalhumans and P 5 0.0078 without the 8-month-old case). For postnatalapes and humans combined, the hemispheric difference for FI wassignificant at P < 0.0001. B: The ratio of VENs in right and left LA.This ratio is less consistent than in area FI, but, in almost all cases,there are more VENs on the right side. When the number of VENs inthe right and left hemispheres in postnatal humans was compared forLA, the result was statistically significant (P 5 0.03). When postnatalapes and humans were combined, the difference was significant at P5 0.001. Significance was determined using the Mann–Whitney test.[Color figure can be viewed in the online issue, which is available atwileyonlinelibrary.com.]



TABLE2.Stereolog

icalcounts

ofVENsin

fron

toinsu

larcortex

Species

Age

Sex

FIVENsL

Gund.C

EFIneu

ronsL

Gund.CE

FIVENsR

Gund.CE

FIneu

ronsR

Gund.CE

VEN

ratioR/L

VEN%

Com

men

ts

H.sa

piens

86

M65,500

0.05*

7,112,500

0.04*

97,920

0.04*

6,178,500

0.04*

1.45

1.21

MU-75–64a

91,580y

H.sa

piens

71

M35,180

0.075{

47,670

0.058{

1.35

b

H.sa

piens

58

M90,000

0.04*

8,987,500

0.04*

128,375

0.03*

10,700,000

0.04*

1.43

1.57

MU-169–87a

H.sa

piens

50

F49,500

4,976,000

60,120

4,912,000

1.24

1.10

v42a

47,500y

60,320y

H.sa

piens

50

M75,420

0.05*

8,010,000

0.05*

86,580

0.05*

9,630,000

0.04*

1.15

0.918

MU-88–65a

H.sa

piens

8F

75,210

2,978,570

#1860c

H.sa

piens

4F

79,340

124,830

2,375,210

1.57

MU-92–65a

H.sa

piens

1yea

r7mon

ths

M100,190

0.04*

1,815,920

0.03*

#4247c

H.sa

piens

8mon

ths

M74,000

322,910

0.05,0.04

5,866,070

0.04,0

.02

4.27

MU-93–65a

308,890y

H.sa

piens

7mon

ths

M27,720

54,840

1.98

RPSL-B

-123–61a

H.sa

piens

4mon

ths

M22,100

0.16,0

.16

30,890

0.1,0.06

1,032,640

0.07,0

.03

1.40

MU-95–65a

H.sa

piens

42wee

kspc

F25,620

37,700

1.47

RPSL-B

-197–61a

H.sa

piens

40wee

kspc

M11

,600

0.09,0

.09

12,400

0.16,0.09

1.07

RPSL-B

-101–61a

H.sa

piens

39wee

kspc

M5,750

0.14,0

.13

5,160

0.13,0.14

0.90

RPSL-B

-250–62

H.sa

piens

38wee

kspc

F11

,010

0.11,0.10

10,710

0.16,0.1

836,750

0.1,0

.05

.97

RPSL-B

-236–61a

H.sa

piens

36weekspc

Frare

rare

RPSL-W

-5–59a

H.sa

piens

35wee

kspc

M0

0RPSL-B

-284–62a

H.sa

piens

35wee

ksPc

M0

0RPSL-W

-123–63a

H.sa

piens

34wee

kspc

F0

0RPSL-W

-232–66a

H.sa

piens

34wee

kspc

F0

0RPSL-W

-242–67a

H.sa

piens

34wee

kspc

F0

0RPSL-W

X-207–65a

H.sa

piens

33wee

kspc

F0

0RPSL-W

-184–64a

H.sa

piens

32wee

kspc

F0

0RPSL-W

-46–62a

G.g

orilla

27

M28,500

0.07*

1,100,000

0.05

d

G.g

orilla

20

F7,260

0.087{

9,450

0.069{

1.30

b

G.g

orilla

39

F2,840

0.1,0

.07

230,480

0.07,0

.04

3,770

186,670

1.33

1.58

d

P.paniscu

s11

F940

0.11{

1,214

0.097{

1.29

b

P.paniscu

s2

F640

0.15{

810

0.14{

1.27

b

P.paniscu

s16

M6,480

0.1,0.06

115,280

0.11,0

.08

d

P.paniscu

sM

7,560

0.12,0

.07

366,410

0.1,0

.06

10,560

0.15,0.06

382,030

0.15,0

.06

1.40

2.42

d

P.troglodytes

5,400

7,180

1.33

a

P.troglodytes

F790

0.11{

1,060

0.12{

1.34

b

P.troglodytes

39

M8,410

419,800

10,760

484,920

1.28

2.12

d

P.troglodytes

F0

0e

P.a

belii

25

F2,510

88,125

3,580

0.09,0.04

159,840

1.43

2.46

d

P.a

belii

16

Mrare

rare

b

P.pyg

maeu

s36

M0

0b

P.pyg

maeu

s34

M0

0b

P.pyg

maeu

s38

Frare

rare

d

P.pyg

maeu

s8mon

ths

rare

rare

d

P.a

belii

17

Frare

rare

d

*Gundersonm

51CEon

ly.

y Cou

ntwasrepea

ted,w

iththeaverageof

bothvalues

usedforcalculation

s.{ G

undersonCEcalculatedmanually.

aYakov

levcollection

attheNation

alMuseum

ofHea

lthandMed

icine.

bSem

endefericollection

.c N

ICHD

Brain

andTissu

eBankforDev

elop

men

talDisorders,University

ofMaryland.

dMou

ntSinai/Hof

Lab/AllmanLab.

eWelker

collection

attheNation

alMuseum

ofHea

lthandMed

icine.



TABLE3.Stereolog

icalcounts

ofVENsin

thelimbic

anterior

(LA)areaof

anterior

cingulate

cortex

Species

Age

Sex

LAVENsL

Gund.CE

LAneu

ronsL

Gund.CE

LAVENsR

Gund.CE

LAneu

ronsR

Gund.C

EVen

ratioR/L

VEN

%Com

men

ts

H.sapiens

86yea

rsM

178,500

0.04a

20,175,000

0.04a

190,500

0.04a

20,450,000

0.04a

1.07

0.908

MU-75–64c

H.sapiens

58yea

rsM

169,920

0.05a

22,208,000

0.04a

208,000

0.04a

18,592,000

0.04a

1.22

0.926

MU-169–87c

H.sapiens

50yea

rsF

132,000

24,576,000

213,500

22,528,000

1.62

0.733

V-42–57c

H.sapiens

50yea

rsM

66,960

14,292,000

127,000

19,764,000

1.90

0.569

MU-88–65c

H.sapiens

4yea

rsF

184,317

0.09,0

.05

190,900

0.09,0

.06

1.04

MU-92–65c

H.sapiens

8mon

ths

M183,110

16,017,160

223,220

13,370,280

1.22

1.38

MU-93–65c

H.sapiens

7mon

ths

M236,290

0.17,0

.06

25,291,150

383,650

0.16,0

.05

26,118,750

1.62

1.21

RPSL-B

-123–61c

H.sapiens

4mon

ths

M103,410

0.16,0

.16

11,116,000

102,290

0.1,0

.06

12,805,330

0.07,0

.03

0.99

0.860

MU-95–65c

H.sapiens

2.5

mon

ths

MRare

Rare

RPSL-97–65c

H.sapiens

48days

FRare

Rare

RPSL-W

-160–64c

H.sapiens

32wee

kspc

FRare

Rare

RPSL-B

-197–61c

H.sapiens

40wee

kspc

MRare

Rare

RPSL-B

-101–61c

H.sapiens

39wee

kspc

MRare

Rare

RPSL-B

-250–62c

H.sapiens

38wee

kspc

FRare

Rare

RPSL-B

-236–61c

H.sapiens

36wee

kspc

FRare

Rare

RPSL-W

-5–59c

H.sapiens

35wee

kspc

MRare

Rare

RPSL-B

-284–62c

H.sapiens

34wee

kspc

F0

0RPSL-W

-242–67c

H.sapiens

34wee

kspc

F0

0RPSL-W

-232–66c

H.sapiens

33wee

kspc

F0

0RPSL-W

-184–64c

G.g

orilla

27

M83,230

4,182,300

97,920

4,281,250

1.18

2.14

e

G.g

orilla

39

F7,670

0.24,0

.13

536,110

0.16,0

.08

17,555

0.16,0

.09

655,550

2.29

2.12

e

P.p

aniscu

s16

M47,333

0.18,0

.06

1,042,670

0.17,0

.06

e

P.p

aniscu

sM

18,740

0.23,0

.09

1,199,790

0.17,0

.06

29,358

0.14,0

.07

1,278,330

0.12,0

.05

1.57

1.94

e

P.troglodytes

39

M49,830

0.13b

1,441,670

0.13b

62,500

0.11b

1,591,670

0.13b

1.25

3.70

e

P.a

belii

25

F29,760

0.13,0

.07

2,652,190

0.09,0

.07

45,750

0.07,0

.05

2,150,000

0.07,0

.04

1.54

1.57

e

P.a

belii

16

MRare

Rare

d

P.p

ygmaeu

s36

MRare

Rare

d

P.p

ygmaeu

s34

MRare

Rare

d

P.p

ygmaeu

s38

FRare

Rare

e

P.p

ygmaeu

s8mon

ths

Rare

Rare

e

P.a

belii

17

FRare

Rare

e

aGundersonm

51CEon

ly.

bGundersonCEcalculatedmanually.

c Yakov

levcollection

attheNation

alMuseum

ofHea

lthandMed

icine.

dSem

endefericollection

.eMou

ntSinai/Hof

Lab/AllmanLab.



have in common a right FI response like that which hasbeen specifically linked to sympathetic arousal as meas-ured by the galvanic skin response (Critchley et al., 2000).A meta-analysis of co-activation of amygdala and insulainvolving 955 responses in 86 papers reported co-activa-tion between the amygdala and inferior anterior insula onboth sides, but found them to be more pronounced on theright (Mutschler et al., 2009). In a meta-analysis of 23functional imaging studies conducted in children and ado-lescents performing various executive functioning taskssuch as go versus nogo, which typically involve intensefocus and self-control, Houde et al. (2010) found that, inchildren, the most consistent site of activation was in an-terior insula on the left side, while, in adolescents, themost consistent site of activation was the inferior anteriorinsula corresponding to FI on the right side. Thus, theright FI becomes strongly engaged in executive function-ing and self-control in adolescents. Houde et al. (2010, p.6) say this change: ‘‘is consistent with the fact that adoles-cents are often psychologically embedded in a period ofgreat emotional reactivity and sensitivity with negativefeelings. Recognizing the necessity of being wrong is nec-essary to achieve high levels of adult adaptation and ma-turity in cognitive control. Our result might reflect a keytransition around the time of adolescence towardincreased influence of negative feedback (i.e. error detec-tion and/or anticipation) on cognitive control.’’

There is also some evidence of preferential leftwardactivation in FI and ACC, which involve positive andcalming emotions (Craig, 2009). The left anterior cingu-late cortex was preferentially activated when subjectsrelaxed and reduced their sympathetic arousal throughbiofeedback (Critchley et al., 2001b). The right hemi-sphere of the brain is related to sympathetic arousal andthe left hemisphere to parasympathetic quietude (Craig,2005; Rogers and Andrew, 2002; Wittling, 1995). This au-tonomic asymmetry is consistent with the proposal thatthe right hemisphere responds to the unexpected and theleft hemisphere to more routine stimuli (MacNeilageet al., 2009). There is also evidence for this autonomicasymmetry from electrical stimulation of the insular cor-tex on the right and left sides in human subjects (Oppen-heimer et al., 1992). Craig (2005) suggests that sympa-thetic activation on the right side and consequent energyexpenditure by the organism, and parasympathetic acti-vation on the left and energy conservation together func-tion to serve as a balancing mechanism for managing theorganism’s energy resources. These mechanism involve inpart highly conserved circuits in the vagal complex thatregulate respiration and the production of vocalizationsthroughout vertebrates (Bass et al., 2008).

THE VENS EXPRESS BOMBESIN PEPTIDES INVOLVED INAPPETITE REGULATION

Figure 10 shows immunocytochemical staining by anantibody to neuromedin B (NMB). The strong NMB stain-ing was largely restricted to layer 5 (Fig. 10A). It is mainlythe VENs that are NMB stained (Fig. 10B), althoughother classes of cells, including the fork cells and otherneurons, are stained in layer 5 of FI in humans (Fig. 10C).We obtained similar staining in FI with antibodies toanother bombesin peptide, gastrin releasing peptide(GRP).

Perhaps, the most basic function of the brain is to regu-late the intake of food into the gut, so that nutritious sub-stances are ingested and toxic substances are rejected orejected. This is probably why the brain is located near theentrance to the gut (Allman, 2000). The gut has its ownhormonal and neuronal mechanisms for the coordinationof food processing, and the bombesin peptides, NMB andGRP are crucially involved in the release of digestiveenzymes, in smooth muscle contractions in peristalsis,and in the mounting of immune responses to potentiallydamaging ingested substances (Jensen et al., 2008). NMBand GRP participate in the local control of the gut, butthese genes and their products also participate in twohigher levels of gut control, first in the hypothalamuswhere the digestive processes are integrated with otherhomeostatic systems of the body, and second in the insularand related cortices, where gut feelings and the control ofthe gut interact with circuitry involved in awareness,

Fig. 10. A: A low-power photomicrograph of immunocytochemicalstaining for NMB in layer 5 neurons of area FI in a 51-year-oldhuman male subject; note the weak staining in the other corticallayers. B: Most of the stained neurons are VENs in layer 5. C: NMBstaining of a VEN (white arrowhead with black border) and a fork cell(black arrowhead with white border) in layer 5 of the same subject.The cause of death in this subject was myocardial infarction. The hor-izontal striations are an artifact of vibratome sectioning.



motivation, and conscious decision-making. In this con-text, one aspect of the functioning of the insular cortexmight be as an encephalization of autonomic control.Thus, our bodies have three interacting systems for thecontrol of the gut, one in the gut itself, one in the hypo-thalamus for automatic homeostatic control, and one inthe cortex that is closely linked to self-awareness, motiva-tion, and decision-making. The capacity for self-aware-ness appears to be linked to social awareness (empathy)and is reduced in autism spectrum disorders (Lombardoet al., 2007).The expression of NMB and GRP is an evolutionarily

conservative aspect of the VENs and related neurons thatreflects very basic functions of the gut and appetite con-trol. Dr. John Morris (personal communication) made usaware of the fact that NMB mRNA is expressed in a veryrestricted population of neurons in the deep layers of theinsula in mice (see Allen Brain Atlas, NMB coronal sec-tions at http://mouse.brain-map.org). We found that theNMB protein is expressed selectively on VENs and a sub-set of other layer 5 neurons in FI in humans (see Fig. 10).GRP mRNA has a similar pattern of expression in mice,and its protein is also selectively expressed on the VENsand a subset of other layer 5 neurons. The selectiveexpression of NMB and GRP in mice and humans sug-gests that it may be possible to identify immunocyto-chemically cell populations related to VENs in mice, de-spite the cells not being morphologically identifiable asVENs. This raises the possibility that this VEN-relatedcell population in mice could be used for a wide variety ofexperimental investigations. The NMB-labeled populationin human FI includes another morphologically distinctiveneuron type, the fork cells (see Fig. 10C). The fork cellswere observed as a distinct neuronal type in the humaninsular cortex by Ngowyang (1932). These cells closelyresemble the VENs except that they have an apical den-drite divided into two instead of single apical dendrite.Thus, the VENs and fork cells may represent morphologi-cal specializations of an ancient cell type found in insularcortex in all mammals.The VENs are prime targets of the pathological proc-

esses in FTD during the early stage of the illness, which ischaracterized by the loss of social awareness and empathy(Seeley et al., 2006, 2007, 2008). However, FTD is also fre-quently associated with compulsive eating (Woolley et al.,2007), and FI is significantly reduced on the right side inthe FTD patients who are compulsive overeater (Seeley,2008). The FTD findings may reflect a basic role for theVENs, fork cells, and related circuitry in the control ofappetite. The anterior insula/FI is activated when subjectsview facial expressions of disgust (Jabbi et al., 2008; Phil-lips et al., 1997). Disgust (literally, bad taste) links appe-tite control and social feedback, which we believe are twokey functions of these circuits. The experience and expres-sion of disgust are intense forms of negative feedback inboth the consumption of food and in social interactions.Components of circuitry for the regulation of the socialemotions may be a direct evolutionary outgrowth from in-sular circuitry involved in appetite regulation and otheraspects of physiological homeostasis (Williamson and All-man, 2010; Woodward and Allman, 2007). The circuitryfor the regulation of appetite through the experience oflust and disgust may have been the evolutionary templatefor dichotomous social emotions such as love and hate;gratitude and resentment; empathy and disdain; and

atonement and guilt. The experience of these dichotomoussocial emotions, which ranges from the poles of prosocialto antisocial feelings and thus regulates social distanceare analogous to the regulation of food consumptionthrough the experience of lust versus digust. As reviewedearlier, the experience of many of these social emotionsactivates anterior insula. Thus, the VENs and related in-sular circuitry may be involved in monitoring changes inthe physiological network of an individual’s own body andthat individual’s social network. In each case, the VENsmay initiate homeostatic corrections to changes in net-work states.In his ‘‘somatic marker hypothesis,’’ Damasio (1994)

proposed that the monitoring of sensations arising fromthe gut is crucial to adaptive decision-making. The pres-ence of NMB, GRP, and the serotonin 2b receptor, whichare rare in the cortex but very common in the viscera, sug-gests an extension of the concept that FI and ACC aremonitoring the activity in the gut (Allman et al., 2005).Possibly, the expression of NMB, GRP, and the serotonin2b receptors in the VENs represents a transposition ofthis activity from the gut to the cortex, as components of aneural model of how the gut would react under given cir-cumstances. Such a model would enable the organism toreact more quickly to changing conditions than if itdepended solely on monitoring sensations arising from thegut itself (Allman et al., 2005). Disruption of this feedbackcould also underlie the recently recognized role of theinsula in the feelings of craving associated with addictionto food or drugs (Naqvi and Bechara, 2009).

THE VENS EXPRESS DISC1 (DISRUPTED INSCHIZOPHRENIA)

Figure 11 illustrates the strong immunocytochemicalstaining of the VEN somas and dendrites in area FI by anantibody to DISC1 (the product of the gene Disrupted inSchizophrenia). This section was counterstained with cre-syl violet, so that cell bodies unlabeled by the DISC1 anti-body appear blue. In the 51-year-old male, we found that90% of the VENs were DISC1-positive, while only 37% ofthe other layer 5 neurons were positive; in the 39-year-oldmale, 94% of the VENs were DISC1-positive, whereasonly 34% of the other neurons were positive. Thus, DISC1is preferentially expressed in the VENs versus other layer5 neurons in area FI, which has several interesting impli-cations. Duan et al. (2007) blocked the expression of theDISC1 gene in postnatally generated neurons in the den-tate gyrus of the mouse hippocampus through the use ofselective interference with DISC1 RNA. When DISC1expression is blocked in these neurons, there is consider-ably more branching of the secondary and tertiary den-drites than when DISC1 expression is normal. Thus,DISC1 reduces secondary and tertiary dendritic branch-ing in postnatally generated neurons, and DISC1 could bepart of the genetic circuitry responsible for the relative ab-sence of higher order branching in the VENs. Crespi et al.(2007) showed that several parts of the DISC1 gene haveundergone substantial positive selective changes, becausehominoids diverged from other anthropoids and becausehumans diverged from other hominoids. The site of thelargest evolutionary divergence maps to exons 1 and 2 inthe part of the DISC1 gene, which binds to MAP1a (mico-tubule associated protein 1a), which is involved in the con-trol of activity-dependent dendritic branching (Szebenyi



et al., 2005). A single nucleotide polymorphism in anotherpart of the DISC1 gene is linked to increased risks ofmajor depression and schizophrenia, and this polymor-phism is also linked to reduced volume of ACC in a largeMRI study (Hashimoto et al., 2006). Variations in theDISC1 gene have been frequently associated with changesin cognitive functioning, particularly with respect to tasksthat involve maintaining and shifting attention [seeChubb et al. (2008) for a review]. Thus, DISC1 is a gene

that has undergone considerable recent evolution andmay be related to enhanced cognition in humans. DISC1is expressed selectively on the soma and dendrites of theVENs and may be related to their distinctive dendriticarchitecture. The recent evolutionary changes associatedwith the VENs and DISC1 may carry increased vulner-abilities to dysfunction, which may manifest in severalneuropsychiatric disorders (Allman et al., 2005; Crespiet al., 2007; Kaufman et al., 2008; Seeley et al., 2006,2007, 2008; Simms et al., 2009; van Kooten, 2008; Wil-liamson and Allman, in press). Further investigation ofgene expression in the VENs could provide insights intothe dysfunctions of neuropsychiatric illnesses and into therecent VEN evolution.

THE CONNECTIONS OF FRONTO-INSULAR ANDANTERIOR SUPERIOR INSULAR CORTEX IN A GORILLA

Figure 12 illustrates tractography arising from seedsplaced in FI and SAI in a gorilla corresponding in locationto sites illustrated for this individual in Figure 3. Figure12A is a lateral view of the brain showing the levelsdepicted in 12 B through L. Each seed depicted in 12B cor-responds to a single voxel and tractography illustrated thefibers passing in either direction through that seed voxel.The connections for the medial seed in FI are illustratedin green, the connections for the lateral FI seed are in red,and the connections for the SAI seed are in blue. Wherethese connections overlap the connections are depicted asmixtures of these colors. Figure 12C–L illustrates the MRsections that contain the color-coded tracts proceedingfrom anterior to posterior. Figure 12C and D shows con-nectivity between the FI seeds and the frontal polar cortexpresent in both hemispheres but stronger on the ipsilat-eral side. Figure 12E shows that the medial FI seed con-nection (green) has shifted laterally at this level, and thelateral FI and superior AI seeds have more dorsal connec-tions depicted in red and purple (for the overlap betweenred and blue) at this level. Figure 12G and H shows thatthe lateral FI and superior AI seeds are connected to theinferior frontal gyrus at these levels. Medial FI is con-nected with the septum, and lateral FI has connections inthe corpus callosum at this level. Figure 12J shows con-nections between the medial FI and the amygdala. Figure12K shows lateral FI and superior AI connections withthe posterior insula and medial FI with connections nearinferotemporal cortex. Figure 12L shows lateral FI andsuperior FI connections just lateral to the hippocampus.In our study of the connections of FI and superior AI in

a gorilla, we found that the FI seeds had connections withthe frontal polar cortex while such connections weresparse from the superior AI seed. In humans, frontal polarcortex is involved in retrieval from episodic memory, mul-titasking, and mentalizing behaviors (Gilbert et al., 2006).Both FI and superior AI seeds were extensively connectedwith more posterior parts of the frontal lobe as well asmuch of insular cortex, and both delineated tracts justmedial to the hippocampus suggesting connection withthat structure. The medial FI seed is also connected withthe amygdala and the septum. Septal activity is associ-ated with the building of trust in human subjects(Krueger et al., 2007). The activity of FI is also directlyassociated with trust (Singer et al., 2004a). More broadly,the septum is linked to social memory and to the control ofanterior hypothalamic functions mediated by vasopressin

Fig. 11. A: A low-power photomicrograph of immunocytochemicalstaining for DISC1 (brown-black) in area FI of a 51-year-old humanmale subject. This section has also been counterstained for cell bodieswith cresyl violet; cells labeled only by the cresyl violet stain are pur-ple-blue rather than dark brown. Note that the VENs are stronglypositive for DISC1, whereas many cells in other layers are not. Somefork cells are also DISC1 positive. B: A higher power image of layer 5illustrating that the VENs and a subset of pyramidal neurons are la-beled with the antibody, whereas most pyramidal neurons are unla-beled, visible only due to the cresyl violet counterstain. The blackarrowheads with white borders indicate DISC1-positive VENs; theblack-bordered white arrowhead indicates a VEN not labeled by theantibody to DISC1. [Color figure can be viewed in the online issue,which is available at wileyonlinelibrary.com.]



and oxytocin involved in parental care and social attach-ment (Lim and Young, 2006; Numan, 2000). The VENs inFI are likely to project to some or all of structures revealedby the tractography.

VENS IN EVOLUTION

The VENs are a phylogenetically recent specializationin hominoid evolution. The VENs in FI and LA tend to bemore numerous on the crowns of gyri, suggesting that theVEN containing areas have undergone differential expan-sion reminiscent of other cortical specializations such asthe representations of the highly sensitive pads of theforepaw in the raccoon somatosensory cortex (Allman,2000; Welker and Seidenstein, 1959). Especially, in thehuman brain, there is considerable variability is the pres-ence and number of small sulci and gyri within FI, and

these influence the VEN distributions. The concentrationof VENs in the crowns of small gyri is also a notable fea-ture of FI in the elephant (Hakeem et al., 2009).The existence of VENs in primates is not related to rela-

tive brain size or encephalization (see Fig. 6). Instead, itappears to be related to absolute brain size. The VENs arepresent in primates with adult brain sizes greater thanabout 300 g. They are also present in the apparent homo-logs of FI and LA in other mammals with very largebrains such as cetaceans and elephants (Butti et al., 2009;Hakeem et al., 2009; Hof and Van der Gucht, 2007).Nearly, all of these mammals are also highly social. Wethink that large brain size and complex social behaviorboth favor specialized neural systems for rapid communi-cation within brain circuits. Large brains may be inher-ently slower because of the greater distances over whichmessages must be sent. Large brains also suffer from the

Fig. 12. Tractography based on diffusion tensor imaging of the brain of a 27-year-old male gorilla. Image A illustrates the levels for the sec-tions illustrated in B through L. In A, the yellow plane corresponds to the plane containing the seed voxels; it corresponds to image I. The trac-tography seeds, shown in image B, which were 1 mm3 voxels, were placed in approximately the same level as the section for this individual go-rilla illustrated in Figure 3. All connections are shown, where there are multiple connection for a voxel, the colors are mixed as in red and blueyielding purple. The right side of each image corresponds to the right side of the brain. [Color figure can be viewed in the online issue, which isavailable at wileyonlinelibrary.com.]



limitations associated with packing large myelinatedaxons into a restricted space. However, fiber pathways inlarge brains have small sets of very large axons, whichmay serve as a compromise between the needs for rapidcommunication and the packing constraint (Wang et al.,2008). Thus, the evolution of the VENs may be an adapta-tion related to large brain size. Complex social behavior isoften fast-paced, and this puts a premium on the capacityto respond quickly to changing conditions. A basic func-tion of FI may be to register feedback, which may be cru-cial for initiating fast adaptive responses to changes,which would be consistent with the activity of FI preced-ing linked activity in ACC and other cortical areas (Srid-haran et al., 2008). We found two interesting differencesbetween the distribution of VENs in humans and apes.The first difference between humans and apes is the rela-tionship between agranular insular cortex, that is, insularcortex lacking a layer 4. In humans, area FI, which isdefined by the presence of VENs, appears to correspond tomost of agranular insular cortex as delinated by Rose(1928). However, in apes, area FI appears to correspond toa smaller part of the total agranular insular cortex. Thisdifference may explain why there are typically consider-ably more VENs in humans than in apes. The second dif-ference between humans and apes is that the density ofVENs relative to other neurons is significantly higher inapes than humans in FI and ACC. One possible explana-tion for this surprising finding is that there may be otherspecialized neuronal populations that are differentiallyexpanded in humans relative to apes. The presence anddistribution of VENs is variable in orangutans, as arereports of their social behavior (Galdikas, 1985; Mitaniet al., 1991; Singleton and Van Schaik, 2002), which rangefrom solitary to relatively social, although typically orang-utans are found to participate in smaller social groupsthan the other great apes. It is of interest that other partsof the neural systems underlying social behavior, such asthe amygdala and the orbitofrontal cortex, are smaller orsimpler in orangutans than in other great apes (Bargeret al., 2007; Schenker et al., 2005, Semendeferi et al.,1998).

VENS MAY BE LINKED TO AWARENESS

Recent work suggests that the anterior insula isinvolved in awareness (Craig, 2010; Nelson et al., 2010;Ploran et al., 2007). This connection with awareness wasinitially suggested in an fMRI experiment by Kikyo et al.(2002), in which they observed activity in anterior insulawhen subjects reported the subjective sense of knowing aword before recalling it in a memory task, which theseauthors called the ‘‘feeling of knowing.’’ More recently,Ploran et al. (2007) found in an experiment using a behav-ioral paradigm in which objects gradually emerge fromnoise that the activity of anterior insula was stronglylinked to the moment when the subjects became aware ofthe identity of the object [allowing for the delays inherentin the fMRI signal, Ploran et al. (2007)]. More recent workfrom the same group has identified several component ofthis activity including one in inferior anterior insula par-ticularly on the right side (Nelson et al., 2010). Allmanet al. (2005) proposed that the VENs and related circuitryare involved in rapid intuition, which, like perceptual rec-ognition, involves immediate effortless awareness ratherthan the engagement of deliberative processes. Recently,

Aziz-Zadeh et al. (2009) found that when subjects weresolving anagrams and arrived at rapid insightful solutions(‘‘aha’’ moments), both anterior insula and anterior cingu-late cortex were activated. These aspects of awareness arenot limited to body states, but involve visual and linguisticexperiences as well, suggesting the hypothesis that therole of anterior insula in awareness may include most orall aspects of perception and cognition. An extension ofthis hypothesis is that the VENs in FI serve as a fast relayof this information to other parts of the brain.Although these social processes are often conscious,

they can also proceed covertly without the subject’s directawareness. For example, when subjects gaze into the eyesof others, if the size of the pupils of the eyes of theobserved subject change in a way that is discordant withthe changes in pupil size in the subject, both anterior cin-gulate and anterior insula are activated (Harrison et al.,2009). This discordance in pupil size change is reflective ofdifferences in autonomic arousal and emotional experi-ence between the observed individual and the subject.This is a covert signal that there is a discordance in theirfeelings about the social transaction that they are con-ducting, another type of social error signal. The use ofGranger causality analysis of temporally resolved func-tional imaging data suggests that activity in FI precedescingulate and other cortical areas, and Sridharan et al.(2008) proposed that the VENs may have a role in initiat-ing this activity in other cortical areas. This initiation ofactivity may be related to the awareness of negative orpositive feedback with respect to a broad range of internaland external states.

ACKNOWLEDGMENTS

The authors thank Dr. Kebreten Manaye, Dr. BarbaraWold, Dr. Joseph Erwin, Dr. Chet Sherwood, Dr. Bill See-ley, Dr. Patrick Hof, and Dr. A. D. Craig for their invalu-able comments and discussion. We thank Dr. MichealTyszka and Dr. Jason Kaufman for the MRIimaging of theape brains. We thank Virginie Goubert for her painstak-ing preparation of the histological sections of many of theape brains used in this paper. We thank Dr. KaterinaSemendeferi for the use of her brain, which enabled us toexpand our sample of ape and human brains. We thankDr. Kristen Tillisch and Dr. Emeran Mayer for the MRi-mages for the young adult human subject. We are gratefulto Dr. John Morris for his suggestion that the expressionof NMB and gastrin releasing peptide in the mouse insu-lar cortex might be related to the VENs. We thank Dr.Heidi Griffith for her help in collecting some of the humanstereological data. We thank Archibald Fobbs, curator ofthe Yakovlev and Welker Brain Collections and Dr.Adrianne Noe, Director, National Museum of Health andMedicine for their crucial role in preserving these collec-tions and making them available to us and to the broaderscientific community. In the Hof lab, technical help wasprovided by B. Wicinski and S. Harry. Several of the greatape brains involved in this study were on loan to the‘‘Great Ape Aging Project’’ from zoological gardens thatare accredited by the Association of Zoos and Aquariumsand that participate in the Ape Taxon Advisory Group. Weespecially appreciate the contribution of zoo veterinariansand staff in collecting and providing specimens. Addi-tional human tissue was obtained from the NICHD Brainand Tissue Bank for Developmental Disorders.



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