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Brain Struct Funct (2010) 214:495–517 DOI 10.1007/s00429-010-0254-0 ORIGINAL ARTICLE The von Economo neurons in frontoinsular and anterior cingulate cortex in great apes and humans John M. Allman • Nicole A. Tetreault • Atiya Y. Hakeem • Kebreten F. Manaye • Katerina Semendeferi • Joseph M. Erwin • Soyoung Park • Virginie Goubert • Patrick R. Hof Received: 1 December 2009 / Accepted: 21 April 2010 / Published online: 29 May 2010 Ó The Author(s) 2010. This article is published with open access at Springerlink.com Abstract The von Economo neurons (VENs) are large activity of the inferior anterior insula, which contains FI, is bipolar neurons located in frontoinsular (FI) and anterior related to physiological changes in the body, decision- cingulate cortex in great apes and humans, but not other making, error recognition, and awareness. The VENs primates. We performed stereological counts of the VENs appear to be projection neurons, although their targets are in FI and LA (limbic anterior, a component of anterior unknown. We made a preliminary study of the connections cingulate cortex) in great apes and in humans. The VENs of FI cortex based on diffusion tensor imaging in the brain are more numerous in humans than in apes, although one of a gorilla. The VEN-containing regions connect to the gorilla approached the lower end of the human range. We frontal pole as well as to other parts of frontal and insular also examined the ontological development of the VENs in cortex, the septum, and the amygdala. It is likely that the FI and LA in humans. The VENs first appear in small VENs in FI are projecting to some or all of these structures numbers in the 36th week post-conception, are rare at birth, and relaying information related to autonomic control, and increase in number during the first 8 months after birth. decision-making, or awareness. The VENs selectively There are significantly more VENs in the right hemisphere express the bombesin peptides neuromedin B (NMB) and than in the left in FI and LA in postnatal brains of apes and gastrin releasing peptide (GRP) which are also expressed in humans. This asymmetry in VEN numbers may be related another population of closely related neurons, the fork to asymmetries in the autonomic nervous system. The cells. NMB and GRP signal satiety. The genes for NMB and GRP are expressed selectively in small populations of neurons in the insular cortex in mice. These populations J. M. Allman (&) Á N. A. Tetreault Á A. Y. Hakeem Á may be related to the VEN and fork cells and may be S. Park Á V. Goubert involved in the regulation of appetite. The loss of these Division of Biology, 216-76, California Institute of Technology, cells may be related to the loss of satiety signaling in Pasadena, CA 91125, USA e-mail: [email protected] patients with frontotemporal dementia who have damage to FI. The VENs and fork cells may be morphological spe- K. F. Manaye cializations of an ancient population of neurons involved in Department of Physiology and Biophysics, College of Medicine, the control of appetite present in the insular cortex in all Howard University, Washington, DC 20059, USA mammals. We found that the protein encoded by the gene K. Semendeferi DISC1 (disrupted in schizophrenia) is preferentially Department of Anthropology, University of California, expressed by the VENs. DISC1 has undergone rapid evo- San Diego, La Jolla, CA 92093, USA lutionary change in the line leading to humans, and since it J. M. Erwin suppresses dendritic branching it may be involved in the Biomedical Sciences and Pathobiology, Virginia Polytechnic distinctive VEN morphology. Institute, Blackburg, VA 24036, USA Keywords von Economo neurons Á Fork cells Á P. R. Hof Department of Neuroscience, Mount Sinai School of Medicine, Anterior cingulate cortex Á Frontoinsular cortex Á New York, NY 10029, USA Hominoid brain Á Disc1 Á Neuromedin B 123 496 Brain Struct Funct (2010) 214:495–517 Introduction be considered as a further elaboration of these homeostatic mechanisms, which, while retaining some aspects of their In their comprehensive study of the cytoarchitecture of the basic physiological functions, such as appetite regulation, human cerebral cortex, von Economo and Koskinas (1925) have extended to the regulation of social interactions and and von Economo (2009) described large bipolar neurons the homeostasis of interpersonal relationships. The inferior in frontoinsular (FI) cortex and in the limbic anterior (LA) anterior insula has been found to be consistently activated area of anterior cingulate cortex. Von Economo (1926) by peripheral autonomic changes in an exhaustive meta- called these specialized neurons the rod and corkscrew analysis of the imaging data (Mutschler et al. 2009). One cells, referring to the straight and twisted variants of this such connection between autonomic arousal and decision- distinct class of neurons. These unusual cells had previ- making is suggested by the findings of Critchley et al. ously been observed by many classical neuroanatomists (2000) who found that anterior insula was activated when including Betz (1881), Hammarberg (1895), and Ramo´ny the subjects had increased galvanic skin responses. The Cajal (1899), but von Economo (1926) made a more activity of anterior insula also increased as a function of complete description of their morphology and mapped their uncertainty during the anticipatory period in a gambling specific locations in human cortex. Rose (1927) addition- task (Critchley et al. 2001a). Preuschhoff et al. (2008) ally described cells of this type in anterior cingulate cortex found that the region of anterior insula closely matching of a chimpanzee brain. They have often been termed the location of FI was specifically activated during ‘‘risk ‘‘spindle cells’’ (Nimchinsky et al. 1995; 1999), but prediction error’’ when the consequences of a gambling because of possible confusion with other uses of this term, decision in which a subject sustained a loss was revealed to we have opted to call then von Economo neurons or VENs. the subject. The anterior inferior insula, in a location also The VENs are projection neurons and are substantially closely corresponding to FI, is strongly activated by neg- larger than their pyramidal cell neighbors (Nimchinsky ative feedback in the form of frowning faces in a decision et al. 1999; Allman et al. 2001). They possess a single large task involving a high degree of uncertainty (Ullsperger and basal dendrite, distinguishing them from pyramidal neu- von Cramon 2004). The region corresponding to FI on the rons, which have an array of smaller basal dendrites right side is also activated when subjects scrutinize facial (Watson et al. 2006). This single large basal dendrite may expressions to discern intentions (Baron-Cohen et al. have resulted from a transformation during evolution of the 1999). The integrative functioning of the lateral part of FI genetic programs for pyramidal neuron development to in response to negative feedback is illustrated in a series of concentrate growth of the primary component of the basal experiments by Jabbi et al. (2008) who elicited activity in dendrite and suppress the secondary and tertiary branching. this VEN-rich region through experiences involving dis- The VENs have a narrow dendritic arborization that spans gust mediated by taste, by the observation of someone else the layers of the cortex and may be able to sample and responding to a disgusting taste, and by imagining a dis- rapidly relay the output from a columnar array of neurons gusting taste. (Note, however, that the activity observed in (Watson et al. 2006). The apical and basal dendrites of the these experiments could also have arisen from the adjacent VENs are remarkably symmetrical. This architecture sug- inferior frontal region.) These data together with many gests that these cells may be comparing inputs to these two other experiments suggest that anterior insula and cingulate symmetrical dendrites (Watson et al. 2006). The VENs in cortex are involved in the recognition of error and the LA are filled retrogradely with the carbocyanin tracer DiI initiation of adaptive responses to error and negative after it is deposited in the cingulum bundle, and thus the feedback (Gehring et al. 1993; Dehaene et al. 1994; Klein VENS are likely to be projection neurons with axonal et al. 2007; Lamm and Singer 2010). Anterior insula and connections extending through the underlying white matter anterior cingulate cortex are major components of the to other parts of the brain (Nimchinsky et al. 1995). The system for the flexible control of goal-directed behavior large size of the VENs and their preferential staining with (Dosenbach et al. 2007). the antibody for non-phosphorylated neurofilament are also Anterior insula and anterior cingulate cortex are acti- characteristic features of cortical projection neurons vated by situations that involve social error, a defect in the (Nimchinsky et al. 1995; Allman et al. 2002). social network in which the individual is participating, or a The posterior insula and anterior cingulate cortex in change in state of one of the participants. For example, anthropoid primates receive differentiated inputs for pain, these structures are activated by resentment (Sanfey et al. itch, warmth, cooling, and sensual touch, which are central 2003), deception (Spence et al. 2001), embarrassment components of highly evolved mechanisms for physiolog- (Berthoz et al. 2002), and guilt (Shin et al. 2000). They are ical homeostasis (Craig 2003, 2009). The VEN-containing also activated by feelings of empathy for the suffering of areas FI, which is located in inferior anterior insula, and others, another type of social error signal (Singer et al. LA, which is a component of anterior cingulate cortex, may 2004a). In mothers, FI in the right hemisphere responds to 123 Brain Struct Funct (2010) 214:495–517 497 the crying of distressed infants (Lorberbaum et al.

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