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  • 1. The Amygdala, Autism and Anxiety<br />David G. Amaral, Ph.D.1,2 and Blythe A. Corbett, Ph.D.2<br />1Department of Psychiatry, Center for Neuroscience and California Regional Primate Research Center<br />2The M.I.N.D. (Medical Investigation of Neurodevelopmental Disorders) Institute<br />University of California, Davis, Center for Neuroscience, 1544 Newton Ct., Davis, CA, 95616<br />Number of pages: 20<br />Number of words: 3755<br />Number of tables: 0<br />Number of figures: 0<br />Running Title: Amygdala and Autism<br />Send correspondence and reprint requests to:<br />David G. Amaral, Ph.D.<br />Center for Neuroscience<br />1544 Newton Court<br />Davis, CA. 95616 USA<br />Telephone(530) 757-8813<br />Fax(530) 754-7016<br />e-maildgamaral@ucdavis.edu<br />Abstract<br />Brothers MQBGAEEANwA1AEQAMgA0ADAAMAA3AEEAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARAAwADAANQBCAEQAMQAwAEIAMAAyADAAMAAwADAAMAAwADEAMAAwADAAMQBEADMAQgAxAEMAMAAyADAAMAAwADAAMAAwADEANgA1AEIANAAyADcAMgA2AEYANwA0ADYAOAA2ADUANwAyADcAMwAyAEMAMgAwADMAMQAzADkAMwA5ADMAMAAyADAAMgAzADMANAAzADEAMwAzADUARAAwADAAMABFADAAMAAwADAAMAAwAA== ADDIN ENRfu (1990) has proposed that the amygdala is an important component of the neural network that underlies social cognition. And, Bauman and Kemper OABEAEUAMQA1AEUAQgBFADAAMAA3ADYAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARAAwADAANQBCAEQAMQAwAEUAMAAyADAAMAAwADAAMAAwADEAOQAzADgAQQBBADcARQBGADAAMAAyADAAMAAwADAAMAAwADEANAA1AEIANAAyADYAMQA3ADUANgBEADYAMQA2AEUAMgBDADIAMAAzADEAMwA5ADMAOAAzADUAMgAwADIAMwAzADQAMwAxADMANAA1AEQAMAAwADAARQAwADAAMAAwADAAMAA= ADDIN ENRfu (1985) observed signs of neuropathology in the amygdala of the postmortem autistic brain. These findings, in addition to recent functional neuroimaging data, have led Baron-Cohen et al. QQBEADcANABFADAAMwA3ADAAMAA4ADAAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARAAwADAANQBCAEQAMQAxADAAMAAyADAAMAAwADAAMAAwADEAQQA3ADMAMgAwAEQAOAA0ADgAMAAyADAAMAAwADAAMAAwADEAOQA1AEIANAAyADYAMQA3ADIANgBGADYARQAyAEQANAAzADYARgA2ADgANgA1ADYARQAyAEMAMgAwADMAMgAzADAAMwAwADMAMAAyADAAMgAzADMANAAzADAAMwA4ADUARAAwADAAMABFADAAMAAwADAAMAAwAA== ADDIN ENRfu (2000) to propose that dysfunction of the amygdala may be responsible, in part, for the impairment of social functioning that is a hallmark feature of autism. Recent data from studies in our laboratory on the effects of amygdala lesions in the macaque monkey are at variance with a fundamental role for the amygdala in social behavior. If the amygdala is not essential for normal social behavior, as seems to be the case in both nonhuman primates and selected patients with bilateral amygdala damage, then it is unlikely to be the substrate for the abnormal social behavior of autism. However, damage to the amygdala does have an effect on a monkey’s response to normally fear-inducing stimuli, such as snakes, and removes a natural reluctance to engage novel conspecifics in social interactions. These findings lead to the conclusion that an important role for the amygdala is in the detection of threats and mobilizing an appropriate behavioral response, part of which is fear. If the amygdala is pathological in subjects with autism, it may contribute to their abnormal fears and increased anxiety rather than their abnormal social behavior. <br />Introduction<br />In the best of biomedical research endeavors, there is a natural symbiosis between basic, and often basic animal research, and careful assessment of clinical populations. The issues raised in this paper draw from efforts to establish the neurobiological basis of primate social behavior, on the one hand, and attempts to determine brain systems that are impacted in autism and lead to impairments of social behavior, on the other hand. One effort has enormous potential to inform the other. If for example, a neural system, let’s call it the Social System, is established that underlies the various components of social interaction, and given that impairments of social interaction are a major deficit in autism spectrum disorders, then a reasonable hypothesis might be that a region of primary brain pathology might be in the Social System. Conversely, if specific and reproducible areas of brain pathology were identified in autism spectrum disorder, this information might provide a useful heuristic as to which brain regions might be components of the Social System. <br />Life, of course, is rarely so simple and autism is certainly one of the most complex of neurological disorders. It is complex because it has many diverse symptoms including social impairment, language problems and motor stereotypies. These symptoms are observed heterogeneously throughout the population that makes up the autism spectrum. There are also a number of co-morbid conditions, such as sleep disturbances, gastrointestinal distress and psychiatric symptoms including anxiety and obsessive-compulsive behavior. The following is a short summary of the thought and experimental process that we have followed - starting with the notion that the amygdala is a fundamental component of the Social System and likely to be heavily involved in the pathophysiology of autism - to our current view that the amygdala is involved in detecting and reacting to environmental threats. And, if the amygdala is impaired in autism, it may be more responsible for alterations in fear and anxiety rather than social behavior.<br />The Amygdala<br />The primate amygdala is a relatively small brain region located in the temporal lobe, just anterior to the hippocampus. In the macaque monkey it is approximately 0.6 cm3 in volume and in the human it is about 3.0 cc3. The amygdala is comprised of at least 13 nuclei and cortical regions, many of which are partitioned into two or more subdivisions. The amygdala has widespread extrinsic connections including those with the neocortex, hippocampal formation, cholinergic basal forebrain, striatum, hypothalamus and brainstem. While neocortical inputs to the amygdala arise mainly from higher order unimodal and polymodal association cortices, projections back to the neocortex extend monosynaptically even to primary sensory areas such as visual area V1. There is an extensive network of intrinsic connections within the amygdala that generally brings information from more laterally situated nuclei, such as the lateral nucleus, to more medially situated nuclei, such as the central nucleus. The amygdala contains a plethora of neuroactive substances and has some of the highest brain levels of benzodiazepine receptors and opiates. Detailed descriptions of the neuroanatomy of the amygdala can be found in Amaral et al. MgAyADEAOQBEADUAQgBDADAAMAA3ADYAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARAAwADAANQBCAEQAMQAxADIAMAAyADAAMAAwADAAMAAwADEANQAwADMAQgBDADAANwAxADYAMAAyADAAMAAwADAAMAAwADEANAA1AEIANAAxADYARAA2ADEANwAyADYAMQA2AEMAMgBDADIAMAAzADEAMwA5ADMAOQAzADIAMgAwADIAMwAzADQAMwAxADMAOQA1AEQAMAAwADAARQAwADAAMAAwADAAMAA= ADDIN ENRfu (1992). One can conclude from the neuroanatomy of the amygdala that it is privy to much of the sensory processing that occurs in the neocortex and, that through its widespread efferent connections, it has the ability to influence the activity of numerous functional systems that range from elemental physiological processes such as heart rate and respiration to the highest processes of perception, attention and memory.<br />The Amygdala and Social Behavior<br />Several lines of evidence have indicated that the amygdala plays an important role in socioemotional behavior. Macaque monkeys with bilateral lesions that include the amygdala are typically more tame than normal animals, demonstrate abnormal food preferences and have alterations of sexual behavior QQAyAEUAOQA2ADMAMgA1ADAAMAA3ADQAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARAAwADAANQBCAEQAMQAxADQAMAAyADAAMAAwADAAMAAwADEAOQAzADkAOAAzAEYARQAyAEMAMAAyADAAMAAwADAAMAAwADEAMwA1AEIANAAyADcAMgA2AEYANwA3ADYARQAyAEMAMgAwADMAMQAzADgAMwA4ADMANwAyADAAMgAzADMANAAzADIAMwAwADUARAAwADAAMABFADAAMAAwADAAMAAwAA== ADDIN ENRfu (Brown and Schafer 1887) (MgAzADAARAA5ADMARgBFADAAMAA5AEMAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARAAwADAANQBCAEQAMQAxADYAMAAyADAAMAAwADAAMAAwADEARABDADkANwBFAEUAOABFADUAMAAyADAAMAAwADAAMAAwADIANwA1AEIANABCADYAQwA3ADUANwA2ADYANQA3ADIAMgBDADIAMAAzADEAMwA5ADMAMwAzADgAMgAwADIAMwAzADQAMwAyADMAMQAzAEIAMgAwADQAQgA2AEMANwA1ADcANgA2ADUANwAyADIAQwAyADAAMwAxADMAOQAzADMAMwA5ADIAMAAyADMAMwA0ADMAMgAzADIANQBEADAAMAAwAEUAMAAwADAAMAAwADAA ADDIN ENRfu Kluver and Bucy 1938, 1939). Rosvold et al. NwA0ADUAMAA2ADIARgBFADAAMAA3ADgAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARAAwADAANQBCAEQAMQAxADgAMAAyADAAMAAwADAAMAAwADEANgAwADcANwA4ADAAQgAyADgAMAAyADAAMAAwADAAMAAwADEANQA1AEIANQAyADYARgA3ADMANwA2ADYARgA2AEMANgA0ADIAQwAyADAAMwAxADMAOQAzADUAMwA0ADIAMAAyADMAMwA0ADMAMgAzADMANQBEADAAMAAwAEUAMAAwADAAMAAwADAA ADDIN ENRfu (1954) designed studies to explicitly evaluate changes in social behavior in macaque monkeys following amygdala damage. They established artificial social groups of male rhesus monkeys and studied the dominance hierarchy that emerged. They then carried out two stage bilateral destructive lesions of the amygdala of the most dominant animal and studied the dominance hierarchy as the group reorganized. They found that the lesions led to a decrease in social dominance with the lesioned animal typically falling to the most subordinate position of the group.<br />A more extensive program of studies was carried out by Kling and colleagues using both captive and free ranging nonhuman primates MwA2ADYANAAxADQANQBGADAAMAA5ADgAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARAAwADAANQBCAEQAMQAxAEEAMAAyADAAMAAwADAAMAAwADIARABFAEQAQgA5ADkANwBCAEQAMAAyADAAMAAwADAAMAAwADIANQA1AEIANABCADYAQwA2ADkANgBFADYANwAyAEMAMgAwADMAMQAzADkAMwA3ADMAMAAyADAAMgAzADMANAAzADIAMwA0ADMAQgAyADAANABCADYAQwA2ADkANgBFADYANwAyAEMAMgAwADMAMQAzADkAMwA3ADMAMQAyADAAMgAzADMANAAzADIAMwA1ADUARAAwADAAMABFADAAMAAwADAAMAAwAA== ADDIN ENRfu (Kling et al. 1970, Kling and Cornell 1971) QgBBADcAOAA0ADIAMgA3ADAAMAA3ADQAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARAAwADAANQBCAEQAMQAxAEMAMAAyADAAMAAwADAAMAAwADEAOQAzAEEARQBBAEEARQBDADYAMAAyADAAMAAwADAAMAAwADEAMwA1AEIANABCADYAQwA2ADkANgBFADYANwAyAEMAMgAwADMAMQAzADkAMwA3ADMANgAyADAAMgAzADMANAAzADIAMwA2ADUARAAwADAAMABFADAAMAAwADAAMAAwAA== ADDIN ENRfu (Kling and Steklis 1976). Dicks et al. QQBGAEEAOABCADIAQQA2ADAAMAA3ADQAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARQAwADAANQBCAEQAMQAxAEUAMAAyADAAMAAwADAAMAAwADEANAAwADEARQA4ADAAMAA0AEMAMAAyADAAMAAwADAAMAAwADEAMwA1AEIANAA0ADYAOQA2ADMANgBCADcAMwAyAEMAMgAwADMAMQAzADkAMwA2ADMAOAAyADAAMgAzADMANAAzADIAMwA3ADUARAAwADAAMABFADAAMAAwADAAMAAwAA== ADDIN ENRfu (1968), for example, retrieved rhesus monkeys from social troops on the island of Cayo Santiago. These animals were subjected to bilateral amygdalectomy and then returned to their social groups. While it was difficult to follow the minute-to-minute interactions of the lesioned animals, the typical finding was that they were invariably ostracized and would often perish without the support of the social group.<br />From the results of these and similar studies carried out by several laboratories, Brothers MQBGAEEANwBCAEIAMgA2ADAAMAA3AEEAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARQAwADAANQBCAEQAMQAyADAAMAAyADAAMAAwADAAMAAwADEAMAAwADAAMQBEADMAQgAxAEMAMAAyADAAMAAwADAAMAAwADEANgA1AEIANAAyADcAMgA2AEYANwA0ADYAOAA2ADUANwAyADcAMwAyAEMAMgAwADMAMQAzADkAMwA5ADMAMAAyADAAMgAzADMANAAzADEAMwAzADUARAAwADAAMABFADAAMAAwADAAMAAwAA== ADDIN ENRfu (1990) formalized the view that the amygdala is one of a small group of brain regions that form the neural substrate for social cognition. This view predicts that the amygdala is essential for certain aspects of the interpretation and production of normal social gestures such as facial expressions and body postures. It also predicts, consistent with the literature that damage to the amygdala would invariably lead to a decrease in the amount or quality of conspecific social interactions. <br />The Amygdala and Autism<br />In their seminal studies on the neuropathology of the autistic brain, Bauman and Kemper OABEAEUAMQBCADAAQgBDADAAMAA3ADYAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARQAwADAANQBCAEQAMQAyADMAMAAyADAAMAAwADAAMAAwADEAOQAzADgAQQBBADcARQBGADAAMAAyADAAMAAwADAAMAAwADEANAA1AEIANAAyADYAMQA3ADUANgBEADYAMQA2AEUAMgBDADIAMAAzADEAMwA5ADMAOAAzADUAMgAwADIAMwAzADQAMwAxADMANAA1AEQAMAAwADAARQAwADAAMAAwADAAMAA= ADDIN ENRfu (1985) noted that the medially situated nuclei of the amygdaloid complex had clusters of small, tightly packed neurons that were not observed in control brains. The amygdala neuropathology was only one area among many that included alterations in the hippocampus, septum, cerebellum and other structures. Unfortunately, these observations have not yet been independently replicated. Neuroimaging studies have thus far produced conflicting results on whether there is a gross change in the volume of the amygdala. Abell et al. MwA4ADgAOQA0ADMARQA3ADAAMAA3ADQAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARQAwADAANQBCAEQAMQAyADUAMAAyADAAMAAwADAAMAAwADEANAAwADEARgAyADAAMwBDAEEAMAAyADAAMAAwADAAMAAwADEAMwA1AEIANAAxADYAMgA2ADUANgBDADYAQwAyAEMAMgAwADMAMQAzADkAMwA5ADMAOQAyADAAMgAzADMANAAzADQAMwA2ADUARAAwADAAMABFADAAMAAwADAAMAAwAA== ADDIN ENRfu (1999) reported an increased left amygdala volume in cases of autism and Asperger syndrome. Howard et al. MQA2ADYANwBEADAAOQBDADAAMAA3ADYAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARQAwADAANQBCAEQAMQAyADcAMAAyADAAMAAwADAAMAAwADEANQAwADMAOQA5ADAANgBFAEMAMAAyADAAMAAwADAAMAAwADEANAA1AEIANAA4ADYARgA3ADcANgAxADcAMgA2ADQAMgBDADIAMAAzADIAMwAwADMAMAAzADAAMgAwADIAMwAzADEAMwA4ADMANAA1AEQAMAAwADAARQAwADAAMAAwADAAMAA= ADDIN ENRfu (2000) also reported an increased amygdala volumes in both hemispheres of the brain in subjects with autism. In contrast to these studies, Aylward et al. NQBFADMARgA1ADIARQAyADAAMAA3ADgAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARQAwADAANQBCAEQAMQAyADkAMAAyADAAMAAwADAAMAAwADEANgAwADcAQwA4ADAARABGAEUAMAAyADAAMAAwADAAMAAwADEANQA1AEIANAAxADcAOQA2AEMANwA3ADYAMQA3ADIANgA0ADIAQwAyADAAMwAxADMAOQAzADkAMwA5ADIAMAAyADMAMwA0ADMAMwAzADgANQBEADAAMAAwAEUAMAAwADAAMAAwADAA ADDIN ENRfu (1999), reported the amygdala to be decreased in volume compared to age matched control cases. Pierce et al. RgA4ADYARQA1AEMAQgBFADAAMAA3ADYAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARQAwADAANQBCAEQAMQAyAEIAMAAyADAAMAAwADAAMAAwADEANQAwADMAOQAxADAANQAwADQAMAAyADAAMAAwADAAMAAwADEANAA1AEIANQAwADYAOQA2ADUANwAyADYAMwA2ADUAMgBDADIAMAAzADIAMwAwADMAMAAzADEAMgAwADIAMwAzADQAMwAzADMAOQA1AEQAMAAwADAARQAwADAAMAAwADAAMAA= ADDIN ENRfu (2001) also reported amygdala volumes to be significantly smaller. Thus, these studies appear inconclusive as to whether there is a size difference in the autistic amygdala. Even if the size was significantly different, it is unclear whether this would imply better or worse function.<br />More suggestive evidence for a role of the amygdala in autism comes from a variety of functional imaging studies. Individuals with high functioning autism or Asperger syndrome showed significantly less amygdala activation than control subjects during a task that required them to judge what a person might be feeling or thinking from images of their eyes (Baron-Cohen et al. 1999). A more recent fMRI study, comparing adult males with autism to control subjects, measured the neural activation in areas of the brain that are associated with a social perception task MwA1AEYAOQAzAEMAMwBGADAAMAA3ADYAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARQAwADAANQBCAEQAMQAyAEQAMAAyADAAMAAwADAAMAAwADEANQAwADMAOQAxADAANgBGADYAMAAyADAAMAAwADAAMAAwADEANAA1AEIANAAxADcAMwA2ADgANwA3ADYAOQA2AEUAMgBDADIAMAAzADIAMwAwADMAMAAzADEAMgAwADIAMwAzADQAMwA0ADMANQA1AEQAMAAwADAARQAwADAAMAAwADAAMAA= ADDIN ENRfu (Ashwin et al. 2001). Subjects were shown images of real faces that varied in intensity of facial affect from neutral expressions to extreme fear expressions, as well as scrambled faces. The subject was simply required to press a button every time they saw a picture on the screen. During this social perception task, the subjects with autism showed less activation of the amygdala and orbitofrontal cortex. Moreover, the subjects with autism showed increased activity (implying greater reliance) on the superior temporal gyrus and anterior cingulate cortex. These data would appear to suggest that when normal subjects are carrying out tasks that require social evaluation, the amygdala is activated. And this activation is decreased in individuals with autism.<br />The Amygdala Theory of Autism<br />Based on these converging lines of evidence, Baron-Cohen et al QQBEADcANABFADIAMwA1ADAAMAA4ADAAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARQAwADAANQBCAEQAMQAzADAAMAAyADAAMAAwADAAMAAwADEAQQA3ADMAMgAwAEQAOAA0ADgAMAAyADAAMAAwADAAMAAwADEAOQA1AEIANAAyADYAMQA3ADIANgBGADYARQAyAEQANAAzADYARgA2ADgANgA1ADYARQAyAEMAMgAwADMAMgAzADAAMwAwADMAMAAyADAAMgAzADMANAAzADAAMwA4ADUARAAwADAAMABFADAAMAAwADAAMAAwAA== ADDIN ENRfu (2000) wrote a very compelling review that concluded, “The amygdala is therefore proposed to be one of several neural regions that are abnormal in autism.” An implication of the paper is that pathology of the amygdala leads to an impairment in social intelligence, which is a hallmark feature of autism. That the amygdala might be at the heart of the pathophysiology of autism was also suggested somewhat earlier by Bachevalier 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 ADDIN ENRfu (1994, 1996) based on observations of neonatal macaque monkeys who had been subjected to bilateral medial temporal lobe lesions. Bachevalier described these monkeys (at 6 months of age) as dramatically decreasing their social behavior as compared to controls in dyadic social encounters with conspecifics. The lesioned animals actively avoided social contacts and had “blank, inexpressive faces and poor body expression (i.e. lack of normal playful posturing) and they displayed little eye contact. Furthermore, animals with early medial temporal lobe lesions developed locomotor stereotypies and self-directed activities” OQA1ADcAOQBEADUAOAAzADAAMAA4ADAAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARQAwADAANQBCAEQAMQAzADUAMAAyADAAMAAwADAAMAAwADEAMwAwADAARQAxADkARgAxADAAMAAyADAAMAAwADAAMAAwADEAOQA1AEIANAAyADYAMQA2ADMANgA4ADYANQA3ADYANgAxADYAQwA2ADkANgA1ADcAMgAyAEMAMgAwADMAMQAzADkAMwA5ADMANAAyADAAMgAzADMANAAzADMAMwA2ADUARAAwADAAMABFADAAMAAwADAAMAAwAA== ADDIN ENRfu (Bachevalier 1994). Since selective lesions of the hippocampus did not produce this pattern of behavioral alterations, Bachevalier attributed them to damage of the amygdala.<br />The literature that figured prominently in the generation of the amygdala theory of autism and the notion that the amygdala is essential for normal social behavior was very influential on our own program of studies aimed at unraveling the neurobiology of primate social behavior. While we would have been delighted to have generated data consistent with the hypothesis that the amygdala is central to social behavior, the data we did generate has led us to a distinctly different conclusion.<br />The Amygdala is not Essential for Social Behavior in the Adult Monkey<br />We have carried out a series of experimental studies to re-examine the role of the amygdala in conspecific social behavior using the rhesus monkey as a model system NABEADgANwAyADcAMgA2ADAAMAA3ADQAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARQAwADAANQBCAEQAMQAzADgAMAAyADAAMAAwADAAMAAwADEANAAwADEAQwA4ADgAMABCAEUAMAAyADAAMAAwADAAMAAwADEAMwA1AEIANAA1ADYARAA2ADUANwAyADcAOQAyAEMAMgAwADMAMgAzADAAMwAwADMAMQAyADAAMgAzADMANAAzADIAMwA4ADUARAAwADAAMABFADAAMAAwADAAMAAwAA== ADDIN ENRfu (Emery et al. 2001). Adult, male rhesus monkeys with bilateral ibotenic acid lesions of the amygdala, and age, sex and dominance matched control monkeys were observed during dyadic interactions with “stimulus monkeys” (two males and two females). This stereotaxic, neurotoxic lesion technique has the merit of removing the neurons of the amygdala while sparing fibers that pass through it. A variety of both affiliative (groom, present sex etc.) and agonistic, (aggression, displace etc.) behaviors were quantitatively recorded while animals interacted in a large (18ft X 7ft X 6.5ft) chain link enclosure. Each experimental animal interacted with each stimulus animal for four, twenty-minute periods in what we called the unconstrained dyad format. In what was initially a very surprising observation, the amygdala-lesioned monkeys generated significantly greater amounts of affiliative social behavior towards the stimulus monkeys than the control monkeys. Control monkeys, when they first met the stimulus monkeys, demonstrated a typical and appropriate reluctance to engage in social interactions. They appeared to go though a period of evaluation to determine the intentions of the other animal. The lesioned monkeys, in contrast, appeared to be socially uninhibited since they did not go through the normal period of evaluation of the social partner before engaging in social interactions. <br />The inevitable conclusion from this study is that in dyadic social interactions, monkeys with extensive bilateral lesions of the amygdala can interpret and generate social gestures and initiate and receive more affiliative social interactions than normal controls. In short, they are clearly not critically impaired in carrying out social behavior. We would suggest that the lesions have produced a socially uninhibited monkey since their normal reluctance to engage a novel animal appears to have been eliminated. This, as well as evidence that the amygdala-lesioned animals are not fearful of normally fear-inducing stimuli such as snakes, has led us to the hypothesis that a primary role of the amygdala is to evaluate the environment for potential threats or dangers. Without a functioning amygdala, macaque monkeys do not evaluate other novel conspecifics as potential adversaries and whatever system(s) are involved in mediating social interactions run in default mode of approach.<br />Early Amygdala Lesions do not Eliminate Social Behavior<br />One caveat of this conclusion that the amygdala is not essential for social behavior is that these experiments were carried out in mature monkeys. One might argue that while the amygdala is not necessary for generating social behavior, perhaps it is essential for gaining social knowledge. We have carried out a series of studies in which the amygdala is lesioned bilaterally in primates at two weeks of age MwAzADgARQA2AEEARgA1ADAAMAA3ADgAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARQAwADAANQBCAEQAMQAzAEIAMAAyADAAMAAwADAAMAAwADEANgAwADcAMgAyADAAMgA0ADgAMAAyADAAMAAwADAAMAAwADEANQA1AEIANQAwADcAMgA2ADEANwA0ADYAOAA2ADUANwAyADIAQwAyADAAMwAyADMAMAAzADAAMwAxADIAMAAyADMAMwA0ADMAMQAzADIANQBEADAAMAAwAEUAMAAwADAAMAAwADAA ADDIN ENRfu (Prather et al. 2001). This is at a point in time when infant macaque monkeys are mainly found in ventral contact with their mothers and there is virtually no play or other types of social interactions with other animals. We found that the interactions of the lesioned animals with their mothers was similar to that of control animals. Moreover, we found that, like adult animals with bilateral amygdala lesions, they showed little fear of normally fear-provoking objects such as rubber snakes. However, they showed increased fear, as indicated by more fear grimaces and more screams during novel dyadic social interactions. Most germane to the discussion, however, is the finding that the lesioned animals generated substantial social behavior that was similar to that generated by age-matched controls. In a larger replication study that is currently under way (Prather et al., unpublished observations 2002) the quality and quantity of social interactions in a number of social formats is being investigated and there may be subtle differences in these parameters. However, the inescapable conclusion from observation of these animals is that there are none that are markedly impaired in generating species typical social behaviors such as grooming, play and facial expressions. All of the animals appear to be visually attentive of the other animals when they are involved in large “play groups” comprised of 2 control animals, 2 animals with amygdala lesions and 2 animals with hippocampal lesions as well as male and female adult animals. And none appear to have developed motor stereotypies despite the fact that they have now reached one year of age.<br />The results from studies carried out both in adult and mature rhesus monkeys with complete bilateral lesions of the amygdala have forced us to consider the conclusion that the amygdala is not essential either for interpretation or expression of species typical social behaviors or for gaining social knowledge. If the amygdala is not a central component of the Social System, it is unlikely that pathology of it would lead directly to the impairments of social behavior that are observed in autism. <br />Subject S.M.<br />There are relatively few human subjects who have bilateral and discrete lesions of the amygdala. One outstanding exception is patient S.M. who has been extensively studied by Adolphs and colleagues MgBGAEQAOQBDADgAMwA3ADAAMABBADAAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARQAwADAANQBCAEQAMQAzAEUAMAAyADAAMAAwADAAMAAwADIAQwBDADcARAA5AEMAMQAwADIAMAAyADAAMAAwADAAMAAwADIAOQA1AEIANAAxADYANAA2AEYANgBDADcAMAA2ADgANwAzADIAQwAyADAAMwAxADMAOQAzADkAMwA1ADIAMAAyADMAMwA0ADMAMwAzADEAMwBCADIAMAA0ADEANgA0ADYARgA2AEMANwAwADYAOAA3ADMAMgBDADIAMAAzADEAMwA5ADMAOQAzADQAMgAwADIAMwAzADQAMwAzADMAMAA1AEQAMAAwADAARQAwADAAMAAwADAAMAA= ADDIN ENRfu (Adolphs et al. 1994, Adolphs et al. 1995). Patient S.M. suffers from Urbach-Wiethe syndrome that has produced bilateral space occupying lesions of the amygdala. Interestingly, she is impaired in her ability to identify fearful faces despite the fact that she can reliably detect happiness and other emotions in faces. S.M. is also unable to determine which individuals would typically be considered untrustworthy based on their facial appearance RAAxADYAMgA5ADgARQAyADAAMAA3ADgAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARQAwADAANQBCAEQAMQA0ADEAMAAyADAAMAAwADAAMAAwADEANgAwADcARAA4ADAAMwAwADIAMAAyADAAMAAwADAAMAAwADEANQA1AEIANAAxADYANAA2AEYANgBDADcAMAA2ADgANwAzADIAQwAyADAAMwAxADMAOQAzADkAMwA4ADIAMAAyADMAMwA0ADMAMwAzADIANQBEADAAMAAwAEUAMAAwADAAMAAwADAA ADDIN ENRfu (Adolphs et al. 1998).<br />Despite these difficulties, patient S.M. leads a reasonably normal life. She is capable of holding a job, has been married and is raising children. One is impressed not so much with the deficits in this subject who has no amygdala but rather by how intact is much of her everyday behavior, including social behavior. A similar conclusion can be drawn from patient H.M. who had bilateral temporal lobectomies for intractable seizures. His surgery has completely removed the amygdala and rostral half of the hippocampal formation OAA3ADQAMQBFAEQAQgBDADAAMAA3ADYAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARQAwADAANQBCAEQAMQA0ADQAMAAyADAAMAAwADAAMAAwADEANQAwADMAOQA0ADAANwA5ADIAMAAyADAAMAAwADAAMAAwADEANAA1AEIANAAzADYARgA3ADIANgBCADYAOQA2AEUAMgBDADIAMAAzADEAMwA5ADMAOQAzADcAMgAwADIAMwAzADQAMwAzADMAMwA1AEQAMAAwADAARQAwADAAMAAwADAAMAA= ADDIN ENRfu (Corkin et al. 1997). While H.M. is densely amnesic, he is nonetheless capable of normal social interactions. And neither he nor patient S.M. demonstrate typical autistic symptomatology. These patients would seem to support the contention that the amygdala is not essential for normal social behavior and that damage to the amygdala does not necessarily lead to autistic behavior. <br />Anxiety in Autism<br />How does the concept of threat detection figure into the picture of autism? In Kanner’s QgBGAEMARgBDADYAMwBDADAAMAA3ADYAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARQAwADAANQBCAEQAMQA0ADcAMAAyADAAMAAwADAAMAAwADAARQAwADAAMAA3ADEANAA4AEEAMAAyADAAMAAwADAAMAAwADEANAA1AEIANABCADYAMQA2AEUANgBFADYANQA3ADIAMgBDADIAMAAzADEAMwA5ADMANAAzADMAMgAwADIAMwAzADQAMwA0ADMAMQA1AEQAMAAwADAARQAwADAAMAAwADAAMAA= ADDIN ENRfu (1943) original report on autism, not only did he describe social and language impairments, but he also highlighted the anxious behavior exhibited in his initial sample of children. Fear of threatening events is considered a common experience among primates and an adaptive response in humans RAAyADIAQwA4AEEAMAA0ADAAMAA3AEEAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARQAwADAANQBCAEQAMQA0ADkAMAAyADAAMAAwADAAMAAwADEARAA4ADQAMwBGAEEANwBEADMAMAAyADAAMAAwADAAMAAwADEANgA1AEIANQAyADYANQA3ADkANgBFADYARgA2AEMANgA0ADcAMwAyAEMAMgAwADMAMQAzADkAMwA5ADMANAAyADAAMgAzADMANAAzADQAMwAzADUARAAwADAAMABFADAAMAAwADAAMAAwAA== ADDIN ENRfu (Reynolds and Richmond 1994). Anxiety, on the other hand, is an emotional response evoked when an individual perceives a situation as threatening even in the absence of direct danger. We would suggest that dysregulation of the amygdala might manifest itself in the individual with autism as alterations either of fear or anxiety. Although the presence of anxiety has been alluded to in descriptions (American Psychological Association 1994) and classifications of autism QgBFADEAQQBGADQANgA2ADAAMAA3AEEAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARQAwADAANQBCAEQAMQA0AEMAMAAyADAAMAAwADAAMAAwADEAMAAwADAAMQBGADAAMgBEADAAMAAyADAAMAAwADAAMAAwADEANgA1AEIANQAyADYANQA3ADMANgAzADYARgA3ADIANgBDADYAMQAyAEMAMgAwADMAMQAzADkAMwA4ADMAOAAyADAAMgAzADMAMQAzADAAMwA0ADUARAAwADAAMABFADAAMAAwADAAMAAwAA== ADDIN ENRfu (Rescorla 1988, NAAyAEMAQwAyAEQAQwBBADAAMAA3ADIAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARQAwADAANQBCAEQAMQA0AEUAMAAyADAAMAAwADAAMAAwADEANgAwADcAQQA5AEIARgA2ADIAMAAyADAAMAAwADAAMAAwADEAMgA1AEIANQA3ADYAOQA2AEUANgA3ADIAQwAyADAAMwAxADMAOQAzADcAMwA5ADIAMAAyADMAMwA0ADMANAAzADAANQBEADAAMAAwAEUAMAAwADAAMAAwADAA ADDIN ENRfu Wing and Gould 1979), the characteristics and pervasiveness of this has not been well studied. However, recent studies suggest that anxiety is an extremely common feature of the autism spectrum disorders. <br />Muris et al. NAA5ADEAOABCADUAOABEADAAMAA3ADIAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARQAwADAANQBCAEQAMQA1ADAAMAAyADAAMAAwADAAMAAwADEANAAwADEARgA2ADAAMAA4ADYAMAAyADAAMAAwADAAMAAwADEAMgA1AEIANABEADcANQA3ADIANgA5ADcAMwAyAEMAMgAwADMAMQAzADkAMwA5ADMAOAAyADAAMgAzADMANQAzADIANQBEADAAMAAwAEUAMAAwADAAMAAwADAA ADDIN ENRfu (1998) examined the presence of co-occurring anxiety symptoms in 44 children with autism spectrum disorder. The sample included 15 children with autism, and 29 with pervasive developmental disorder-not otherwise specified (PDD-NOS). They found that 84.1% of the children met criteria for at least one anxiety disorder. In descending order, the percentage of children meeting diagnostic criteria for an anxiety disorder were as follows: simple phobia (63.6%), agoraphobia (45.5%), separation anxiety (27.3%), overanxious (22.7%), social phobia (20.5%), avoidant disorder (18.2%), obsessive-compulsive disorder (11.4%), and panic disorder (9.1%). While the authors raised the caveat that anxiety symptoms were assessed via parental interview, they noted that parents often underreport internalizing symptoms, such an anxiety. <br />More recently, Gillott et al. NwBCADUANgBBADcANQA1ADAAMAA3ADYAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARQAwADAANQBCAEQAMQA1ADMAMAAyADAAMAAwADAAMAAwADEANgAwADcAMgAyADAANAA0ADIAMAAyADAAMAAwADAAMAAwADEANAA1AEIANAA3ADYAOQA2AEMANgBDADYARgA3ADQANwA0ADIAQwAyADAAMwAyADMAMAAzADAAMwAxADIAMAAyADMAMwAxADMAMQA1AEQAMAAwADAARQAwADAAMAAwADAAMAA= ADDIN ENRfu (2001) compared high-functioning children with autism to two control groups including children with specific language impairment and normally developing children on measures of anxiety and social worry. Children with autism were found to be more anxious on both indices. In fact, four of the six factors on the anxiety scale were elevated with obsessive-compulsive disorder and separation anxiety showing the highest elevations. <br />These studies do not provide much insight into the pervasiveness of anxiety in autism. Both clinical and parental reports indicate that not all children with autism demonstrate symptoms of anxiety. The DSM-IV summarizes that children with autism may exhibit “a lack of fear in response to real dangers, and an excessive fearfulness in response to harmless objects” (APA 1994, p. 68). Wing and Gould NAAyAEMAQwBDAEEAQwBBADAAMAA3ADIAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARQAwADAANQBCAEQAMQA1ADYAMAAyADAAMAAwADAAMAAwADEANgAwADcAQQA5AEIARgA2ADIAMAAyADAAMAAwADAAMAAwADEAMgA1AEIANQA3ADYAOQA2AEUANgA3ADIAQwAyADAAMwAxADMAOQAzADcAMwA5ADIAMAAyADMAMwA0ADMANAAzADAANQBEADAAMAAwAEUAMAAwADAAMAAwADAA ADDIN ENRfu (1979) highlighted the heterogeneity in the occurrence of anxiety in their classification system. Specifically, the active-but-odd subtype tend to exhibit extreme reactions to social situations, whereas the aloof subtype may be completely oblivious to environmental changes. Rescorla QgBFADEAQQAxADEANgA2ADAAMAA3AEEAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARQAwADAANQBCAEQAMQA1ADgAMAAyADAAMAAwADAAMAAwADEAMAAwADAAMQBGADAAMgBEADAAMAAyADAAMAAwADAAMAAwADEANgA1AEIANQAyADYANQA3ADMANgAzADYARgA3ADIANgBDADYAMQAyAEMAMgAwADMAMQAzADkAMwA4ADMAOAAyADAAMgAzADMANAAzADMAMwA0ADUARAAwADAAMABFADAAMAAwADAAMAAwAA== ADDIN ENRfu (1988), conducted a factor and cluster analysis using the Child Behavior Checklist (CBCL, RQA5ADgARQAxADQARgBDADAAMAA3AEMAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARgAwADAANQBCAEQAMQA1AEIAMAAyADAAMAAwADAAMAAwADEAMQAwADAAMwBBAEQAMgBGADYAMAAyADAAMAAwADAAMAAwADEANwA1AEIANAAxADYAMwA2ADgANgA1ADYARQA2ADIANgAxADYAMwA2ADgAMgBDADIAMAAzADEAMwA5ADMAOQAzADEAMgAwADIAMwAzADQAMwA0ADMANAA1AEQAMAAwADAARQAwADAAMAAwADAAMAA= ADDIN ENRfu Achenbach 1991), a general instrument of childhood behavior, to distinguish boys with autism from other disorders. Among many differences, the analysis demonstrated that the more severe cases of autism were distinguished from the milder ones based on the presence or absence of anxiety. <br />The Amygdala and Anxiety<br />A number of recent studies have provided evidence that the amygdala may be dysregulated in emotional disorders such as anxiety and depression OQA4AEEAQgA0ADYANgBBADAAMAA3AEEAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARgAwADAANQBCAEQAMQA1AEUAMAAyADAAMAAwADAAMAAwADEANwAwAEYAOQAwADEAOQBDADQAMAAyADAAMAAwADAAMAAwADEANgA1AEIANAA0ADYAMQA3ADYANgA5ADYANAA3ADMANgBGADYARQAyAEMAMgAwADMAMQAzADkAMwA5ADMAOQAyADAAMgAzADMANAAzADMAMwA1ADUARAAwADAAMABFADAAMAAwADAAMAAwAA== ADDIN ENRfu (Davidson et al. 1999). Tillfors et al. NQA4AEMAMAAwAEMAMwBEADAAMAA3AEEAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARgAwADAANQBCAEQAMQA2ADEAMAAyADAAMAAwADAAMAAwADEANwAwAEUANAA0ADAARAA4ADQAMAAyADAAMAAwADAAMAAwADEANgA1AEIANQA0ADYAOQA2AEMANgBDADYANgA2AEYANwAyADcAMwAyAEMAMgAwADMAMgAzADAAMwAwADMAMQAyADAAMgAzADMANAAzADEAMwA3ADUARAAwADAAMABFADAAMAAwADAAMAAwAA== ADDIN ENRfu (2001), for example, demonstrated increased blood flow in the amygdala in social phobics anticipating a public presentation. Recently, Thomas et al. OAA4ADYAQgA4ADUAQgA4ADAAMAA3ADYAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARgAwADAANQBCAEQAMQA2ADMAMAAyADAAMAAwADAAMAAwADEANQAwADMAOQAxADAAMQA2ADgAMAAyADAAMAAwADAAMAAwADEANAA1AEIANQA0ADYAOAA2AEYANgBEADYAMQA3ADMAMgBDADIAMAAzADIAMwAwADMAMAAzADEAMgAwADIAMwAzADQAMwAxADMANgA1AEQAMAAwADAARQAwADAAMAAwADAAMAA= ADDIN ENRfu (2001) used fearful faces as probes and demonstrated that the amygdala of anxious children showed heightened activity in the amygdala. De Bellis MgBDADEAQQAyADcAOAA3ADAAMAA3AEMAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADcAMgA2ADYAMAAwAEIAOQAyADYARAAzADQARgAwADAANQBCAEQAMQA2ADcAMAAyADAAMAAwADAAMAAwADEAOAAxAEMAQwA4ADAAMgBCADQAMAAyADAAMAAwADAAMAAwADEANwA1AEIANAA0ADYANQAyADAANAAyADYANQA2AEMANgBDADYAOQA3ADMAMgBDADIAMAAzADIAMwAwADMAMAAzADAAMgAwADIAMwAzADQAMwAxADMAOAA1AEQAMAAwADAARQAwADAAMAAwADAAMAA= ADDIN ENRfu (2000) also showed that the right amygdala of children with generalized anxiety disorder was larger than age matched controls. These findings are consistent with the results of our studies in nonhuman primates in that removal of the amygdala produced animals that were less fearful of inanimate objects as well as other monkeys. <br />Conclusions<br />The amygdala has been proposed to play an essential role in the elucidation of normal social behavior. And, its dysfunction has been proposed to play a role in the social pathology of autism. Studies both in the rhesus monkey and data from human subjects with bilateral lesions of the amygdala indicate that the amygdala is not essential for many facets of normal social interaction. Rather, it appears that the amygdala may have a more selective role in detecting threats in the environment. If this proves to be correct, it would be unlikely that dysfunction of the amygdala alone could provide the substrate for the impairments of social interaction that are a hallmark feature of autism. If, however, the amygdala is indeed dysfunctional in autism, this could contribute to the abnormalities of fear and anxiety that appear to be a common feature of autism. If this were the case, one might expect the amygdala to be hyperfunctional in autism rather than hypofunctional as predicted by the current theories of the role of the amygdala in autism. <br />Acknowledgements<br />This original research described in this paper was supported, in part, by grants from the National Institute of Mental Health and by the base grant of the California National Primate Research Center. This work was also supported through the Early Experience and Brain Development Network of the MacArthur Foundation. <br />Literature Cited<br />MQAyADUAMgBGADkAMgA2ADAAMAA0ADIAQQAzADYAOAA1ADYAMQAwADAAMAAwADgAMwAyAEMARgA2ADUANgBFADYAMgA2ADIAMAAwAEIAOQAyADYARAAzADYAMAAwADAANQBCAEQANQA2ADcAMAAyADAAMAAwADAAMQA2ADkAQgAxAEQAQQAyAEUARgBCAEYAMAAwADAAMAAwADAA ADDIN ENBbu Abell F, Krams M, Ashburner J, et al. 1999 The neuroanatomy of autism: a voxel-based whole brain analysis of structural scans. 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