The amygdala theory of autism

Brothers (Brothers L. Concepts in Neuroscience 1990;1:27-51) proposed a network of neural regions that comprise the "social brain", which includes the amygdala. Since the childhood psychiatric condition of autism involves deficits in "social intelligence", it is plausible that autism may be caused by an amygdala abnormality. In this paper we review the evidence for a social function of the amygdala. This includes reference to the Kluver-Bucy syndrome (which Hetzler and Griffin suggested may serve as an animal model of autism). We then review evidence for an amygdala deficit in people with autism, who are well known to have deficits in social behaviour. This includes a detailed summary of our recent functional magnetic resonance imaging (fMRI) study involving judging from the expressions of another person's eyes what that other person might be thinking or feeling. In this study, patients with autism or AS did not activate the amygdala when making mentalistic inferences from the eyes, whilst people without autism did show amygdala activity. The amygdala is therefore proposed to be one of several neural regions that are abnormal in autism. We conclude that the amygdala theory of autism contains promise and suggest some new lines of research.     

Differential activation of the amygdala and the 'social brain' during fearful face-processing in Asperger Syndrome

Impaired social cognition is a core feature of autism. There is much evidence showing people with autism use a different cognitive style than controls for face-processing. We tested if people with autism would show differential activation of social brain areas during a face-processing task. Thirteen adults with high-functioning autism or Asperger Syndrome (HFA/AS) and 13 matched controls. We used fMRI to investigate 'social brain' activity during perception of fearful faces. We employed stimuli known to reliably activate the amygdala and other social brain areas, and ROI analyses to investigate brain areas responding to facial threat as well as those showing a linear response to varying threat intensities. We predicted: (1) the HFA/AS group would show differential activation (as opposed to merely deficits) of the social brain compared to controls and (2) that social brain areas would respond to varied intensity of fear in the control group, but not the HFA/AS group. Both predictions were confirmed. The controls showed greater activation in the left amygdala and left orbito-frontal cortex, while the HFA/AS group showed greater activation in the anterior cingulate gyrus and superior temporal cortex. The control group also showed varying responses in social brain areas to varying intensities of fearful expression, including differential activations in the left and right amygdala. This response in the social brain was absent in the HFA/AS group. HFA/AS are associated with different patterns of activation of social brain areas during fearful emotion processing, and the absence in the HFA/AS brain of a response to varying emotional intensity.     

Neural bases for impaired social cognition in schizophrenia and autism spectrum disorders

Schizophrenia and autism both feature significant impairments in social cognition and social functioning, but the specificity and mechanisms of these deficits remain unknown. Recent research suggests that social cognitive deficits in both disorders may arise from dysfunctions in the neural systems that underlie social cognition. We explored the neural activation of discrete brain regions implicated in social cognitive and face processing in schizophrenia subgroups and autism spectrum disorders during complex social judgments of faces. Twelve individuals with autism spectrum disorders (ASD), 12 paranoid individuals with schizophrenia (P-SCZ), 12 non-paranoid individuals with schizophrenia (NP-SCZ), and 12 non-clinical healthy controls participated in this cross sectional study. Neural activation, as indexed by blood oxygenation level dependent (BOLD) contrast, was measured in a priori regions of interest while individuals rated faces for trustworthiness. All groups showed significant activation of a social cognitive network including the amygdala, fusiform face area (FFA), superior temporal sulcus (STS), and ventrolateral prefrontal cortex (VLPFC) while completing a task of complex social cognition (i.e. trustworthiness judgments). ASD and P-SCZ individuals showed significantly reduced neural activation in the right amygdala, FFA, and left VLPFC as compared to controls and in the left VLPFC as compared to NP-SCZ individuals during this task. These findings lend support to models hypothesizing well-defined neural substrates of social cognition and suggest a specific neural mechanism that may underlie social cognitive impairments in both autism and paranoid schizophrenia.     

Superior temporal gyrus volumes in pediatric generalized anxiety disorder.

BACKGROUND: The essential symptoms of generalized anxiety disorder (GAD) are intrusive worry about everyday life circumstances and social competence, and associated autonomic hyperarousal. The amygdala, a brain region involved in fear and fear-related behaviors in animals, and its projections to the superior temporal gyrus (STG), thalamus, and to the prefrontal cortex are thought to comprise the neural basis of our abilities to interpret social behaviors. Larger amygdala volumes were previously reported in pediatric GAD; however, the brain regions involved in social intelligence were not examined in this pilot study. METHODS: Magnetic resonance imaging (MRI) was used to measure the STG, thalamus, and prefrontal volumes in 13 medically healthy child and adolescent subjects with generalized anxiety disorder (GAD) and 98 comparison subjects, who were at low familial risk for mood and psychotic disorders. Groups were similar in age, gender, height, weight, handedness, socioeconomic status, and full-scale IQ. RESULTS: The total, white matter, and gray matter STG volumes were significantly larger in GAD subjects compared with control subjects. Thalamus and prefrontal lobe volumes did not differ between groups. Findings of significant side-by-diagnosis interactions for STG and STG white matter volumes suggest that there is a more pronounced right > left asymmetry in total and STG white matter volumes in pediatric GAD subjects compared with control subjects. A significant correlation between the STG white matter percent asymmetry index with the child report of the Screen for Child Anxiety Related Emotional Disorders Scale was seen. CONCLUSIONS: These data agree with previous work implicating posterior right-hemispheric regions in anxiety disorders and may suggest developmental alterations in pediatric GAD.     

The 'amygdala theory of autism' revisited: linking structure to behavior

The 'amygdala theory of autism' suggests a crucial role for the amygdala in the neurobiological basis of autism spectrum disorders. However, to date evidence is lacking of a direct relationship between amygdala measures and behavioral manifestations of autism in affected individuals. In 17 adult individuals with Asperger syndrome (AS) and 17 well-matched controls we therefore assessed associations between MRI-derived amygdala volume and behavioral variables of emotion recognition and social cognition, as well as with core AS symptomatology. Results revealed that individuals with AS exhibited impairments in emotion recognition and social cognition compared to controls and also showed atypical relationships between amygdala volumes and overall head size. We found positive associations between emotional and social understanding and amygdala volume in the control group, but not in the AS group. In the AS group however, amygdala size was negatively related to diagnostic parameters, with smaller amygdala volumes involving higher levels of restricted-repetitive behavior domains. Our data seem to indicate that in AS the amygdala is not crucially involved in social and emotional understanding. It may, however, be a mediator for narrow interest patterns and the imposition of routines and rituals. Our data, in conjunction with current literature, seem to argue for a modification of the 'amygdala theory of autism'.     

Hypersensitivity to low intensity fearful faces in autism when fixation is constrained to the eyes

Previous studies that showed decreased brain activation in people with autism spectrum disorder (ASD) viewing expressive faces did not control that participants looked in the eyes. This is problematic because ASD is characterized by abnormal attention to the eyes. Here, we collected fMRI data from 48 participants (27 ASD) viewing pictures of neutral faces and faces expressing anger, happiness, and fear at low and high intensity, with a fixation cross between the eyes. Group differences in whole brain activity were examined for expressive faces at high and low intensity versus neutral faces. Group differences in neural activity were also investigated in regions of interest within the social brain, including the amygdala and the ventromedial prefrontal cortex (vmPFC). In response to low intensity fearful faces, ASD participants showed increased activation in the social brain regions, and decreased functional coupling between the amygdala and the vmPFC. This oversensitivity to low intensity fear coupled with a lack of emotional regulation capacity could indicate an excitatory/inhibitory imbalance in their socio‐affective processing system. This may result in social disengagement and avoidance of eye‐contact to handle feelings of strong emotional reaction. Our results also demonstrate the importance of careful control of gaze when investigating emotional processing in ASD. Hum Brain Mapp 38:5943–5957, 2017. © 2017 Wiley Periodicals, Inc.     

A failure to grasp the affective meaning of actions in autism spectrum disorder subjects

The ability to grasp emotional messages in everyday gestures and respond to them is at the core of successful social communication. The hypothesis that abnormalities in socio-emotional behavior in people with autism are linked to a failure to grasp emotional significance conveyed by gestures was explored. We measured brain activity using fMRI during perception of fearful or neutral actions and showed that whereas similar activation of brain regions known to play a role in action perception was revealed in both autistics and controls, autistics failed to activate amygdala, inferior frontal gyrus and premotor cortex when viewing gestures expressing fear. Our results support the notion that dysfunctions in this network may contribute significantly to the characteristic communicative impairments documented in autism.     

A functional and structural study of emotion and face processing in children with autism

Children with autism exhibit impairment in the processing of socioemotional information. The amygdala, a core structure centrally involved in socioemotional functioning, has been implicated in the neuropathology of autism. We collected structural and functional magnetic resonance images (MRI) in children 8 to 12 years of age with high-functioning autism (n = 12) and typical development (n = 15). The functional MRI experiment involved matching facial expressions and people. Volumetric analysis of the amygdala was also performed. The results showed that children with autism exhibited intact emotion matching, while showing diminished activation of the fusiform gyrus (FG) and the amygdala. Conversely, the autism group showed deficits in person matching amidst some FG and variable amygdala activation. No significant between-group differences in the volume of the left or right amygdala were found. There were associations between age, social anxiety and amygdala volume in the children with autism such that smaller volumes were generally associated with more anxiety and younger age. In summary, the data are consistent with abnormalities in circuits involved in emotion and face processing reported in studies of older subjects with autism showing reductions in amygdala activation related to emotion processing and reduced fusiform activation involved in face processing.     

Defining the Behavioral Phenotype of Asperger Syndrome

Asperger syndrome (AS) is characterized by social deficits and restricted interests in the absence of mental retardation and language delay. However, it is unclear to what extent the social deficits of AS differ from those of traditional autism. To address this issue, 58 subjects with AS were compared with 39 subjects with autism. Social deficits were classified according to Wing and Gould’s method. Forty-six (79%) subjects with AS were rated as active but odd, while 32 (82%) with autism were described as aloof and passive, while a few subjects showed mixed features. Thus, despite the overlap between AS and autism, subjects with AS showed a distinct pattern of social impairment. Implications of these findings are discussed.     

A Family History Study of Asperger Syndrome

Asperger syndrome (AS) is a childhood-onset disorder often described as a mild variant of autism. Although classified as a distinct disorder in the DSM-IV, its overlap with autism continues to be a matter of ongoing debate. While the family genetic origins of autism are well established, few studies have investigated this topic in AS using current operational criteria. In this report, we examined the family psychiatric history of 58 subjects with AS diagnosed according to DSM-IV criteria (48 males; mean age 13.34; mean full scale IQ 104.87). All subjects had a history of mild autistic social deficits; focused special interests; normal level of intelligence; and an odd and often pedantic manner of speaking. None had a previous diagnosis of autism. Of the 58 subjects with Asperger syndrome, three had first degree relatives with AS; nine (15%) had a family history of schizophrenia; and 35 (60%) had a family history of depression. Of the 64 siblings, four had a diagnosis of AS and none of autism. Compared with a group of 39 subjects with normal intelligence autism (high functioning autism, HFA; 33 males; mean age 15.34; mean full scale IQ 85.89) subjects with AS were more likely to have relatives with depression; schizophrenia; and the broader autistic phenotype. Possible reasons for and implications of these findings are discussed.     

Defining the Intellectual Profile of Asperger Syndrome: Comparison with High-Functioning Autism

Asperger syndrome (AS) is a disorder of early childhood characterized by autistic social deficits, subtle communication impairment, and excessive isolated interests. There is no history of language delay or of mental retardation. Despite its increasing popularity as a distinct condition, its diagnostic validity remains uncertain. It is still unclear to what extent AS differs from autism with normal intelligence sometimes referred to as high-functioning autism (HFA). However, some reports have suggested that persons with AS possess a distinct profile on tests of intelligence characterized by a high verbal IQ and a low performance IQ, whereas in most cases with HFA, the pattern is reversed. Since few studies have directly compared AS subjects with HFA controls using unmodified diagnostic criteria and standardized measures of assessment, in this report we compared 22 AS subjects with 12 HFA controls, matched on age, sex and level of intelligence. As a group, subjects with AS showed a higher verbal IQ and higher scores on information and vocabulary subtests than those with HFA. However, scores of several AS and HFA subjects showed a mixed pattern. Implications of these findings are discussed in the context of the validity of Asperger Syndrome.     

Social Competence Intervention for Elementary Students with Aspergers Syndrome and High Functioning Autism

Despite frequent reports of academic success, individuals with high functioning autism or Aspergers Syndrome (HFA/AS) often manifest deficits in social abilities. These deficits can lead to daily difficulties, and negative long-term outcomes. Deficits in social competency are evident in this population from an early age, as children with HFA/AS present unique challenges relating to peers, interpreting complex contextual cues, and transitioning across settings. A paucity of social interventions exist that target elementary-age children with HFA/AS and their combination of core social competence deficit areas: theory of mind (ToM), emotional recognition, and executive functioning. The current study expanded on the Social Competence Intervention (for adolescents; SCI-A), as detailed in Stichter et al. (J Autism Dev Disorders 40:1067–1079, 2010), by adjusting the curriculum to meet the needs of an elementary population. Results indicate significant improvements on direct assessments measuring theory of mind and problem solving, and parent perceptions of overall social abilities and executive functioning for 20 students, aged 6-10, with HFA/AS. The elementary SCI program appears promising, however, additional replications are necessary including expansion to school settings.     

Amygdala volume and nonverbal social impairment in adolescent and adult males with autism

BACKGROUND: Autism is a syndrome of unknown cause, marked by abnormal development of social behavior. Attempts to link pathological features of the amygdala, which plays a key role in emotional processing, to autism have shown little consensus. OBJECTIVE: To evaluate amygdala volume in individuals with autism spectrum disorders and its relationship to laboratory measures of social behavior to examine whether variations in amygdala structure relate to symptom severity. DESIGN: We conducted 2 cross-sectional studies of amygdala volume, measured blind to diagnosis on high-resolution, anatomical magnetic resonance images. Participants were 54 males aged 8 to 25 years, including 23 with autism and 5 with Asperger syndrome or pervasive developmental disorder not otherwise specified, recruited and evaluated at an academic center for developmental disabilities and 26 age- and sex-matched community volunteers. The Autism Diagnostic Interview-Revised was used to confirm diagnoses and to validate relationships with laboratory measures of social function. MAIN OUTCOME MEASURES: Amygdala volume, judgment of facial expressions, and eye tracking. RESULTS: In study 1, individuals with autism who had small amygdalae were slowest to distinguish emotional from neutral expressions (P=.02) and showed least fixation of eye regions (P=.04). These same individuals were most socially impaired in early childhood, as reported on the Autism Diagnostic Interview-Revised (P<.04). Study 2 showed smaller amygdalae in individuals with autism than in control subjects (P=.03) and group differences in the relation between amygdala volume and age. Study 2 also replicated findings of more gaze avoidance and childhood impairment in participants with autism with the smallest amygdalae. Across the combined sample, severity of social deficits interacted with age to predict different patterns of amygdala development in autism (P=.047). CONCLUSIONS: These findings best support a model of amygdala hyperactivity that could explain most volumetric findings in autism. Further psychophysiological and histopathological studies are indicated to confirm these findings.     

Intact emotion facilitation for nonsocial stimuli in autism: is amygdala impairment in autism specific for social information?

Atypical amygdala development may play a key role in the emergence of social disability and other symptoms of autism (Baron-Cohen et al., 2000; Schultz, 2005). The mechanisms by which this may occur have received little attention, however, and most support from behavioral and imaging studies has been concerned with socially relevant stimuli such as faces. Given the complexity of amygdala function and its known role in many other emotional tasks, we examined whether individuals with autism would demonstrate impaired performance on several tasks that have been shown to require activation of the amygdala but that do not have any explicit social meaning. Relative to a typical comparison group matched for age and IQ, our sample of 37 adolescents and adults with autism (mean age=19.7 years) demonstrated equivalent facilitation for perception and learning of emotionally relevant stimuli. On each of four tasks, there were significant main effects of emotion condition on performance for both groups. Future research regarding atypical amygdala function and emotion processing in autism should consider whether the response to nonsocial emotion factors (including negative valence or high arousal) may be intact, despite difficulties in responding to socially relevant stimuli.     

Overlapping and specific neural correlates for empathizing,affective mentalizing,and cognitive mentalizing: A coordinate‐based meta‐analytic study

While the discussion on the foundations of social understanding mainly revolves around the notions of empathy, affective mentalizing, and cognitive mentalizing, their degree of overlap versus specificity is still unclear. We took a meta‐analytic approach to unveil the neural bases of cognitive mentalizing, affective mentalizing, and empathy, both in healthy individuals and pathological conditions characterized by social deficits such as schizophrenia and autism. We observed partially overlapping networks for cognitive and affective mentalizing in the medial prefrontal, posterior cingulate, and lateral temporal cortex, while empathy mainly engaged fronto‐insular, somatosensory, and anterior cingulate cortex. Adjacent process‐specific regions in the posterior lateral temporal, ventrolateral, and dorsomedial prefrontal cortex might underpin a transition from abstract representations of cognitive mental states detached from sensory facets to emotionally‐charged representations of affective mental states. Altered mentalizing‐related activity involved distinct sectors of the posterior lateral temporal cortex in schizophrenia and autism, while only the latter group displayed abnormal empathy related activity in the amygdala. These data might inform the design of rehabilitative treatments for social cognitive deficits.     

Acquired theory of mind impairments in individuals with bilateral amygdala lesions

Studies in humans suggest that the amygdala plays a role in processing social information. A key component of social information processing is what developmental psychologists call "theory of mind": the ability to infer others' mental states. Recent studies have raised the possibility that the amygdala is involved in theory of mind, showing amygdala activation during a theory of mind task, or showing impairment on theory of mind tasks in a patient with amygdala damage acquired in childhood. Here, we present the first evidence of theory of mind deficits following amygdala damage acquired in adulthood. Two participants, D.R. and S.E., with acquired bilateral amygdala damage showed difficulties with two theory of mind tasks, "Recognition of Faux Pas" (for D.R., z=-5.17; for S.E., z=-1.83) and "Reading the Mind in the Eyes" (for S.E., z=-1.91; for D.R., z=-1.4). The items on which D.R. and S.E. made errors on these tasks were uncorrelated with the items that control participants found most difficult, indicating that these deficits cannot be attributed solely to the cognitive difficulty of the tasks. These results indicate that the amygdala's critical role in theory of mind may not be just in development, but also in "on-line" theory of mind processing in the adult brain.     

Social Competence Intervention for Youth with Asperger Syndrome and High-functioning Autism: An Initial Investigation

Individuals with high functioning autism (HFA) or Asperger Syndrome (AS) exhibit difficulties in the knowledge or correct performance of social skills. This subgroup’s social difficulties appear to be associated with deficits in three social cognition processes: theory of mind, emotion recognition and executive functioning. The current study outlines the development and initial administration of the group-based Social Competence Intervention (SCI), which targeted these deficits using cognitive behavioral principles. Across 27 students age 11–14 with a HFA/AS diagnosis, results indicated significant improvement on parent reports of social skills and executive functioning. Participants evidenced significant growth on direct assessments measuring facial expression recognition, theory of mind and problem solving. SCI appears promising, however, larger samples and application in naturalistic settings are warranted.     

Lasting changes in social behavior and amygdala function following traumatic experience induced by a single series of foot-shocks

Neuronal plasticity within the amygdala mediates many behavioral effects of traumatic experience, and this brain region also controls various aspects of social behavior. However, the specific involvement of the amygdala in trauma-induced social deficits has never been systematically investigated. We exposed rats to a single series of electric foot-shocks - a frequently used model of trauma - and studied their behavior in the social avoidance and psychosocial stimulation tests (non-contact versions of the social interaction test) at different time intervals. Social interaction-induced neuronal activation patterns were studied in the prefrontal cortex (orbitofrontal and medial), amygdala (central, medial, and basolateral), dorsal raphe and locus coeruleus. Shock exposure markedly inhibited social behavior in both tests. The effect lasted at least 4 weeks, and amplified over time. As shown by c-Fos immunocytochemistry, social interactions activated all the investigated brain areas. Traumatic experience exacerbated this activation in the central and basolateral amygdala, but not in other regions. The tight correlation between the social deficit and amygdala activation patterns suggest that the two phenomena were associated. A real-time PCR study showed that CRF mRNA expression in the amygdala was temporarily reduced 14, but not 1 and 28 days after shock exposure. In contrast, amygdalar NK1 receptor mRNA expression increased throughout. Thus, the trauma-induced social deficits appear to be associated with, and possibly caused by, plastic changes in fear-related amygdala subdivisions.     

Reward Circuitry Function in Autism During Face Anticipation and Outcomes

The aim of this study was to investigate reward circuitry responses in autism during reward anticipation and outcomes for monetary and social rewards. During monetary anticipation, participants with autism spectrum disorders (ASDs) showed hypoactivation in right nucleus accumbens and hyperactivation in right hippocampus, whereas during monetary outcomes, participants with ASDs showed hyperactivation in left midfrontal and anterior cingulate gyrus. Groups did not differ in nucleus accumbens responses to faces. The ASD group demonstrated hyperactivation in bilateral amygdala during face anticipation that predicted social symptom severity and in bilateral insular cortex during face outcomes. These results add to the growing body of evidence that autism is characterized by altered functioning of reward circuitry. Additionally, atypical amygdala activation during the processing of social rewards may contribute to the development or expression of autistic features.     

Functional magnetic resonance imaging of autism spectrum disorders

This review presents an overview of functional magnetic resonance imaging findings in autism spectrum disorders (ASDs), Although there is considerable heterogeneity with respect to results across studies, common themes have emerged, including: (i) hypoactivation in nodes of the “social brain” during social processing tasks, including regions within the prefrontal cortex, the posterior superior temporal sulcus, the amygdala, and the fusiform gyrus; (ii) aberrant frontostriatal activation during cognitive control tasks relevant to restricted and repetitive behaviors and interests, including regions within the dorsal prefrontal cortex and the basal ganglia; (iii) differential lateralization and activation of language processing and production regions during communication tasks; (iv) anomalous mesolimbic responses to social and nonsocial rewards; (v) task-based long-range functional hypoconnectivity and short-range hyper-connectivity; and (vi) decreased anterior-posterior functional connectivity during resting states. These findings provide mechanistic accounts of ASD pathophysiology and suggest directions for future research aimed at elucidating etiologic models and developing rationally derived and targeted treatments.