Amygdala Enlargement in Toddlers with Autism Related to Severity of Social and Communication Impairments

doi:10.1016/j.biopsych.2009.07.007

Biological Psychiatry

Volume 66, Issue 10, 15 November 2009, Pages 942-949

https://doi.org/10.1016/j.biopsych.2009.07.007 Get rights and content

Background

Autism is a heterogeneous neurodevelopmental disorder of unknown etiology. The amygdala has long been a site of intense interest in the search for neuropathology in autism, given its role in emotional and social behavior. An interesting hypothesis has emerged that the amygdala undergoes an abnormal developmental trajectory with a period of early overgrowth in autism; however this finding has not been well established at young ages nor analyzed with boys and girls independently.

Methods

We measured amygdala volumes on magnetic resonance imaging scans from 89 toddlers at 1–5 years of age (mean = 3 years). Each child returned at ∼5 years of age for final clinical evaluation.

Results

Toddlers who later received a confirmed autism diagnosis (32 boys, 9 girls) had a larger right (p < .01) and left (p < .05) amygdala compared with typically developing toddlers (28 boys, 11 girls) with and without covarying for total cerebral volume. Amygdala size in toddlers with autism spectrum disorder correlated with the severity of their social and communication impairments as measured on the Autism Diagnostic Interview and Vineland scale. Strikingly, girls differed more robustly from typical in amygdala volume, whereas boys accounted for the significant relationship of amygdala size with severity of clinical impairment.

Conclusions

This study provides evidence that the amygdala is enlarged in young children with autism; the overgrowth must begin before 3 years of age and is associated with the severity of clinical impairments. However, neuroanatomic phenotypic profiles differ between males and females, which critically affects future studies on the genetics and etiology of autism.

Section snippets

Diagnostic Assessment

Eighty-nine toddlers (n = 66 males, 23 females) between the ages of 18 and 60 months were included in amygdala volumetric analyses as part of a longitudinal MRI study of early brain development in autism (Table 1). A parent or guardian gave informed consent for participation in this research program as approved by the Institutional Review Board of Rady Children's Hospital San Diego and the University of California, San Diego.

Provisionally autistic 12- to 36-month-old children were initially

Results

Clinical diagnostic and behavioral measures collected at final clinical visit are listed in Table 1. There was no difference in the age of the groups at the time of MRI acquisition. There was, as expected, a significant group effect for all IQ and Vineland measures (p < .001).

Mean volumetric data for all participants are given in Table 2. Amygdala volumes in all groups significantly correlated with age at time of scan (r = .49, p < .05); however, there was no age × group effect for autism and

Discussion

This study provides evidence that the amygdala is enlarged in young children with autism and that the overgrowth must begin before 3 years of age at approximately the time symptoms become clinically evident. This finding is consistent with early overgrowth found in cortical regions (19, 20) but differs in that the amygdala may remain enlarged later into childhood than the rest of the brain (10). Additionally, the enlargement in right amygdala volume in males and females and left amygdala volume

References (47)

R. Adolphs
Fear, faces, and the human amygdala
Curr Opin Neurobiol
(2008)
D.G. Amaral et al.
Neuroanatomy of autism
Trends Neurosci
(2008)
S.J. Bishop
Neurocognitive mechanisms of anxiety: An integrative account
Trends Cogn Sci
(2007)
A. Pitkanen et al.
Amygdala damage in experimental and human temporal lobe epilepsy
Epilepsy Res
(1998)
J.N. Giedd
Normal development
Child Adolesc Psychiatr Clin North Am
(1997)
E. Courchesne et al.
Mapping early brain development in autism
Neuron
(2007)
R.A. Carper et al.
Cerebral lobes in autism: Early hyperplasia and abnormal age effects
Neuroimage
(2002)
R.A. Robb et al.
Analyze: A comprehensive, operator-interactive software package for multidimensional medical image display and analysis
Comput Med Imaging Graph
(1989)
N. Akshoomoff et al.
Outcome classification of preschool children with autism spectrum disorders using MRI brain measures
J Am Acad Child Adolesc Psychiatry
(2004)
C.S. Bloss et al.
MRI neuroanatomy in young girls with autism: A preliminary study
J Am Acad Child Adolesc Psychiatry
(2007)

R.T. Schultz

Developmental deficits in social perception in autism: The role of the amygdala and fusiform face area

Int J Dev Neurosci

(2005)

M.H. Johnson et al.

Newborns' preferential tracking of face-like stimuli and its subsequent decline

Cognition

(1991)

R. Adolphs

The neurobiology of social cognition

Curr Opin Neurobiol

(2001)

G. Dawson et al.

Neuropsychological correlates of early symptoms of autism

Child Dev

(1998)

E. Werner et al.

Brief report: Recognition of autism spectrum disorder before one year of age: A retrospective study based on home videotapes

J Autism Dev Disord

(2000)

Diagnostic and Statistical Manual of Mental Disorders

(1994)

E. DiCicco-Bloom et al.

The developmental neurobiology of autism spectrum disorder

J Neurosci

(2006)

C.M. Schumann et al.

The human amygdala and autism

C.M. Schumann et al.

The amygdala is enlarged in children but not adolescents with autism; the hippocampus is enlarged at all ages

J Neurosci

(2004)

M.W. Mosconi et al.

Longitudinal study of amygdala volume and joint attention in 2- to 4-year-old children with autism

Arch Gen Psychiatry

(2009)

B.F. Sparks et al.

Brain structural abnormalities in young children with autism spectrum disorder

Neurology

(2002)

M.M. Haznedar et al.

Limbic circuitry in patients with autism spectrum disorders studied with positron emission tomography and magnetic resonance imaging

Am J Psychiatry

(2000)

E.H. Aylward et al.

MRI volumes of amygdala and hippocampus in non-mentally retarded autistic adolescents and adults

Neurology

(1999)

Cited by (248)

Associations between early trajectories of amygdala development and later school-age anxiety in two longitudinal samples
2024, Developmental Cognitive Neuroscience
Amygdala function is implicated in the pathogenesis of autism spectrum disorder (ASD) and anxiety. We investigated associations between early trajectories of amygdala growth and anxiety and ASD outcomes at school age in two longitudinal studies: high- and low-familial likelihood for ASD, Infant Brain Imaging Study (IBIS, n = 257) and typically developing (TD) community sample, Early Brain Development Study (EBDS, n = 158). Infants underwent MRI scanning at up to 3 timepoints from neonate to 24 months. Anxiety was assessed at 6–12 years. Linear multilevel modeling tested whether amygdala volume growth was associated with anxiety symptoms at school age. In the IBIS sample, children with higher anxiety showed accelerated amygdala growth from 6 to 24 months. ASD diagnosis and ASD familial likelihood were not significant predictors. In the EBDS sample, amygdala growth from birth to 24 months was associated with anxiety. More anxious children had smaller amygdala volume and slower rates of amygdala growth. We explore reasons for the contrasting results between high-familial likelihood for ASD and TD samples, grounding results in the broader literature of variable associations between early amygdala volume and later anxiety. Results have the potential to identify mechanisms linking early amygdala growth to later anxiety in certain groups.
Autism in Women
2023, Neurologic Clinics
Lactobacillus reuteri normalizes altered fear memory in male Cntnap4 knockout mice
2022, eBioMedicine
Autism spectrum disorder (ASD) is a common neurodevelopmental disease, characterized by deficits in social communication, restricted and repetitive behaviours, and impaired fear memory processing. Severe gastrointestinal dysfunction and altered gut microbiome have been reported in ASD patients and animal models. Contactin associated protein-like 4 (CNTNAP4) has been suggested to be a novel risk gene, though its role in ASD remains unelucidated.
Cntnap4^−/− mice were generated to explore its role in ASD-related behavioural abnormalities. Electrophysiological recording was employed to examine GABAergic transmission in the basolateral amygdala (BLA) and prefrontal cortex. RNA-sequencing was performed to assess underlying mechanisms. 16S rDNA analysis was performed to explore changes in faecal microbial composition. Male Cntnap4^−/− mice were fed with Lactobacillus reuteri (L. reuteri) or faecal microbiota to evaluate the effects of microbiota supplementation on the impaired fear conditioning mediated by Cntnap4 deficiency.
Male Cntnap4^−/− mice manifested deficiency in social behaviours and tone-cue fear conditioning. Notably, reduced GABAergic transmission and GABA receptor expression were found in the BLA but not the prefrontal cortex. In addition, gut Lactobacillus were less abundant in male Cntnap4^−/− mice, and L. reuteri treatment or faecal microbiota transplantation rescued abnormal tone-cued fear memory and improved local GABAergic transmission in the BLA of male Cntnap4^−/− mice.
Cntnap4 shapes GABAergic transmission of amygdala and fear conditioning, and microbial intervention represents a promising therapy in ASD intervention.
National Natural Science Foundation of China, Science and Technology Planning Project of Guangzhou, Guangzhou Medical University, and China Postdoctoral Science Foundation.
Abnormal gray matter structure in children and adolescents with high-functioning autism spectrum disorder
2022, Psychiatry Research - Neuroimaging
The present study aimed to explore the brain structural mechanisms underlying clinical dysfunction in patients with ASD using magnetic resonance imaging (MRI). After screening T1 structural images from the Autism Brain Imaging Data Exchange (ABIDE) database, 111 children and adolescents with high-functioning ASD and 151 typically developing (TD) subjects matched were included in this study. We first compared the differences in gray matter volume (GMV) and gray matter density (GMD) between the two groups. Then, the relationships between GMV/GMD and clinical assessments in ASD patients were evaluated. We found that compared with the TD group, the ASD group showed increased GMV/GMD in the precuneus, thalamus, hippocampus and cingulate gyrus. Moreover, in the ASD group, social interaction was negatively correlated with GMD in the bilateral superior temporal gyrus and limbic system; communication was positively correlated with GMD in the right middle temporal gyrus, inferior frontal gyrus, and anterior cingulate gyrus; and repetitive behavior was positively correlated with GMD in the cerebellum and negatively correlated with GMV in the prefrontal cortex. In conclusion, the gray matter structure in children and adolescents with ASD was abnormal, and different clinical dysfunctions in ASD patients were related to structural abnormalities in specific regions.
Prefrontal circuits guiding social preference: Implications in autism spectrum disorder
2022, Neuroscience and Biobehavioral Reviews
Although Autism Spectrum Disorder (ASD) is increasing in diagnostic prevalence, treatment options are inadequate largely due to limited understanding of ASD’s underlying neural mechanisms. Contributing to difficulties in treatment development is the vast heterogeneity of ASD, from physiological causes to clinical presentations. Recent studies suggest that distinct genetic and neurological alterations may converge onto similar underlying neural circuits. Therefore, an improved understanding of neural circuit-level dysfunction in ASD may be a more productive path to developing broader treatments that are effective across a greater spectrum of ASD. Given the social preference behavioral deficits commonly seen in ASD, dysfunction in circuits mediating social preference may contribute to the atypical development of social cognition. We discuss some of the animal models used to study ASD and examine the function and effects of dysregulation of the social preference circuits, notably the medial prefrontal cortex-amygdala and the medial prefrontal cortex-nucleus accumbens circuits, in these animal models. Using the common circuits underlying similar behavioral disruptions of social preference behaviors as an example, we highlight the importance of identifying disruption in convergent circuits to improve the translational success of animal model research for ASD treatment development.
Examining Associations Between Amygdala Volumes and Anxiety Symptoms in Autism Spectrum Disorder
2022, Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
Anxiety is one of the most common co-occurring conditions in people with autism spectrum disorder. The amygdala has been identified as being associated with anxiety in populations with and without autism, yet associations in autism were based on relatively small or developmentally constrained samples, leaving questions as to whether these results hold at different developmental ages and in a larger, more robust sample.
Structural neuroimaging and parent report of anxiety symptoms of children ages 5–13 years with (n = 123) and without (n = 171) a diagnosis of autism were collected from the University of Maryland and three sites from the Autism Brain Imaging Data Exchange. Standardized residuals for bilateral amygdala volumes were computed adjusting for site, hemispheric volumes, and covariates (age, sex, Full Scale IQ).
Clinically significant anxiety symptoms did not differentiate amygdala volumes between groups (i.e., autism and anxiety, autism without anxiety, without autism or anxiety). No significant association between left or right amygdala volumes and anxiety scores was observed among the sample of individuals with autism. Meta-analytic and Bayes factor estimations provided additional support for the null hypothesis. Age, sex, and autism severity did not moderate associations between anxiety and amygdala volumes.
No relation between amygdala volumes and anxiety symptoms in children with autism was observed in the largest sample to investigate this question. We discuss directions for future research to determine whether additional factors including age or method of assessment may contribute to this lack of association.

View all citing articles on Scopus

View full text

Archival ReportAmygdala Enlargement in Toddlers with Autism Related to Severity of Social and Communication Impairments

Background

Methods

Results

Conclusions

Section snippets

Diagnostic Assessment

Results

Discussion

Curr Opin Neurobiol

Trends Neurosci

Trends Cogn Sci

Epilepsy Res

Child Adolesc Psychiatr Clin North Am

Neuron

Neuroimage

Comput Med Imaging Graph

J Am Acad Child Adolesc Psychiatry

J Am Acad Child Adolesc Psychiatry

Int J Dev Neurosci

Cognition

Curr Opin Neurobiol

Neuropsychological correlates of early symptoms of autism

Child Dev

Brief report: Recognition of autism spectrum disorder before one year of age: A retrospective study based on home videotapes

J Autism Dev Disord

Diagnostic and Statistical Manual of Mental Disorders

The developmental neurobiology of autism spectrum disorder

J Neurosci

The human amygdala and autism

The amygdala is enlarged in children but not adolescents with autism; the hippocampus is enlarged at all ages

J Neurosci

Longitudinal study of amygdala volume and joint attention in 2- to 4-year-old children with autism

Arch Gen Psychiatry

Brain structural abnormalities in young children with autism spectrum disorder

Neurology

Limbic circuitry in patients with autism spectrum disorders studied with positron emission tomography and magnetic resonance imaging

Am J Psychiatry

MRI volumes of amygdala and hippocampus in non-mentally retarded autistic adolescents and adults

Neurology

Archival Report
Amygdala Enlargement in Toddlers with Autism Related to Severity of Social and Communication Impairments