David Amaral

University of California, Davis | UCD · Department of Medical Microbiology and Immunology

Altered amygdala development is implicated in the neurobiology of autism, but little is known about the coordinated development of the brain regions directly connected with the amygdala. Here we investigated the volumetric development of an amygdala-connected network, defined as the set of brain regions with monosynaptic connections with the amygda...

The structure of large-scale intrinsic connectivity networks is atypical in adolescents diagnosed with autism spectrum disorder (ASD or autism). However, the degree to which alterations occur in younger children, and whether these differences vary by sex, is unknown. We utilized structural magnetic resonance imaging (MRI) data from a sex- and age-...

Individuals’ social contexts are broadly recognized to impact both their psychology and neurobiology. These effects are observed in people and in nonhuman animals who are the subjects for comparative and translational science. The social contexts in which monkeys are reared have long been recognized to have significant impacts on affective processi...

Background The amygdala is widely implicated in both anxiety and autism spectrum disorder. However, no studies have investigated the relationship between co-occurring anxiety and longitudinal amygdala development in autism. Here, the authors characterize amygdala development across childhood in autistic children with and without traditional DSM for...

An individual's autism symptom severity level can change across childhood. The prevalence and direction of change, however, are still not well understood. Nor are the characteristics of children that experience change. Symptom severity trajectories were evaluated from early to middle childhood (approximately ages 3-11) for 182 autistic children. Sy...

One of the most universally accepted facts about autism is that it is heterogenous. Individuals diagnosed with autism spectrum disorder have a wide range of behavioral presentations and a variety of co-occurring medical and mental health conditions. The identification of more homogenous subgroups is likely to lead to a better understanding of etiol...

Background: Intellectual disability affects approximately one third of individuals with autism spectrum disorder (autism), yet a major unresolved question remains concerning the neurobiology that differentiates autistic individuals with and without intellectual disability. IQ is highly variable during childhood. We previously identified subgroups o...

Varying rates of anxiety have been reported in children with Autism Spectrum Disorder (ASD) and Intellectual Disability (ID). Recent reports, using an adapted semi-structured interview approach, suggest that the risk for anxiety in these children is equal to that found in those with ASD and average or above average IQ. This wide range in rates deri...

Human epidemiological studies implicate exposure to infection during gestation in the etiology of neurodevelopmental disorders. Animal models of maternal immune activation (MIA) have identified the maternal immune response as the critical link between maternal infection and aberrant offspring brain and behavior development. Here we evaluate neurode...

Despite many observations of anterior cingulate cortex (ACC) activity related to cognition and affect in humans and nonhuman animals, little is known about the causal role of the ACC in psychological processes. Here, we investigate the ACC's causal role in affective responding to threat in rhesus monkeys (Macaca mulatta), a species with an ACC larg...

In recent years, a large population of immature neurons has been documented in the paralaminar nucleus of the primate amygdala. A substantial fraction of these immature neurons differentiate into mature neurons during postnatal development or following selective lesion of the hippocampus. Notwithstanding a growing number of studies on the origin an...

Background Recent neuroimaging studies have highlighted differences in cerebral maturation in individuals with autism spectrum disorder (ASD) in comparison to typical development. For instance, the contrast of the gray-white matter boundary is decreased in adults with ASD. To determine how gray-white matter boundary integrity relates to early ASD p...

The established literature clearly demonstrates that whether or not monkeys are socially reared has long term consequences for their affective behavior. Yet, in the context of behavioral neuroscience and pharmacological studies, social context of adult animals is often ignored. When social context has been studied in adult monkeys, such studies hav...

Behavioral inhibition is a temperamental disposition to react warily when confronted by unfamiliar people, objects, or events. Behaviorally inhibited children are at greater risk of developing anxiety disorders later in life. Previous studies reported that individuals with a history of childhood behavioral inhibition exhibit abnormal activity in th...

De novo mutations in the chromatin-remodeling factor CHD8 (Chromodomain-Helicase DNA-binding protein 8) have emerged as a key genetic risk factor for Autism Spectrum Disorder (ASD) and, more generally, neurodevelopmental disorders. Individuals with heterozygous mutations in CHD8 typically present hallmarks of ASD with comorbid cognitive disability...

Autism symptom severity change was evaluated during early childhood in 125 children diagnosed with autism spectrum disorder (ASD). Children were assessed at approximately 3 and 6 years of age for autism symptom severity, IQ and adaptive functioning. Each child was assigned a change score, representing the difference between ADOS Calibrated Severity...

Atypical responses to fearful stimuli and the presence of various forms of anxiety are commonly seen in children with autism spectrum disorder (ASD). The fear potentiated startle paradigm (FPS), which has been studied both in relation to anxiety and as a probe for amygdala function, was carried out in 97 children aged 9–14 years including 48 (12 fe...

Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case–control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a to...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

We report neuropsychological and neuropathological findings for a patient (A.B.), who developed memory impairment after a cardiac arrest at age 39. A.B. was a clinical psychologist who, although unable to return to work, was an active participant in our neuropsychological studies for 24 y. He exhibited a moderately severe and circumscribed impairme...

Background Cerebral overgrowth is frequently reported in children but not adults with autism spectrum disorder (ASD). This suggests that early cerebral over-growth is followed by normalization of cerebral volumes. However, this notion is predicated upon cross-sectional research that is vulnerable to sampling bias. For example, autistic individuals...

Background Maternal immune activation (MIA) is a proposed risk factor for multiple neuropsychiatric disorders, including schizophrenia. However, the molecular mechanisms through which MIA imparts risk remain poorly understood. A recently developed nonhuman primate model of exposure to the viral mimic poly:ICLC during pregnancy shows abnormal social...

Background Cross-sectional diffusion-weighted magnetic resonance imaging studies suggest that young autistic children have alterations in white matter structure that differ from older autistic individuals. However, it is unclear whether these differences result from atypical neurodevelopment or sampling differences between young and older cohorts....

Context.—: Autism spectrum disorder is a neurodevelopmental condition that affects over 1% of the population worldwide. Developing effective preventions and treatments for autism will depend on understanding the neuropathology of the disorder. While evidence from magnetic resonance imaging indicates altered development of the autistic brain, it la...

Gastrointestinal (GI) symptoms are frequently reported in children with autism spectrum disorder (ASD). We evaluated the frequency and severity of GI symptoms in preschool‐aged children with ASD compared to participants with typical development (TD). Our goal was to ascertain whether GI symptoms are associated with differences in sex or development...

Background Human epidemiologic studies have implicated exposure to infectious or inflammatory insults during gestation in the etiology of neurodevelopmental disorders. Rodent models of maternal immune activation (MIA) have identified the maternal immune response as the critical link between maternal infection and aberrant brain and behavior develop...

Autism spectrum disorder (ASD) is biologically and behaviorally heterogeneous. Delayed diagnosis of ASD is common and problematic. The complexity of ASD and the low sensitivity of available screening tools are key factors in delayed diagnosis. Identification of biomarkers that reduce complexity through stratification into reliable subpopulations ca...

The entorhinal cortex is the main gateway for interactions between the neocortex and the hippocampus. Distinct regions, layers and cells of the hippocampal formation exhibit different profiles of structural and molecular maturation during postnatal development. Here, we provide estimates of neuron number, neuronal soma size, and volume of the diffe...

Objective: To evaluate how distinct presentations of anxiety symptoms and intellectual impairment influence the measurement and estimated rate of clinically significant anxiety in autism spectrum disorder (ASD). Method: The sample included 75 children (ages 9–13 years) with ASD and varied IQ and 52 typically developing (TD) controls and parents. Pa...

Objective: 1) To identify a subset of children with autism spectrum disorder (ASD) and co-occurring symptoms of psychopathology. 2) To evaluate associations between this subgroup and biological sex and amygdala volume. Method: Participants included 420 children (ASD: 91 girls, 209 boys; typically developing controls: 57 girls, 63 boys). Latent p...

Background: Fear of autism has led to a decline in childhood-immunization uptake and to a resurgence of preventable infectious diseases. Identifying characteristics of parents who believe in a causal role of vaccines for autism spectrum disorder (ASD) in their child may help targeting educational activities and improve adherence to the immunizatio...

Background: The core symptoms of autism spectrum disorder (ASD) are widely theorized to result from altered brain connectivity. Diffusion-weighted magnetic resonance imaging (DWI) has been a versatile method for investigating underlying microstructural properties of white matter (WM) in ASD. Despite phenotypic and etiological heterogeneity, DWI st...

Background: Multifactorial liability models predict greater dissimilarity in the neural phenotype of autism spectrum disorder (ASD) in female individuals than in male individuals, while gender incoherence and extreme male brain models predict attenuated sex differences in ASD. The amygdala is an informative target to explore these models because i...

Autism spectrum disorder (ASD), characterized by impairments in social communication and repetitive behaviors, often includes altered responses to sensory inputs as part of its phenotype. The neurobiological basis for altered sensory processing is not well understood. The UC Davis Medical Investigation of Neurodevelopmental Disorders Institute Auti...

Emerging evidence suggests that the human amygdala undergoes extensive growth through adolescence, coinciding with the acquisition of complex socioemotional learning. Our objective was to longitudinally map volumetric growth of the nonhuman primate amygdala in a controlled, naturalistic social environment from birth to adulthood. Magnetic resonance...

Background: Autism spectrum disorder (ASD) is behaviorally and biologically heterogeneous and likely represents a series of conditions arising from different underlying genetic, metabolic, and environmental factors. There are currently no reliable diagnostic biomarkers for ASD. Based on evidence that dysregulation of branched-chain amino acids (BC...

Background: We previously showed, in two separate cohorts, that high-risk infants who were later diagnosed with autism spectrum disorder had abnormally high extra-axial cerebrospinal fluid (CSF) volume from age 6-24 months. The presence of increased extra-axial CSF volume preceded the onset of behavioural symptoms of autism and was predictive of a...

The entorhinal cortex is a prominent structure of the medial temporal lobe, which plays a pivotal role in the interaction between the neocortex and the hippocampal formation in support of declarative and spatial memory functions. We implemented design‐based stereological techniques to provide estimates of neuron numbers, neuronal soma size, and vol...

Local gyrification index (LGI), a metric quantifying cortical folding, was evaluated in 105 boys with autism spectrum disorder (ASD) and 49 typically developing (TD) boys at 3 and 5 years-of-age. At 3 years-of-age, boys with ASD had reduced gyrification in the fusiform gyrus compared with TD boys. A longitudinal evaluation from 3 to 5 years reveale...

Remarkably little is known about the postnatal cellular development of the human amygdala. It plays a central role in mediating emotional behavior and has an unusually protracted development well into adulthood, increasing in size by 40% from youth to adulthood. Variation from this typical neurodevelopmental trajectory could have profound implicati...

The Simons Foundation Autism Research Initiative (SFARI) has launched SPARKForAutism.org, a dynamic platform that is engaging thousands of individuals with autism spectrum disorder (ASD) and connecting them to researchers. By making all data accessible, SPARK seeks to increase our understanding of ASD and accelerate new supports and treatments for...

Autism spectrum disorder (ASD or autism) is a neurodevelopmental condition that affects over 1% of the population worldwide. Developing effective preventions and treatments for autism will depend on understanding the genetic perturbations and underlying neuropathology of the disorder. While evidence from magnetic resonance imaging and other noninva...

Hippocampal damage in adult humans impairs episodic and semantic memory, whereas hippocampal damage early in life impairs episodic memory but leaves semantic learning relatively preserved. We have previously shown a similar behavioral dissociation in nonhuman primates. Hippocampal lesion in adult monkeys prevents allocentric spatial relational lear...

Lay summary: We examined how the IQs of children with autism spectrum disorder change between ages 2 and 8, and identified four patterns. Two groups exhibited persistently lower IQs. One group showed IQ increases of greater than 30 points with improved communicate abilities and declining disruptive behaviors. The final group had IQs in the average...

[This corrects the article DOI: 10.1371/journal.pgen.1006425.].

Background:Sex differences in neuropathology and neural phenotypes of autism spectrum disorder (ASD) are currently poorly understood. The structure and function of the amygdala is altered in males with ASD (Schumann & Amaral, 2006). While prior research in pre-school aged males with ASD implicated altered amygdala resting-state fMRI connectivity (S...

It is generally believed that neural damage that occurs early in development is associated with greater adaptive capacity relative to similar damage in an older individual. However, few studies have surveyed whole brain changes following early focal damage. In this report, we employed multimodal magnetic resonance imaging analyses of adult rhesus m...

Children with autism vary widely in their language abilities, yet the neural correlates of this language variability remain unclear, especially early in development. Diffusion tensor imaging (DTI) was used to examine diffusivity measures along the length of 18 major fiber tracts in 104 preschool-aged boys with autism spectrum disorder (ASD). The bo...

Background: We previously reported that infants who developed ASD had increased CSF in the subarachnoid space (i.e., extra-axial CSF) from 6-24 months of age (Shen et al., 2013; Brain). We attempt to confirm and extend this finding in a larger, independent sample. Methods: A longitudinal MRI study of infants at-risk for ASD was carried out on 343...

Gene-disruptive mutations contribute to the biology of neurodevelopmental disorders (NDDs), but most of the related pathogenic genes are not known. We sequenced 208 candidate genes from >11,730 cases and >2,867 controls. We identified 91 genes, including 38 new NDD genes, with an excess of de novo mutations or private disruptive mutations in 5.7% o...

A consensus has emerged that despite common core features, autism spectrum disorder (ASD) has multiple etiologies and various genetic and biological characteristics. The fact that there are likely to be subtypes of ASD has complicated attempts to develop effective therapies. The UC Davis MIND Institute Autism Phenome Project is a longitudinal, mult...

This study continues a longitudinal analysis of rhesus macaque social behavior following bilateral neonatal ibotenic acid lesions of the amygdala or hippocampus, or sham operations. The social behavior of female subjects was evaluated at a critical developmental time point-the transition to adulthood. At approximately 4 years of age, female subject...

Editor’s Note Autism is a broad, complex, and increasingly important brain disorder. New data from the Center for Disease Control and Prevention indicate that one in sixty-eight children is born with some degree of autism. Autism is also more common in males by a four to one ratio. Making it especially difficult to discuss in finite, conclusive ter...

The present report details the final phase of a longitudinal evaluation of the social behavior in a cohort of adult rhesus monkeys that received bilateral neurotoxic lesions of the amygdala or hippocampus, or sham operations at 2 weeks of age. Results were compared to previous studies in which adult animals received amygdala lesions and were tested...

A large population of immature neurons is present in the ventromedial portion of the adult primate amygdala, a region that receives substantial direct projections from the hippocampal formation. Here, we show the effects of neonatal (n = 8) and adult (n = 6) hippocampal lesions on the populations of mature and immature neurons in the paralaminar, l...

Author Summary Autism Spectrum Disorders (ASDs) make up a debilitating neurodevelopmental disorder class. It has been known for a long time that more males than females are affected, but despite much speculation there is no clear etiological reason for this sex bias. As ASDs are highly heritable, we examined evidence in single nucleotide polymorphi...

Sex heterogeneity results for top GWAS association results. Heterogeneity (Cochran's Q P-value) between male versus female association results for the most significant SNPs in the sex-combined, male-specific and female-specific results. Logistic regression results are shown comparing low IQ (< 70) and high IQ (> 80) groups by sex. (DOCX)

Genetic risk scores by sex and IQ group. Boxplots of genetic risk scores are shown for each within-sex IQ group overlapping with the independent test datasets (low: IQ < 70 [Nfemale = 313, Nmale = 299]; high: IQ > 80 [Nfemale = 189, Nmale = 235]). Female data are shown in light grey and male data in dark grey. No evidence for significant difference...

Additional Materials and Methods. The first section describes the methods used for diagnosis of ASD in each dataset and the second section reports the IQ and DQ data available for a subset of cohorts and the criteria applied to assign each individual to low IQ or high IQ categories. (PDF)