Association of Amygdala Development with Different Forms of Anxiety in Autism Spectrum Disorder

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 forms of anxiety and anxieties distinctly related to autism. Methods: Longitudinal MRI scans were acquired at up to four timepoints for 71 autistic and 55 typically developing (TD) children (∼2.5-12 years, 411 timepoints). Traditional DSM anxiety and anxieties distinctly related to autism were assessed at study Time 4 (∼8-12 years) using a diagnostic interview tailored to autism: The Anxiety Disorders Interview Schedule-IV with the Autism Spectrum Addendum. Mixed effects models were used to test group differences at study Time 1 (3.18 years), Time 4 (11.36 years), and developmental differences (age-by-group interactions) in right and left amygdala volume between autistic children with and without DSM or autism distinct anxieties, and TD. Results: Autistic children with DSM anxiety had significantly larger right amygdala volumes compared to TD at both study Time 1 (5.10% increase) and Time 4 (6.11% increase). Autistic children with autism distinct anxieties had significantly slower right amygdala growth compared to TD, autism-no anxiety, and autism-DSM anxiety groups and smaller right amygdala volumes at Time 4 compared to the autism-no anxiety (-8.13% decrease) and autism-DSM anxiety (-12.05% decrease) groups. Conclusions: Disparate amygdala volumes and developmental trajectories between DSM and autism distinct forms of anxiety suggest different biological underpinnings for these common, co-occurring conditions in autism

Does the Severity of Autism Symptoms Change during Childhood? What characterizes children who increase or decrease in symptom severity?

It is unclear how common is change in the severity of autism symptoms during childhood, whether symptoms change consistently across development, and what characterizes children that either increase or decrease in autism symptom severity during childhood. We evaluated these questions across three studies incorporating children from the University of California, Davis MIND Institute’s Autism Phenome Project and Girls with Autism imaging of Neurodevelopment cohorts. Autism symptoms and severity level were evaluated using the ADOS Calibrated Severity Score (CSS). Around half (46%-51%) of the children in the cohort changed in symptom severity level over time, with the other half remaining stable. Change in symptom severity was not consistent but rather fluctuated over time; severity decreases were more common during early childhood while severity increases occurred at both early and middle childhood. Most children experienced change during only one period and remained stable during the other. Social-communication challenges and restricted/repetitive behaviors (RRBs) changed differently across childhood. During middle childhood, increase in social-communication symptoms was especially prominent in parallel to RRBs severity decrease. Being female, having higher and increasing IQ, higher adaptive functioning, and having older, more educated parents were associated with decrease in symptom severity. Decreasing RRBs severity during middle childhood was associated with higher anxiety and probability for having an anxiety disorder at 11 years of age. Increasing symptom severity was associated with having lower and stable IQ, lower adaptive functioning and not making peer-equivalent gains over time, lower parental education level and younger parental age at the child’s birth. Increasing severity of social-communication challenges during middle childhood was associated with elevated and increasing anxiety, ADHD, disruptive behavior problems and overall psychopathology. Symptom severity change patterns were not associated with either initial severity level at 3-years-of-age or intervention history. We discuss findings in light of the literature and implications for defining autism severity level and suitable interventions

Does the severity of autism symptoms change over time? A review of the evidence, impacts, and gaps in current knowledge

Studies evaluating change in autism symptom severity across the lifespan have yielded inconsistent results, making it difficult to assess the prevalence of meaningful change in autism symptom severity, and what characterizes it. Better understanding the ways in which autism symptoms change over time is crucial, with important implications for intervention. Synthesizing information across past studies, autism symptom severity change (especially decreases) appears common, though stability of symptoms is also frequent. Symptom severity change is characterized by variability in patterns of change between different individuals (between-person), variability in change within a person's trajectory across time (within-person), and variability in change patterns across symptom domains (i.e., social-communication, restricted/repetitive behaviors). Variability in severity change is likely impacted by differences in person-level characteristics (e.g., sex, IQ, sociodemographic factors) as well as developmental processes across time. Numerous methodological issues may impact our ability to understand how common change in symptom severity is, including varying measurement tools, analytic approaches, and change patterns between symptom domains across time. Potential implications of better understanding and characterizing symptom severity change include incorporation of severity change patterns and predictors of change into research on biomarkers, and consideration of such predictors as moderators or mediators of change in clinical practice

Trajectories of Autism Symptom Severity Change During Early Childhood.

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 Scores (CSS) at the two ages. A Decreased Severity Group (28.8%) decreased by 2 or more points; a Stable Severity Group (54.4%) changed by 1 point or less; and an Increased Severity Group (16.8%) increased by 2 or more points. Girls tended to decrease in severity more than boys and increase in severity less than boys. There was no clear relationship between intervention history and membership in the groups

Trajectories of Autism Symptom Severity Change During Early Childhood.

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 Scores (CSS) at the two ages. A Decreased Severity Group (28.8%) decreased by 2 or more points; a Stable Severity Group (54.4%) changed by 1 point or less; and an Increased Severity Group (16.8%) increased by 2 or more points. Girls tended to decrease in severity more than boys and increase in severity less than boys. There was no clear relationship between intervention history and membership in the groups

A Longitudinal Study of White Matter Development in Relation to Changes in Autism Severity Across Early Childhood.

BackgroundCross-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. Furthermore, the relationship between altered white matter development and longitudinal changes in autism symptoms is unknown.MethodsUsing longitudinal diffusion-weighted magnetic resonance imaging acquired over 2 to 3 time points between the ages of approximately 2.5 to 7.0 years in 125 autistic children and 69 typically developing control participants, we directly tested the hypothesis that autistic individuals have atypical white matter development across childhood. Additionally, we sought to determine whether changes in white matter diffusion parameters were associated with longitudinal changes in autism severity.ResultsAutistic children were found to have slower development of fractional anisotropy in the cingulum bundle, superior longitudinal fasciculus, internal capsule, and splenium of the corpus callosum. Furthermore, in the sagittal stratum, autistic individuals who increased in autism severity over time had a slower developmental trajectory of fractional anisotropy compared with individuals whose autism decreased in severity. In the uncinate fasciculus, autistic individuals who decreased in autism symptom severity also had greater increases in fractional anisotropy with age.ConclusionsThese longitudinal findings indicate that previously reported differences in diffusion-weighted magnetic resonance imaging measures between younger and older autism cohorts are attributable to an atypical developmental trajectory of white matter. Differences in white matter development between individuals whose autism severity increased, remained stable, or decreased suggest that these functional differences are associated with fiber development in the autistic brain

The Autism Phenome Project: Toward Identifying Clinically Meaningful Subgroups of Autism.

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 etiologies as well as more targeted interventions and treatments. In 2006, we initiated the UC Davis MIND Institute Autism Phenome Project (APP) with the overarching goal of identifying clinically meaningful subtypes of autism. This ongoing longitudinal multidisciplinary study now includes over 400 children and involves comprehensive medical, behavioral, and neuroimaging assessments from early childhood through adolescence (2-19 years of age). We have employed several strategies to identify sub-populations within autistic individuals: subgrouping by neural, biological, behavioral or clinical characteristics as well as by developmental trajectories. In this Mini Review, we summarize findings to date from the APP cohort and describe progress made toward identifying meaningful subgroups of autism