Associations Between White Matter Integrity and Anxiety Symptoms in Children with Autism Spectrum Disorders

Background:  Anxiety symptoms are highly prevalent among individuals with autism spectrum disorders (ASD).  However, there are almost no studies to date on the neurobiology of anxiety symptoms in ASD, despite the theoretical overlap between “social” and “emotional” brain structures and networks.  Recent studies on the core diagnostic symptoms of ASD have identified abnormalities in white matter (WM) tracts in individuals with ASD; some of these tracts are associated with limbic structures (e.g., uncinate fasciculus and cingulum).  As current neuroscience research on anxiety disorders among typically developing individuals emphasizes the modulation of amygdala by prefrontal cortex, tracts connecting these areas may prove important in understanding the etiology of anxiety symptoms in ASD.

Objectives:  The purpose of this project is to test the hypothesis that anxiety symptoms in children with ASD are associated with the structural integrity of WM tracts connecting two key emotion regulation structures: amygdala and ventral prefrontal cortex (vPFC).

Methods:  Diffusion tensor imaging (DTI) data were collected on 94 well-characterized children with ASD between the ages of 6-18 years (M = 12.4, SD = 3.1). Diagnoses for children with ASD were established by expert clinicians using gold standard assessments (i.e., Autism Diagnostic Observation Schedule and Autism Diagnostic Interview – Revised). All participants also received the Differential Ability Scales 2^nd Edition (DAS-II). Parent report measures of the core symptoms of ASD (i.e., Social Responsiveness Scale [SRS] and Social Communications Questionnaire [SCQ]) were also collected. Anxiety symptoms were measured using the parent version of the Screen for Child Anxiety Related Emotional Disorders (SCARED). Diffusion-weighted imaging data were acquired using a 30-direction imaging sequence (80 axial slices, voxel size 2 mm isotropic, TR/TE=11000/75 ms, b=1000 s/mm²).  For the main analyses, multiple regression models were used to predict standard per-voxel estimates of WM integrity (i.e., fractional anisotropy [FA]).  The resulting statistical maps were controlled for family-wise error (FWE, corrected p < .05) via the application of a per-voxel statistical threshold (p < .005) and size thresholds derived from Monte Carlo simulations (i.e., a small volume correction).  Post-hoc analyses were performed on average FA scores within each of the significant clusters.

Results:  The separation anxiety subscale of the SCARED was significantly negatively correlated with WM integrity on separate, bilateral portions of the cingulum immediately adjacent to amygdala and immediately above cingulate cortex (correlations ranged from -.32 to -.38).  Post-hoc analyses indicated that these correlations remained statistically significant after controlling for variance associated with questionnaire measures of core ASD symptoms (SRS and SCQ total scores) and age.

Conclusions:  The present data indicate that anxiety symptoms in ASD may be related to abnormalities in pathways connecting amygdala to vPFC.  The emphasis on separation anxiety in these data likely reflects the salience of this form of anxiety for children with ASD in this age group: dependence on caregivers is typically prominent, and interactions with strangers are often aversive.  Future research on this topic will benefit from a more detailed assessment of anxiety symptoms in ASD samples.