Amygdala-Frontal Functional Connectivity Predicts Longitudinal Anxiety during the Transition to Adulthood in Autism

Background: The prevalence of anxiety disorders in individuals with Autism Spectrum Disorders (ASDs) is estimated at approximately 40%, and the transition to adulthood is a period of particular vulnerability. Functional connectivity between amygdala and prefrontal cortices has been hypothesized to reflect a circuit tied to emotion down-regulation and anxiety in the general population, with some research indicating that these circuits are also linked to anxiety in ASDs (Kleinhans et al., 2016). Fishman et al. (2018) reported an absence of age-related increases in amygdala-prefrontal connectivity during adolescence in ASDs compared with typically developing (TD) individuals, suggesting that lower amygdala-frontal connectivity could be a risk factor for developing anxiety later on. However, longitudinal studies that could directly test this hypothesis are required. Characterizing the neural predictors of risk and resilience for anxiety disorders in ASDs may help increase the efficacy of clinical interventions, resulting in improved care and higher quality of life during this crucial transition period.

Objectives: To examine, in a longitudinal design, whether amygdala-frontal connectivity patterns predict anxiety in ASDs during the transition to adulthood.

Methods: Longitudinal data from 10 adolescents and young adults with ASDs participating in an ongoing study are presented. Data include diagnostic evaluations, T1-weighted anatomical MRI, and eyes-open resting-state fMRI acquired at baseline [mean age(sd) at Time1 = 13.6(2.0) years], and measures of anxiety symptoms acquired at follow-up [mean age(sd) at Time2 = 18.3(3.8) years, inter-timepoint interval = 4.6(2.8) years] using the parent-report form of the Multidimensional Anxiety Scale for Children 2^nd edition (MASC-2, a = .9). Following standard image preprocessing, we extracted mean time series from the left and right amygdala (from the Harvard Oxford subcortical atlas, thresholded at 50% probability), and tested the correlation between seed to frontal-lobe connectivity at baseline and Time2 anxiety using AFNI 3dttest++. Due to the currently limited sample size, we report results at a voxelwise p < .05, cluster size > 100.

Results: As in previous studies, we found remarkable elevations in anxiety in ASD participants, with 40% showing elevated MASC-2 T scores of >60 (i.e., evidence of clinically significant anxiety). Lower functional connectivity between the left amygdala and right dorsolateral prefrontal cortex at baseline was strongly associated with higher anxiety scores at follow-up. We also observed a negative correlation between baseline amygdala connectivity (bilaterally) with medial frontal gyrus and anxiety at Time2. Specifically, higher anxiety scores at Time2 were associated with lower connectivity between the amygdala and medial frontal gyrus.

Conclusions: These results suggest that functional connectivity within previously hypothesized circuits of emotion regulation and anxiety (amygdala-frontal circuits) may predict long-term anxiety levels in adolescents and young adults with ASDs. Notably, weaker connectivity between amygdala and prefrontal regions, even during a resting-state, predicted risk for anxiety later on. Although these results should be viewed with caution given the as yet small sample size, they suggest that effective preventative interventions for anxiety disorders during the transition to adulthood in ASDs could potentially target amygdala-prefrontal circuitry.