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

Abstract

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 magnetic resonance imaging scans were acquired at up to four time points for 71 autistic and 55 typically developing (TD) children (∼2.5-12 years, 411 time points). 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) and 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 children.

Results: Autistic children with DSM anxiety had significantly larger right amygdala volumes than TD children 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 than TD, autism-no anxiety, and autism-DSM anxiety groups and smaller right amygdala volumes at time 4 than 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.

Keywords: Anxiety; Autism; Brain; Development; Longitudinal; MRI.

Figure 1

Associations between amygdala volume and DSM and autism-distinct anxieties. Longitudinal development of (A) left and (B) right amygdala volumes are plotted for autistic children with and without DSM anxiety (ASD-DSM ANX and ASD-no DSM ANX, respectively). Compared with autistic children without DSM anxiety, those with DSM anxiety showed larger right amygdala volumes at both time 1 (5.87% larger, p = .005, false discovery rate–adjusted p = .048) and time 4 (6.15% larger, p = .005, false discovery rate–adjusted p = .048). Compared with autistic children without autism-distinct anxieties (ASD-no DIST ANX), those with distinct anxieties (ASD-DIST ANX) showed statistical trends (p < .05, false discovery rate–adjusted p > .05) of (C) smaller left amygdala volumes at both time 1 (−5.44% smaller, p = .024) and time 4 (−6.75% smaller, p = .011) and (D) right amygdala volumes at time 4 (−5.75% mean decrease, p = .020) compared with ASD-no DIST ANX. Vertical dotted lines indicate mean ages at study time 1 (38.11 mo/3.18 years) and time 4 (136.30 mo/11.36 years). Note that here, some individuals within the DSM/DIST ANX groups have duel DSM and distinct anxiety diagnoses; in addition, individuals within the no DSM group may have distinct clinical severity rating scores ≥4 (and vice versa for the no DIST group). These overlapping anxieties are accounted for by modeling separate DSM and distinct categorical variables.

Figure 2

Associations between amygdala volume and different forms of anxiety in autism spectrum disorder (ASD). Longitudinal development of (A) left and (B) right amygdala volumes are plotted for autistic children with only DSM anxiety (ASD-DSM ANX), with only autism-distinct anxiety (ASD-DIST ANX), with both DSM and distinct anxieties (ASD-BOTH ANX) and without anxiety (ASD-no ANX) and typically developing (TD) children without anxiety. Vertical dotted lines indicate mean ages at study time 1 (38.11 mo/3.18 years) and time 4 (136.30 mo/11.36 years). ASD-DSM ANX was found to have significantly larger right amygdala volumes at both study time 1 (4.59% larger, p = .012, false discovery rate [FDR]–adjusted p = .044) and time 4 (5.19% larger, p = .01, FDR-adjusted p = .044) compared with TD children. ASD-DIST ANX had a significantly altered developmental trajectory of the right amygdala marked by slower growth compared with the TD (p = .009, FDR-adjusted p = .044), ASD-no ANX (p = .009, FDR-adjusted p = .044), and ASD-DSM ANX (p = .007, FDR-adjusted p = .044) groups, which resulted in significantly smaller right amygdala volumes at time 4 compared with the ASD-no ANX (−8.85% smaller, p = .004, FDR-adjusted p = .044), ASD-DSM (−11.04% smaller, p < .001, FDR-adjusted p = .013), and ASD-both anxieties (−8.26% smaller, p = .011, FDR-adjusted p = .044) groups.