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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 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.

participants and one TD participant did not complete DAS assessments at study Time 4. Thus, for all analyses of IQ the latest DQ/IQ measure available for these individuals was assigned. Informed consent was obtained from the parent or guardian of each participant. All aspects of the study protocol were approved by the University of California Davis Institutional Review Board.

Anxiety and Behavioral Assessments
Anxiety was assessed at Time 4 by research reliable, trained doctoral level psychologists with expertise in autism and anxiety using the Anxiety Disorders Interview Schedule-IV-Parent Interview (ADIS) (8) with the Autism Spectrum Addendum (ADIS-ASA), a semi-structured diagnostic interview designed to differentiate anxiety and autism symptoms and assess a range of problematic anxiety in autistic youth (9). The ADIS includes modules relating to separation, social, specific phobia, and generalized anxiety disorders. In addition to these modules, the ADIS-ASA also assesses forms of anxiety distinctly related to autism, including idiosyncratic fears, fear relating to social confusion, special interest fears, and fears of change. For each module a clinical severity rating (CSR) ranging from 0 (no interference) to 8 (severe interference) is prescribed, with 4 being the cutoff for clinical determination of significant interference. Three TD children had an ADIS CSR>=4 while four autistic children met ADIS or ADIS-ASA criteria for an OCD condition, these participants were excluded and are not described in the current study. Rates of anxiety and anxiety assessment within this cohort have been described in detail previously (10). The current study included 53/71 of the autistic and 43/55 of the TD participants from this previous study.
Behavioral measures were acquired at both Time 1 and Time 4 and utilized for post hoc behavioral analyses. However, not all ASD participants completed all assessments, these included; Rates of anxiety and anxiety assessment within this cohort have been described in detail previously (10). The current study included 53/71 of the autistic and 43/52 of the TD participants from this previous study. This study also included 64/71 autistic and 51/55 children from a recent publication detailing sex differences in amygdala volume in relation to psychopathology symptoms in autism (16).

Magnetic Resonance Imaging Acquisition and Region of Interest Approach
All MRI scans were acquired between May 2006 and September 2019 at the UC Davis Imaging Research Center on a 3T Siemens Trio MRI system using an eight-channel head coil.
High resolution T1-weighted structural scans were obtained using 3-dimensional magnetizationprepared rapid acquisition gradient-echo (MPRAGE) (T1-T3: TR 2,170 ms, TE (17). Time 4 scans were acquired while participants were awake using previously described methods (18). Image distortion associated with changes in software over time was controlled for by scanning a calibration phantom (ADNI MAGPHAM, The Phantom Laboratory) at the end of each MRI session and subsequently applying distortion correction to each MPRAGE image (Image Owl, Inc, Greenwich, NY; http://www.imageowl.com/). Distortion corrected, anonymized, and defaced MPRAGE images were uploaded to MRICloud (https://mricloud.org) (19) and segmented into 289 anatomically defined regions using a multi-atlas approach (20) within the fully automated MRICloud T1-Segmentation pipeline version 7A. According to age in years at the time of the scan an age-specific atlas set was used for each participant. For 2-and 3-year-olds, the multi-atlas sets (each comprising 13 pediatric atlases) were optimized using data from the APP cohort at each age group and are available on MRI Cloud (UC Davis 2 Years and UC Davis 3 Years). For older children the appropriate MRI Cloud Pediatric 4-8 Years multi-atlas (based on 10 pediatric atlases) or Pediatric 8-12 Years multi-atlas (based on 28 atlases) was utilized. The whole-brain segmentation output for each participant was downloaded and visually inspected for segmentation quality. This protocol has been used previously and validated against manual tracing of the amygdala (16). Volumes from the left and right amygdala, and left and right hemisphere, were exported for statistical modeling.