Role of Autonomic, Nociceptive, and Limbic Brainstem Nuclei in Core Autism Features

The first biology-based theories of autism posited that the brainstem?s reticular formation was associated with the behavioral features of autism. However, almost 60 years later, we still know very little about the brainstem?s role in human behaviors because of the challenges of accurately imaging the brainstem?s small and intricate anatomy. Using techniques to optimize brainstem magnetic resonance images, the present study set out to elucidate the role of the autonomic, nociceptive, and limbic brainstem nuclei in the core autism features of children. Data were collected in a sample of 73 non-autistic children (i.e., children with no known psychiatric conditions) and 74 autistic children (6.0-10.9 years-old). Individual differences in core autism features were assessed using caregiver-reported measures of social communication and repetitive and/or restricted behaviors. Participants completed diffusion-weighted imaging and T1-weighted structural scans with acquisition and post-processing techniques aimed to improve brainstem images. Data reduction of the autism features and the microstructural measures of 22 brainstem nuclei was performed via principal component analyses. Correlational analyses examined associations among autism features and brainstem cluster values within the autistic group and across the whole sample. Replication analyses were performed in a sample of adolescents (24 autistic, 21 non-autistic; 13.0-17.9 years-old). Results found that the summary measure of autism features had moderate-sized associations with the bilateral parvicellular reticular formation-alpha (P<.05, FDR-corrected). Follow-up analyses with specific autism features demonstrated that the parvicellular reticular formation-alpha was primarily associated with social communication behaviors, whereas the lateral parabrachial nucleus was associated with insistence on sameness (P<.05, FDR-corrected). The parvicellular reticular formation-alpha associations with social communication measures were independently found in the replication sample, whereas the lateral parabrachial associations were only partially replicated. In all, these findings suggest that the parvicellular reticular formation-alpha is a key brainstem nucleus associated with autism features, particularly behaviors around social communication, while the lateral parabrachial nucleus appears to be associated with specific repetitive behaviors. These nuclei have been previously linked with eating, digestion, facial movements, cardio-respiration, and pain experiences. These findings shed light on the role of the specific aspects of the pontine reticular formation that appear to explain individual variation in the prominence of autistic features. As these nuclei are highly connected with each other, other brainstem nuclei, the thalamus, amygdala, cerebellum, and cortex, understanding the pattern of connections at the whole-brain-network level will be a key future direction.