Multimodal associations between brain morphology, immune-inflammatory markers, spatial transcriptomics, and behavioural symptoms in autism spectrum disorder.

Abstract

Background: Aggressive behaviour is a common and disruptive feature of autism spectrum disorder (ASD), affecting up to 68% of individuals and significantly burdening families and caregivers. Despite its prevalence, the mechanisms underlying aggression in ASD remain poorly understood, with evidence pointing to complex interactions between behavioural, neurobiological, and environmental factors. Emerging research suggests that neuroinflammation, along with structural brain changes, may contribute to aggressive behaviour in ASD.

Objectives: This study investigated the behavioural and neurobiological profiles of individuals with ASD who exhibit aggressive behaviour by examining neuroendocrine and inflammatory markers, structural brain differences, and spatial transcriptomics. The overarching goal was to identify the mechanisms underlying aggression in ASD and inform potential therapeutic strategies.

Methods: Forty-two male individuals with ASD aged 11-38 years were included in the study, divided into aggressive (Case; n = 21) and non-aggressive (Control; n = 21) groups based on Modified Overt Aggression Scale scores. A series of standardized questionnaires were used to investigate behaviour patterns and quality of life. Plasma levels of neuroendocrine and inflammatory markers, including cytokines and neuropeptides, were measured using a multiplex assay. For a subset of aggressive participants (n = 13), MRI scans were acquired, and deformation-based morphometry (DBM) was performed to evaluate structural brain differences. Spatial transcriptomics investigated gene expression patterns in brain regions exhibiting volume alterations.

Results: Aggression in ASD was associated with more severe core symptoms (higher CARS scores) and pervasive behavioural disturbances, including hyperactivity, irritability, and stereotypy, as well as poorer quality of life. Aggressive individuals exhibited elevated levels of TNF-α, IL-6, IL-8, IL-13, IFN-γ, vasopressin, and epidermal growth factor (EGF), suggesting a pro-inflammatory state. Neuroimaging revealed distinct volume differences between patients with high- compared to medium-aggression, with enlargements in the anterior cingulate cortex, orbitofrontal cortex, and hippocampus and reductions in the amygdala, insula, and basal ganglia. Spatial transcriptomics identified two gene expression clusters: regions associated with emotional regulation exhibit overexpression of pro-inflammatory genes. In contrast, sensory and cognitive regions have relative anti-inflammatory gene upregulation, potentially reflective of a compensatory mechanism.

Conclusions: This study identifies a complex interplay between heightened neuroinflammation and structural brain differences related to gene expression patterns in aggressive ASD. The findings suggest that aggression is associated with imbalances in the fronto-limbic-striatal network, compounded by a pervasive pro-inflammatory state. These insights highlight the potential for targeted interventions integrating behavioural therapies with adjunctive treatments addressing neuroinflammation and neural dysregulation. Future research should explore longitudinal dynamics, genetic and environmental influences, and broader ASD populations to develop personalized strategies for managing aggression in ASD.