Sex-specific cerebrovascular reactivity differences in autistic children related to functional connectivity

Many studies utilize resting-state functional magnetic resonance imaging (rs-fMRI) metrics, such as functional connectivity (FC), to investigate the neuronal underpinnings of autism and identify functional brain networks related to autistic behaviors. However, fMRI indirectly measures neuronal activity by imaging local fluctuations in the blood oxygen level dependent (BOLD) signal, which, in turn, rely on the cerebrovascular system to efficiently direct oxygenated blood flow. Most rs-fMRI studies of autism interpret group differences in FC as autism-related changes in neuronal activity, without considering the underlying vascular function. Yet, atypical cerebrovasculature has been identified in preclinical and post-mortem studies of autism, strongly underscoring the need to characterize cerebrovascular differences to enhance our neurobiological understanding of autism. We evaluated relative cerebrovascular reactivity (rCVR) in autistic and non-autistic children using a novel measure of local brain vasodilatory capacity based on rs-fMRI. We leveraged the cross-sectional Autism Brain Imaging Data Exchange repository to quantify rCVR in 199 non-autistic (74 female) and 95 autistic (16 female) children, 9-12 years old. We identified sex-specific differences in rCVR in autism, particularly in right-frontal brain regions, where rCVR was increased in autistic females compared to non-autistic females. Then, within the same rs-fMRI scans, we demonstrated that rCVR in the right inferior frontal gyrus was positively associated with its FC to regions associated with attentional control in girls, suggesting that cerebrovascular differences may differentially affect FC findings between regions and sexes in children. Our study highlights potential sex differences in cerebrovascular function in autism that enhance our neurobiological understanding of autism and improve interpretations of rs-fMRI findings in children.