Sex-specific differences in resting-state functional brain activity in pediatric concussion
Authors: Sharma Bhanu , DeMatteo Carol , Noseworthy Michael D. , Timmons Brian W. 
Published: July 2021

ABSTRACTImportancePediatric concussion has a rising incidence and can lead to long-term symptoms in nearly 30% of children. Resting state functional magnetic resonance imaging (rs-fMRI) disturbances are a common pathological feature of concussion, though no studies have examined sex-differences with respect to this outcome. Despite known sex-differences in how pediatric concussion presents, females have remained understudied in rs-fMRI studies, precluding a sex-specific understanding of the functional neuropathology of pediatric concussion.ObjectiveTo provide the first insights into sex-specific rs-fMRI differences in pediatric concussion.Design, setting, and participantsSecondary data analysis of rs-fMRI data collected on children with concussion recruited from in a pediatric hospital setting, with control data accessed from the open-source ABIDE-II database. In total, 27 children with concussion (14 females) approximately one-month post-injury and 1:1 age- and sex-matched healthy controls comprised our sample.ExposurePatients received a physician diagnosis of concussion. ABIDE-II healthy controls were typically developing.Main outcomes & measuresSeed-based (which permitted an examination of whole-brain connectivity, fitting with the exploratory nature of the present study) and region of interest (ROI) analyses were used to examine sex-based rs-fMRI differences. Threshold-free cluster enhancement (TFCE) and a family-wise error (FWE) corrected p-values were used to identify significantly different clusters.ResultsIn comparing females with concussion to healthy females, seed-based analyses (in order of largest effect) showed hypo-connectivity between the anterior cingulate cortex of the salience network and the precuneus (TFCE=1173.6, p=FWE=0.002) and cingulate gyrus (TFCE=1039.7, p-FWE=0.008), and the posterior cingulate cortex (PCC) of the default mode network and the paracingulate gyrus (TFCE=870.1, p-FWE=0.015) and sub-callosal cortex (TFCE=795.4, p-FWE=0.037); hyper-connectivity was observed between the lateral pre-frontal cortex and inferior frontal gyrus (TFCE=1215.4, p-FWE=0.002) and lateral occipital cortex (TFCE=854.9, p-FWE=0.020) and between the PCC and cerebellum (TFCE=791.0, p-FWE=0.038). ROI analyses showed primarily patterns of hyper-connectivity in females. No differences were observed between males with concussion and healthy males on seed-based or ROI analyses.Conclusions and relevanceThere are alterations in rs-fMRI in females with concussion at one-month post-injury that are not present in males, which provides further evidence that recovery timelines in pediatric concussion may differ by sex.KEY FINDINGSQuestionAre there sex-differences in resting state functional brain activity in pediatric concussion?FindingsFemales with concussion show both hyper- and hypo-connectivity between multiple brain regions when compared to healthy age- and sex-matched controls. The same analyses revealed no differences in resting state brain activity when comparing males with concussion to their age- and sex-matched healthy peers.MeaningThere are sex-differences in resting state brain activity in pediatric concussion. This suggests that the functional neuropathology of the injury differs between males and females, which may account for sex-differences in the clinical presentation of pediatric concussion.