%0 Journal Article %A Stavros Trakoshis %A Pablo Martínez-Cañada %A Federico Rocchi %A Carola Canella %A Wonsang You %A Bhismadev Chakrabarti %A Amber N. V. Ruigrok %A Edward T. Bullmore %A John Suckling %A Marija Markicevic %A Valerio Zerbi %A MRC AIMS Consortium %A Simon Baron-Cohen %A Stefano Panzeri %A Alessandro Gozzi %A Meng-Chuan Lai %A Michael V. Lombardo %T Intrinsic excitation-inhibition imbalance affects medial prefrontal cortex differently in autistic men versus women %D 2020 %R 10.1101/2020.01.16.909531 %J bioRxiv %P 2020.01.16.909531 %X Imbalance between neurophysiological excitation versus inhibition (E:I) has been theorized as a pathophysiological mechanism of autism. However, a majority of the evidence behind the E:I theory comes from animal models of rare genetic mutations that account for only a small fraction of the autistic population. Scale-free metrics of neural time-series data could represent biomarkers for E:I imbalance and could enable a greater understanding of how E:I imbalance affects different types of autistic individuals and how such mechanisms relate to behavior. Here we show that a measure of scale-free dynamics, the Hurst exponent (H), measured in-vivo in resting state fMRI (rsfMRI) data, is a surrogate marker of E:I imbalance and differentially affects autistic males versus females. In-silico modeling of local field potentials (LFP) from recurrent networks of interacting excitatory and inhibitory neurons shows that increasing the E:I ratio by specifically enhancing excitation attenuates H and flattens the 1/f slope. These in-silico predictions are confirmed in-vivo with chemogenetic manipulations to enhance excitation of prefrontal cortex in mice. In humans, social brain areas such as ventromedial prefrontal cortex (vMPFC), show decreased H specifically in autistic males but not females. However, continuous variation in vMPFC H correlates with ability to behaviorally camouflage social-communicative difficulties in autistic females but not males. These effects may be underpinned by the male-specific effect of androgen hormones on autism-associated genes expressed in excitatory neuronal cell types. This work provides insight into how in-vivo neuroimaging readouts can be utilized to understand E:I imbalance in human clinical populations. E:I imbalance in social brain circuitry may differentially affect autistic males versus females and may help explain sex-related differences in compensatory phenomena. %U https://www.biorxiv.org/content/biorxiv/early/2020/02/01/2020.01.16.909531.full.pdf