RT Journal Article SR Electronic T1 Intrinsic excitation-inhibition imbalance affects medial prefrontal cortex differently in autistic men versus women JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.01.16.909531 DO 10.1101/2020.01.16.909531 A1 Stavros Trakoshis A1 Pablo Martínez-Cañada A1 Federico Rocchi A1 Carola Canella A1 Wonsang You A1 Bhismadev Chakrabarti A1 Amber N. V. Ruigrok A1 Edward T. Bullmore A1 John Suckling A1 Marija Markicevic A1 Valerio Zerbi A1 MRC AIMS Consortium A1 Simon Baron-Cohen A1 Stefano Panzeri A1 Alessandro Gozzi A1 Meng-Chuan Lai A1 Michael V. Lombardo YR 2020 UL http://biorxiv.org/content/early/2020/02/01/2020.01.16.909531.abstract AB 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.