Intrinsic excitation-inhibition imbalance affects medial prefrontal cortex differently in autistic men versus women

Abstract

Imbalance between neurophysiological excitation versus inhibition (E:I) has been theorized as a core 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. 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 sexrelated differences in compensatory phenomena.

Developmental increase of inhibition drives decorrelation of neural activity

“…In agreement with previous results 24,46 , increases in the network’s net inhibition strength robustly tilted the PSD slope (in the range from 30 – 100 Hz). Increased levels of net inhibition were associated with a steeper decay of power as a function of frequency (Figure 2B) and a corresponding increase of the 1/f exponent, across a range of AMPA conductance levels (Figure 2C; Person correlation coefficient, averaged across AMPA levels: r = 0.768; 95% C.I.…”

Brain mapping across 16 autism mouse models reveals a spectrum of functional connectivity subtypes

“…Similarly, hyperactivity and excessive self-grooming have been described in many models included in this study, most notably Shank3 55 and CNTNAP2 56 , and repetitive/restricted behavior has also been observed in En2, Fmr1, BTBR and MECP2 mutants 57 , recapitulating hallmark ASD symptoms commonly related to compromised fronto-striatal-motor signaling 58–60 . Future research employing targeted cellular and circuit manipulations in rodents combined with similar fMRI recordings 61,62 may crucially uncover the bases of these network-level alterations, their behavioral significance, and their translational relevance with respect to analogous measurement in clinical populations 11,63 .…”

Paradoxical fMRI overconnectivity upon chemogenetic silencing of the prefrontal cortex

“…To account for the relatively slow pharmacokinetic profile of CNO in the rodent brain 29,30 , both imaging and electrophysiological recordings were split into a pre-CNO injection baseline, a transitory (0 -15 min) drug-equilibration period, and an active time window (15-50 min post CNO injection) to which all our analyses refer to, unless otherwise specified (Fig. 2B-C).…”

“…The first 900 fMRI volumes of this first timeseries scan were used as pre-CNO baseline rsfMRI reference in time-resolved analyses. Based on the pharmacokinetic profile of CNO, the post CNO window was split into temporal domains as follows: the first 15 min post injection (900 volumes) were considered part of a drug equilibration window, while the following 35 min (2100 volumes) were considered to cover the DREADD active time window30 . All group comparisons in the chemo-fMRI study were carried out within this latter time window, unless otherwise stated.…”