Summary: Researchers report that autistic males show unusually increased neural excitation in the medial prefrontal cortex (mPFC), a region linked to social cognition and self-reflection. Autistic females displayed a more typical mPFC response, which corresponded with a greater ability to mask or “camouflage” social difficulties in everyday interactions.
Source: eLife
New findings on sex differences in autistic brains appear in the open-access journal eLife.
A multidisciplinary team has identified distinct patterns of neural excitation and inhibition between autistic men and women. Their results indicate that autistic men, unlike many autistic women, tend to show elevated excitatory activity in specific brain regions involved in social thinking and self-related processing, which may shape how they navigate social contexts.
These results reinforce the hypothesis that an imbalance between neuronal excitation and inhibition contributes to autism for some individuals, while underscoring that this imbalance can present differently by sex. The study also demonstrates how non-invasive neuroimaging measures can be used to estimate underlying cellular-level changes, opening pathways for research that evaluates how targeted interventions might modify this aspect of brain function.
The brain relies on a dynamic balance between excitation and inhibition, and that balance varies across people. Elevated excitation has links to genes relevant to autism—some located on sex chromosomes—and may be influenced by sex hormones such as testosterone, which are typically higher in males. These sex-linked biological mechanisms are important to explore because autism is diagnosed more frequently in males than females.
“We set out to better understand whether excitation-inhibition balance might affect autistic males and females in different ways,” says Stavros Trakoshis, a lead author and graduate student at the Laboratory for Autism and Neurodevelopmental Disorders at the Istituto Italiano di Tecnologia (IIT) in Rovereto, Italy, who is also affiliated with the University of Cyprus.
The team combined computational modeling, animal experiments, and human neuroimaging. They began with a computer model that simulates interacting excitatory and inhibitory neurons. By adjusting the ratio of excitation to inhibition in the model, they produced synthetic neuronal population signals comparable to those recorded by common neuroimaging methods such as electroencephalography (EEG) and functional magnetic resonance imaging (fMRI).
Analysis of the simulated signals showed predictable changes in measurable statistical properties as the excitation-inhibition balance shifted. To validate these findings, the researchers compared the model predictions with fMRI data from live mice that had been administered drugs known to increase neural excitation. The mouse data supported the model’s predictions, demonstrating that non-invasive fMRI metrics can indeed reflect underlying changes in synaptic excitation and inhibition.
After establishing that fMRI-derived measures can signal shifts in cellular excitation-inhibition balance, the researchers applied the same analytic approach to fMRI scans from adult men and women with autism. They found that autistic men showed atypically increased excitation in the medial prefrontal cortex (mPFC), while autistic women did not exhibit this elevated excitation pattern. In autistic women, a more typical mPFC signal—reflecting less enhanced excitation—was linked to a greater ability to behaviorally camouflage social-communicative difficulties in real-world situations.
“Sex-related biological factors appear to play a meaningful role in how excitation-inhibition balance develops in autistic males versus females,” says senior author Michael Lombardo, Director of the Laboratory for Autism and Neurodevelopmental Disorders at IIT. “This difference may help explain why social behaviors like camouflaging show distinct patterns between autistic men and women.”
The authors also suggest that their approach could be adapted to investigate other neurodevelopmental conditions with sex-skewed prevalence, such as attention deficit hyperactivity disorder (ADHD), by using non-invasive imaging metrics to probe underlying cellular dynamics.
About this autism research article
Source: eLife
Media Contacts: Emily Packer – eLife
Image Source: The image is in the public domain.
Original Research: Open access. DOI: 10.7554/eLife.55684. Title: “Intrinsic excitation-inhibition imbalance affects medial prefrontal cortex differently in autistic men versus women” by Stavros Trakoshis et al., eLife.
Abstract
Intrinsic excitation-inhibition imbalance affects medial prefrontal cortex differently in autistic men versus women
Excitation-inhibition (E:I) imbalance is proposed as a key pathophysiological mechanism in autism. Because autism is more common in males and because sex-linked mechanisms (for example, genes on the X chromosome and androgen hormones) can shape E:I balance, E:I imbalance might influence autism differently across sexes. Using a combination of in-silico modeling and in-vivo chemogenetic manipulations in mice, the researchers demonstrate that a time-series metric derived from fMRI blood-oxygen-level-dependent (BOLD) signals—the Hurst exponent (H)—can serve as an index of synaptic E:I ratio. In human data, H was reduced in the medial prefrontal cortex (mPFC) of autistic males, indicating increased excitation, but this reduction was not observed in autistic females. Moreover, a more typical (less reduced) mPFC H was associated with greater behavioral camouflaging of social-communicative difficulties in autistic females only. These results suggest that the Hurst exponent in BOLD signals can index synaptic E:I balance and that E:I imbalance impacts autistic males and females in different ways.