A leading theory behind the cause of autism is rooted in an imbalance in levels of excitation and inhibition in the brain. A new study published in eLife takes this one step further, suggesting that autistic men, but not women, have enhanced neural excitability in specific brain regions that are important for social cognition and self-reflection, and that this may differentially impact their ability to navigate social situations. This is especially interesting given that roughly four times as many men and boys compared to women and girls are diagnosed with autism.

The brain possesses its own natural balance between excitation and inhibition. In non-autistic individuals, inhibitory activity outweighs excitatory activity. The presence of an imbalance in excitation and inhibition is a possible explanation for autism.

“With this study, we wanted to gain a better understanding of how excitation-inhibition imbalance may affect autistic men differently to women,” said one of the study’s lead authors, Stavros Trakoshis, a graduate student at the Laboratory for Autism and Neurodevelopmental Disorders at the Istituto Italiano di Tecnologia (IIT) in Rovereto, Italy.

The researchers sought to ask whether an imbalance in excitation and inhibition in the brain occurs differently in men and women. To do this, Trakoshis and his colleagues started by using a computer model that simulates excitatory and inhibitory neurons as they interact and influence each other within the brain. Using computer modeling, they identified a signal in brain scans that corresponds to an imbalance of excitation and inhibition which they then looked for in brain scans of people with and without autism. The model allowed them to control the ratio of mixture between excitation and inhibition, simulated these interactions, and then reported neuronal population responses over time. The outputs are similar to data commonly measured with neuroimaging techniques, such as electroencephalography (EEG) and functional magnetic resonance imaging (fMRI).

This work is published in eLife in a paper titled, “Intrinsic excitation-inhibition imbalance affects medial prefrontal cortex differently in autistic men versus women.

Trakoshis and the team observed that specific statistical attributes of the simulated data changed systematically with changes to the underlying excitation-inhibition ratios. These statistical changes were also validated using data from fMRI scans of brains in living mice that were given drugs to induce enhanced excitation.

After validating that non-invasive fMRI can reveal changes to the underlying cellular excitation-inhibition ratio, the team next applied their technique to fMRI data from adult men and women with autism. This revealed that autistic men, but not women, have atypically enhanced excitation in a brain region called the medial prefrontal cortex. The function of this brain region is typically associated with social cognition and self-reflection. The analysis also showed that in women with autism, a more intact medial prefrontal cortex response (with less enhanced excitation, for example) was associated with better camouflaging of social difficulties in real-world social situations.

“Our work suggests that sex-related biological mechanisms could be integral for how excitation-inhibition balance develops in autistic men versus women,” said Michael Lombardo, PhD, director of the Laboratory for Autism and Neurodevelopmental Disorders at the IIT. “This could help explain why we see phenomena such as camouflaging manifesting differently in autistic males versus females.”

Excitation-inhibition imbalance may thus affect specific brain regions involved in socializing and communication more in men who have autism than in women with the condition. The more balanced excitation and inhibition in these brain areas may enable some women with autism to camouflage their difficulties socializing or communicating.

Being able to detect imbalances in activity using standard brain imaging could be useful for clinical trials. Future studies could use this biomarker to monitor responses to drug treatments that aim to adjust the balance between excitation and inhibition.

These findings pave the way for further research to measure the imbalance of excitation and inhibition with non-invasive neuroimaging techniques. This could help scientists evaluate how different treatments may affect this aspect of the brain’s biology. “Our approach could also be useful for understanding other neurodevelopmental conditions that affect males more than females, such as attention-deficit hyperactivity disorder,” Lombardo concluded.

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