Revisiting the excitation/inhibition imbalance hypothesis of ASD through a clinical lens

Autism spectrum disorder (ASD) currently affects 1 in 59 children, although the aetiology of this disorder remains unknown. Faced with multiple seemingly disparate and noncontiguous neurobiological alterations, Rubenstein and Merzenich hypothesized that imbalances between excitatory and inhibitory neurosignaling (E/I imbalance) underlie ASD. Since this initial statement, there has been a major focus examining this exact topic spanning both clinical and preclinical realms. The purpose of this article is to review the clinical neuroimaging literature surrounding E/I imbalance as an aetiology of ASD. Evidence for E/I imbalance is presented from several complementary clinical techniques including magnetic resonance spectroscopy, magnetoencephalography and transcranial magnetic stimulation. Additionally, two GABAergic potential interventions for ASD, which explicitly attempt to remediate Ell imbalance, are reviewed. The current literature suggests E/I imbalance as a useful framework for discussing the neurobiological etiology of ASD in at least a subset of affected individuals, While not constituting a completely unifying aetiology, Eli imbalance may be relevant as one of several underlying neuropathophysiologies that differentially affect individuals with ASD. Such statements do not diminish the value of the E/I imbalance concept-instead they suggest a possible role for the characterization of E/I imbalance, as well as other underlying neuropathophysiologies, in the biologically-based subtyping of individuals with ASD for potential applications including clinical trial enrichment as well as treatment triage.