Exploratory evidence for differences in GABAergic regulation of auditory processing in autism spectrum disorder.

Researchers studied brain responses to sounds in adults with and without autism. People with autism showed weaker brain responses to repeated sounds. When given a medication that affects brain chemicals (arbaclofen), the autism group's brain responses improved, but the typical group's responses got worse. This suggests that autism involves differences in how the brain processes sounds, which might be treatable.

This randomized controlled trial investigated GABAergic regulation of auditory processing in 66 adults (28 with ASD). Participants completed auditory testing using an oddball paradigm after receiving placebo or arbaclofen (GABA-B receptor agonist). Results showed that while mismatch negativity responses were comparable between ASD and typically developing groups, auditory repetition suppression was significantly weaker in ASD participants at baseline. Arbaclofen administration reversed the weaker spectral suppression in ASD but disrupted suppression in typical development.

Post hoc analysis revealed correlations between arbaclofen-induced changes and autism symptom severity across the full sample, supporting GABAergic dysfunction in ASD auditory processing.

Findings support GABAergic dysfunction in ASD auditory processing and suggest arbaclofen may be a potential therapeutic intervention. Results may inform development of objective biomarkers for autism severity and treatment response monitoring.

Small sample size (n=66), post hoc analysis showed correlations only in the full group but not when ASD and TD groups were examined separately, single-dose medication trial limits understanding of sustained effects.

Altered reactivity and responses to auditory input are core to the diagnosis of autism spectrum disorder (ASD). Preclinical models implicate ϒ-aminobutyric acid (GABA) in this process. However, the link between GABA and auditory processing in humans (with or without ASD) is largely correlational. As part of a study of potential biosignatures of GABA function in ASD to inform future clinical trials, we evaluated the role of GABA in auditory repetition suppression in 66 adults (n = 28 with ASD).

Neurophysiological responses (temporal and frequency domains) to repetitive standard tones and novel deviants presented in an oddball paradigm were compared after double-blind, randomized administration of placebo, 15 or 30 mg of arbaclofen (STX209), a GABA type B (GABA) receptor agonist. We first established that temporal mismatch negativity was comparable between participants with ASD and those with typical development (TD). Next, we showed that temporal and spectral responses to repetitive standards were suppressed relative to responses to deviants in the two groups, but suppression was significantly weaker in individuals with ASD at baseline. Arbaclofen reversed weaker suppression of spectral responses in ASD but disrupted suppression in TD.

A post hoc analysis showed that arbaclofen-elicited shift in suppression was correlated with autistic symptomatology measured using the Autism Quotient across the entire group, though not in the smaller sample of the ASD and TD group when examined separately. Thus, our results confirm: GABAergic dysfunction contributes to the neurophysiology of auditory sensory processing alterations in ASD, and can be modulated by targeting GABAactivity. These GABA-dependent sensory differences may be upstream of more complex autistic phenotypes.