Differential GABA dynamics across brain functional networks in autism

Differences in the ϒ-aminobutyric acid (GABA) system contribute to an excitatory-inhibitory imbalance in autism, particularly affecting sensory processing. However, the brain’s broader response to interventions targeting GABA pathways in individuals with autism remains poorly understood. This study tested the hypothesis that GABAergic control of information transfer across large-scale brain functional networks is altered in autism. We conducted a phase-amplitude coupling (PAC) analysis of resting-state EEG signals within and between these networks. Responses were compared after double-blind, randomized oral administration of either a placebo or 15/30 mg of arbaclofen, a GABAB receptor agonist. Twenty-four non-autistic (9 males; 19-53 years) and 15 autistic participants (9 males; 20-51 years) completed 93 study visits. Autistic participants exhibited significantly higher theta-beta PAC, especially within the limbic network. High-dose arbaclofen shifted PAC metrics in visual and somatomotor networks towards non-autistic levels, but had minimal effects on networks related to higher cognitive functions. Interestingly, altered PAC within and between networks in the limbic system of autistic participants was normalized by low-dose arbaclofen, yet reemerged after high-dose administration. These findings provide compelling evidence for altered GABAergic responsivity in autism, helping explain some of the challenges in prescribing medications for autistic individuals, such as paradoxical reactions and dose sensitivity. Distinct functional networks in the autistic brain respond differently to pharmacological modulation targeting GABA B receptors. This finding offers new insights into the paradoxicality of clinical interventions for autism and provides inspiration for subsequent precision interventions.