Potential <scp>TMS</scp> biomarkers for <scp> GABA _B </scp> receptor engagement in alcohol use disorder: A systematic review of existing evidence

Alcohol use disorder (AUD) is a major global health issue, with current treatments often limited in efficacy and patient acceptance. The gamma-aminobutyric acid (GABA) system, particularly GABA_B receptors (GABA_BR), is crucial in the pathophysiology of AUD. This review aimed to evaluate the potential of transcranial magnetic stimulation (TMS) as a tool for identifying neurophysiological biomarkers of GABA_BR engagement in AUD. Two independent systematic literature reviews were conducted using MEDLINE, PsychINFO, and EMBASE databases to evaluate: (1) the neurophysiological effects of GABA_BR pharmacological manipulation, and (2) the neurophysiological alterations linked to alcohol consumption and addiction. Studies included human subjects and assessed cortical excitability using TMS-EMG or TMS-EEG. Data on study design, sample characteristics, TMS protocols, and neurophysiological outcomes were extracted and analyzed. The final analysis included 13 studies evaluating the effects of GABA_BR agonism (mainly baclofen administration) and 16 studies on acute and chronic alcohol consumption. The GABA_BR agonism studies were primarily randomized, placebo-controlled experimental medicine studies in healthy controls. Results showed that GABA_BR agonism enhanced long-interval intracortical inhibition (LICI) and increased post-TMS N100 amplitude, indicating the sensitivity of these parameters to GABA_BR manipulation. The alcohol consumption studies were mostly case-control or within-subject designs, with fewer randomized controlled trials. Acute and chronic alcohol consumption was found to alter LICI, N100 amplitude, and the cortical silent period (CSP). However, no alcohol-induced changes were observed in short-interval intracortical inhibition (SICI), which depends on GABA_AR activation. Despite limitations, this review indicates GABA_BR functioning to be measurable and different in AUD compared to healthy controls. Overall, the reviewed literature supports the hypothesis that GABA_BR is involved in the neurotransmission imbalances induced by both acute and chronic alcohol intake, with potential regional differences that warrant further investigation. Standardized protocols and larger studies are needed to validate these findings and their clinical relevance.