Probing the neurochemical mechanisms of rTMS for alcohol use disorder: Results from a randomized, sham-controlled, double-blind, crossover, proton MR Spectroscopy study.

With growing knowledge of the neural circuitry involved in alcohol use disorder (AUD), interest in developing neural-circuit-based therapeutic tools, including transcranial magnetic stimulation (TMS), for people with AUD has increased. While mounting evidence supports the efficacy of TMS for AUD, multiple dosing protocols are currently under consideration, and little is known about the neurobiological mechanisms through which TMS leads to clinical improvement. This randomized, sham-controlled, double-blind, crossover study was designed to address this gap by evaluating the impact of a single session of two prominent TMS protocols (each relative to sham), 10 Hz TMS to dorsolateral prefrontal cortex (dlPFC) and continuous theta burst stimulation (cTBS) to medial PFC (mPFC), on levels of excitatory (glutamate, glutamine, glycine) and inhibitory (GABA) neurometabolites, using proton MR spectroscopy (MRS), in the tissue beneath the TMS coil in treatment-naïve individuals with AUD. Seventy men and women, aged 21-40 years, with moderate-severe AUD were enrolled into the study and randomly assigned to complete one of six experimental condition orders, each consisting of three TMS sessions (cTBS, 10 Hz TMS, sham) conducted on three separate days, each immediately followed by MRI/MRS. Whereas cTBS to mPFC was associated with relatively lower levels of excitatory neurometabolites (glutamine and glycine, with additional mixed support for glutamate), 10 Hz TMS to dlPFC was not, and neither protocol was associated with GABA levels. Together, these findings demonstrate acute neurochemical target engagement under the coil with a single session of cTBS to mPFC, pointing to the utility of assaying neurometabolites in further optimizing this and other candidate targets for AUD.