Effects of Intermittent Theta Burst to the Left Dorsolateral Prefrontal Cortex on Brain Volumes and Neurometabolites in people with Alcohol Use Disorder: A preliminary Investigation

Timothy Durazzo^1,2*Lauren H Beauregard²Meng Gu³Eric P Kraybill¹Brian D P Joseff²Amy A Herrold^4,5Keith Humphreys^1,2M Windy Mcnerney^1,2Brian Knutson³Claudia Padula^1,2

• ¹VA Palo Alto Health Care System, Veterans Health Administration, United States Department of Veterans Affairs, Palo Alto, California, United States
• ²School of Medicine, Stanford University, Stanford, California, United States
• ³Stanford University, Stanford, United States
• ⁴Northwestern University, Evanston, Illinois, United States
• ⁵Edward Hines, Jr. VA Hospital, United States Department of Veterans Affairs, Hines, Illinois, United States

Background: Randomized, placebo-controlled clinical trials (RCT) employing repetitive transcranial magnetic stimulation (TMS) in the treatment of alcohol use disorder (AUD) have shown promising results. However, the mechanism(s) by which TMS produces improved outcomes in AUD is not established. The goal of these secondary analyses was to assess for longitudinal changes in brain volumes and neurometabolites in the left dorsolateral prefrontal cortex (DLPFC)-the stimulation site across two published RCTs evaluating intermittent theta burst (iTBS) for the treatment for AUD. Materials and methods: Veterans with AUD (n=44) were recruited from a residential treatment program. Participants were in RCTs evaluating the efficacy of iTBS for the treatment of AUD (Padula et al., 2024) and (Durazzo et al., 2025). Twenty-one participants were randomized to Active iTBS and 23 to Sham iTBS (20 total iTBS sessions), delivered over approximately 2-weeks. Bilateral volumes of the rostral and caudal middle frontal and superior frontal gyri and left DLPFC neurometabolites were quantitated pre-and-post iTBS sessions. Results: Over the 2-week interval, significant volume increases were observed, collapsed across groups, in the bilateral rostral and caudal middle frontal and superior frontal gyri as well as in left DLPFC choline-containing compounds. No group (Active vs. Sham) x time (2-week interval) interactions were apparent for any measure. Preliminary volume simple effect tests indicated the Active group demonstrated significant increases in the bilateral rostral and caudal middle frontal and superior frontal gyri, while Sham only showed significantly increased left superior frontal volume. Preliminary metabolite simple effect tests indicated the Active group had significant increases in left DLPFC choline-containing and creatine-containing compounds, while Sham had no significant metabolite changes. In the Active group, a higher number of iTBS pulses delivered at target treatment level were associated with increased left DLPFC n-acetylaspartate, glutamate and gamma aminobutyric acid. Conclusions: This study provided novel preliminary indications that iTBS promoted adaptive structural and neurometabolites changes, in the left DLPFC site of stimulation. Replication of these findings, in a larger sample, and examination of other neuroimaging-based markers of TMS-induced neurobiological changes, is critical to informing modifications of existing TMS protocols to maximize positive treatment outcomes in those with AUD.