DIFFERENCES IN BRAIN STRUCTURE AND FUNCTION AMONG MALES AND FEMALES WITH ALCOHOL USE DISORDER: IMPLICATIONS FOR TMS TREATMENT

Abstract

Alcohol Use Disorder (AUD) is a chronic, relapsing condition characterized by high prevalence, severe health consequences, and limited treatment efficacy. Transcranial magnetic stimulation (TMS) has emerged as a promising circuit-based intervention for AUD, yet treatment outcomes remain variable, and the influence of sex remains poorly understood. This dissertation integrates structural, functional, and neuromodulatory evidence to examine how sex influences TMS mechanisms and efficacy in individuals with AUD.Chapter 1 introduces the neurobiological framework of AUD, emphasizing sex-specific vulnerabilities in brain structure and function that may influence responsiveness to neuromodulation. Chapter 2 evaluates anatomical determinants of stimulation strength using MRI and electric field modeling. Findings reveal site-specific sex differences in scalp-to-cortex distance, with males exhibiting greater distance at ventromedial prefrontal and motor cortex sites. Further, age-related declines in modeled electric field strength were most pronounced in females. These results highlight the need for individualized dosing approaches that expand beyond motor-threshold-based protocols. Chapter 3 examines task-based functional connectivity during alcohol cue exposure. Results identify context-dependent sex and age effects within medial prefrontal-to-striatal and salience-related regions. Older females showed heightened medial prefrontal cortex (MPFC)-to-amygdala connectivity during alcohol cues and reduced MPFC-to-striatal connectivity during neutral beverage cues, where males demonstrated more stable patterns. These findings reveal a nuanced interplay between sex, age, and cue context. Chapter 4 assesses acute TMS effects in a sham-controlled crossover design comparing MPFC and dorsolateral prefrontal cortex (DLPFC) stimulation. MPFC stimulation attenuated alcohol-versus-neutral cue-reactivity primarily by increasing connectivity to neutral beverage cues, with females demonstrating significant reductions in alcohol cue-reactivity. DLPFC stimulation produced broader decreases in connectivity to both cue types, with the strongest effects in males. These patterns suggest sex-dependent mechanisms: MPFC stimulation may enhance engagement with alternative reinforcers, whereas DLPFC stimulation may exert more global inhibitory effects on cue-reactive circuits. Chapter 5 synthesizes these findings into a model proposing that anatomical structure may constrain functional organization, thereby shaping susceptibility to neuromodulation. Collectively, this work identifies sex and age as critical moderators of TMS efficacy and supports precision neuromodulation approaches that incorporate electric field modeling, connectivity mapping, and demographic tailoring to improve treatment outcomes for individuals with AUD.