SPECIFIC AIMS The appropriate interplay of cognitive and reward systems is essential for adaptive human behavior, allowing a homeostatic balance between immediate basic pleasures and long-term planned rewards. Deficits in inhibitory control from cortical cognitive systems over subcortical reward circuits is a key pathophysiological feature of addictive behavior that has not been studied satisfactorily in gambling disorder (GD). The clinical phenotype of this population is characterized by unsuccessful efforts to reduce or stop gambling despite negative outcomes, suggestive of faulty inhibitory control of gambling impulses that sustain the chronicity and comorbidities of this clinical syndrome. Deficits in behavioral and cognitive control constitute a symptom dimension associated with diminished response inhibition in experimental tasks such as the Stop Signal Task (SST). The pre-supplementary motor area (pre-SMA) is a key node of the cognitive control network responsible for response inhibition. Pre-SMA activation has been associated to response inhibition performance in fMRI studies using the SST and recent evidence also suggests that its activity represents a motivational signal for movement. In fact, pre-SMA seems to have a dominant role in bridging the delay between expected reward and specific actions rather than determining whether an action is made. Although the pathophysiology of GD is not well understood, studies have shown altered brain activity in prefrontal regions (including pre-SMA) of GD patients during response inhibition tasks in addition to functional connectivity abnormalities of SMA during rest. These circuit-level abnormalities represent a potential therapeutic target that could be modulated by brain stimulation therapies such as transcranial magnetic stimulation (TMS). Theta burst stimulation (TBS), is a particularly brief and effective form of TMS that can be inhibitory (continuous or cTBS) or excitatory (intermittent or iTBS). Although pre-SMA has been successfully targeted with traditional TMS and TBS for impulse-control disorders like OCD, this approach has never been tested for GD in therapeutic or mechanistic studies. Despite the significant morbidity and mortality of GD, there is a dramatic shortage of effective treatment options for these patients, partly due to the lack of valid pathophysiological models for target discovery and experimental therapeutics. In this project the investigators propose a randomized double-blind placebo-controlled design in which 40 patients with GD will receive active or sham cTBS to the pre-SMA for 2 weeks. The investigators will combine TMS, multimodal structural and functional MRI and behavioral measures in order to identify circuit-level mechanisms of action and therapeutic targets (connectivity changes that explain clinical improvement) and assess the efficacy of TMS in modulating inhibitory control and symptom severity in this population.

Aim 1 (ACUTE MECHANISM OF ACTION): To assess circuit-level effects of a single session of cTBS to the pre-SMA in GD patients. Hypothesis 1.1: cTBS will lead to increase in functional connectivity between cortical inhibitory nodes (pre-SMA) and reward subcortical structures (Nucleus Accumbens, NAc), and these changes will correlate with improvement in reaction time in SST. Hypothesis 1.2: cTBS will not lead to acute changes in FA, RD or AD in the mesocorticolimbic pathway. Hypothesis 1.3: cTBS will lead to increased cognitive control network and decreased NAc activation during SST. Exploratory analyses will test the predictive value of acute circuit changes for clinical improvement after 2 weeks and 1 month follow up.

Aim 2 (CHRONIC MECHANISM OF ACTION): To assess circuit-level effects of 10 session of cTBS to the pre-SMA in GD patients Hypothesis 2.1: cTBS will lead to increases in functional connectivity between preSMA and NAc, and these will correlate with behavioral and clinical improvement. Hypothesis 2.2: cTBS will lead to increased FA and decreased RD and AD in the mesocorticolimbic pathway, and these will correlate with clinical improvement. Hypothesis 2.3: cTBS will lead to further increased cognitive control network and decreased NAc activation during SST, and these will correlate with clinical improvement.

Aim 3 (BEHAVIORAL/CLINICAL): To determine the behavioral and clinical changes of cTBS to the preSMA in GD. Hypothesis 3.1: A single session of cTBS will lead to improvement in reaction time in the SST, but not in symptom severity measured with clinical scales. Hypothesis 3.2: 10 sessions of cTBS will lead to improvement in reaction time in the behavioral inhibition task, in addition to a reduction in clinical severity (including craving/urges) as measured by clinical scales.