Abstract Loss of control (i.e., unsuccessful efforts to control, cut back, or stop gambling) represents a core symptom of gambling disorder (GD). This symptom cluster appears to be associated with diminished response inhibition. To date, little is known regarding the exact mechanisms of cognitive control in DG. 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. This is because we lack valid pathophysiological models that provide the right framework to discover therapeutic targets and develop clinically useful biomarkers. In this project we will combine TMS with multimodal structural and functional magnetic resonance imaging (MRI) methods to study patients with GD, in order to identify circuit-level biomarkers, propose therapeutic targets and assess the efficacy of TMS to modulate cognitive control in this population. This study will be in collaboration of Massachusetts General Hospital/Harvard Medical School (Dr. Makris (contact PI) and Dr. Camprodon (PI)) with the University of Florence (Pallanti, subcontract PI), where they have a well- established clinical and research program in GD and a cohort of well-characterized patients. In this project we will implement multimodal structural magnetic resonance imaging (MRI) and functional MRI methods of analysis in a population of pathological gamblers undergoing neuromodulation for motor inhibition control in order to further our understanding in this areas of inquiry. Our investigations are unique in their focus on differences in brain structural, functional, and neurobehavioral analyses of pathological gamblers, with particular emphasis on motor control networks activation.

Project Narrative Loss of control (i.e., unsuccessful efforts to control, cut back, or stop gambling) represents a core symptom of gambling disorder, however, little is known regarding the exact mechanisms of inhibitory control modulation of cortical cognitive systems over subcortical reward circuits. Effects of neuromodulation techniques such as continuous theta burst stimulation (cTBS) have been investigated in response inhibition. In this project we will implement multimodal structural magnetic resonance imaging (MRI) and functional MRI methods of analysis in a population of patients affected by gambling disorder undergoing neuromodulation for cognitive control in order to further our understanding in this areas of inquiry.