Manipulating the Reward Circuit with TMS

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PROJECT SUMMARY Abnormalities of the reward circuit have been identified in numerous psychiatric disorders including major depressive disorder, substance abuse, obsessive-compulsive disorder, and schizophrenia. Reward circuit dysfunction is associated with anhedonia – a subjective loss in reactivity to pleasurable stimuli. Normalization of the reward circuit thus holds promise in the treatment of anhedonia and associated disorders. This end requires measures that reliably track anhedonia, and interventions that modulate anhedonia. We have done extensive work identifying a reliable event-related potential (ERP) marker of reward sensitivity referred to as the reward positivity (RewP). The RewP relates to behavioral and self-report measures of reward sensitivity, structural and functional MRI measures of the reward circuit, risk for depression, and recovery from depression. In preliminary data, we have found that a single session of intermittent theta- burst transcranial magnetic stimulation (iTBS) targeted at the reward circuit increases the RewP in healthy, young adults relative to iTBS delivered to a control site. If reward circuit targeted iTBS can improve the RewP, this holds promise as an intervention that could modulate anhedonia. However, this end requires better understanding of the mechanisms by which iTBS alters the reward circuit, the RewP, and anhedonia. The present proposal aims to meet this challenge. Sixty individuals with elevated anhedonia will be recruited to receive reward circuit targeted iTBS for 5 days over 1 week, as well as iTBS to a control site for 5 days over 1 week, each followed by a week of washout in a counter-balanced, cross-over design. Reward sensitivity will be tracked by the RewP measured at the end of each week along with self-reported anhedonia. The reward circuit will be examined at baseline, and at the end of each iTBS week using blood-oxygenation level dependent (BOLD) connectivity and reward-related activations. We hypothesize that reward circuit targeted iTBS will have both local (cortical target) and downstream (sub-cortical) effects on BOLD activation, as well as effects on connectivity within the reward circuit. We hypothesize that these effects on the reward circuit will also be borne out in changes in the RewP and self-reported anhedonia. Collectively, these data will test the hypothesis that reward circuit targeted iTBS impacts the reward circuit, reward sensitivity, and anhedonia, paving the way towards interventions for the treatment of anhedonia.