Dopamine's Role in Impulse Control and Reward Learning in Humans

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Project Summary The DSM-V categorized gambling disorder as the first behavioral addiction. The World Health Organization (WHO) identified problem gambling as a necessary area for further research, with a burden of harm surpassing substance use disorder and diabetes. Impulsivity is an important trait found on clinical assessment of gambling disorder, and gambling disorder can be induced by dopamine replacement medications in a clinical syndrome termed impulse control disorder (ICD). Dopamine agonist therapy is more responsible than other dopamine replacement options, with patients on dopamine agonists experiencing roughly three times greater odds of developing ICD. Neuroimaging studies have pinpointed the striatum as a culprit brain region for dopamine abnormalities, with recent technologic advances in human electrochemistry providing the temporal specificity necessary to correlate sub-second dopamine fluctuations to differences in reward learning. The NIMH RDoC construct ‘Reward Learning’ and its subconstructs, ‘Reward Prediction Error’ and ‘Probabilistic and Reinforcement Learning’ provide a framework to investigate temporal differences in dopamine fluctuations corresponding to differences in decision-making in ICD. Based on preliminary data showing dopaminergic signaling is altered in ICD corresponding to impulsivity, this proposal will investigate the following specific aims: (1) Quantify patients’ threshold for risk-taking and the behavioral influence of RPEs in patients with a history of ICD both on and off dopaminergic medications. (2) Measure sub-second dopamine fluctuations in the striatum during decision-making under risk. Methods will employ human reward learning tasks and simultaneous human electrochemistry. Training will take place at the Wake Forest School of Medicine in the Neuroscience and the Medical programs as a part of the MD/PhD program. The applicant will receive training in the human electrochemistry and behavioral science methods necessary to accomplish the proposed aims. The applicant also places an emphasis on analytical training in R programming. Mentorship includes a multidisciplinary team with individuals in the neurosurgery and neuroscience departments. This team will provide the applicant with feedback regarding project implementation, data collection and analysis, and manuscript preparation. The proposed aims have the potential to provide new therapeutic targets for the treatment of mental health disorders that involve reward learning.