Parkinson?s disease (PD) affects 10 million people worldwide, and roughly half of the disease- related morbidity from PD arises not from the motor symptoms, but rather from debilitating neuropsychiatric symptoms that respond inadequately to current modes of treatment. Whereas deep brain stimulation (DBS) of the subthalamic nucleus (STN) relieves many motor symptoms in moderate to severe PD, it can worsen cognitive and psychiatric function. A deeper understanding of how STN stimulation alters cognitive network function is required to understand these cognitive symptoms and, ultimately, to support development of new approaches to DBS that could treat neuropsychiatric symptoms. Working with patients treated with DBS for Parkinson?s disease, this project utilizes a novel form of phasic DBS to deliver brief bursts of stimulation to the STN while subjects engage in a computerized gambling task that assesses risk-taking behavior. Our preliminary results show that phasic STN stimulation biased subjects to bet more conservatively, but only when precisely-timed after subjects had information about their likelihood of winning. Single-neuron recordings from the STN obtained intraoperatively showed that STN neurons exhibited greater activity prior to low-risk than high-risk wagers and suggested an optimal time for STN stimulation shortly before the subject?s decision. This proposal tests this hypothesis directly and studies the effect of phasic STN stimulation on the medial prefrontal ? ventral STN circuit that we hypothesize mediates mediates the behavioral effect of stimulation. Dr. Todd Herrington is a movement disorders neurologist at Harvard Medical School and Massachusetts General Hospital. His clinical specialization is in the treatment of patients with DBS and use of intraoperative neurophysiology to assist placement of DBS electrodes. Dr. Herrington?s career goal is to be an independently-funded scientist using novel forms of brain stimulation and invasive and non-invasive neurophysiology to study human brain function, with the ultimate goal of developing new approaches to neuromodulation to treat human neurologic and psychiatric illness. This career development plan provides a critical education in human subjects study design, translational research, and training in advances methods of non-invasive neurophysiology through high-density, high-sampling rate EEG recordings. Dr. Emad Eskandar, the mentor on this project, is an internationally recognized expert in deep brain stimulation, the development of novel approaches to brain stimulation in animal models and translational research in human subjects. Dr. Sydney Cash, the co-mentor on this project, is an expert in studying cortical neurophysiology in human subjects using EEG. Dr. Thilo Deckersbach, is a neuropsychologist and cognitive neuroscientist with expertise in neuropsychiatric pathology. All of these mentors are successful physician scientists committed to Dr. Herrington?s development as an independent physician scientist. 1
Parkinson?s disease (PD) affects 10 million people worldwide with progressive motor, cognitive and psychiatric symptoms. This project uses a novel from of deep brain stimulation (DBS) of the subthalamic nucleus to study the cognitive effects of DBS, and contribute to the knowledge required to develop new approaches to DBS that can help alleviate cognitive and psychiatric disability in PD. This project also serves as a training and career development platform to establish the recipient as an expert in translational human neurophysiology. 1
