Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

Deep brain stimulation (DBS) is a surgical therapy in which electrical current is passed through implanted electrodes to affect specific groups of neurons in the brain. DBS has been successfully used to treat several movement disorders, particularly parkinsonism. More recently DBS trials have been reported for tardive dyskinesia (TD), a syndrome induced by chronic therapy with antipsychotic medications. Despite its clinical use, little is known about how this therapy exerts its effects. We propose that DBS exerts its effects by decreasing serotonin release in the brain. In support of this hypothesis, medications that inhibit serotonin action are used to treat dyskinesias, while psychiatric symptoms linked to serotonergic dysfunction (such as depression and impulsivity) have emerged in the clinic after long-term DBS. To test this hypothesis, we will measure serotonin release in motor areas in animals undergoing DBS applied to the subthalamic or entopeduncular nucleus and will determine if the motor benefits of DBS are still observed if levels of serotonin in the brain are first elevated pharmacologically. We will also treat rats with DBS daily, and test for depression-like symptoms after several weeks using validated animal models. In these same rats, we will examine changes in proteins associated with the brain's serotonin system induced by long-term DBS. These experiments will be performed both in healthy rats and in rats that have developed motor symptoms (abnormal movements of the tongue and jaw) after chronic therapy with the classical antipsychotic medication, haloperidol. Determining the mechanisms by which DBS exerts its effects is a necessary step in optimizing the application of DBS to human movement disorder patients. Teasing apart the mechanisms underlying the therapeutic motor effects and the adverse psychiatric effects of DBS will have important implications for the management and quality of life of patients undergoing DBS in the clinic.