Functional Dissection of Neural Circuitry in Temporally Patterned Deep Brain Stimulation

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Deep brain stimulation (DBS) is an established treatment for various neurological and psychiatric disorders including Parkinson’s disease (PD). Subthalamic nucleus (STN) and globus pallidus interna (GPi) are current anatomical targets and clinically effective for DBS in PD. Clinical studies reported no significant difference in effective treatment between these two targets, although additional interest has been prompted in GPi-DBS due to increased concerns about cognitive and behavioral side effects of STN-DBS. The therapeutic effects of DBS are highly dependent on stimulation parameters. With the selection of appropriate stimulation amplitude and pulse duration, high frequencies of DBS alleviate PD motor symptoms. Recent studies demonstrated that the effects of DBS were also strongly dependent on the timing between stimulation pulses (temporal pattern). Optimized temporal patterns of stimulation at a lower average frequency could relieve motor deficits and reduce adverse side effects. Despite the promising clinical benefits, the lack of understanding of the effects of temporal patterns of DBS on neuronal and behavioral dynamics limits the development of this promising treatment strategy as well as optimal selection of DBS targets. The goal of our research is to reveal the relationships between specific temporal patterns of DBS in STN and GPi and (i) neural activity in STN and GPI associated circuits and (ii) motor function in PD. We will combine computational design, optogenetic manipulation, electrophysiological recording, and behavioral assays to dissect and optimize the therapeutic effects of temporally patterned STN-DBS and GPi-DBS in a rodent model of PD. Our specific aims are to: (1) Design and validate temporal patterns of optogenetic STN-DBS and GPi-DBS to treat parkinsonian motor symptoms; (2) Determine the relationship between neural activity in the STN-thalamic or GPi-thalamic neural circuits and motor function during temporally patterned optogenetic STN-DBS and GPi-DBS. The results from this proposed research will shed light on the functional role of the temporal patterns of DBS in PD treatment. A better understanding of how temporally patterned DBS exerts its therapeutic effects will make a significant contribution to optimal target selection and the development of novel treatment strategies to improve the efficacy and efficiency of DBS in PD and other neurological and psychiatric disorders.