Neural Engineering Center & Young Innovators in Biomedical Engineering Seminar
""On the Therapeutic Mechanisms of Deep Brain Stimulation for Parkinson's Disease: Why High Frequency?"
Sridevi V. Sarma, PhD
Johns Hopkins University
Assistant Professor, Department of Biomedical Engineering
Institute for Computational Medicine
Deep brain stimulation (DBS) is clinically recognized to treat movement disorders in Parkinson's disease (PD), but its therapeutic mechanisms remain elusive. One thing is clear though: high frequency periodic DBS (130-180Hz) is therapeutic, while low frequency DBS is not therapeutic and may even worsen symptoms. So, what is so special about high frequency? In this talk, we address this question by discussing our viewpoint supported by recent results from our key studies of the thalamo-cortical-basal ganglia motor loop. First, thalamic cells play a pivotal role in performing movements by selectively relaying motor-related information back to cortex under the control of modulatory signals from the basal ganglia (BG). Through computational models of the thalamic cells, bifurcation analysis, and single unit recordings from healthy primates and PD patients engaged in motor tasks, we show that (i) there is a set of BG signals ("Proper Relay Set", PRS), under which the thalamic cells can reliably relay the motor commands, and that (ii) the BG signals belong to the PRS in healthy conditions but are outside the PRS under PD conditions. Then, we use a detailed computational model of the motor loop under PD conditions to study the effects of DBS on the BG signals projecting to the thalamic cells. We show that high frequency periodic DBS steers the BG signals back to the PRS while lower frequency regular DBS and irregular DBS do not. Furthermore, through numerical simulation of the model we show that DBS pulses evoke inputs that propagate through the motor loop both orthodromically (i.e., forward) and antidromically (i.e., backward) and fade away within a few milliseconds, thus having little effects on the BG signals. However, when the latency between consecutive DBS pulses is small (i.e., DBS is high frequency) and constant over time (i.e., DBS is periodic), then orthodromic and antidromic effects can overlap within the loop and result into a strong, long-lasting perturbation that ultimately drives the BG signals. Taken together, these results provide a holistic, albeit abstract, view of motor control in healthy and PD conditions, account for the neural mechanisms of therapeutic DBS, and suggest that the merit of DBS likely depend on the closed-loop nature of the thalamo-cortical-basal ganglia system.
There will be a Neural Engineering Center reception to follow in the BME Atrium.