Spring 2015 MnDRIVE Seminar Series
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Sridevi Sarma,
Johns Hopkins University
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Abstract
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 network.
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 thalamic cells, systems theory and analysis, and single unit recordings from primates, 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 network 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, we show that DBS pulses evoke inputs that propagate through the motor circuit 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 overlap in the loop and result in a strong, long-lasting perturbation that ultimately drives the BG signals back to the PRS.
Taken together, these results provide a holistic view of motor control in healthy and PD conditions, account for the neural mechanisms of therapeutic DBS, and suggest that the merit of DBS critically depends on loop delays in the closed-loop thalamo-cortical-basal ganglia system.
Biosketch
Sridevi V. Sarma received the B.S. degree in electrical engineering from Cornell University, Ithaca NY, in 1994; and an M.S. and Ph.D. degrees in Electrical Engineering and Computer Science from Massachusetts Institute of Technology in, Cambridge MA, in 1997 and 2006, respectively. She was a Postdoctoral Fellow in the Brain and Cognitive Sciences Department at the Massachusetts Institute of Technology, Cambridge, from 2006-2009. She is now an assistant professor in the Institute for Computational Medicine, Department of Biomedical Engineering, at Johns Hopkins University, Baltimore MD. Her research interests include modeling, estimation and control of neural systems using electrical stimulation. She is a recipient of the GE faculty for the future scholarship, a National Science Foundation graduate research fellow, a L'Oreal For Women in Science fellow, the Burroughs Wellcome Fund Careers at the Scientific Interface Award, the Krishna Kumar New Investigator Award from the North American Neuromodulation Society, and a recipient of the Presidential Early Career Award for Scientists and Engineers (PECASE).