Collaborative research: Optimal stimulus waveform design for Parkinson's disease

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PI: Netoff, Theoden I. and Moehlis, Jeffrey M.Proposal Number: 1264432 & 1264535Intellectual Merit: Populations of neurons must dynamically synchronize and desynchronize for transmission of information within the brain. The disruption of this dynamic synchronization is thought to underlie the symptomatology of several neurological disorders. Deep Brain Stimulation (DBS) therapy is being used to treat many of these neurological disorders, such as Parkinsons disease (PD). It is generally believed that DBS leads are placed in regions of brain that are pathologically synchronous, and periodic DBS pulses then "over pace" these areas, blocking the pathological activity. The PIs have recently developed an alternative hypothesis for the mechanism of DBS which focuses on DBS's modulation of the firing times of neurons. Stimulation at certain frequencies can induce a chaotic response that desynchronizes a population; we term this chaotic desynchronization. The response of a neuron to a DBS pulse is characterized by its phase response curve (PRC), a measure of how the stimulus advances the phase depending on the phase the stimulus is applied at. The PRC can then be used to determine if two neurons in the population starting at nearly the same phase will entrain to the stimulus pulses, or will diverge and effectively become desynchronized. In this grant the PIS propose to use PRCs to determine the optimal stimuli to desynchronize population oscillations. Preliminary experiments show that small periodic stimulus pulses at certain frequencies can desynchronize populations; the frequency and amplitude that desynchronize can be predicted from the PRC of the neurons to the stimulus. Moreover, continuous stimulus waveforms can be designed that desynchronize populations with much less energy than the pulsatile stimuli. The aims of this grant are to further the theoretical work in designing these waveforms from measured PRCs, and then to test chaotic de-synchronization in physical and biological systems. Specific Aim 1 will use measured phase response curves and control theory to determine the optimal stimulus waveforms to maximize desynchronization of neuronal ensembles. Specific Aim 2 will be to apply this theory to desynchronize oscillations in a chemical oscillator model, the photosensitive Belousov-Zhabotinsky (pBZ) reaction, through pulsatile and continuous waveform photo stimulation. Specific Aim 3 will test the theory in neurons in vitro basal ganglia preparation. Neurons will be recorded and stimulated using a dynamic clamp experimental protocol. The PRCs from single neurons will be measured in response to DBS pulses, and we will test for chaotic behavior in their stimulus response patterns.Broader Impacts: The motivation of this research is to 1) understand how behaviors relate to oscillatory synchronization in and between the basal ganglia and motor cortex, and 2) improve DBS treatment of PD, for which the selection of stimulus electrodes, frequency, and amplitudes are currently tuned manually by a clinician. The goal of this research is to determine the optimal stimulus properties based on simple physiological measures of the neurophysiological response to DBS. This approach will enable faster and more robust programming of neurostimulators and will decrease the amount of required injected current, which will reduce side effects and battery power consumption. This approach has high potential for closed loop control algorithms where DBS parameters are automatically tuned to maintain maximal efficacy. This approach may also be applied to seizure suppression and other neurological diseases. These studies leverage a recently funded IGERT training plan at UMN for neuromodulation. To maximize our clinical impact, we have discussed with Dwight Nelson (Neuromodulation department at Medtronic) what basic research will enable the next steps in developing new DBS stimulus parameters and the yet unmet clinical needs (letter of support included). The results from this research will be disseminated to the public through various education programs including ones focused on underrepresented undergraduate students, high school educators, high school students and junior-high school students. Finally, this award will train graduate students and undergraduates in interdisciplinary research activities, and enhance the education of other graduate students through results that will be incorporated into courses taught by the PI and co-PI.