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

合作研究：帕金森病的最佳刺激波形设计

• 批准号: 1264535
• 负责人: Jeffrey Moehlis
• 金额: $ 21.59万
• 依托单位: University of California-Santa Barbara
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2017-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1264535&HistoricalAwards=false
• 关键词: Collaborative; research; Optimal; stimulus; waveform

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.

PI：Netoff，Theoden I.和Moehlis，Jeffrey M.Proposal编号：1264432＆1264535Intlectual Feerit：神经元的种群必须动态同步和对同步，以使大脑内的信息传播。这种动态同步的破坏被认为是几种神经系统疾病的症状。深脑刺激（DBS）疗法被用于治疗许多这些神经系统疾病，例如帕金森病（PD）。人们普遍认为，DBS引线被放置在病理同步的大脑区域，然后定期DBS脉冲，然后“超越节奏”这些区域，阻止病理活性。 PI最近为DBS的机制开发了一种替代假设，该假设侧重于DBS对神经元的发射时间的调节。在某些频率下的刺激会引起混乱的反应，使人口不同步。我们称这种混乱的干扰性。神经元对DBS脉冲的响应的特征是其相响应曲线（PRC），这是刺激如何取决于相位刺激的相位的量度。然后，可以使用中国来确定在几乎相同阶段开始的种群中的两个神经元是否会夹住刺激脉冲，或者会发散并有效地变得不同步。在这笔赠款中，PIS建议使用PRC来确定最佳刺激，以使人口振荡不同步。初步实验表明，某些频率下的小周期刺激脉冲可以使种群具有异步性。可以从神经元的PRC到刺激的频率和振幅可以预测。 此外，可以设计连续的刺激波形，使人群具有比脉冲刺激少得多的人群。该赠款的目的是进一步从测量的PRC设计这些波形，然后在物理和生物系统中测试混乱的DE同步。特定目标1将使用测量的相响应曲线和控制理论来确定最佳刺激波形，以最大程度地提高神经元集合的非同步。具体目的2将通过脉冲和连续的波形光刺激在化学振荡器模型，光敏的Belousov-Zhabotinsky（PBZ）反应中应用该理论来使振荡变为振荡。特定的目标3将在体外基底神经节制备中测试神经元中的理论。 将使用动态夹具实验方案记录和刺激神经元。 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目前由临床医生手动调整。这项研究的目的是基于对DBS的神经生理反应的简单生理测量来确定最佳刺激特性。这种方法将使神经刺激器的更快，更强大的编程能够减少所需的注入电流的量，这将减少副作用和电池功耗。这种方法对于自动调整DBS参数以保持最大功效的封闭环控制算法具有很高的潜力。这种方法也可以应用于癫痫发作和其他神经系统疾病。 这些研究利用了最近在UMN上获得的IGERT培训计划进行神经调节。为了最大程度地发挥临床影响，我们与德怀特·纳尔逊（Dwight Nelson）（Medtronic的神经调节部门）讨论了基础研究将在开发新的DBS刺激参数和尚未满足的临床需求的下一步步骤（包括支持信）。这项研究的结果将通过各种教育计划将其传播给公众，包括专注于代表性不足的本科生，高中教育工作者，高中生和初中生。最后，该奖项将在跨学科研究活动中培训研究生和本科生，并通过成绩加强其他研究生的教育，这些结果将纳入PI和Co-Pi教授的课程中。