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.的建议编号：1264432 1264535智力优点：神经元群体必须动态地同步和去同步以在脑内传输信息。这种动态同步的中断被认为是几种神经系统疾病的基础。脑深部电刺激（DBS）疗法被用于治疗许多神经系统疾病，如帕金森病（PD）。通常认为，DBS导线放置在病理同步的大脑区域中，然后周期性DBS脉冲“过起搏”这些区域，从而阻止病理活动。PI最近开发了DBS机制的替代假设，其重点是DBS对神经元放电时间的调制。在某些频率下的刺激可以诱导一种混沌反应，使种群去混沌化;我们称这种混沌去混沌化。神经元对DBS脉冲的响应的特征在于其相位响应曲线（PRC），这是刺激如何根据施加刺激的相位来推进相位的度量。然后，PRC可以用于确定在几乎相同的相位开始的群体中的两个神经元是否会夹带刺激脉冲，或者是否会发散并有效地变得去极化。在这项补助金中，PIS建议使用PRCs来确定最佳刺激，以消除人口振荡。初步的实验表明，在某些频率的小周期性刺激脉冲可以deserminize种群; deserminize的频率和幅度可以预测从PRC的神经元的刺激。 此外，可以设计连续刺激波形，其以比脉动刺激少得多的能量使群体去兴奋。这项资助的目的是进一步的理论工作，在设计这些波形从测量PRCs，然后测试混沌去同步在物理和生物系统。具体目标1将使用测得的相位响应曲线和控制理论来确定最佳刺激波形，以最大限度地消除神经元集合。具体目标2将应用该理论通过脉冲和连续波形光刺激来消除化学振荡器模型中的振荡，即光敏Belousov-Zhabotinsky（pBZ）反应。具体目标3将在基底神经节制备的体外神经元中测试该理论。 将使用动态钳夹实验方案记录和刺激神经元。我们将测量单个神经元对DBS脉冲的响应，并测试其刺激响应模式中的混沌行为。更广泛的影响：本研究的动机是1）了解行为如何与基底神经节和运动皮层中以及基底神经节和运动皮层之间的振荡同步相关，以及2）改善PD的DBS治疗，其中刺激电极的选择，频率，并且振幅当前由临床医生手动调节。本研究的目的是确定最佳的刺激特性的基础上简单的生理措施的神经生理反应DBS。这种方法将使神经刺激器的编程更快、更稳健，并将减少所需的注入电流量，这将减少副作用和电池功耗。这种方法对于闭环控制算法具有很高的潜力，其中DBS参数被自动调整以保持最大功效。这种方法也可以应用于癫痫发作抑制和其他神经系统疾病。 这些研究利用UMN最近资助的IGERT神经调节培训计划。为了最大限度地发挥我们的临床影响，我们与德怀特纳尔逊（Medtronic神经调节部门）讨论了哪些基础研究将有助于开发新DBS刺激参数的下一步工作以及尚未满足的临床需求（包括支持函）。这项研究的结果将通过各种教育方案向公众传播，包括重点关注代表性不足的大学生、高中教育工作者、高中生和初中生的方案。最后，该奖项将培训研究生和本科生的跨学科研究活动，并通过将被纳入PI和co-PI教授的课程的结果，提高其他研究生的教育。