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: 1264432
• 负责人: Theoden Netoff
• 金额: $ 22.66万
• 依托单位: University of Minnesota-Twin Cities
• 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=1264432&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.建议编号：1264432&1264535智力优点：神经元群体必须动态同步和去同步，才能在大脑内传输信息。这种动态同步性的中断被认为是几种神经疾病症状的基础。脑深部刺激(DBS)疗法正被用于治疗许多此类神经疾病，如帕金森氏病(PD)。一般认为，DBS导联被放置在大脑病理同步的区域，周期性的DBS脉冲然后超速这些区域，阻断病理活动。最近，PI们对DBS的机制提出了另一种假说，重点是DBS对神经元放电时间的调节。在特定频率下的刺激可以引起一种混沌反应，使群体失去同步性；我们称之为混沌去同步化。神经元对DBS脉冲的响应是由其相位响应曲线(PRC)来表征的，该曲线衡量了刺激如何根据施加刺激的相位来推进相位。然后，PRC可以用来确定群体中在几乎相同阶段开始的两个神经元是否会被刺激脉冲缠绕，或者是否会发散并有效地变得不同步。在这项拨款中，PIS建议使用PRCS来确定使种群振荡失去同步的最佳刺激。初步实验表明，特定频率的小周期刺激脉冲可以使群体去同步；去同步的频率和幅度可以从神经元到刺激的PRC来预测。此外，可以设计连续的刺激波形，以比脉动刺激少得多的能量使人群去同步。这项资助的目的是进一步从测量的PRC中设计这些波形的理论工作，然后测试物理和生物系统中的混沌去同步。具体目标1将使用测量的相响应曲线和控制理论来确定最优刺激波形，以最大限度地消除神经元集合的去同步化。具体目标2将是应用这一理论通过脉动和连续的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将在神经元的体外基底节制备中检验这一理论。神经元将被记录并使用动态钳制实验方案进行刺激。我们将测量单个神经元对DBS脉冲的反应，并测试其刺激反应模式中的混沌行为。广泛影响：本研究的动机是1)了解行为如何与基底节和运动皮质内及之间的振荡同步有关，2)改进DBS对帕金森病的治疗，目前刺激电极、频率和幅度的选择由临床医生手动调整。本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优的刺激特性。这种方法将使神经刺激器的编程更快、更强大，并将减少所需的注入电流量，从而减少副作用和电池功耗。这种方法在闭环控制算法中具有很高的潜力，其中DBS参数被自动调整以保持最大效率。这种方法也可以应用于癫痫抑制和其他神经疾病。这些研究利用了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，我们与美敦力神经调节科的Dwight Nelson讨论了哪些基础研究将使下一步开发新的DBS刺激参数以及尚未满足的临床需求(包括支持函)成为可能。这项研究的结果将通过各种教育项目向公众传播，包括针对人数不足的本科生、高中教育工作者、高中生和初中生的教育项目。最后，该奖项将对研究生和本科生进行跨学科研究活动的培训，并通过将成果纳入私营部门和私营部门共同教授的课程来加强对其他研究生的教育。