NON-REGULAR STIMULATION PATTERNS FOR DEEP BRAIN STIMULATION

描述(申请人提供)：脑深部刺激(DBS)作为一种治疗运动障碍的方法迅速出现，目前正在研究中，用于治疗癫痫和精神障碍。然而，DBS的作用机制(S)仍不清楚，这种认识的缺乏限制了这一有前途的治疗方法的充分发展和优化。目前，DBS使用规则的(恒定脉冲间隔)高频刺激序列，并且DBS的有益(病变样)效应仅在高(&gt；100赫兹)刺激频率下观察到。虽然高频刺激产生的副作用比低频刺激更强，但产生预期临床效果的电压(S)和产生副作用的电压之间的治疗窗口随着频率的增加而减小，与低频刺激相比，高频刺激会增加功耗并缩短植入物的寿命。我们建议在一个基底节的计算模型中，确定非规则(可变脉冲间隔)刺激序列对帕金森病患者的运动功能和副作用以及对神经元活动的影响。我们将应用具有可变脉冲间隔的刺激模式，预计将产生从症状加重到症状缓解的一系列运动效应，这些数据将被用来检验以下假设：DBS的疗效需要刺激核输出的规律化。这一结果将为进一步深入了解DBS的作用机制和指导新的刺激模式的设计提供依据。随后，我们将设计和测试新的、非规则的刺激模式，这些模式有望在比连续、高比率刺激更低的平均频率下产生缓解运动症状的效果。这些刺激序列有望通过降低副作用的强度、增加预期临床效果(S)开始和副作用之间的动态范围(从而降低对电极位置的敏感性)以及降低功耗来提高DBS的疗效。该项目的成果将是加深对DBS作用机制的了解，这将有助于选择最佳手术靶点以及治疗新的疾病。第二个结果将是新的脉冲模式，预计将通过减少副作用和延长电池寿命来改善DBS的结果。

DESCRIPTION (provided by applicant): Deep brain stimulation (DBS) has emerged rapidly as a treatment for movement disorders and is under investigation for treatment of epilepsy and psychiatric disorders. However, the mechanism(s) of action of DBS are still unclear, and this lack of understanding limits full development and optimization of this promising treatment. Presently, DBS uses regular (constant interpulse interval) high frequency stimulus trains, and the beneficial (lesion-like) effects of DBS are only observed at high (>100 Hz) stimulation frequencies. Although effective, high frequency stimulation generates stronger side-effects than low frequency stimulation, the therapeutic window between the voltage that generates the desired clinical effect(s) and the voltage that generates side effects decreases with increasing frequency, and high stimulation frequencies increase power consumption and shorten implant lifetime, as compared to lower frequencies. We propose to determine the effect of non-regular (variable interpulse interval) stimulation trains on motor function and side effects in persons with Parkinson's disease and on neuronal activity in a computational model of the basal ganglia. We will apply stimulation patterns with variable interpulse intervals expected to create a range of motor effects from exacerbation of symptoms to relief of symptoms, and these data will be used to test the hypothesis that regularization of the output of the stimulated nucleus is required for efficacy of DBS. The results will provide further insight into the mechanisms of action of DBS and guide design of novel stimulation patterns. Subsequently, we will design and test novel, non-regular stimulation patterns that are expected to produce relief of motor symptoms at lower average frequencies than continuous, high rate stimulation. These stimulus trains are expected to increase the efficacy of DBS by reducing the intensity of side effects, increasing the dynamic range between the onset of the desired clinical effect(s) and side effects (and thereby reducing sensitivity to the position of the electrode), and decreasing power consumption. The outcome of this project will be an increased understanding of the mechanisms of action of DBS, and this will facilitate selection of optimal surgical targets as well as treatments for new disorders. The second outcome will be novel pulse patterns that are expected to improve outcomes of DBS by reducing side effects and prolonging battery life.