NON-REGULAR STIMULATION PATTERNS FOR DEEP BRAIN STIMULATION

描述（由申请人提供）：脑深部电刺激（DBS）已迅速成为运动障碍的治疗方法，目前正在研究其用于癫痫和精神疾病的治疗。然而，DBS的作用机制仍不清楚，这种缺乏了解限制了这种有前途的治疗方法的全面发展和优化。目前，DBS使用规则的（恒定的脉冲间间隔）高频刺激序列，并且DBS的有益（病变样）效果仅在高（>100 Hz）刺激频率下观察到。虽然有效，但是高频刺激比低频刺激产生更强的副作用，但是产生期望的临床效果的电压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，并且与较低频率相比，高刺激频率增加功耗并缩短植入物寿命。我们建议确定不定期（可变脉冲间隔）刺激列车对运动功能和副作用的帕金森氏病患者和基底神经节的计算模型中的神经元活动的影响。我们将应用具有可变脉冲间间隔的刺激模式，预期产生从症状加重到症状缓解的一系列运动效应，这些数据将用于测试DBS疗效所需的刺激核输出规则化的假设。这些结果将为DBS的作用机制提供进一步的见解，并指导新刺激模式的设计。随后，我们将设计和测试新的，不规则的刺激模式，预计将产生缓解运动症状的平均频率低于连续，高速率的刺激。预期这些刺激串通过降低副作用的强度、增加期望临床效应的开始与副作用之间的动态范围（并且由此降低对电极位置的敏感性）以及降低功耗来增加DBS的功效。该项目的结果将是对DBS作用机制的进一步了解，这将有助于选择最佳手术靶点以及治疗新疾病。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.