NON-REGULAR STIMULATION PATTERNS FOR DEEP BRAIN STIMULATION

描述（由申请人提供）：深部脑刺激（DBS）作为一种治疗运动障碍的方法迅速出现，并且正在研究用于治疗癫痫和精神疾病。然而，DBS的作用机制尚不清楚，这一认识的缺乏限制了这种有前景的治疗方法的充分开发和优化。目前，DBS采用规则的（脉冲间隔恒定的）高频刺激序列，而DBS的有益（病变样）效果仅在高（bb0 ~ 100hz）刺激频率下观察到。高频刺激虽然有效，但产生的副作用比低频刺激更强，产生预期临床效果的电压与产生副作用的电压之间的治疗窗口期随着频率的增加而减小，并且与低频相比，高频率刺激会增加功率消耗，缩短种植体寿命。我们建议在基底神经节计算模型中确定不规则（可变脉间间隔）刺激训练对帕金森病患者运动功能和副作用的影响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，期望产生从症状加剧到症状缓解的一系列运动效应，并且这些数据将用于验证受刺激核输出的正则化是DBS有效性所必需的假设。研究结果将进一步揭示DBS的作用机制，并指导新的刺激模式的设计。随后，我们将设计和测试新的、非规则的刺激模式，以期在比连续的、高频率的刺激更低的平均频率下产生运动症状的缓解。这些刺激序列有望通过降低副作用的强度、增加预期临床效果和副作用发生之间的动态范围（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。该项目的结果将是增加对DBS作用机制的理解，这将有助于选择最佳手术靶点以及治疗新疾病。第二个结果将是新颖的脉冲模式，有望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.