Mechanisms for pattern specificity of deep-brain stimulation in Parkinson’s disease

Deep brain stimulation (DBS) has become a widely used technique for treating advanced stages of neurological and psychiatric illness. In the case of motor disorders related to basal ganglia (BG) dysfunction, several mechanisms of action for the DBS therapy have been identified which might be involved simultaneously or in sequence. However, the identification of a common key mechanism underlying the clinical relevant DBS configurations has remained elusive due to the inherent complexity related to the interaction between the electrical stimulation and the neural tissue, and the intricate circuital structure of the BG-thalamocortical network. In this work, it is shown that the clinically relevant range for both, the frequency and intensity of the electrical stimulation pattern, is an emergent property of the BG anatomy at the system-level that can be addressed using mean-field descriptive models of the BG network. Moreover, it is shown that the activity resetting mechanism elicited by electrical stimulation provides a natural explanation to the ineffectiveness of irregular (i.e., aperiodic) stimulation patterns, which has been commonly observed in previously reported pathophysiology models of Parkinson’s disease. Using analytical and numerical techniques, these results have been reproduced in both cases: 1) a reduced mean-field model that can be thought as an elementary building block capable to capture the underlying fundamentals of the relevant loops constituting the BG-thalamocortical network, and 2) a detailed model constituted by the direct and hyperdirect loops including one-dimensional spatial structure of the BG nuclei. We found that the optimal ranges for the essential parameters of the stimulation patterns can be understood without taking into account biophysical details of the relevant structures.

深部脑刺激（Deep brain stimulation, DBS）现已成为治疗神经及精神疾病晚期阶段的一项广泛应用的技术。针对与基底神经节（Basal Ganglia, BG）功能障碍相关的运动障碍而言，目前已明确DBS疗法存在多种作用机制，这些机制可能同时或依次参与治疗过程。然而，由于电刺激与神经组织间相互作用的固有复杂性，以及基底神经节-丘脑皮层网络复杂的环路结构，目前仍难以明确临床适用的DBS刺激参数配置背后共有的关键作用机制。本研究表明，电刺激模式的频率与强度的临床适用范围，是基底神经节网络在系统层面的涌现属性，可通过基底神经节网络的平均场描述模型（mean-field descriptive models）进行分析。此外，本研究还发现，电刺激引发的活动重置机制，可自然解释不规则（即非周期性）刺激模式为何无效——这一现象在既往报道的帕金森病（Parkinson’s disease）病理生理模型中常被观察到。本研究通过解析与数值方法，在两类模型中复现了上述结果：1）简化平均场模型，该模型可作为基本构建单元，能够捕捉构成基底神经节-丘脑皮层网络的相关环路的核心本质；2）包含基底神经节核团一维空间结构的详细模型，由直接通路与超直接通路构成。本研究发现，即便不考虑相关结构的生物物理细节，也可明确刺激模式关键参数的最优取值范围。