Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139.
Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA 02114.
Proc Natl Acad Sci U S A. 2022 May 10;119(19):e2120808119. doi: 10.1073/pnas.2120808119. Epub 2022 May 2.
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is highly effective in alleviating movement disability in patients with Parkinson’s disease (PD). However, its therapeutic mechanism of action is unknown. The healthy striatum exhibits rich dynamics resulting from an interaction of beta, gamma, and theta oscillations. These rhythms are essential to selection and execution of motor programs, and their loss or exaggeration due to dopamine (DA) depletion in PD is a major source of behavioral deficits. Restoring the natural rhythms may then be instrumental in the therapeutic action of DBS. We develop a biophysical networked model of a BG pathway to study how abnormal beta oscillations can emerge throughout the BG in PD and how DBS can restore normal beta, gamma, and theta striatal rhythms. Our model incorporates STN projections to the striatum, long known but understudied, found to preferentially target fast-spiking interneurons (FSI). We find that DBS in STN can normalize striatal medium spiny neuron activity by recruiting FSI dynamics and restoring the inhibitory potency of FSIs observed in normal conditions. We also find that DBS allows the reexpression of gamma and theta rhythms, thought to be dependent on high DA levels and thus lost in PD, through cortical noise control. Our study highlights that DBS effects can go beyond regularizing BG output dynamics to restoring normal internal BG dynamics and the ability to regulate them. It also suggests how gamma and theta oscillations can be leveraged to supplement DBS treatment and enhance its effectiveness.
深部脑刺激（DBS）对丘脑底核（STN）的刺激对缓解帕金森病（PD）患者的运动障碍非常有效。然而，其治疗作用机制尚不清楚。健康的纹状体表现出丰富的动力学，这是由于β、γ和θ振荡的相互作用产生的。这些节律对于运动程序的选择和执行至关重要，而由于 PD 中多巴胺（DA）耗竭导致它们的丧失或夸大是行为缺陷的主要来源。恢复自然节律可能有助于 DBS 的治疗作用。我们开发了一个 BG 通路的生物物理网络模型，以研究异常β振荡如何在 PD 中整个 BG 中出现，以及 DBS 如何恢复正常的β、γ和θ纹状节律。我们的模型包含了已知但研究较少的 STN 到纹状体的投射，这些投射被发现优先靶向快速放电中间神经元（FSI）。我们发现，通过招募 FSI 动力学并恢复在正常条件下观察到的 FSIs 的抑制能力，STN 中的 DBS 可以使纹状体中间神经元的活动正常化。我们还发现，DBS 允许重新表达γ和θ节律，这些节律被认为依赖于高 DA 水平，因此在 PD 中丢失，通过皮质噪声控制。我们的研究强调，DBS 的效果不仅可以使 BG 输出动力学正常化，还可以恢复正常的内部 BG 动力学并使其能够调节它们。它还表明了如何利用γ和θ振荡来补充 DBS 治疗并增强其有效性。
