Beyond theta: analyzing oscillations across the frequency spectrum in patients with dystonia implanted with sensing-enabled pulse generators

项目总结/摘要 肌张力障碍是一种以持续或重复的肌肉运动为特征的致残性神经系统疾病 导致不正常的动作或姿势。调查局部场电位（LFP）的研究记录 从脑深部电刺激（DBS）-直接电刺激皮层下的大脑结构，使用慢性 肌张力障碍患者的植入电极-导线已在诊所或围手术期记录，而患者 进行着受限的运动这些研究的特点是病理性增加的低- 频率活动[即，θ（3-8 Hz）]及其与肌张力障碍症状的关系。然而，功能 该活动的相关性仍然是难以捉摸的并且最近的发现暗示了额外的振荡（例如， 微调或窄带γ）可能与病理生理学有关。本申请的目的是 以数据驱动的方式跨基底神经节和皮质识别肌张力障碍的个体化LFP生物标志物， 同时揭示了DBS期间生物标志物波动与症状抑制之间的关系。我们将 使用第二代试验用双向器械（Medtronic RC+S）实现这一点， 我们可以长期感知LFP并在患者在家时提供DBS治疗。这些新颖 记录和设备提供了对复杂生物标志物和自然行为的见解，允许直接 个体化生物标志物与症状监测或抑制的比较。这将推动我们的 了解与肌张力障碍和DBS相关的神经变化，最终改善电流 神经刺激疗法。我们的中心假设是自然主义的神经记录，特别是那些 结合多模式信号采集在皮层和皮层下记录（即，视频运动学 和加速度），可以检测肌张力障碍症状的个性化生物标志物， 了解疾病及其症状表现，同时帮助优化DBS治疗。在 目的1，我们将识别和表征与病理活动相关的个体化功率带， 使用慢性皮质下和皮质记录的肌张力障碍患者。我们将解码病理状态 监督和自我监督机器学习技术。在目标2中，我们将确定个性化电源 在使用慢性皮质下和皮质下肌张力障碍患者的深部脑刺激期间调制的频带 记录并利用这些关系来优化刺激编程。这项研究意义重大， 创新，因为它将是第一个慢性，多位点LFP记录范式，以研究肌张力障碍的影响， 症状和DBS对苍白球LFP、皮质LFP和皮质下-皮质相互作用的影响 RC+S，提供了关于基底神经节和皮质功能，肌张力障碍网络相互作用的丰富信息 以及DBS的作用机制。最后，我们的目标是将这种模式扩展到商业化的，感知功能的 DBS设备-个性化神经调节的初步步骤。

Project Summary/Abstract Dystonia is a disabling neurological condition characterized by sustained or repetitive muscle movements causing abnormal movements or postures. Studies that have investigated local field potentials (LFPs) recorded from deep brain stimulation (DBS) – direct electrical stimulation of subcortical brain structures using chronically implanted electrodes – leads in dystonia patients have been in-clinic or perioperative recordings while the patient was performing constrained movements. These studies have characterized pathologically increased low- frequency activity [i.e., theta (3-8 Hz)] and its relationship to dystonic symptoms. However, the functional relevance of this activity remains elusive and recent findings have implicated that additional oscillations (e.g., finely-tuned or narrowband gamma) may be related to pathophysiology. The objective of this application is to identify individualized LFP biomarkers of dystonia in a data-driven manner across the basal ganglia and cortex, while revealing the relationship between fluctuations in biomarkers to symptom suppression during DBS. We will accomplish this using a second-generation investigational, bidirectional device (Medtronic RC+S), which allows us to chronically sense LFPs and deliver DBS therapy while patients are in at-home settings. These novel recordings and devices provide insights into complex biomarkers and naturalistic behaviors, allowing a direct comparison of individualized biomarkers to symptom monitoring or suppression. This will advance our understanding of neural changes associated with dystonia and DBS, ultimately improving current neurostimulation therapy. Our central hypothesis is that naturalistic neural recordings, specifically those recorded both cortically and subcortically in conjunction with multimodal signal acquisition (i.e., video kinematics and acceleration), can detect personalized biomarkers of dystonic symptoms that can illuminate our network understanding of the disease and its symptom manifestation, while aiding in the optimization of DBS therapy. In Aim 1, we will identify and characterize individualized power bands associated with pathological activity in patients with dystonia using chronic subcortical and cortical recordings. We will decode pathological states using supervised and self-supervised machine learning techniques. In Aim 2, we will determine personalized power bands modulated during deep brain stimulation in patients with dystonia using chronic subcortical and cortical recordings and utilize these relationships to optimize stimulation programming. This research is significant and innovative because it will be the first chronic, multisite LFP recording paradigm to study effects of dystonic symptoms and DBS on pallidal LFPs, cortical LFPs, and subcortical-cortical interactions using the Medtronic RC+S, providing ample information about basal ganglia and cortical functions, network interactions in dystonia and the mechanisms of DBS. Lastly, our goal is to expand this paradigm into commercialized, sensing-enabled DBS devices – the preliminary steps towards personalized neuromodulation.