Chang Stephano J, Cajigas Iahn, Guest James D, Noga Brian R, Widerström-Noga Eva, Haq Ihtsham, Fisher Letitia, Luca Corneliu C, Jagid Jonathan R
The Miami Project to Cure Paralysis, Miami, FL, USA.
Department of Neurosurgery, University of British Columbia, Vancouver, BC, Canada.
Pilot Feasibility Stud. 2021 Jun 2;7(1):117. doi: 10.1186/s40814-021-00855-7.
Freezing of gait (FOG) is a particularly debilitating motor deficit seen in a subset of Parkinson's disease (PD) patients that is poorly responsive to standard levodopa therapy or deep brain stimulation (DBS) of established PD targets such as the subthalamic nucleus and the globus pallidus interna. The proposal of a DBS target in the midbrain, known as the pedunculopontine nucleus (PPN) to address FOG, was based on its observed pathology in PD and its hypothesized involvement in locomotor control as a part of the mesencephalic locomotor region, a functionally defined area of the midbrain that elicits locomotion in both intact animals and decerebrate animal preparations with electrical stimulation. Initial reports of PPN DBS were met with much enthusiasm; however, subsequent studies produced mixed results, and recent meta-analysis results have been far less convincing than initially expected. A closer review of the extensive mesencephalic locomotor region (MLR) preclinical literature, including recent optogenetics studies, strongly suggests that the closely related cuneiform nucleus (CnF), just dorsal to the PPN, may be a superior target to promote gait initiation.
We will conduct a prospective, open-label, single-arm pilot study to assess safety and feasibility of CnF DBS in PD patients with levodopa-refractory FOG. Four patients will receive CnF DBS and have gait assessments with and without DBS during a 6-month follow-up.
This paper presents the study design and rationale for a pilot study investigating a novel DBS target for gait dysfunction, including targeting considerations. This pilot study is intended to support future larger scale clinical trials investigating this target.
ClinicalTrials.gov identifier: NCT04218526 (registered January 6, 2020).
冻结步态（FOG）是帕金森病（PD）患者中出现的一种特别使人衰弱的运动缺陷，对标准左旋多巴治疗或对已确定的PD靶点（如丘脑底核和苍白球内侧部）进行深部脑刺激（DBS）反应不佳。在中脑提出一个称为脚桥核（PPN）的DBS靶点来解决FOG问题，是基于在PD中观察到的其病理情况以及假设它作为中脑运动区的一部分参与运动控制，中脑运动区是中脑的一个功能定义区域，在完整动物和去大脑动物制剂中通过电刺激均可引发运动。PPN DBS的初步报告引发了很多热情；然而，随后的研究结果不一，最近的荟萃分析结果远不如最初预期的那样令人信服。对广泛的中脑运动区（MLR）临床前文献进行更仔细的回顾，包括最近的光遗传学研究，强烈表明与PPN紧邻且位于其背侧的楔形核（CnF）可能是促进步态起始的更优靶点。
我们将进行一项前瞻性、开放标签、单臂试点研究，以评估CnF DBS在左旋多巴难治性FOG的PD患者中的安全性和可行性。4名患者将接受CnF DBS，并在6个月的随访期间进行有和没有DBS时的步态评估。
本文介绍了一项试点研究的研究设计和基本原理，该研究调查了一种用于步态功能障碍的新型DBS靶点，包括靶点选择的考量。这项试点研究旨在支持未来针对该靶点的更大规模临床试验。
ClinicalTrials.gov标识符：NCT04218526（2020年1月6日注册）。
