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, United States.
Department of Neurosurgery, University of British Columbia, Vancouver, BC, Canada.
Front Hum Neurosci. 2021 Jun 8;15:676755. doi: 10.3389/fnhum.2021.676755. eCollection 2021.
Freezing of gait (FOG) is a debilitating motor deficit in a subset of Parkinson's Disease (PD) patients that is poorly responsive to levodopa or deep brain stimulation (DBS) of established PD targets. The proposal of a DBS target in the midbrain, known as the pedunculopontine nucleus (PPN), to address FOG was based on its observed neuropathology in PD and its hypothesized involvement in locomotor control as a part of the mesencephalic locomotor region (MLR). Initial reports of PPN DBS were met with enthusiasm; however, subsequent studies reported mixed results. A closer review of the MLR basic science literature, suggests that the closely related cuneiform nucleus (CnF), dorsal to the PPN, may be a superior site to promote gait. Although suspected to have a conserved role in the control of gait in humans, deliberate stimulation of a homolog to the CnF in humans using directional DBS electrodes has not been attempted.
As part of an open-label Phase 1 clinical study, one PD patient with predominantly axial symptoms and severe FOG refractory to levodopa therapy was implanted with directional DBS electrodes (Boston Science Vercise Cartesia) targeting the CnF bilaterally. Since the CnF is a poorly defined reticular nucleus, targeting was guided both by diffusion tensor imaging (DTI) tractography and anatomical landmarks. Intraoperative stimulation and microelectrode recordings were performed near the targets with leg EMG surface recordings in the subject.
Post-operative imaging revealed accurate targeting of both leads to the designated CnF. Intraoperative stimulation near the target at low thresholds in the awake patient evoked involuntary electromyography (EMG) oscillations in the legs with a peak power at the stimulation frequency, similar to observations with CnF DBS in animals. Oscillopsia was the primary side effect evoked at higher currents, especially when directed posterolaterally. Directional DBS could mitigate oscillopsia.
DTI-based targeting and intraoperative stimulation to evoke limb EMG activity may be useful methods to help target the CnF accurately and safely in patients. Long term follow-up and detailed gait testing of patients undergoing CnF stimulation will be necessary to confirm the effects on FOG.
Clinicaltrials.gov identifier: NCT04218526.
冻结步态（FOG）是帕金森病（PD）患者中的一种致残性运动缺陷，对左旋多巴或已确定的PD靶点进行脑深部电刺激（DBS）反应不佳。提出将中脑的一个DBS靶点，即脚桥核（PPN），作为解决FOG的靶点，是基于其在PD中观察到的神经病理学以及其作为中脑运动区（MLR）的一部分在运动控制中的假定作用。PPN DBS的初步报告令人兴奋；然而，随后的研究结果喜忧参半。对MLR基础科学文献的进一步回顾表明，与PPN背侧紧密相关的楔形核（CnF）可能是促进步态的更佳部位。尽管怀疑其在人类步态控制中具有保守作用，但尚未尝试使用定向DBS电极对人类的CnF同源物进行有意刺激。
作为一项开放标签的1期临床研究的一部分，一名主要表现为轴性症状且对左旋多巴治疗难治的严重FOG的PD患者双侧植入了靶向CnF的定向DBS电极（波士顿科学公司的Vercise Cartesia）。由于CnF是一个定义不明确的网状核，靶向定位由弥散张量成像（DTI）纤维束成像和解剖标志引导。术中在靶点附近进行刺激和微电极记录，并在受试者身上进行腿部肌电图表面记录。
术后成像显示两根导线均准确靶向指定的CnF。在清醒患者中，在低阈值下于靶点附近进行术中刺激，可诱发腿部非自愿肌电图（EMG）振荡，其峰值功率在刺激频率处，类似于动物中CnF DBS的观察结果。视振荡是在较高电流下诱发的主要副作用，尤其是当向后外侧方向刺激时。定向DBS可减轻视振荡。
基于DTI的靶向定位和术中刺激以诱发肢体EMG活动可能是在患者中准确、安全地靶向CnF的有用方法。对接受CnF刺激的患者进行长期随访和详细的步态测试，对于确认对FOG的影响是必要的。
Clinicaltrials.gov标识符：NCT04218526。
