Hitting the brakes: pathological subthalamic nucleus activity in Parkinson's disease gait freezing
Hitting the brakes: pathological subthalamic nucleus activity in Parkinson's disease gait freezing
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DOI：
10.1093/brain/awz325
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发表时间：
2019-12-01
期刊：
影响因子：
14.5
通讯作者：
Lewis, Simon J. G.
中科院分区：
文献类型：
--
作者：
Georgiades, Matthew J.;Shine, James M.;Lewis, Simon J. G.
步态冻结是帕金森病患者常见的一种复杂且破坏性的阵发性运动停止，可导致活动能力显著受损，通常导致福尔斯跌倒和随后的损伤。帕金森病步态冻结的神经生物学基础知之甚少，因此，目前可用的治疗方法充其量是部分有效的。我们使用经过验证的虚拟现实步态范式，在八名接受丘脑底核脑深部刺激手术的患者中引发术中冻结行为，同时获得微电极记录。这使我们能够直接检验以下假设：丘脑底核中病理性多单位活动的增加与真实的时间内的冻结发作相关，表现为通过EMG检测到的典型冻结的下肢肌肉的功能障碍性放电。我们目前的证据表明，冻结是有关的病理丘脑底核活动的短暂增加。我们进行了时间-频率分析，以表征与冻结发作一致的丘脑底核活动的振荡动力学，表明病理性β和θ节律的增加，随后是活动的时间链，最终在EMG检测到的特征性异常下肢肌肉放电。最后，我们询问我们的研究结果的潜在临床效用，通过对比丘脑底核活动签名在病理冻结与有目的的停止。这些结果推进了我们对帕金森病步态冻结的神经生物学基础的理解，突出了丘脑底核和基底神经节回路中的紧急同步活动在帕金森病患者中驱动无目的运动停滞的作用。与冷冻相关的病理性丘脑底核活动与意志性停止活动是可辨别的，为更有效的治疗方法铺平了道路，如自适应闭环脑深部电刺激方案。
Gait freezing is a complex and devastating paroxysmal motor arrest commonly suffered in Parkinson's disease that causes significant impairment to mobility, commonly resulting in falls and subsequent injury. The neurobiological basis of gait freezing in Parkinson's disease is poorly understood and thus, currently available therapies are partially effective at best. We used a validated virtual reality gait paradigm to elicit freezing behaviour intraoperatively in eight patients undergoing subthalamic nucleus deep brain stimulation surgery while microelectrode recordings were obtained. This allowed us to directly test the hypothesis that increases in pathological multi-unit activity in the subthalamic nucleus are associated with freezing onset in real time, manifest as dysfunctional firing of lower limb muscles typical of freezing that were detected by EMG. We present evidence that freezing is related to transient increases in pathological subthalamic nucleus activity. We performed time-frequency analysis to characterize the oscillatory dynamics of subthalamic nucleus activity coincident with freezing onset, demonstrating an increase in pathological beta and theta rhythms that are followed by a temporal chain of activity culminating in characteristically abnormal lower limb muscle firing detected by EMG. Finally, we interrogate the potential clinical utility of our findings by contrasting the subthalamic nucleus activity signature during pathological freezing against purposeful stopping. These results advance our understanding of the neurobiological basis of gait freezing in Parkinson's disease, highlighting the role of the subthalamic nucleus and emergent synchronous activity in basal ganglia circuits in driving non-purposeful motor arrests in individuals with Parkinson's disease. Pathological subthalamic nucleus activity identified in association with freezing is discernible from that of volitional stopping, paving the way towards more effective therapeutics such as adaptive closed-loop deep brain stimulation protocols.