1 Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, West Wing Level 6, OX3 9DU, Oxford, UK.
2 Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, WC1N 3BG, UK.
Brain. 2014 Dec;137(Pt 12):3223-34. doi: 10.1093/brain/awu250. Epub 2014 Sep 8.
Tremor is a cardinal feature of Parkinson's disease and essential tremor, the two most common movement disorders. Yet, the mechanisms underlying tremor generation remain largely unknown. We hypothesized that driving deep brain stimulation electrodes at a frequency closely matching the patient's own tremor frequency should interact with neural activity responsible for tremor, and that the effect of stimulation on tremor should reveal the role of different deep brain stimulation targets in tremor generation. Moreover, tremor responses to stimulation might reveal pathophysiological differences between parkinsonian and essential tremor circuits. Accordingly, we stimulated 15 patients with Parkinson's disease with either thalamic or subthalamic electrodes (13 male and two female patients, age: 50-77 years) and 10 patients with essential tremor with thalamic electrodes (nine male and one female patients, age: 34-74 years). Stimulation at near-to tremor frequency entrained tremor in all three patient groups (ventrolateral thalamic stimulation in Parkinson's disease, P=0.0078, subthalamic stimulation in Parkinson's disease, P=0.0312; ventrolateral thalamic stimulation in essential tremor, P=0.0137; two-tailed paired Wilcoxon signed-rank tests). However, only ventrolateral thalamic stimulation in essential tremor modulated postural tremor amplitude according to the timing of stimulation pulses with respect to the tremor cycle (e.g. P=0.0002 for tremor amplification, two-tailed Wilcoxon rank sum test). Parkinsonian rest and essential postural tremor severity (i.e. tremor amplitude) differed in their relative tolerance to spontaneous changes in tremor frequency when stimulation was not applied. Specifically, the amplitude of parkinsonian rest tremor remained unchanged despite spontaneous changes in tremor frequency, whereas that of essential postural tremor reduced when tremor frequency departed from median values. Based on these results we conclude that parkinsonian rest tremor is driven by a neural network, which includes the subthalamic nucleus and ventrolateral thalamus and has broad frequency-amplitude tolerance. We propose that it is this tolerance to changes in tremor frequency that dictates that parkinsonian rest tremor may be significantly entrained by low frequency stimulation without stimulation timing-dependent amplitude modulation. In contrast, the circuit influenced by low frequency thalamic stimulation in essential tremor has a narrower frequency-amplitude tolerance so that tremor entrainment through extrinsic driving is necessarily accompanied by amplitude modulation. Such differences in parkinsonian rest and essential tremor will be important in selecting future strategies for closed loop deep brain stimulation for tremor control.
震颤是帕金森病和特发性震颤这两种最常见的运动障碍的主要特征。然而，震颤产生的机制在很大程度上仍然未知。我们假设，以接近患者自身震颤频率的频率驱动深部脑刺激电极应该与负责震颤的神经活动相互作用，并且刺激对震颤的影响应该揭示不同深部脑刺激靶点在震颤产生中的作用。此外，震颤对刺激的反应可能揭示帕金森氏症和特发性震颤回路之间的病理生理学差异。因此，我们用丘脑或丘脑下刺激电极刺激 15 名帕金森病患者（13 名男性和两名女性，年龄：50-77 岁）和 10 名特发性震颤患者（9 名男性和 1 名女性，年龄：34-74 岁）。在三组患者中，接近震颤频率的刺激使震颤有节律（丘脑腹外侧刺激帕金森病，P=0.0078，丘脑下刺激帕金森病，P=0.0312；丘脑腹外侧刺激特发性震颤，P=0.0137；双侧配对 Wilcoxon 符号秩检验）。然而，只有特发性震颤的丘脑腹外侧刺激根据刺激脉冲相对于震颤周期的时间调制姿势震颤的幅度（例如，震颤放大的 P=0.0002，双侧 Wilcoxon 秩和检验）。当不施加刺激时，帕金森病静止期和特发性姿势性震颤的严重程度（即震颤幅度）对震颤频率的自发变化的相对耐受性不同。具体而言，尽管震颤频率发生变化，帕金森病静止期震颤的幅度保持不变，而特发性姿势性震颤的幅度则降低当震颤频率偏离中值时。基于这些结果，我们得出结论，帕金森病静止期震颤是由一个神经网络驱动的，该网络包括丘脑下核和丘脑腹外侧核，具有广泛的频率-幅度容忍度。我们提出，正是这种对震颤频率变化的容忍度决定了帕金森病静止期震颤可能会被低频刺激显著节律化，而无需刺激时间依赖性幅度调制。相比之下，特发性震颤中受低频丘脑刺激影响的回路具有较窄的频率-幅度容忍度，因此通过外部驱动进行震颤节律化必然伴随着幅度调制。帕金森病静止期和特发性震颤之间的这些差异将在为震颤控制选择未来的闭环深部脑刺激策略时非常重要。
