深部脑刺激的逆行皮质激活作用对改善帕金森式症运动及技能学习障碍的机制研究

Although deep brain stimulation (DBS) in the subthalamic nucleus (STN) is now a recognized therapeutic option for Parkinson's disease (PD), the exact mechanism of DBS is still not fully settled. In our recent research, we monitored the activities of putative projection neurons and interneurons of the primary motor cortex (MI) in hemi-Parkinsonian rats, and presented evidence for an essential role of antidromic cortical activation in alleviating Parkinsonian motor dysfunction. Our results demonstrate that the action of DBS is not confined to the local stimulation site, but more importantly, activates antidromic spikes that transferred back to the MI through the MI-STN 'hyper-direct' pathway. This effect helps break the pathological synchronized burst firing and oscillation in MI. Our work, published in <Neuron>, was selected by <Nature China> as one of the best published papers in China, and also highlighted by the prestigious journal <Nature Reviews Neuroscience>. In this project, we aim to explore the impact, and decipher the exact mechanism, of STN-DBS in modifying the cortical circuitry and synaptic plasticity, and also the novel hypothesis that STN-DBS can alleviate motor skill learning dysfunction in Parkinsonism. As STN-DBS has become an effective way to treat not only PD-related motor dysfunctions, but many other cognitive disorders such as depression, dementia and schizophrenia, the present project is of significance in helping to improve the therapeutic efficacy of DBS, avoid side effects and also broaden its clinical application in the foreseeable future.

丘脑底核深部脑刺激作为现今治疗帕金森式症最为有效的干预手段，其确切的作用机制仍未阐明。近期研究中，我们运用在体多通道神经电活动记录技术成功在帕金森大鼠的运动皮质记录到投射神经元与中间神经元的电活动，证实丘脑底核的高频电刺激脉冲诱发的锋电位能逆向传导至皮质，成功阻断病理情况下皮质的同步爆发式放电及低频振荡，从而缓解帕金森式症的运动功能障碍。此项研究已发表《Neuron》杂志,并被Nature China及Nature Review Neuroscience推荐为研究亮点。 本项目在于深入探讨深部脑刺激的逆行皮质激活效应对改善帕金森式症运动及技能学习障碍的作用机制。做为治疗多项运动障碍及精神异常疾病最有效的外科手段，研究深部脑刺激的真正作用机制不但有利于确定其针对不同病症最为有效的刺激模式，减少副作用，更有助于拓展其在治疗其他运动及认知功能障碍疾病的实际应用范畴。这也正是本项研究的重点。

帕金森病是一种常见的神经退行性疾病，影响患者在运动执行和学习新运动技能方面的能力。 这种疾病是不可治愈的，但治疗性深度脑刺激对许多帕金森病患者是有益的在这项研究中，我们的目标是研究深层脑刺激的主要运动皮层的治疗效果和机制。我们已经取得如下成果：1)建立帕金森病动物模型; 2)建立丘脑底核高频电刺激模型;.3)帕金森病理状态下运动皮质的电生理信号; 4) 研究运动皮质的多巴胺能输入对皮质神经元突触可塑性及行为的影响; 和 5)研究腹側被蓋區到运动皮质的多巴胺能神经投射的作用。与我们的假设一致，初级运动皮层是帕金森病异常活动的主要部位，也是治疗范式的目标。我们的研究结果为探索治疗帕金森病的创新治疗方法奠定了基础。