Motor cortex plasticity induction by pairing subthalamic nucleus deep brain stimulation and dorsal premotor cortical transcranial magnetic stimulation in Parkinsons disease

人类大脑能够塑造神经元集合的兴奋性和相互作用，以适应不断变化的外部影响。这种不同皮质区域的可塑性，如运动网络，代表了人类大脑功能的基本要求。帕金森病（PD）的可塑性改变主要是由于多巴胺能细胞的神经变性。由于PD中明确的细胞损失和神经递质缺陷，这种疾病可以作为多巴胺缺乏的模型疾病，最初主要在基底节区，后来扩展到其他大脑区域，如何在皮质运动网络中产生疾病相关的变化，以及运动系统如何适应这些变化。PD的皮质可塑性首先通过对初级运动皮层（M1）的正中神经进行感觉刺激和经颅磁刺激（TMS）配对来测试。最近创新的配对联想刺激（PAS）方案在健康受试者中改进了这一方法，通过反复配对经颅磁刺激（TMS）脉冲给M1和那些应用于次级运动区域的脉冲来分析皮质-皮质运动网络的可修改性。由于先前的功能性磁共振成像（fMRI）研究一再显示PD患者皮质连接模式改变，因此将这些方案应用于PD患者具有特殊的意义。这些模式的特点是在多巴胺能药物戒断后（关闭状态）基底节区-额-中皮层回路的活动丧失，可能代偿性亢进的基底节区-背侧PM （PMd）连接在左旋多巴给药后恢复正常（开启状态）。这些发现得到了神经生理学研究的证实，例如经颅磁刺激研究表明，左旋多巴和重复经颅磁刺激可以逆转PMd- m1相互作用的改变。丘脑下核深部脑刺激（DBS）已经成为PD治疗中除了口服多巴胺能替代疗法之外的一种确定的治疗选择，并且可以补充PAS方案。在此背景下，我们现在提出使用一种新的PAS方案，即STN-DBS与PMd-M1-TMS相结合，在DBS刺激下的PD患者处于OFF和On状态，来探索PD中基底节区pmd - m1可塑性的变化。在PD中证明这些皮层-皮层下关联可塑性回路有助于理解PD中皮层可塑性的潜在机制，以及运动网络的改变，并可能加深我们对DBS治疗这些患者效果的理解。这些信息对于进一步制定策略以促进这些患者和其他神经退行性疾病的可塑性功能至关重要。

The human brain is capable of shaping the excitability and interaction in neuronal assemblies as an adaptation to changing external influences. Such plasticity of different cortical regions, e.g. motor networks, represents a fundamental requirement of human brain functions. Plasticity is altered in Parkinsons disease (PD) predominantly because of neurodegeneration of dopaminergic cells. Due to the defined cellular loss and neurotransmitter deficits in PD, this disease can serve as a model disease of how dopamine deficiency, initially predominantly in the basal ganglia and later expanding to other brain regions, produces disease-related changes in cortical motor networks, but also how the motor system adapts to these alterations. Cortical plasticity in PD was first tested by pairing sensory stimulation of the median nerve with transcranial magnetic stimulus (TMS) over the primary motor cortex (M1). Recent innovative paired associative stimulation (PAS) protocols modified this approach in healthy subjects by repeatedly pairing TMS pulses given over M1 with those applied to secondary motor areas to analyze the modifiability of cortico-cortical motor networks. Applying these protocols in PD patients is of special interest due to the fact that previous functional magnetic resonance imaging (fMRI) studies have repeatedly shown altered cortical connectivity patterns in PD. These patterns are characterized by a loss of activity within basal ganglia-fronto-mesial cortical loops and probably compensatory hyperactive basal ganglia-dorsal PM (PMd) connections after a dopaminergic drug withdrawal (OFF state) and normalisation after L-Dopa administration (On state). These findings were corroborated by neurophysiological studies, e.g. TMS studies showing altered PMd-M1 interactions that were reversed by L-dopa administration and repetitive TMS of the PMd. Deep brain stimulation (DBS) of the subthalamic nucleus has become an established treatment option in PD in addition to oral dopaminergic replacement therapy and can complement PAS protocols. Against this background, we now propose to explore alterations in basal ganglia-PMd-M1 plasticity in PD using a novel PAS protocol where STN-DBS is coupled with PMd-M1-TMS applied in DBS stimulated PD patients in the OFF and On state. Demonstrating these cortical-subcortical associative plasticity circuits in PD can help understanding the underlying mechanisms of cortical plasticity, as well as motor network alterations in PD and may deepen our understanding of the therapeutic effects of DBS in these patients. Such information are essential for further developing strategies to foster plasticity functions in these patients and other neurodegenerative disorders.