Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, 44106, USA.
Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, 44106, USA.
Brain Stimul. 2018 Sep-Oct;11(5):1140-1150. doi: 10.1016/j.brs.2018.05.008. Epub 2018 May 12.
High frequency (∼130 Hz) deep brain stimulation (DBS) of the subthalamic region is an established clinical therapy for the treatment of late stage Parkinson's disease (PD). Direct modulation of the hyperdirect pathway, defined as cortical layer V pyramidal neurons that send an axon collateral to the subthalamic nucleus (STN), has emerged as a possible component of the therapeutic mechanisms. However, numerous questions remain to be addressed on the basic biophysics of hyperdirect pathway stimulation.
Quantify action potential (AP) initiation, propagation, and cortical invasion in hyperdirect neurons during subthalamic stimulation.
We developed an anatomically and electrically detailed computational model of hyperdirect neuron stimulation with explicit representation of the stimulating electric field, axonal response, AP propagation, and synaptic transmission.
We found robust AP propagation throughout the complex axonal arbor of the hyperdirect neuron. Even at therapeutic DBS frequencies, stimulation induced APs could reach all of the intracortical axon terminals with ∼100% fidelity. The functional result of this high frequency axonal driving of the thousands of synaptic connections made by each directly stimulated hyperdirect neuron is a profound synaptic suppression that would effectively disconnect the neuron from the cortical circuitry.
The synaptic suppression hypothesis integrates the fundamental biophysics of electrical stimulation, axonal transmission, and synaptic physiology to explain a generic mechanism of DBS.
高频（∼130Hz）丘脑下核深部脑刺激（DBS）是治疗晚期帕金森病（PD）的一种成熟的临床疗法。皮质层 V 锥体神经元的直接调制，定义为发送轴突侧支到丘脑下核（STN）的神经元，已经成为治疗机制的一个可能组成部分。然而，关于超直接通路刺激的基本生物物理学，仍有许多问题需要解决。
在丘脑下刺激时量化超直接神经元中的动作电位（AP）起始、传播和皮质入侵。
我们开发了一种超直接神经元刺激的解剖学和电详细的计算模型，具有刺激电场、轴突反应、AP 传播和突触传递的明确表示。
我们发现超直接神经元复杂的轴突树突中存在强大的 AP 传播。即使在治疗性 DBS 频率下，刺激诱导的 AP 也可以以约 100%的保真度到达所有的皮质内轴突末梢。每个直接刺激的超直接神经元形成的数千个突触连接的这种高频轴突驱动的功能结果是深刻的突触抑制，这将有效地将神经元与皮质回路断开。
突触抑制假说将电刺激、轴突传递和突触生理学的基本生物物理学结合起来，解释了 DBS 的一种通用机制。
