Group for Neural Theory, Department d'Etudes Cognitives, Ecole Normale Superieure, 29 rue d'Ulm, 75005 Paris, France.
Eur J Neurosci. 2012 Jul;36(2):2240-51. doi: 10.1111/j.1460-9568.2012.08085.x.
Deep brain stimulation (DBS) is a remarkably successful treatment for the motor symptoms of Parkinson's disease. High-frequency stimulation of the subthalamic nucleus (STN) within the basal ganglia is a main clinical target, but the physiological mechanisms of therapeutic STN DBS at the cellular and network level are unclear. We set out to begin to address the hypothesis that a mixture of responses in the basal ganglia output nuclei, combining regularized firing and inhibition, is a key contributor to the effectiveness of STN DBS. We used our computational model of the complete basal ganglia circuit to show how such a mixture of responses in basal ganglia output naturally arises from the network effects of STN DBS. We replicated the diversification of responses recorded in a primate STN DBS study to show that the model's predicted mixture of responses is consistent with therapeutic STN DBS. We then showed how this 'mixture of response' perspective suggests new ideas for DBS mechanisms: first, that the therapeutic frequency of STN DBS is above 100 Hz because the diversification of responses exhibits a step change above this frequency; and second, that optogenetic models of direct STN stimulation during DBS have proven therapeutically ineffective because they do not replicate the mixture of basal ganglia output responses evoked by electrical DBS.
深部脑刺激（DBS）是治疗帕金森病运动症状的一种非常成功的方法。高频刺激基底神经节中的丘脑底核（STN）是主要的临床靶点，但 STN-DBS 的治疗效果在细胞和网络水平上的生理机制尚不清楚。我们着手开始验证以下假设：基底神经节输出核中混合的反应，包括规则的放电和抑制，是 STN-DBS 有效性的关键因素。我们使用完整的基底神经节回路的计算模型来展示这种基底神经节输出的混合反应是如何自然地从 STN-DBS 的网络效应中产生的。我们复制了在灵长类动物 STN-DBS 研究中记录的反应多样化，以表明模型预测的反应混合与治疗性 STN-DBS 一致。然后，我们展示了这种“反应混合”观点如何为 DBS 机制提出新的想法：首先，STN-DBS 的治疗频率高于 100Hz，因为反应的多样化在这个频率以上发生了阶跃变化；其次，DBS 期间直接 STN 刺激的光遗传学模型已被证明在治疗上无效，因为它们不能复制电 DBS 诱发的基底神经节输出反应的混合。
