Santaniello Sabato, McCarthy Michelle M, Montgomery Erwin B, Gale John T, Kopell Nancy, Sarma Sridevi V
Institute for Computational Medicine and
Department of Mathematics and Statistics, Boston University, Boston, MA 02215;
Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):E586-95. doi: 10.1073/pnas.1406549111. Epub 2015 Jan 26.
High-frequency deep brain stimulation (HFS) is clinically recognized to treat parkinsonian movement disorders, but its mechanisms remain elusive. Current hypotheses suggest that the therapeutic merit of HFS stems from increasing the regularity of the firing patterns in the basal ganglia (BG). Although this is consistent with experiments in humans and animal models of Parkinsonism, it is unclear how the pattern regularization would originate from HFS. To address this question, we built a computational model of the cortico-BG-thalamo-cortical loop in normal and parkinsonian conditions. We simulated the effects of subthalamic deep brain stimulation both proximally to the stimulation site and distally through orthodromic and antidromic mechanisms for several stimulation frequencies (20-180 Hz) and, correspondingly, we studied the evolution of the firing patterns in the loop. The model closely reproduced experimental evidence for each structure in the loop and showed that neither the proximal effects nor the distal effects individually account for the observed pattern changes, whereas the combined impact of these effects increases with the stimulation frequency and becomes significant for HFS. Perturbations evoked proximally and distally propagate along the loop, rendezvous in the striatum, and, for HFS, positively overlap (reinforcement), thus causing larger poststimulus activation and more regular patterns in striatum. Reinforcement is maximal for the clinically relevant 130-Hz stimulation and restores a more normal activity in the nuclei downstream. These results suggest that reinforcement may be pivotal to achieve pattern regularization and restore the neural activity in the nuclei downstream and may stem from frequency-selective resonant properties of the loop.
高频深部脑刺激（HFS）在临床上被公认为可治疗帕金森氏运动障碍，但其机制仍不清楚。目前的假说是，HFS的治疗效果源于增加基底神经节（BG）中放电模式的规律性。尽管这与帕金森病患者和动物模型的实验结果一致，但尚不清楚这种模式正则化是如何由HFS产生的。为了解决这个问题，我们构建了正常和帕金森病状态下皮质 - BG - 丘脑 - 皮质回路的计算模型。我们模拟了丘脑底核深部脑刺激在刺激部位近端以及通过顺行和逆行机制在远端对几种刺激频率（20 - 180 Hz）的影响，相应地，我们研究了回路中放电模式的演变。该模型紧密再现了回路中每个结构的实验证据，并表明近端效应和远端效应单独都不能解释观察到的模式变化，而这些效应的综合影响随着刺激频率的增加而增加，并且对HFS具有显著意义。在近端和远端诱发的扰动沿着回路传播，在纹状体中会合，并且对于HFS，正向重叠（增强），从而在纹状体中引起更大的刺激后激活和更规则的模式。对于临床相关的130 Hz刺激，增强作用最大，并恢复了下游核团中更正常的活动。这些结果表明，增强作用可能是实现模式正则化和恢复下游核团神经活动的关键，并且可能源于回路的频率选择性共振特性。
