期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：6
页码：E586-E595
DOI：10.1073/pnas.1406549111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceWe investigated the therapeutic mechanisms of high-frequency stimulation (HFS) in Parkinson's disease by developing a computational model of the cortico-basal ganglia-thalamo-cortical loop in normal and parkinsonian conditions under the effects of stimulation at several frequencies. We found that the stimulation injected in the loop elicits neural perturbations that travel along multiple pathways with different latencies and rendezvous in striatum (one of the basal ganglia). If the stimulation frequency is high enough, these perturbations overlap (reinforcement) and cause more regular, stimulus-locked firing patterns in striatum. Overlap is maximal at clinically relevant HFS and restores more normal activity in the remaining structures of the loop. This suggests that neural restoration and striatal reinforcement may be a therapeutic merit and mechanism of HFS, respectively. 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.
