Continuous high-frequency deep brain stimulation (DBS) is a widely used therapy for advanced Parkinson's disease (PD) management. However, the mechanisms underlying DBS effects remain enigmatic and are the subject of an ongoing debate. Here, we present and test a closed-loop stimulation strategy for PD in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate model of PD. Application of pallidal closed-loop stimulation leads to dissociation between changes in basal ganglia (BG) discharge rates and patterns, providing insights into PD pathophysiology. Furthermore, cortico-pallidal closed-loop stimulation has a significantly greater effect on akinesia and on cortical and pallidal discharge patterns than standard open-loop DBS and matched control stimulation paradigms. Thus, closed-loop DBS paradigms, by modulating pathological oscillatory activity rather than the discharge rate of the BG-cortical networks, may afford more effective management of advanced PD. Such strategies have the potential to be effective in additional brain disorders in which a pathological neuronal discharge pattern can be recognized.
Bibliographical noteFunding Information:
We thank Abraham Solomon (Department of Ophthalmology, Hadassah University Hospital, Jerusalem, Israel), Genela Morris (Department of Neurobiology, University of Haifa, Israel), Ahmed Moustafa (Center for Molecular and Behavioral Neuroscience, Rutgers University, NJ), Harry Xenias (Center for Molecular and Behavioral Neuroscience, Rutgers University, NJ), Eden Chlamtac (School of Computer Science, Tel Aviv University, Israel), and Timothy Denison (Medtronic Technology, MN) for reviewing early versions of this manuscript; Mati Joshua (Department of Clinical Neurobiology, The Hebrew University School of Medicine, Jerusalem, Israel) for suggestions in experimental design; Alpha-Omega Engineering (Nazareth, Israel) for providing the DSP used in the experiments; Tuvia Kurz for the primate illustrations in Figure 1; and Esther Singer for English editing. This study was supported by the Netherlands friends of the Hebrew University (HUNA) “Fighting against Parkinson,” the Vorst family, and Dekker foundation grants. Authors' contributions: B.R. assembled the experimental setup and wrote the necessary software; B.R. and H.B. designed the experimental paradigm; E.V. performed the primate surgeries, together with M.R.-E (first primate) and Z.I. (second primate); H.B. and B.R. served as anesthesiologist and an assistant in the surgeries, respectively; B.R., M.S., R.M., and M.R.-E performed the experiments; S.N.H. performed the histological analysis; and B.R. and H.B. conducted the analysis and wrote the manuscript. All authors discussed the results, reviewed the manuscript, and made their comments.