Objective/Rationale:
Current deep brain stimulation (DBS) does not take advantage of the latest discoveries of Parkinson’s disease (PD) pathophysiology which may explain some of its limitations. Abnormal synchronization in the basal ganglia network has recently been proposed as a key feature of PD. In detailed theoretical studies, we have shown that multisite coordinated reset stimulation (MCRS) desynchronizes the activity within a given network. The goal of the present project is to assess the efficacy of MCRS in a model of parkinsonism.
Project Description:
MCRS of the subthalamic nucleus will be performed in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin treated pre-clinical models. MCRS consists on the application of brief high-frequency pulse trains through pairs of the different electrode contacts (0-1, 1-2 and 2-3) at different times. The effect of MCRS will be documented by a video-taped assessment of disability scores which will be rated by two experienced and blinded raters. The best stimulation parameters will be determined by varying (i) the frequency of burst delivery, (ii) the number of cycles “on” per 5 cycles and (iii) the stimulation order through the different pairs of electrode contacts. Each protocol will be applied for three days. Before the application of the next MCRS protocol, stimulation will be stopped until clinical ratings return to baseline.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Current DBS is effective in the treatment of late stage PD. However, its therapeutic effect decreases over time, a relevant number of patients have an unsatisfactory outcome despite proper electrode placement and the DBS generator has to be replaced after some years. MCRS is an innovative and pathophysiology driven stimulation technique with the potential to replace current DBS in the future.
Anticipated Outcome:
The present study will allow the “proof of concept” validation in pre-clinical models that MCRS reduces parkinsonism. It would further allow (i) to define the best stimulation parameters for obtaining maximal clinical improvement, both in terms of the magnitude of reversal and benefit duration, and (ii) to provide important information for future clinical studies in PD patients.
Final Outcome
Coordinated reset stimulation (CR) is an innovative form of deep brain stimulation (DBS). According to theoretical studies, it may provide sustained symptom relief in PD beyond the time of stimulation by reshaping abnormal synaptic connectivity. In the present study, CR has been applied for two hours daily in four parkinsonian models. The primary outcome measures were the change in locomotor activity and disability scoring. The behavioral assessment was done immediately after each CR session and for ten more days once CR has been stopped. Our preliminary results show that CR increases locomotor activity in parkinsonian models. Interestingly, the effect is more important with low intensities (1/3 of classical DBS). The increase in locomotor activity persisted for several days after the last CR session. This latter observation endorses the hypothesis that CR may exert its beneficial effects through anti-kindling properties. Ongoing study progress will allow to define the best stimulation parameters and to provide important information for a future clinical trial in PD patients.