Objective/Rationale:
Coordinated Reset (CR) stimulation improved locomotor activity in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP)-treated pre-clinical model in a “proof of concept” study. Compared to classical DBS, CR stimulation had a sustained benefit on locomotor activity lasting for up to 40 days after the end of stimulation. The main goal of the present study is to validate CR stimulation in additional experiments in an MPTP-treated pre-clinical model to make this technique ready for translation into a clinical trial in PD patients.
Project Description:
CR stimulation of the subthalamic nucleus will be performed in an MPTP-treated pre-clinical model. The effect of CR stimulation will be documented by an automated evaluation of locomotor activity and a video-taped assessment of disability scores. In theoretical models, CR stimulation is most effective when the stimulation frequency is close to the frequency of abnormal basal ganglia oscillations. Accordingly, the relationship between CR stimulation frequency and the peak frequency of abnormal local field potential activity will be assessed in the first part of the study. In a second step, the effect of CR stimulation with an implantable device and the most effective CR stimulation frequency will be tested and compared to classical DBS and l-dopa.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Classical DBS is effective in the treatment of late stage PD. However, its therapeutic effect decreases over time, a relevant number of patients have side effects and/or an unsatisfactory outcome despite proper electrode placement, and the DBS generator has to be replaced after some years. CR stimulation is an innovative and pathophysiology driven stimulation technique with the potential to replace classical DBS in the future.
Anticipated Outcome:
The expected outcome is the validation of CR stimulation in an MPTP-treated pre-clinical model to make this technique ready for translation into a clinical trial in PD patients.
Final Outcome
Our study shows that Coordinated Reset (CR) neuromodulation with an implantable device has acute effects on motor function in pre-clinical models. Similar to the results of our previous MJFF-sponsored study, CR neuromodulation also showed sustained, long-lasting aftereffects on motor behavior that were not observed with classical deep brain stimulation. Our study provides some evidence that CR neuromodulation with a frequency close or identical to abnormal basal ganglia activity is most effective, but this observation only relies on the data of one subject. Beyond the encouraging results in pre-clinical models, we conducted a clinical pilot study that confirmed positive effects on motor control and abnormal basal ganglia activity in six patients with Parkinson’s disease (PD). Taken together, these observations encourage further development of CR neuromodulation for treating motor symptoms in PD patients.