Coordinated reset neuromodulation for Parkinson's disease: proof-of-concept study

Abstract

Background: The discovery of abnormal synchronization of neuronal activity in the basal ganglia in Parkinson's disease (PD) has prompted the development of novel neuromodulation paradigms. Coordinated reset neuromodulation intends to specifically counteract excessive synchronization and to induce cumulative unlearning of pathological synaptic connectivity and neuronal synchrony.

Methods: In this prospective case series, six PD patients were evaluated before and after coordinated reset neuromodulation according to a standardized protocol that included both electrophysiological recordings and clinical assessments.

Results: Coordinated reset neuromodulation of the subthalamic nucleus (STN) applied to six PD patients in an externalized setting during three stimulation days induced a significant and cumulative reduction of beta band activity that correlated with a significant improvement of motor function.

Conclusions: These results highlight the potential effects of coordinated reset neuromodulation of the STN in PD patients and encourage further development of this approach as an alternative to conventional high-frequency deep brain stimulation in PD.

Keywords: DBS; Parkinson's disease; STN; beta band oscillation; coordinated reset neuromodulation.

Figure 1

Effect of CR neuromodulation on normalized LFP activity and motor performance in six PD patients. Coordinated reset neuromodulation and measurements followed the experimental scheme in (A) on each of the 3 stimulation days. Example of the raw LFP signal at baseline (B, first day before stimulation) and after 3 days of CR neuromodulation (C, in the evening of the third day of stimulation) and the LFP power spectrum (D) obtained from the patient 3 where an extended spontaneous LFP was obtained before and 1 hour after cessation of CR neuromodulation illustrate the effect of CR neuromodulation. The normalized reduction of UPDRS motor scores and the reduction of the averaged beta band power obtained at the third stimulation day (E, after stimulation) were positively correlated. Effects of CR neuromodulation on normalized individual LFP activity and individual motor performance in six PD patients (F, G, H, I) on the evening of the third day of stimulation. Patients 1 and 2 did not show tremor, and therefore theta band activity was not analyzed in these two patients. The averaged normalized beta band power (K), the average normalized theta band power (L, obtained from the 4 patients with tremor), as well as UPDRS motor score (items 18-31) (M) and UPDRS motor score subitems 20 through 26 (N), improved cumulatively and consistently over 3 days of stimulation. Wilcoxon matched-pairs test was performed to evaluate changes of LFP activity and scores. Significant results are marked by the star (P < 0.05). Please note, because of the small sample size of this exploratory proof of concept study, the statistical analysis has limited explanatory power. Therefore, the beneficial clinical effects observed in all subjects consistently are of more importance. Abbreviations: CR, coordinated reset; LFP, local field potential; UPDRS, Unified Parkinson's Disease Rating Scale.