High-frequency stimulation of the subthalamic nucleus suppresses oscillatory beta activity in patients with Parkinson's disease in parallel with improvement in motor performance

Abstract

High-frequency stimulation (HFS) of the subthalamic nucleus (STN) is a well-established therapy for patients with severe Parkinson's disease (PD), but its mechanism of action is unclear. Exaggerated oscillatory synchronization in the beta (13-30 Hz) frequency band has been associated with bradykinesia in patients with PD. Accordingly, we tested the hypothesis that the clinical benefit exerted by STN HFS is accompanied by suppression of local beta activity. To this end, we explored the after effects of STN HFS on the oscillatory local field potential (LFP) activity recorded from the STN immediately after the cessation of HFS in 11 PD patients. Only patients that demonstrated a temporary persistence of clinical benefit after cessation of HFS were analyzed. STN HFS led to a significant reduction in STN LFP beta activity for 12 s after the end of stimulation and a decrease in motor cortical-STN coherence in the beta band over the same time period. The reduction in LFP beta activity correlated with the movement amplitude during a simple motor task, so that a smaller amount of beta activity was associated with better task performance. These features were absent when power in the 5-12 Hz frequency band was considered. Our findings suggest that HFS may act by modulating pathological patterns of synchronized oscillations, specifically by reduction of pathological beta activity in PD.

Figures

Figure 1.

Schema of the experimental paradigm with LFP recordings at rest (A) and motor task (B). The horizontal gray line represents the 200 s time period of HFS of the STN during one cycle of the experiment. The horizontal black line represents the time period of LFP recordings. The thick black line in A marks the period taken as baseline (100–140 s), and the boxes in B represent hand movements (interleaved by 30 s rest). Hand movements were performed once during HFS and three times after the end of HFS (post-HFS 1–3).

Figure 2.

Power spectrum averaged across all patients off medication, estimated using the contact pairs displaying the maximum β power per macroelectrode during the baseline period from 100 to 140 s after the end of HFS. Power is expressed as a percentage of total power in the 5–100 Hz range. Note that there is no distinct peak of activity above 30 Hz off medication.

Figure 3.

Time–frequency plot showing LFP activity after the end of HFS at time 0 expressed as a percentage change from baseline activity taken from 100 to 140 s after cessation of stimulation. Top, Mean relative power across 12 sides shows a suppression of β activity after HFS (blue colors) followed by a relative increase in β power (red colors) that was observed in some patients. Bottom, Corresponding Z scores as determined by Wilcoxon's signed rank test thresholded at Z = ±1.9, confirming significant β suppression that persists for ∼20 s after the end of HFS.

Figure 4.

Time course of mean low-frequency (5–12 Hz; black line) and mean β (13–30 Hz; gray line) power after the end of HFS expressed as a percentage change from baseline activity (100–140 s after HFS). Time-evolving p value (Student's t test) revealed a significant suppression of β activity for 12 s after the end of HFS compared with baseline (significant time period is indicated by horizontal black line). Note that power suppression after HFS is frequency specific, and no significant change occurred in the 5–12 Hz band.

Figure 5.

Top, Time–frequency plot of power changes after HFS in case 1. The average of three sessions of 200 s HFS and subsequent LFP recordings is shown. Note that β activity ∼15 Hz is completely suppressed for ∼30 s and then slowly recurs over the following 40 s, paralleling a decrease in movement amplitude (bottom). Bottom, Mean RMS movement amplitude from three separate sessions in case 1. The movements were performed for 30 s each with the first movement occurring just before cessation of HFS (gray column). The three subsequent movement periods followed after HFS had been stopped (post-HFS 1–3; black columns) and were interleaved by 30 s of rest.

Figure 6.

RMS movement amplitude averaged across all sessions in all patients (n = 12 sides) during (gray) and post-HFS (black) expressed as a percentage change from the amplitude of the last (fourth) movement. Movement amplitude is highest during HFS and shows a significant stepwise decrease over time after the end of HFS (Wilcoxon signed rank test with stepwise correction for multiple comparisons). *p < 0.05; **p < 0.01.

Figure 7.

Scatter plot showing the correlation between individual β activity (mean STN β power over 20 s before start of the corresponding contralateral hand movement) and movement amplitude (mean RMS movement amplitude over 20 s), both expressed as a percentage change from the last (fourth) trial in each session (n = 11 sides). The plot includes post-HFS periods 1 and 2. The significant negative correlation (r = −0.555; p = 0.007) suggests that reduced β activity was associated with better motor performance in the patients. Dotted lines represent 95% confidence limits.

Figure 8.

Mean Fisher-transformed STN LFP-EEG coherence values (n = 8) for 5–12 Hz, 13–30 Hz, and individual β activity over the time periods of 0–12 s after the end of HFS and during baseline from 128 to 140 s. Note the significant decrease in STN LFP-EEG in the individual β band (*p < 0.05) after HFS (gray) compared with baseline (black). A similar trend is shown for coherence within the broad β band (13–30 Hz; p = 0.06) but not for low-frequency coherence.

Figure 9.

Oscillatory activity recorded from left GPi (contact pair 01) in case 11 during and after bilateral STN HFS. Power is averaged across three sessions of HFS. HFS and rest recordings were performed for 200 s each (HFS period is indicated by the red horizontal line). Note that β power is reduced during STN HFS and recurs shortly after the end of HFS (indicated by the black vertical line). Artifact at ∼43 Hz is a subharmonic of HFS at 130 Hz.