Movement-related changes in local and long-range synchronization in Parkinson's disease revealed by simultaneous magnetoencephalography and intracranial recordings

Abstract

Functional neurosurgery has afforded the opportunity to assess interactions between populations of neurons in the human cerebral cortex and basal ganglia in patients with Parkinson's disease (PD). Interactions occur over a wide range of frequencies, and the functional significance of those >30 Hz is particularly unclear. Do they improve movement, and, if so, in what way? We acquired simultaneously magnetoencephalography and direct recordings from the subthalamic nucleus (STN) in 17 PD patients. We examined the effect of synchronous and sequential finger movements and of the dopamine prodrug levodopa on induced power in the contralateral primary motor cortex (M1) and STN and on the coherence between the two structures. We observed discrete peaks in M1 and STN power at 60-90 Hz and at 300-400 Hz. All these power peaks increased with movement and levodopa treatment. Only STN activity at 60-90 Hz was coherent with activity in M1. Directionality analysis showed that STN gamma activity at 60-90 Hz tended to drive gamma activity in M1. The effects of levodopa on both local and distant synchronization at 60-90 Hz correlated with the degree of improvement in bradykinesia-rigidity as did local STN activity at 300-400 Hz. Despite this, there were no effects of movement type, nor interactions between movement type and levodopa in the STN, nor in the coherence between STN and M1. We conclude that synchronization at 60-90 Hz in the basal ganglia cortical network is prokinetic but likely through a modulatory effect rather than any involvement in explicit motor processing.

Figures

Figure 1.

Artifact rejection criteria and validation of robust averaging. A, Fifty trials from one subject showing the spike artifacts in STN–LFP. The red lines indicate the rejection threshold that was used for STN–LFP data (5 SDs). B, Distribution of STN–LFP artifacts in trial time. The rate of artifact occurrence increased around the button press, peaking at ∼0.5%. If an artifact occurred within the boundaries marked by the red lines, the corresponding trial was excluded from analysis of power. C, Difference time series for 50 trials of M1 virtual electrode data. The red lines indicate the rejection threshold that was used for these data (1.5 SDs). D, Distribution of M1 artifacts in trial time. The rate of artifact occurrence increased around the button press, peaking below 1%. If an artifact occurred within the boundaries marked by the red lines, the corresponding trial was excluded from analysis of power. E, Results of simulations aimed at validating the robust averaging method. The top row shows the results of time–frequency analysis for synthetic data contaminated with artifacts taken from the real data. The second row shows similar analysis on simulated data without artifacts, and the third row shows the results of analysis of contaminated data when using robust averaging. The simulated data were based on real data from all the subjects used in the actual data analysis and one experimental condition (synchronous button presses with the right-hand ON drug). To assess reproducibility of these results, the simulation was repeated with eight different sets of artifacts taken from all the eight experimental conditions. The results were summarized by averaging the power and coherence in 15–35 Hz range. The bottom row shows the mean and SD of these eight repetitions for contaminated signals (black), clean signals (red), and robust averaging results (green). The units in all plots are change from baseline in percentage.

Figure 2.

Power responses induced by the button press in contralateral M1 and STN. A, Average time–frequency images. Induced responses were baseline corrected (baseline −8 to −5 s) and averaged across conditions. Separate t tests were performed for dominant and nondominant hemispheres and for 0–100 and 100–600 Hz ranges (each condition has 2 spectrograms). The top row shows unthresholded mean time–frequency images relating to M1 (leftmost 4 panels) and STN power change (rightmost 4 panels), and the bottom row reports the corresponding significant positive (white) and negative (black) clusters (p < 0.01, cluster-level FWE correction). B, Induced responses of individual hemispheres. The individual responses whose averages are presented in A were averaged between 0 and 1 s relative to the button press. Dominant and nondominant hemispheres are presented together. Note the presence of clear gamma activity in the 40–90 Hz range in many of the individual hemispheres as well as 300–400 Hz activity clearly present in four hemispheres (for details see Table 2).

Figure 3.

Effect of drug on power responses induced by button press in the contralateral M1 and STN. The top row shows the unthresholded contrast images corresponding to the effect of drug in the ANOVA, and the bottom row reports the corresponding significant clusters (p < 0.01, cluster-level FWE correction).

Figure 4.

Effect of task on power responses induced by button press in the contralateral M1 and STN. A, The top row shows the unthresholded contrast images [in pairs of low (0–100 Hz) and high (100–600 Hz) frequency spectrograms] corresponding to the effect of task in the ANOVA, and the bottom row reports the corresponding significant clusters (p < 0.01, cluster-level FWE correction). B, Averaged power responses (in the 0–100 Hz band only) in M1 and STN for each of the two tasks separately.

Figure 5.

Contralateral M1–STN coherence responses induced by the button press. Coherence images were baseline corrected (baseline −8 to −5 s) and averaged across conditions. Separate t tests were performed for dominant and nondominant hemispheres and for 0–100 and 100–600 Hz ranges. Only 0–100 Hz results are shown because for 100–600 Hz there were no significant effects. The top row shows unthresholded mean time–frequency images, and the bottom row reports the corresponding significant clusters (p < 0.01, cluster-level FWE correction).

Figure 6.

Effects of experimental condition on M1–STN coherence responses. A, The top row shows the unthresholded contrast of M1–STN coherence images corresponding to the effects of drug and task in the ANOVA, and the bottom row reports the corresponding significant clusters (p < 0.01, cluster-level FWE correction). B, Effect of drug on coherence responses in individual hemispheres. Differences between ON and OFF drug coherence images (collapsed across the task factor) were averaged between −0.5 and 0.5 s relative to the button press. The red line corresponds to the localization results in C. C, Localization of gamma coherence in an individual subject (subject 11 left hemisphere). DICS beamformer was applied to button presses with the contralateral hand ON drug pooled across tasks. The time range for the analysis was −0.5 to 0.5 s relative to the button press, and the frequency range was 65–85 Hz. The image was transformed to MNI template space and overlaid on the template structural image. The peak coherence was observed at MNI coordinates (−30, −4, 64).

Figure 7.

Narrow band coherence peaks in the gamma range were not caused by artifacts. Coherence computation was repeated for the data ON drug from the five hemispheres showing clear gamma coherence peaks after excluding trials with artifacts in the window −1 to 1 s relative to the button press in either M1 or STN signal. The criteria for exclusion were the same as for power analysis (see Materials and Methods and Fig. 1). Time–frequency decomposition was the same as for Figures 5 and 6, and the coherence values were averaged between −0.5 and 0.5 s relative to the button press. Raw data for all the trials are shown as well as the coherence spectra. The subject identification numbers and the trial numbers are detailed on the right.

Figure 8.

Correlations between drug-induced changes in power and coherence responses with drug-induced changes in clinical scores. Repeated measures ANCOVA was performed with contralateral hemibody bradykinesia-rigidity scores as an additional regressor. The sign of the scores was changed to negative so that positive correlations would correspond to clinical improvement. A, The top row shows unthresholded contrast images corresponding to the effect of clinical score in the ANCOVA (the units are percentage change from baseline per unit change in motor UPDRS), and the bottom row reports the corresponding significant positive (white) and negative (black) clusters (p < 0.01, cluster-level FWE correction). B, Relationship between the effects of drug in STN power and coherence responses in the 60–90 Hz range and clinical improvement. Power and coherence responses were averaged over −0.5 to 0.5 s window. The solid lines show linear fit to the data (for STN power, r2 = 0.27, p = 0.01; for coherence, r2 = 0.42, p = 0.001).

Figure 9.

Directionality of M1–STN coupling. Coherence and nonparametric Granger causality were computed for individual hemispheres (the data were combined across conditions). This analysis was done for two 1 s windows: baseline, −6 to −5 s, and movement, −0.5 to +0.5 s relative to the button press. Note that, in the baseline period, coherence is present in the beta band with the predominant direction being from M1 to STN, whereas in the movement period, coherence is present in the gamma band with the predominant direction being from STN to M1. In both cases, there is clear correspondence between coherence and Granger causality results.