Dopaminergic therapy in Parkinson's disease decreases cortical beta band coherence in the resting state and increases cortical beta band power during executive control

Abstract

It is not yet well understood how dopaminergic therapy improves cognitive and motor function in Parkinson's disease (PD). One possibility is that it reduces the pathological synchronization within and between the cortex and basal ganglia, thus improving neural communication. We tested this hypothesis by recording scalp electroencephalography (EEG) in PD patients when On and Off medication, during a brief resting state epoch (no task), and during performance of a stop signal task that is thought to engage two partially overlapping (or different) frontal-basal-ganglia circuits. For resting state EEG, we measured pair-wise coherence between scalp electrodes in several frequency bands. Consistent with previous studies, in the Off medication state, those patients with the greatest clinical impairment had the strongest coherence, especially in the beta band, indicating pathological over-synchronization. Dopaminergic medication reduced this coherence. For the stop signal task, On vs. Off medication increased beta band power over right frontal cortex for successful stopping and over bilateral sensorimotor cortex for going, especially for those patients who showed greater clinical improvement. Thus, medication reduced pathological coherence in beta band at rest and increased task related beta power for two potentially dissociable cortico-basal ganglia circuits. These results support the hypothesis that dopaminergic medication in PD improves neural communication both at rest and for executive and motor function.

Keywords: Levodopa; Response inhibition; Resting state EEG; Stop-signal task.

Figures

Fig. S1

Dopaminergic medication does not modulate mean power in PD patients. Mean power estimates (Pxx) in delta, theta, alpha, beta and gamma bands across the 32 channel locations for control subjects, patients On and Off medication. An analysis using 2-way ANOVA of all groups and frequency bands was performed at each electrode. A main effect of group was observed at PO3, O2, PO4 and P4 (F2,4 = 18.20, 16.81, 14.01, 17.90 all P < 0.05). Further analysis at these electrodes was performed using paired and unpaired sample t-tests for each frequency band. In the theta band, On had more theta compared to controls at PO3, O2, PO4 and P4 t30 = 2.16, 2.41, 2.21, 2.38 all P < 0.05; Off had more theta compared to controls at PO3 and O2 t30 = 2.05, 2.21, all P < 0.05. Medication related changes in each frequency band were studied using a repeated measures ANOVA with two within subject factors, medication (On/Off) and channel (32 channels). There was no main effect of medication in any frequency band (delta F1,31 = 0.33, P = 0.57; theta F1,31 = 0.72, P = 0.41; alpha F1,31 = 0.10, P = 0.74; beta F1,31 = 0.002, P = 0.96; gamma F1,31 = 0.18, P = 0.67).

Fig. S2

Beta and gamma band power is increased over right frontal cortex for all stop trials (successful and failed combined) condition. Time-frequency results are shown for the right frontal cluster (F8, FC6). Plots are generated from trials time-locked to the stop signal, here corresponding to 0 ms. T-score significance values are displayed as color; t-score values reach significance at t14 = 2.14 (PD On and Off) and t15 = 2.13 (controls). Significance at P < 0.05 is outlined in black indicating positive direction and red indicating negative direction.

Fig. S3

Comparison of all stop trials (successful and failed combined) condition for left and right cluster. Time-frequency results are shown for the left frontal cluster (F7, FC5) and the right cluster (F8, FC6). Plots are generated from trials time-locked to the stop signal, here corresponding to 0 ms. T-score significance values are displayed as color; t-score values reach significance at t13 = 2.16 (high vs low and On vs Off comparison).Significance at P < 0.05 is outlined in black indicating positive direction and red indicating negative direction. The mean beta t-score is higher for the right cluster around the time of stopping.

Fig. S4

Mu and beta band power of right frontal cortex during Go trials. A. Go trials for the On medication condition for high and low improvement groups. B. Go trials for the Off medication condition for high and low improvement groups. C. Go trials for the On vs Off between-session comparison for high and low improvement groups. D. Go trials for On vs Off medication for the high vs low improvement group comparison. Time-frequency results are shown for the right frontal cluster (F8, FC6). Plots are generated from trials time-locked to the button press, here corresponding to 0 ms. T-score significance values are displayed as color; t-score values reach significance at t7 = 2.36 (high improvement group), t6 = 2.44 (low improvement group) and t13 = 2.16 (high vs low and On vs Off comparison). Significance at P < 0.05 is outlined in black indicating positive direction and red indicating negative direction.

Fig. 1

Stop-signal task: Each trial began with a fixation cross, followed 500 ms later by the appearance of a white square (Go signal). The square appeared to either the left or the right of the fixation cross requiring a response from the corresponding hand. Stop trials were identical to Go trials, except they were less likely (33% of trials) and the white square turned red after a variable delay (stop signal delay).

Fig. 2

Correlation between scalp-level coherence and UPDRS scores. A. An example plot of coherence values at f = 21.1 Hz (beta) Gaussian frequency filter for channels 7 and 18 (Coh21.17,18) plotted vs UPDRS for each subject (15 subjects) in the Off medication condition resulting in a Pearson correlation coefficient, r = 0.51 and significance, P = 0.02. B. Grid for 32 channels in beta band (f = 21.1 Hz) showing correlation (r) of pair-wise coherence with UPDRS per subject, red indicating positive correlation and blue indicating negative correction. C. Grid for 32 channels in beta band (f = 21.1 Hz) showing significant correlation pairs at P < 0.05. D. The total number of significant positively correlated pairs in the Off medication state computed at each of the individual Gaussian frequency filters (where e.g. 18% significant pairs at 30 Hz means that 18% of all the 496 possible pairs showed a significant correlation, across subjects, between coherence and UPDRS score). E. The total number of significant positively correlated pairs computed at each of the individual Gaussian frequency filters of Off Medication state (left lower panel; same as Panel D), On medication state (middle lower panel) and the Off–On difference (right lower panel). Those patients with greater clinical impairment had stronger coherence in the Off state, with more pairs positively correlated in the beta band. The correlation between coherence values and UPDRS scores for patients is weaker On medication. The reduction in coherence in beta and gamma bands with medication is strongest in those patients who show the greatest clinical improvement, where positive correlations indicate that greater reductions in coherence correspond to greater clinical improvement as indicated by the UPDRS scores. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Stop signal task results A. Mean Go RTs for controls and patients On and Off medication. There is no significant difference between the groups. B. Mean SSRTs for controls and patients On and Off medication. There are significant differences between the controls and patients On medication (t30 = 2.07, P < 0.05); as well as between the controls and patients Off medication sessions (t30 = 2.47, P < 0.05).

Fig. 4

Beta and gamma band power of right frontal cortex is increased for stop trials in the high improvement group. A. All stop trials (successful and failed combined) for the On medication condition for high and low improvement groups. B. All stop trials for the Off medication condition for high and low improvement groups. C. All stop trials for the On vs Off between-session comparison for high and low improvement groups. Time-frequency results are shown for the right frontal cluster (F8, FC6). Plots are generated from trials time-locked to the stop signal, here corresponding to 0 ms. T-score significance values are displayed as color; t-score values reach significance at t7 = 2.36 (high improvement group) and t6 = 2.44 (low improvement group). Significance at P < 0.05 is outlined in black indicating positive direction and red indicating negative direction. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 5

Medication increases right frontal beta band power for stopping more in the high than low improvement group. Successful stop and all stop (successful and failed combined) trials for On vs Off medication for the high vs low improvement group comparison. There is a significant increase in beta power starting from the time of the stop signal and peaking around the time of SSRT. Time-frequency results are shown for the right frontal cluster (F8, FC6). Plots are generated from trials time-locked to the stop signal, corresponding to 0 ms here. T-score significance values are displayed as color. T-score significance values are displayed as color; t-score values reach significance at t13 = 2.16 (high vs low and On vs Off comparison). Significance at P < 0.05 is outlined in black indicating positive direction and red indicating negative direction. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 6

Time and frequency averaged beta frequency t-score values for On vs Off medication for the high vs low improvement group comparison displayed as a topography map. A. Successful stop trials where 0 ms corresponds to the time of the stop signal. B. Successful Go trials where 0 ms corresponds to the time of the button press. Trials include Go stimulus that appeared on both left and right. T-score significance values are displayed as color; t-score values reach significance at t13 = 2.16 (high vs low and On vs Off comparison). Arrows point to critical regions of increase; the increase in beta for stopping begins and is concentrated more at the right frontal regions, in the time associated with stopping (0–400 ms). The increase in beta while going and post movement is concentrated more at the sensorimotor regions.