Subthalamic stimulation modulates cortical motor network activity and synchronization in Parkinson's disease

Abstract

Dynamic modulations of large-scale network activity and synchronization are inherent to a broad spectrum of cognitive processes and are disturbed in neuropsychiatric conditions including Parkinson's disease. Here, we set out to address the motor network activity and synchronization in Parkinson's disease and its modulation with subthalamic stimulation. To this end, 20 patients with idiopathic Parkinson's disease with subthalamic nucleus stimulation were analysed on externally cued right hand finger movements with 1.5-s interstimulus interval. Simultaneous recordings were obtained from electromyography on antagonistic muscles (right flexor digitorum and extensor digitorum) together with 64-channel electroencephalography. Time-frequency event-related spectral perturbations were assessed to determine cortical and muscular activity. Next, cross-spectra in the time-frequency domain were analysed to explore the cortico-cortical synchronization. The time-frequency modulations enabled us to select a time-frequency range relevant for motor processing. On these time-frequency windows, we developed an extension of the phase synchronization index to quantify the global cortico-cortical synchronization and to obtain topographic differentiations of distinct electrode sites with respect to their contributions to the global phase synchronization index. The spectral measures were used to predict clinical and reaction time outcome using regression analysis. We found that movement-related desynchronization of cortical activity in the upper alpha and beta range was significantly facilitated with 'stimulation on' compared to 'stimulation off' on electrodes over the bilateral parietal, sensorimotor, premotor, supplementary-motor, and prefrontal areas, including the bilateral inferior prefrontal areas. These spectral modulations enabled us to predict both clinical and reaction time improvement from subthalamic stimulation. With 'stimulation on', interhemispheric cortico-cortical coherence in the beta band was significantly attenuated over the bilateral sensorimotor areas. Similarly, the global cortico-cortical phase synchronization was attenuated, and the topographic differentiation revealed stronger desynchronization over the (ipsilateral) right-hemispheric prefrontal, premotor and sensorimotor areas compared to 'stimulation off'. We further demonstrated that the cortico-cortical phase synchronization was largely dominated by genuine neuronal coupling. The clinical improvement with 'stimulation on' compared to 'stimulation off' could be predicted from this cortical decoupling with multiple regressions, and the reduction of synchronization over the right prefrontal area showed a linear univariate correlation with clinical improvement. Our study demonstrates wide-spread activity and synchronization modulations of the cortical motor network, and highlights subthalamic stimulation as a network-modulating therapy. Accordingly, subthalamic stimulation may release bilateral cortical computational resources by facilitating movement-related desynchronization. Moreover, the subthalamic nucleus is critical to balance inhibitory and facilitatory cortical players within the motor program.

Keywords: Parkinson’s disease; deep brain stimulation; subthalamic nucleus; synchronization, cortex.

© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Figures

Figure 1

Grand averages of the time-frequency spectra of muscular movement-related spectral pertubations (individual spectra were bootstrap thresholded). No significant differences of M. flexor digitorum (agonist; FD) or M. extensor digitorum (antagonist; ED) activation patterns were found between StimOff and StimOn, i.e. no differences in activation onset, activation strength and frequency response were present, respectively. x-axis: Time (ms), where time ‘0’ denotes registration of the finger tap; y-axis: Frequency (Hz); activity is coded in colour with warm colours indicating stronger activity (colour bar).

Figure 2

Time-frequency spectra of the cortical movement-related spectral pertubations (multiplots). At each of the 64 electrode positions, a time-frequency plot is given. Grand average spectra of the cortical electrodes are given in StimOff (A) and StimOn (B), and StimOn minus StimOff (C) including the statistical comparison and correction for multiple comparisons using a cluster-based correction method (Maris and Oostenveld, 2007). Non-significant time-frequency samples are ‘zeroed out’ and given in green. The time-frequency representations of the left sensorimotor region of interest (‘C3’) are given for StimOff (D), StimOn (E), and StimOn minus StimOff (F). x-axis: Time (ms), where time ‘0’ denotes registration of the finger tap; y-axis: Frequency (Hz).

Figure 3

Time-frequency cross-coherence between cortical regions of interest. The first column indicates the grand average spectra in StimOff, the second column in StimOn. The coherence magnitude is indicated by the colour bar (scale from 0.06 to 0.16). As third column, the statistical comparison between StimOff and StimOn (uncorrected) is given, and the fourth column includes correction for multiple comparisons. The difference in coherence magnitude StimOn minus StimOff is indicated by the right colour bar, and non-significant time-frequency samples are ‘zeroed out’ and masked in green (scaled from 0.06 to −0.06). x-axis: Time (ms), where time ‘0’ denotes registration of the finger tap; y-axis: Frequency (Hz).

Figure 4

Topographic differentiation of the cortico-cortical phase synchronization in StimOff and StimOn, and difference of StimOn minus StimOff. In the latter column significant desynchronizations between conditions are indicated by asterisks. Colour bars indicate the magnitude of cortico-cortical phase-synchronization with warmer colors indicating stronger phase synchronization.

Figure 5

Linear correlation of the topographic differentiation of the global phase synchronization index. Indices are shown for the right inferior prefrontal cortex (‘F10’ electrode; difference StimOn minus StimOff) and clinical improvement (left) in the UPDRS III (StimOn minus StimOff) and reaction time difference (right; StimOn minus StimOff) in the 12 patients with significant global phase synchronization in both StimOff and StimOn conditions. The correlations were performed on data from the ‘premovement period’ in which 12 patients had significant phase synchronization.