Motor effects of deep brain stimulation correlate with increased functional connectivity in Parkinson's disease: An MEG study

Abstract

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an established symptomatic treatment in Parkinson's disease, yet its mechanism of action is not fully understood. Locally in the STN, stimulation lowers beta band power, in parallel with symptom relief. Therefore, beta band oscillations are sometimes referred to as "anti-kinetic". However, in recent studies functional interactions have been observed beyond the STN, which we hypothesized to reflect clinical effects of DBS. Resting-state, whole-brain magnetoencephalography (MEG) recordings and assessments on motor function were obtained in 18 Parkinson's disease patients with bilateral STN-DBS, on and off stimulation. For each brain region, we estimated source-space spectral power and functional connectivity with the rest of the brain. Stimulation led to an increase in average peak frequency and a suppression of absolute band power (delta to low-beta band) in the sensorimotor cortices. Significant changes (decreases and increases) in low-beta band functional connectivity were observed upon stimulation. Improvement in bradykinesia/rigidity was significantly related to increases in alpha2 and low-beta band functional connectivity (of sensorimotor regions, the cortex as a whole, and subcortical regions). By contrast, tremor improvement did not correlate with changes in functional connectivity. Our results highlight the distributed effects of DBS on the resting-state brain and suggest that DBS-related improvements in rigidity and bradykinesia, but not tremor, may be mediated by an increase in alpha2 and low-beta functional connectivity. Beyond the local effects of DBS in and around the STN, functional connectivity changes in these frequency bands might therefore be considered as "pro-kinetic".

Keywords: Deep brain stimulation; Magnetoencephalography; Motor symptoms; Parkinson's disease; Resting-state.

Fig. 1

Experimental setup. Overview of the different DBS settings during the MEG recordings. The bilateral electrodes, each having four contact points are depicted (the two middle contact points consisted of triplets of segments, together used as one contact point). During the first MEG recording (1) both electrodes were stimulated in the optimal settings of the patient. The second to tenth MEG recordings took place in a randomized order, during which each of the eight individual contact points were stimulated once (2 & 6, dorsal; 3 & 7, dorsomedial; 4 & 8, ventromedial; 5 & 9 ventral; outside the scope of this study), and one recording took place during DBS OFF (10). During the last MEG recording, both electrodes were, again, stimulated in the optimal settings of the patient (11).

Fig. 2

Overall power spectrum. Average of normalised frequency spectra for all patients (n = 18) and all regions of interest (n = 90), shaded areas indicate standard error of the means. Despite tSSS filtering and the beamforming approach, stimulation artefact peaks remained present at 27 Hz and 35 Hz during DBS ON (red). DBS, deep brain stimulation; tSSS, spatiotemporal Signal Space Separation. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Regional band power changes. Distribution of significant differences (p < 0.05, FDR corrected) in absolute band power between DBS ON and DBS OFF. Significant increases (decreases) are displayed in red (blue) on a parcellated template brain viewed from, in clockwise order, the left, top, right, left-midline and right-midline. For visualisation purposes, only cortical brain regions are displayed. During DBS ON, a decrease in (mostly occipital) power was observed in the delta and theta band, and an increase in band power was observed in the alpha2, low-beta and high-beta band, suggesting a spectral shift towards the higher frequencies during DBS ON. Note that the sensorimotor regions were hardly involved in this shift and, instead, showed a decrease in absolute band power for the delta, theta, alpha1, alpha2 and low-beta band.

Fig. 4

Correlation of functional connectivity changes with improvement in motor scores. Scatter plots of clinical improvement values and low-beta functional connectivity changes (averaged for respectively the sensorimotor cortices, whole cortex and subcortical regions). Left: Significant correlations between MDS-UPDRS-III improvement (% comparing ON versus OFF-DBS) and cAEC changes (absolute difference ON versus OFF-DBS). Sensorimotor cortices (r-_SM (16)= 0.58, p = 0.011), whole cortex (r-_WC (16)= 0.50, p = 0.035), and all subcortical regions (r_-SC (16)= 0.62, p = 0.006). Middle: Significant correlations between bradykinesia/rigidity improvement and cAEC changes (r-_SM (16)= 0.61, p = 0.007; r-_WC(16)= 0.70, p = 0.001; r_-SC (16)= 0.76, p < 0.001). Right: Tremor improvement (n = 13 patients) and cAEC change, no significant correlation. All correlations tested can be found in Supplementary Table 1. cAEC, corrected Amplitude Envelope Correlation; MDS-UPDRS-III, Movement Disorders Society Unified Parkinson's Disease Rating Scale motor ratings.

Fig. 5

Model of antidromic and downstream activation in STN-DBS. Stimulation effects in the antidromic direction take place upon stimulation of axons of the hyperdirect pathway. These stimulation effects may cause a suppression of band power in frontal cortical brain regions, as well as a lowering of functional connectivity between the frontal cortex and the STN (in blue; see also (Abbasi et al., 2018; Luoma et al., 2018; Oswal et al., 2016)). At the same time, stimulation effects can propagate in the downstream direction and thereby mainly affect the cortico-striato-thalamic loop. Downstream stimulation effects may lead to an increase in cortical functional connectivity via disinhibition of the thalamus (in red; (Mueller et al., 2018; Nambu et al., 2002)). Gpi, internal globus pallidus; SNr, substantia nigra pars reticulate; STN, subthalamic nucleus; DBS, deep brain stimulation. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)