Deep brain stimulation modulates synchrony within spatially and spectrally distinct resting state networks in Parkinson's disease

Abstract

Chronic dopamine depletion in Parkinson's disease leads to progressive motor and cognitive impairment, which is associated with the emergence of characteristic patterns of synchronous oscillatory activity within cortico-basal-ganglia circuits. Deep brain stimulation of the subthalamic nucleus is an effective treatment for Parkinson's disease, but its influence on synchronous activity in cortico-basal-ganglia loops remains to be fully characterized. Here, we demonstrate that deep brain stimulation selectively suppresses certain spatially and spectrally segregated resting state subthalamic nucleus-cortical networks. To this end we used a validated and novel approach for performing simultaneous recordings of the subthalamic nucleus and cortex using magnetoencephalography (during concurrent subthalamic nucleus deep brain stimulation). Our results highlight that clinically effective subthalamic nucleus deep brain stimulation suppresses synchrony locally within the subthalamic nucleus in the low beta oscillatory range and furthermore that the degree of this suppression correlates with clinical motor improvement. Moreover, deep brain stimulation relatively selectively suppressed synchronization of activity between the subthalamic nucleus and mesial premotor regions, including the supplementary motor areas. These mesial premotor regions were predominantly coupled to the subthalamic nucleus in the high beta frequency range, but the degree of deep brain stimulation-associated suppression in their coupling to the subthalamic nucleus was not found to correlate with motor improvement. Beta band coupling between the subthalamic nucleus and lateral motor areas was not influenced by deep brain stimulation. Motor cortical coupling with subthalamic nucleus predominantly involved driving of the subthalamic nucleus, with those drives in the higher beta frequency band having much shorter net delays to subthalamic nucleus than those in the lower beta band. These observations raise the possibility that cortical connectivity with the subthalamic nucleus in the high and low beta bands may reflect coupling mediated predominantly by the hyperdirect and indirect pathways to subthalamic nucleus, respectively, and that subthalamic nucleus deep brain stimulation predominantly suppresses the former. Yet only the change in strength of local subthalamic nucleus oscillations correlates with the degree of improvement during deep brain stimulation, compatible with the current view that a strengthened hyperdirect pathway is a prerequisite for locally generated beta activity but that it is the severity of the latter that may determine or index motor impairment.

Keywords: Parkinson’s disease; deep brain stimulation; local field potential; magnetoencephalography; resting state networks.

Oswal et al . characterise the effect of deep brain stimulation (DBS) on STN–cortical synchronisation in Parkinson–s disease. They propose that cortical driving of the STN in beta frequencies is subdivided anatomically and spectrally, corresponding to the hyperdirect and indirect pathways. DBS predominantly suppresses the former.

Figure 1

Changes at STN level. ( A ) Group average normalized power spectra of the stimulated STN during the no DBS and the 130 Hz DBS conditions. The shaded regions represent standard errors of the mean. In the no DBS condition spectral peaks are evident in the alpha (8–12 Hz), low beta (13–21 Hz) and high beta (21–30 Hz) frequency ranges. DBS results in a suppression of power in the frequency range indicated by the grey bar (11–14 Hz). ( B ) Group average spectra of the unstimulated STN contralateral to the stimulated side. There are no significant spectral changes associated with DBS. ( C ) Correlation between DBS-related changes in relative power in the 11–14 Hz frequency range across hemispheres and changes in contralateral hemibody akinesia/rigidity scores. A linear regression line is plotted with 95% confidence intervals indicated by the dotted lines. Clinical improvement (no DBS-130 Hz DBS contralateral rigidity/akinesia scores) correlated significantly with suppression of 11-14 Hz power (presented as No DBS-130 Hz DBS; F = 13.6, r ² = 0.38, P = 0.0013). ( D ) Group average coherence spectra between stimulated and contralateral STNs. Unilateral DBS does not affect coherence between the two STNs.

Figure 2

Effect of 130 Hz DBS on STN-MEG coherence. ( A ) Group thresholded SPM of the simple main effect of DBS on the beta band network. The coloured region indicates areas where DBS significantly suppressed STN-cortical beta band coherence. Values indicated by the colour bar are t -statistics. The SPM is superimposed on a T ₁ -weighted canonical MRI with cross-hairs centred on the value of the peak t statistic at MNI co-ordinates 2 −4 64. For the simple main effect of DBS on the alpha band network, no clusters survived correction for multiple comparisons. ( B ) Group mean spectra of coherence computed between the STN and locations of the peak t statistic of simple main effects separately for the alpha and beta networks. Black bars denote alpha (8–12 Hz) and beta bands (13–30 Hz) in the left and right hand side plots, respectively.

Figure 3

Differences between STN-MEG coherence in low and high beta bands. ( A ) Thresholded SPMs superimposed onto a T ₁ -weighted canonical MRI with region in yellow representing voxels where STN-cortical coupling was significantly greater in the beta band than in the alpha band in the resting block. Region in green represents voxels within the resting beta network where STN-cortical coupling in the high beta frequency range (21–30 Hz) exceeded coupling within the low beta range (13–21 Hz). Colour bars for the yellow and green images represent t-statistics. ( B ) Resting beta network (yellow), high beta network (green) and the cortical region where STN-cortical beta band coupling is suppressed by DBS (red) are all superimposed.

Figure 4

Results of Granger causality analysis. Group mean difference in Granger causality between original and time reversed data in no DBS and 130 Hz DBS conditions for the high and low beta sub-bands. Source time series were extracted from the location of the peak t -statistic of the simple main effect of DBS in the beta band (at MNI co-ordinates 2 −4 64 corresponding to mesial motor regions) and additionally from a source within primary motor cortex (M1), which we term lateral motor. The difference in Granger causality is significantly greater than zero in the direction of cortex leading the STN for both cortical regions in the no DBS and the 130 Hz DBS conditions (see ‘Results’ section).Vertical bars represent standard errors of the mean. In contrast the difference in Granger causality is less than zero in the direction of STN leading the cortex, confirming that cortical activity led that in STN.

Figure 5

Estimated conduction delays. Group mean conduction delays between cortical regions (Source within M1and the location of the peak t-statistic for the simple main effect of DBS on the beta network at MNI co-ordinates 2 −4 64) and the STN are shown for the low (13–21 Hz) and high beta (21–30 Hz) sub-bands in both experimental conditions. The vertical bars represent standard errors of the mean. Conduction delays are significantly greater for the low beta frequency range than for the high beta frequency range.

Figure 6

Schematic of DBS effects on STN-cortical networks. Mesial premotor areas, including the SMA are preferentially coupled to the STN at rest at high (red) rather than at low (green) beta frequencies. This pattern is not observed for lateral motor areas, including parts of M1, where coupling to the STN is more evenly distributed across beta frequencies. STN DBS acts to suppress driving of the STN by mesial premotor regions in the low and high beta sub-bands. Crucially these effects of DBS are limited to the STN-mesial premotor network and are not observed in the patterns of DBS reactivity of the STN-lateral motor network (see ‘Discussion’ section).