CHAPTER 3 DISCUSSION AND CONCLUSIONS
4. Functional network stimulation
Network analysis with EEG is a promising technique to elucidate on the question of the network effects induced by noninvasive brain stimulation (Shafi et al., 2013). We therefore tested the effects of cTBS on alpha-band coherence in a group of nine healthy young participants (Rizk, accepted). According to the intrahemispheric inhibition model, we hypothesized that the inhibitory cTBS protocol, applied over right posterior parietal cortex (right PPC), will affect other nodes of the attention network particularly in the contralateral hemisphere. Based on the observation in our previous studies that alpha-band coherence is specifically related to behavior, we expected stimulation-induced changes to involve the alpha-band.
We targeted the network responsible for spatial attention in healthy volunteers. The stimulation induced a mild transitory reduction in attention to the left visual field, qualitatively similar as it can be observed in patients with hemispatial neglect due to right-sided hemispheric damage (Nyffeler et al., 2008). On the network level, FC between the stimulated node (right PPC) and the rest of the brain decreased as a result of stimulation, while connectivity between the contralateral left PPC and the rest of the brain increased. The connectivity changes were spatially specific to the nodes of the stimulated network and spectrally to the frequencies of applied magnetic pulses and the alpha frequency band (Figure 5). More importantly, the electrophysiological changes correlated linearly with behavioral effects, hence suggesting that effects on network communication are associated with behavioral effects. These results are also in line with studies combining TMS and fMRI (Chouinard et al., 2003) and TMS and PET (Paus et al., 1997) reporting network-specific local and remote changes in metabolism after TMS. In addition, a clinical study in patients with unilateral paresis demonstrated that inhibitory TMS of left premotor cortex induced a compensatory increase in the right premotor activity that was in turn associated with behavioral recovery (O'Shea et al., 2007).Thus, these studies together show that the TMS-induced compensatory increase of activity and connectivity in the contralateral hemisphere is behaviorally relevant and occurs in region- and frequency-specific manners. Our results demonstrate that functionally important changes especially occur in the alpha-band.
The increase of FC contralateral to the stimulation site was linearly associated with transient inhibition of left-ward visual exploration behavior. This result is in agreement with the model of inter-hemispheric inhibition and with recent studies demonstrating that TMS-induced suppression of the dominant right parietal region leads to disinhibition and hence to an increase of excitation in the left parietal homologue (Koch et al., 2008). Our findings add to these results by showing that similar inter-hemispheric competition occurs in alpha-band coherence. cTBS induced a disruption of alpha-band connectivity in the right PPC, which was paralleled by a contralateral left parietal increase in alpha-band coherence. Our observation of the involvement of the alpha frequency alpha-band is supported by previous reports of TMS-induced changes in endogenous alpha oscillations (Klimesch et al., 2003;
Hamidi et al., 2009) and serve to extend them to network interactions.
48 Figure 5
cTBS effects on networks and behavior. a Individual TMS-induced changes in leftward exploration. Only stimulation of the right PPC decreased leftward exploration in most subjects. Yet, in two subjects it showed the inverse behavioral effect. b Changes in alpha-band IC after stimulation over the right PPC (p<0.05, uncorrected). c Spectrogram of IC changes in four ROIs of the spatial attention network (*p<.05, uncorrected).
d Comparison of IC changes at 10Hz and 30Hz in ROIs of the spatial attention network in the 3 different stimulation conditions. Changes in each ROI are shown immediately after and 30 min after stimulation (*p<.05;
x p<0.07).
Changes in resting-state alpha activity seem to be particularly implicated in mediating behavioral effects of rTMS. The reason for this is incompletely understood. Klimesch et al. (2003) suggested that rTMS induces high baseline alpha activity before a task which enables a larger alpha suppression during the task and hence better task performance. Alternatively, alpha rhythms and particularly alpha coherence may have an active role in the resting-state integration of activity in specialized brain areas (Palva & Palva, 2007). Gamma power (>30 Hz), which is thought to reflect neural computation (Crone et al., 1998), is phase-locked to alpha oscillations (Palva et al., 2005a; Osipova et al., 2008). Alpha rhythms therefore seem to synchronize and structure processing in distributed networks by gating the
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timing of higher frequency oscillations. In this view, the calculation of cross-frequency FC could deliver additional important information on the role of single frequencies and of spectral interplay within functional networks.Another important finding was that not all participants responded equally to the stimulation. The induced effect of cTBS was highly dependent on the pre-stimulation state of alpha-band connectivity between the right temporo-parietal junction (TPJ) and the rest of the brain. In subjects with high levels of connectivity before stimulation, cTBS produced a remarkable decrease of local coherence and a decrease of the leftward attention. In contrast, the participants who had a low level of alpha-band coherence between the right TPJ and the rest of the brain prior to stimulation responded with an inverse behavioral change; they showed an increased leftward visual exploration. Our data cannot explain if observed difference in the baseline alpha-band connectivity is state-dependent or represent a stable feature of individual electrophysiology. Nevertheless, these findings suggest that electrophysiological and behavioral effects of cTBS result from an interaction between the stimulation signal and individual patterns of network interactions. They might therefore potentially explain the inconsistency of the therapeutic effects of the TMS. Previous studies have already observed that the effects of TMS result from interaction between the applied stimulus and the level of activity of the affected brain region (Silvanto & Pascual-Leone, 2008). For instance, it was reported that less active neural populations are more susceptible to stimulation, which in turn reduced the stimulation effects on behavior (Bestmann et al., 2008). Our findings confirm these results and can further enhance them by suggesting that magnitudes of alpha-band coherence in the concerned networks before stimulation might predict individual responses. In Dubovik et al. (2012) we showed that alpha-band coherence is functionally relevant in stroke patients when they arrive at the acute stage. We therefore hypothesize that the analysis of alpha-band connectivity in patients may enable a selective application of cTBS in candidates who are most likely to benefit from these therapies.