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For successful cognitive functioning, engagement of cognitive control networks seems to be crucial. Some of these networks are known to be active during execution of goal-oriented tasks. In contrast, a task-negative network called the default mode network (DMN) is deactivated while the brain is involved in task behaviour. Disruption of both task-positive and task-negative networks is a common finding in many diseases including Alzheimerʼs disease (AD) [
To this date, little is known about how we can noninvasively influence task-related activity of these networks. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive tool that was shown to influence the underlying brain region and also distant brain areas. Moreover, it was shown to have positive effects on altered cognitive functions in AD [
]. The main goal of this study was to assess the effect of rTMS on the activity of task-related brain networks.
We examined twenty healthy young right-handed subjects (mean age 25.2 ± 2.7 years, men/women ratio: 7/13) that underwent fMRI measurement using 3T Siemens Prisma machine with 64 channel head coil before and immediately after rTMS. The fMRI measurement consisted of an fMRI Stroop task [
]). The goal of the fMRI Stroop task was to match the colour of a cue stimulus to the colour of a Stroop target stimulus that appeared after an interstimulus interval. Cue and target colours were either red, green or blue. The colour cue either matched or did not match the colour of the Stroop target, which was either congruent (e.g. word blue written in blue ink) or incongruent (e.g. word blue written in red ink). All subjects practiced the task before entering the scanner. Subjects used index and middle fingers of their dominant hand to press a YES-key for cue-target colour matches and a NO-key for nonmatches. We measured response times (RT) and error rates for congruent and incongruent stimuli of the fMRI Stroop task (TR 2050 ms; TE 35 ms; voxel size 3 × 3 × 3.5 mm; FoV 192 mm; base resolution 64; flip angle 70°; 35 slices; 165 scans; iPAT 2).
As TMS targets, we selected the right inferior frontal gyrus (rIFG, 46 14 32) and the left superior parietal lobule (lSPL, −24 –68 48), which are both involved in the top-down control of complex visual tasks [
]. TMS sessions were performed using a frameless stereotaxy neuronavigation with Brainsight2, either intermittent theta burst stimulation (iTBS; 190 s duration, 600 pulses) or continuous TBS (cTBS; 40 s duration, 600 pulses) protocols [
] using Deymed DuoMAG XT stimulator with 70BF-Cool coil at 80% of individual active motor threshold intensity. Crossover design was used, and the order of stimulation protocols and sites (4 rTMS sessions: iTBS rIFG, cTBS rIFG, iTBS lSPL, cTBS lSPL) was randomised across subjects and sessions to make them counterbalanced across the group. The individual stimulation sessions were separated by at least a one-day interval without stimulation. Each participant gave their written informed consent, and the study was approved by the Ethics Committee of St. Anne’s University Hospital in Brno (3G/2016).
The fMRI data were analysed using SPM12 running under Matlab. Standard preprocessing [
] and general linear modeling (using task time course convoluted with canonical hemodynamic response function) with contrasting incongruent vs. congruent stimuli (i.e. our main fMRI outcome) were used. Quality of the data was checked using the tool mask explorer [
]. Group results were assessed using cluster level inference at p (FWE) < 0.05 with initial cut-off p < 0.005.
TMS was very well tolerated with no major adverse effects. The behavioural data were evaluated using a paired sample t-test and the results were published previously [
]. They showed a trend toward decreased RT due to iTBS of the lSPL (p = 0.060 for congruent stimuli, p = 0.056 for incongruent stimuli). The overall task accuracy reached 97% (ceiling effect), and it was not influenced by any stimulation protocol.
Based on the behavioural results, we specifically aimed at identifying neural correlates of the effects of iTBS applied over the lSPL using task fMRI analysis contrasting incongruent vs. congruent stimuli (post vs. pre-stimulation). The stimulation induced the significant decrease of activity in medial frontal and parietal regions of DMN with the peak in the left anterior cingulate cortex (lACC, -3 56 1) p = 0.00013 (344 voxels in cluster), see Fig. 1. Moreover, we found a significant difference when directly comparing effects of the excitatory (iTBS) and inhibitory (cTBS) stimulations over the lSPL with regard to BOLD signal changes within this cluster (paired sample t-test, p = 0.005), indicating that our result is stimulation protocol specific (see Table S1 in Supplementary materials). Neither iTBS over the rIFG nor cTBS rIFG produced any significant changes in task-induced brain activations. We did not observe with any significant effect of the sessions order on either RT changes or BOLD signal changes in the ACC.
Fig. 1Significant decrease of activity in medial frontal and parietal regions of default mode network after intermittent theta burst stimulation over the left superior parietal lobule.
Our exploratory study showed that even a single session of brief TMS may have an influence on a cognitive task and activity of related cognitive brain networks. The pattern of decreased activation was stimulation protocol specific and it was observed in regions known to be part of the DMN with the peak in ACC, which is a major anterior hub of the network.
Age-related differences in default-mode network connectivity in response to intermittent theta-burst stimulation and its relationships with maintained cognition and brain integrity in healthy aging.
] reported that iTBS to the left inferior parietal lobule increases resting state functional connectivity (rs-FC) to the anterior part of DMN in young adults and in part of the older adults with superior cognitive performance. Using cTBS to the left dorsolateral prefrontal cortex (DLPFC), the rs-FC was reduced between the targeted region and posterior part of the DMN (posterior cingulate and precuneus) in young subjects [
In patients with amnestic mild cognitive impairment, repeated sessions of high frequency rTMS of the right DLPFC led to reductions of rs-FC between the posterior node of DMN and other regions including the ACC which was associated with clinical cognitive improvements [
Repetitive transcranial magnetic stimulation induced hypoconnectivity within the default mode network yields cognitive improvements in amnestic mild cognitive impairment: a randomized controlled study.
]. The authors hypothesized that rTMS might have “normalized” pathological increases of rs-FC within the anterior part of DMN in this patient population, however, healthy subjects were not included. Finally, a study combining high frequency rTMS to precuneus with EEG in early AD patients also showed that memory improvement after rTMS was accompanied by modulation of activity and connectivity within DMN [
]. However, results of rs-FC and task-related activations cannot be directly compared.
Limitations of our study are its exploratory nature and the lack of placebo control. In summary, this study demonstrates iTBS-induced task-related BOLD signal decreases of the DMN. The future therapeutic strategies using TMS in patients with cognitive dysfunctions such as AD may be beneficial through normalizing disrupted activity and connectivity of large-scale brain networks and the DMN in particular. We want to highlight a network-based approach for studying neuromodulation for therapeutic purposes.
Declaration of competing interest
We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us. We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property. We further confirm that any aspect of the work covered in this manuscript that has involved either experimental animals or human patients has been conducted with the ethical approval of all relevant bodies and that such approvals are acknowledged within the manuscript.
Acknowledgement
Supported by the Ministry of Health of the Czech Republic, grant No. AZV 16-31868A. All rights reserved. This research was financially supported by the Ministry of Education, Youth and Sports of the Czech Republic within CEITEC 2020 (LQ1601) project. We acknowledge the core facility MAFIL of CEITEC supported by the Ministry of Education, Youth and Sports of the Czech Republic within Czech-BioImaging(LM2018129) for their support with obtaining scientific data presented in this paper.
Appendix A. Supplementary data
The following is the Supplementary data to this article:
Age-related differences in default-mode network connectivity in response to intermittent theta-burst stimulation and its relationships with maintained cognition and brain integrity in healthy aging.
Repetitive transcranial magnetic stimulation induced hypoconnectivity within the default mode network yields cognitive improvements in amnestic mild cognitive impairment: a randomized controlled study.
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