ABSTRACT
Transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS) have been shown to modulate functional connectivity. Their specific effects seem to be dependent on the pre-existing neuronal state. We aimed to precondition frontal networks using tDCS and subsequently stimulate the left dorsolateral prefrontal cortex (lDLPFC) using TMS. Thirty healthy participants underwent excitatory, inhibitory, or sham tDCS for 10 min, as well as an excitatory intermittent theta-burst (iTBS) protocol (600 pulses, 190 s, 20 × 2-s trains), applied over the lDLPFC at 90% of the individual resting motor threshold. Functional connectivity was measured in three task-free resting state fMRI sessions, immediately before and after tDCS, as well as after iTBS. Testing the whole design did not yield any significant results. Analysis of the connectivity between the stimulation site and all other brain voxels, contrasting only the interaction effect between the experimental groups (excitatory vs. inhibitory) and the repeated measure (post-tDCS vs. post-TMS), revealed significantly affected voxels bilaterally in the anterior cingulate and paracingulate gyri, the caudate nuclei, the insula and operculum cortices, as well as the Heschl's gyrus. Post-hoc ROI-to-ROI analyses between the significant clusters and the striatum showed post-tDCS, temporo-parietal-to-striatal and temporo-parietal-to-fronto-cingulate differences between the anodal and cathodal tDCSgroup, as well as post-TMS, striatal-to-temporo-parietal differences between the anodal and cathodal groups and frontostriatal and interhemispheric temporo-parietal cathodal-sham group differences. Excitatory iTBS to a tDCS-inhibited lDLPFC thus yielded more robust functional connectivity to various areas as compared to excitatory iTBS to a tDCS-enhanced DLPFC. Even considering reduced statistical power due to low subject numbers, results demonstrate complex, whole-brain stimulation effects. They are possibly facilitated by cortical homeostatic control mechanisms and show the feasibility of using tDCS to modulate subsequent TMS effects. This proof-of-principle study might stimulate further research into the principle of preconditioning that might be useful in the development of protocols using DLPFC as a stimulation site for the treatment of depression.
ABSTRACT
Background: The fronto-striatal network is involved in various motor, cognitive, and emotional processes, such as spatial attention, working memory, decision-making, and emotion regulation. Intermittent theta burst transcranial magnetic stimulation (iTBS) has been shown to modulate functional connectivity of brain networks. Long stimulation intervals, as well as high stimulation intensities are typically applied in transcranial magnetic stimulation (TMS) therapy for mood disorders. The role of stimulation intensity on network function and homeostasis has not been explored systematically yet. Objective: In this pilot study, we aimed to modulate fronto-striatal connectivity by applying iTBS at different intensities to the left dorso-lateral prefrontal cortex (DLPFC). We measured individual and group changes by comparing resting state functional magnetic resonance imaging (rsfMRI) both pre-iTBS and post-iTBS. Differential effects of individual sub- vs. supra-resting motor-threshold stimulation intensities were assessed. Methods: Sixteen healthy subjects underwent excitatory iTBS at two intensities [90% and 120% of individual resting motor threshold (rMT)] on separate days. Six-hundred pulses (2 s trains, 8 s pauses, duration of 3 min, 20 s) were applied over the left DLPFC. Directly before and 7 min after stimulation, task-free rsfMRI sessions, lasting 10 min each, were conducted. Individual seed-to-seed functional connectivity changes were calculated for 10 fronto-striatal and amygdala regions of interest with the SPM toolbox DPABI. Results: Sub-threshold-iTBS increased functional connectivity directly between the left DLPFC and the left and right caudate, respectively. Supra-threshold stimulation did not change fronto-striatal functional connectivity but increased functional connectivity between the right amygdala and the right caudate. Conclusion: A short iTBS protocol applied at sub-threshold intensities was not only sufficient, but favorable, in order to increase bilateral fronto-striatal functional connectivity, while minimizing side effects. The absence of an increase in functional connectivity after supra-threshold stimulation was possibly caused by network homeostatic effects.
