Modulation of Fronto-Striatal Functional Connectivity Using Transcranial Magnetic Stimulation

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.

Keywords: DLPFC; fronto-striatal network; functional connectivity; intermittent theta burst stimulation (iTBS); prefrontal cortex; resting state; striatum.

Figure 1

Summary of the experimental design and durations. Day 1 and day 2 took 1.5 h each. Determining the resting-motor threshold took approximately 45 min. All anatomical and functional magnetic resonance imaging (fMRI) scans took approximately 10 min each. The experimental procedure took in total approximately 5.5 h per participant. rMT, resting motor threshold.

Figure 2

Visualization of results. (A,B) Each arrow represents a significant test result. Significant analysis of variance (ANOVA) effects are shown in (A) and significant paired t-tests in (B). It can be seen that functional connectivity between the left prefrontal cortex (PFC; stimulation site) and the left and right caudate, respectively, as well as between the right caudate and the left and right amygdala, respectively, was modulated by the experimental stimulation. (A) White arrows indicate a significant intensity effect and black arrows a significant interaction effect. White ellipses indicate a seed region of interest. (B) Only pre-post transcranial magnetic stimulation (TMS) comparisons were calculated. All significant changes were increases from pre to post. Functional connectivity increased significantly only in the 90% condition between the stimulation site and the striatum. Analyzing the functional connectivity patterns between the stimulation site and each of the subregions of the striatum revealed that only the increase in functional connectivity between the stimulation site and the right and left caudate, respectively was significant. Additionally, functional connectivity between the right amygdala and the right caudate was increased only in the 120% condition. (C) Mean functional connectivity results. Shown are mean Fisher-Z-transformed correlations for the significant ANOVAs of functional connectivity between seeds, in the four different conditions 90% pre and post (gray line) and 120% pre and post (black line) measurements. Positive values indicate a positive coupling of signals between the two seeds. The first graph visualizes results between the stimulation site (left DLFC) and the entire striatum [consisting of left and right caudate (CA), left and right nucleus accumbens (NA), as well as left and right putamen (PU)]. AM, amygdala.