The Effects of Functionally Guided, Connectivity-Based rTMS on Amygdala Activation

Abstract

While repetitive transcranial magnetic stimulation (rTMS) is widely used to treat psychiatric disorders, innovations are needed to improve its efficacy. An important limitation is that while psychiatric disorders are associated with fronto-limbic dysregulation, rTMS does not have sufficient depth penetration to modulate affected subcortical structures. Recent advances in task-related functional connectivity provide a means to better link superficial and deeper cortical sources with the possibility of increasing fronto-limbic modulation to induce stronger therapeutic effects. The objective of this pilot study was to test whether task-related, connectivity-based rTMS could modulate amygdala activation through its connectivity with the medial prefrontal cortex (mPFC). fMRI was collected to identify a node in the mPFC showing the strongest connectivity with the amygdala, as defined by psychophysiological interaction analysis. To promote Hebbian-like plasticity, and potentially stronger modulation, 5 Hz rTMS was applied while participants viewed frightening video-clips that engaged the fronto-limbic network. Significant increases in both the mPFC and amygdala were found for active rTMS compared to sham, offering promising preliminary evidence that functional connectivity-based targeting may provide a useful approach to treat network dysregulation. Further research is needed to better understand connectivity influences on rTMS effects to leverage this information to improve therapeutic applications.

Keywords: amygdala; fMRI; functional connectivity; repetitive transcranial magnetic stimulation.

Figure 1

Consort diagram showing the recruitment, exclusion and inclusion numbers.

Figure 2

(A) Activities done during each study visit. (B) Scans during MRI acquisition. (C) Illustration of MRI task showing passive viewing of IAPS pictures. (D) rTMS parameters. (E) Illustration of rTMS task showing passive viewing of frightening video-clips from the Schaefer et al. database. In order to maintain attention in both the MRI and rTMS tasks, participants were asked to rate whether the scene was indoor, outdoor, or both.

Figure 3

Results from the 2*2 ANOVA on BOLD signal. (A) Main effect of Timing (Pre versus Post rTMS). (B) Main effect of Stimulation (Active versus Sham rTMS), and (C) Interaction between Timing and Stimulation.

Figure 4

BOLD signal analysis with for the Fear versus Other contrast on Visit 1 (A), Visit 2 (B), and comparison of the effects of Active versus Sham rTMS on the second visit (C). Heat maps indicate Z-scores, blue colors indicate a decrease in BOLD signal and red colors indicate increase. Yellow shading represents the amygdala; and green shading represents masks used to define left mPFC and right amygdala.

Figure 5

fMRI activation in the right amygdala (z-scores) obtained before rTMS (Visit 1) and after rTMS (Visit 2) for subjects receiving active stimulation (blue) or sham stimulation (red). The p-values are reported for independent t-tests comparing amygdala activation in each group, within each visit.

Figure 6

Results from the 2*2 ANOVA on task-related functional connectivity. (A) Main effect of Timing (Pre versus Post rTMS). (B) Main effect of Stimulation (Active versus Sham rTMS), and (C) Interaction between Timing and Stimulation.

Figure 7

PPI analysis for the Fear versus Other contrast on Visit 1 (A), Visit 2 (B), and comparison of the effects of Active versus Sham rTMS on the second visit (C). Blue colors indicate decreased connectivity; and red colors indicate increased in functional connectivity.