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.

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Repetitive transcranial magnetic stimulation (rTMS) has fundamentally transformed how we treat psychiatric disorders, but is still in need of innovation to optimally correct dysregulation that occurs throughout the fronto-limbic network. rTMS is often applied over the prefrontal cortex, a central node in this network, but less attention is given to subcortical areas because they lie at depths beyond the electric field penetration of rTMS. Recent studies have demonstrated that the effectiveness of rTMS is dependent on the functional connectivity between deep subcortical areas and superficial targets, indicating that leveraging such connectivity may improve dosing approaches for rTMS interventions. The current preliminary study, therefore, sought to test whether task-related, fMRI-connectivity-based rTMS could be used to modulate amygdala activation through its connectivity with the medial prefrontal cortex (mPFC). For this purpose, fMRI was collected on participants to identify a node in the mPFC that showed the strongest negative connectivity with right amygdala, as defined by psychophysiological interaction analysis. To promote long-lasting Hebbian-like effects, and potentially stronger modulation, 5Hz rTMS was then applied to this target as participants viewed frightening video-clips that engaged the fronto-limbic network. Post-rTMS fMRI results revealed promising increases in both the left mPFC and right amygdala, for active rTMS compared to sham. While these modulatory findings are promising, they differ from the a priori expectation that excitatory 5Hz rTMS over a negatively connected node would reduce amygdala activity. As such, further research is needed to better understand how connectivity influences TMS effects on distal structures, and to leverage this information to improve therapeutic applications.