Global connectivity and local excitability changes underlie antidepressant effects of repetitive transcranial magnetic stimulation

Abstract

Repetitive transcranial magnetic stimulation (rTMS) is a commonly-used treatment for major depressive disorder (MDD). However, our understanding of the mechanism by which TMS exerts its antidepressant effect is minimal. Furthermore, we lack brain signals that can be used to predict and track clinical outcome. Such signals would allow for treatment stratification and optimization. Here, we performed a randomized, sham-controlled clinical trial and measured electrophysiological, neuroimaging, and clinical changes before and after rTMS. Patients (N = 36) were randomized to receive either active or sham rTMS to the left dorsolateral prefrontal cortex (dlPFC) for 20 consecutive weekdays. To capture the rTMS-driven changes in connectivity and causal excitability, resting fMRI and TMS/EEG were performed before and after the treatment. Baseline causal connectivity differences between depressed patients and healthy controls were also evaluated with concurrent TMS/fMRI. We found that active, but not sham rTMS elicited (1) an increase in dlPFC global connectivity, (2) induction of negative dlPFC-amygdala connectivity, and (3) local and distributed changes in TMS/EEG potentials. Global connectivity changes predicted clinical outcome, while both global connectivity and TMS/EEG changes tracked clinical outcome. In patients but not healthy participants, we observed a perturbed inhibitory effect of the dlPFC on the amygdala. Taken together, rTMS induced lasting connectivity and excitability changes from the site of stimulation, such that after active treatment, the dlPFC appeared better able to engage in top-down control of the amygdala. These measures of network functioning both predicted and tracked clinical outcome, potentially opening the door to treatment optimization.

Repetitive Transcranial Magnetic Stimulation for Adolescent Major Depressive Disorder: A Focus on Neurodevelopment

“…Neuroimaging measures can also serve as predictive biomarkers for response to rTMS. Multiple studies have linked intrinsic functional connectivity between the targeted region of PFC and ACC, anterior insula and striatum with later response to rTMS ( 74 , 125 , 200 , 245 – 254 ) and other antidepressant treatments ( 101 , 255 – 258 ). Interleaved rTMS/fMRI has shown acute effects on BOLD activation of both local and distal brain regions immediately following 1 Hz DLPFC rTMS in adults with MDD ( 89 ).…”

Connectivity changes in major depressive disorder after rTMS: a review of functional and structural connectivity data

“…Consistently with these results, in an RCT on 33 unipolar depressed patients evaluating rs-fMRI connectivity changes before and after 4 weeks of rTMS, Eshel et al . (2020) observed a decreased FC in active compared to sham group between both targeted (left) DLPFC and controlateral DLPFC and between the left DLPFC and bilateral amygdala. Moreover, the authors demonstrated an increased targeted (left) DLPFC global FC in active compared to sham group.…”

Repetitive Transcranial Magnetic Stimulation Target Location Methods for Depression

“…This meta-analysis indicated that depression associated with abnormal brain network models includes various cortical and subcortical brain regions. Some clinical studies have shown that rTMS can affect the stimulated site and a transsynaptic network of interconnected areas ( Tik et al, 2017 ; Eshel et al, 2020 ). FC might be used to identify an optimal TMS target for use in MDD patients ( Wang et al, 2019 ; Cash et al, 2020 ).…”