Predicting rTMS treatment efficacy in depression based on modular flexibility of functional connectivity

Major depressive disorder (MDD) is conceptualized as a disorder of brain circuit function, particularly involving the default mode network (DMN). Repetitive transcranial magnetic stimulation (rTMS) emerged as an effective treatment for major depressive disorder (MDD), while its mechanisms and predictors of response remain poorly understood.

We retrospectively analyzed 70 patients with MDD received either active (n = 41) or sham (n = 29) rTMS. The resting-state fMRI was performed before and after treatment to assess dynamic functional connectivity. The left dorsal lateral prefrontal cortex (lDLPFC) was selected as the target site for rTMS, based on individualized functional connectivity with the right nucleus accumbens (NAcc) as the seed region. We tested the hypothesis that rTMS remediates depression by increasing modular flexibility, a measure of a brain region's dynamic functional integration and that baseline flexibility would predict clinical outcomes.

Active rTMS produced a significantly greater reduction in Hamilton Depression Rating Scale (HAMD) scores, when compared to sham group (t = -2.70, p = .009). This clinical improvement was paralleled by a significant increase in the modular flexibility of the bilateral medial prefrontal cortex (MPFC), a key DMN hub. The magnitude of this flexibility increase was directly correlated with the degree of symptom reduction in the active group (r = 0.323, p = .045). Importantly, a support vector regression model demonstrated that pre-treatment modular flexibility in DMN nodes significantly predicted post-treatment HAMD scores (r = 0.391, p = .011).

These findings provide compelling evidence that rTMS exerts its therapeutic effects by remodeling the dynamic architecture of the DMN, enhancing its flexibility. Baseline modular flexibility constitutes a promising, mechanistically inspired biomarker for personalizing rTMS therapy. This work advances a dynamic network model of neuromodulation, shifting the focus from static dysfunction to the restoration of neural adaptability.