Effects of individualized rTMS on functional connectivity related to the default mode network and frontal-parietal network in major depressive disorder: exploratory analysis of a randomized controlled trial

Objective: Repetitive transcranial magnetic stimulation (rTMS) has been shown to alleviate depressive and anxiety symptoms in patients with major depressive disorder (MDD), typically by targeting the dorsolateral (DLPFC) or dorsomedial prefrontal cortex (DMPFC). Based on a pre-registered randomized controlled trial, this study presents an exploratory neuroimaging analysis investigating the impact of rTMS targeting the DLPFC versus the DMPFC on functional connectivity with the default mode network (DMN) and frontal-parietal network (FPN) in patients with MDD. Methods: Sixty-four MDD patients were randomly assigned to DLPFC-rTMS (n = 36) or DMPFC-rTMS (n = 28) groups for a 21-day intervention. Symptoms were evaluated with Hamilton Depression Rating Scale (HAMD) and Hamilton Anxiety Rating Scale (HAMA). Changes in individualized functional connectivity (inFC) between individualized targets and DMN/FPN were assessed and correlated with symptom improvements. As a control analysis, FC was evaluated based on the group-based seeds of DLPFC or DMPFC. Additionally, symptom-specific circuit map comparisons were conducted. Results: Both groups showed symptom improvements and changes in inFC with the DMN and FPN, but the specific connectivity profiles differ. In the DMN, the DLPFC-rTMS group showed decreased negative connectivity between left DLPFC and precuneus (t = -2.39, p = 0.022), while the DMPFC-rTMS group showed increased positive inFC between DMPFC and precuneus (t = -2.78, p = 0.01, FDR adjusted p = 0.034) and PCC (t = -3.15, p = 0.004, FDR adjusted p = 0.028). In the FPN, the DLPFC group showed decreased negative inFC with medial superior frontal gyrus (t = -2.35, p = 0.024) and decreased positive inFC with inferior parietal lobule (t = 2.3, p = 0.028). The DMPFC group showed increased positive connectivity with inferior frontal gyrus (t = -3.65, p = 0.001, FDR adjusted p = 0.019) and su pplementary motor area (t = -2.24, p = 0.033), and decreased negative connectivity with middle cingulate cortex (t = 2.27, p = 0.032). Canonical correlation analysis revealed a strong association between inFC changes and depression symptom improvement in the DMPFC-rTMS group (r = 0.57). Group seed-based FC changes were limited to the FPN and correlated with depressive improvement in the DLPFC-rTMS group (r = 0.52). Symptom-specific circuit maps linked to depression and anxiety were consistent across targets. Conclusion: Both DLPFC and DMPFC rTMS alleviate depressive and anxiety symptoms, displaying similar overall circuit patterns but distinct connectivity changes specific to their targets.