TMS-induced modulation of brain networks and its associations to rTMS treatment for depression: a concurrent fMRI-EEG-TMS study

Abstract

Transcranial magnetic stimulation (TMS) over the left dorsolateral prefrontal cortex (L-DLPFC) is an established intervention for treatment-resistant depression (TRD), yet the underlying therapeutic mechanisms remain not fully understood. This study employs an integrative approach that combines TMS with concurrent functional magnetic resonance imaging (fMRI) and electroencephalography (EEG), aimed at assessing the acute/immediate effects of TMS on brain network dynamics and their correlation with clinical outcomes. Our study demonstrates that TMS acutely modulates connectivity within vital brain circuits, particularly the cognitive control and default mode networks. We found that the baseline TMS-evoked responses in the cognitive control and limbic networks significantly predicted clinical improvement in patients receiving a novel EEG-synchronized repetitive TMS treatment. Furthermore, this study explored the brain-state dependent effects of TMS, as the brain-state indexed by the phase of EEG prefrontal alpha oscillation. We found that clinical outcomes in this novel treatment are linked to state-specific TMS-modulated functional connectivity within a pivotal brain circuit of the L-DLPFC and the posterior subgenual anterior cingulate cortex within the limbic system. These findings contribute to our understanding of the therapeutic effects underlying TMS treatment in depression and support the potential of assessing state-dependent TMS effects in TMS timing target selection. This study emphasizes the importance of personalized timing of TMS for optimizing target engagement of specific clinically relevant brain circuits. Our results are crucial for future research into the development of personalized neuromodulation therapies for TRD patients.

Fig. 1.

Experimental procedure and data analyses. TMS-induced effects were assessed at both pre- and post-treatment fMRI-EEG-TMS (fET) scans. Both baseline TMS-induced effects and the longitudinal changes in TMS effects were related to the clinical outcome (HRSD percent change). HRSD, Hamilton Rating Scale for Depression.

Fig. 2.

Quantification of baseline TMS-evoked responses on whole-brain BOLD signal. (A) group-level activation map (t-value; p < 0.05 FWE multiple comparison correction; mixed effect); (B) Amplitude of TMS-induced BOLD response in brain networks (Schaefer atlas brain parcellation); (C) The spatial extent of TMS induced-activity propagation coverage through the networks was computed (percentage coverage). The red line indicates the median across subjects. The blue lines indicate the lower and upper quartile across subjects. TMS evoked the strongest response in the SalVentAttn network (subnetwork A, RH), with the highest inter-subject variability in the SomMot network (subnetwork A, RH). We found that the SomMot network (subnetwork B, RH) had the highest extent of propagation coverage of TMS-induced activity, and the VisPeri network in the RH had the highest inter-subject variability in the propagation coverage. LH, left hemisphere; RH, right hemisphere; SomMot, somatomotor network; VisPeri, visual peripheral network; SalVentAttn, salience/ventral attention network. Default, default mode network; VisCent, visual central network; Cont, control network; TempPar, temporal parietal network; DorsAttn, dorsal attention network.

Fig. 3.

Quantification of TMS-induced functional connectivity at baseline fMRI-EEG-TMS (fET) scan. (A) Group level whole-brain psychophysiological interaction analysis results. TMS induced significant negative effects on the connectivity between cortical networks (FDR multiple comparison corrected p < 0.05). No significant positive effect was observed after multiple comparison correction. (B) and (C) represent negative and positive node strength by computing the sum of all the negative and positive connection weights between one node and all other nodes, respectively. The positive hubs are mostly within the visual and somatomotor networks, and the negative hubs are regions in the default, control, and salience ventral attention networks. LH, left hemisphere; RH, right hemisphere; SalVentAttn, salience/ventral attention network. Default, default mode network; Cont, control network; TempPar, temporal parietal network.

Fig. 4.

State-dependency analysis of TMS-evoked BOLD response using baseline fMRI-EEG-TMS (fET) scan. (A) TMS response contrast between the conditions of TMS trials in the high-load-phase (HLP) bins and low-load-phase (LLP) bins. Regions in the lateral frontoparietal network were identified as significant clusters (t-value; p < 0.001). Because HLP and LLP conditions were defined based solely on the BOLD signal from L-DLPFC region, the activation pattern resulting from their contrast highlight brain areas associated with greater TMS-induced effects on the L-DLPFC, indicating a whole-brain spreading pattern of the phase-dependent TMS-induced response. (B) Spatial overlap between the TMS response contrast and L-DLPFC seed-based functional connectivity. The TMS response contrast (green) and overlap (yellow) areas encompass the same regions shown in the panel (A). L-DLPFC functional connectivity map showed a network overlapped with the TMS response contrast map, suggesting the propagation of TMS-induced acute effects is related to the functional connectivity.

Fig. 5

Associations of TMS-induced acute/immediate effects to the clinical response in rTMS treatment for depression patients. (A) We observed a significant correlation between the clinical outcome (percent change in the HRSD) and the pre-treatment TMS evoked response in the bilateral ContB network and RH-LimbicB network only for the SYNC group. (B) State-specific TMS modulations on the connectivity were assessed for four L-DLPFC regions (EEG F3, L-DLPFC in DefaultA, L-DLPFC in DefaultB, and L-DLPFC in SalVentAttnB). (C) As for the L-DLPFC in DefaultA, the pre- and post-treatment state-specific TMS-modulated connectivity changes (between L-DLPFC in the DefaultB network and RH orbitofrontal cortex in LimbicB network) are significantly associated with the clinical outcome only for the SYNC group. No significant result was found for the other three L-DLPFC regions after multiple comparison correction. Panel (A) includes the results of 23 patients (11 SYNC patients and 12 UNSYNC patients) with pre-treatment fET and HRSD available. Panel (C) includes the results of 14 patients (8 SYNC patients and 6 UNSYNC patients) with complete pre- and post-treatment data. HRSD: Hamilton Rating Scale for Depression; fET: integrated fMRI-EEG-TMS. LH, left hemisphere; RH, right hemisphere; SalVentAttnB, salience/ventral attention network (subnetwork B); DefaultA/B, default mode network (subnetwork A/B); ContB, control network (subnetwork B); LimbicB, limbic network (subnetwork B).

Fig. 6.

Brain-state dependency analysis of TMS-induced acute effects using alpha phase from the prefrontal EEG signal. TMS trials were grouped into four categories with different prefrontal alpha phase bins (illustrated with different colors), where the prefrontal alpha oscillation was extracted from the concurrent EEG recordings at electrodes FP1, F3, and F7. Effects from the TMS trials in different phase bins were modeled with general linear modeling, where the BOLD signal at L-DLPFC (EEG F3 stimulation site) was modeled with the TMS trials in each phase bin as a separate regressor. The phase bins that generated the highest and lowest BOLD response at L-DLPFC were identified as the subject-wise high-load-phase (HLP) and low-load-phase (LLP) conditions, respectively.