Advanced imaging–integrated rTMS therapy for frontal network recovery after traumatic brain injury

Abstract

Background Traumatic brain injury is frequently followed by persistent executive dysfunction linked to disruption of frontal and frontoparietal networks. High-frequency repetitive transcranial magnetic stimulation (rTMS) targeting the dorsolateral prefrontal cortex (DLPFC) has been proposed as a potential adjunctive intervention to support frontal-network recovery. Still, evidence remains heterogeneous and biomarker-guided interpretation is limited. Methods This retrospective multicenter observational cohort study evaluated adults with traumatic brain injury and persistent executive dysfunction who received standard neurorehabilitation with or without adjunctive high-frequency rTMS. Patients were classified into an rTMS-exposed cohort and a non-rTMS comparison cohort according to documented treatment exposure. Primary outcomes were changes in Frontal Assessment Battery (FAB) and MoCA executive-domain scores. Secondary outcomes included Glasgow Outcome Scale–Extended and Trail-Making Test A/B performance. Multimodal biomarkers included TMS-EEG N100/P200 amplitudes, fNIRS task-evoked left DLPFC oxyhemoglobin (HbO2) response, and resting-state fMRI DLPFC–frontoparietal connectivity. Adjusted regression analyses were performed to estimate associations between documented rTMS exposure and study outcomes. Results Forty-eight patients were included, with 24 in the rTMS-exposed cohort and 24 in the non-rTMS comparison cohort. Documented rTMS exposure was associated with greater improvement in FAB score at post-treatment assessment (+3.1 points; 95% CI, 1.6 to 4.6; p < 0.001) and MoCA executive-domain score (+2.8 points; 95% CI, 1.3 to 4.3; p = 0.001). Functional recovery and Trail-Making Test performance also favored the rTMS-exposed cohort. Biomarker analyses showed greater N100/P200 modulation, increased left DLPFC HbO response, and stronger DLPFC–frontoparietal connectivity. Observed biomarker changes were correlated with executive-function improvement; however, these associations should be interpreted as exploratory and hypothesis-generating given the observational design and limited sample size. Adverse events were mild, with no documented seizures or serious adverse events. Conclusion High-frequency left-DLPFC rTMS exposure was associated with improved executive recovery and measurable frontal-network modulation after traumatic brain injury. These findings suggest that multimodal neurophysiological and imaging biomarkers may provide useful measures of target engagement for future prospective studies. Given the retrospective observational design, modest sample size, and short-term follow-up, causal inferences regarding treatment effects or biomarker-guided neurorehabilitation cannot be established.