Left DLPFC as a Frontal-Vagal Hub in Post-Brain Injury Dysregulation: iTBS Evidence From Dual-Modality Neuronavigation

Abstract

BackgroundPost-brain injury autonomic dysfunction, mediated by frontal-vagal network (FVN) dysregulation, lacks noninvasive tools for functional mapping and targeted neuromodulation.ObjectiveTo characterize autonomic impairment after brain injury, testify left dorsolateral prefrontal cortex (DLPFC) as an FVN hub, and validate a closed-loop intermittent theta-burst stimulation coupled with heart rate variability monitoring (iTBS-HRV) paradigm for FVN assessment.MethodsThis exploratory, secondary analysis integrated data from 3 coordinated investigations conducted using a dual-modality platform that combined structural magnetic resonance imaging (MRI)-guided optical neuronavigation with real-time HRV biofeedback: (1) autonomic profiling through HRV analysis comparing 59 brain-injured patients with 30 healthy controls; (2) A randomized crossover trial using MRI-neuronavigation iTBS to compare left versus right DLPFC stimulation effects on HRV in 15 participants; and (3) a translation study applied closed-loop iTBS-HRV intervention in 17 patients to quantify FVN responsivity. Key HRV metrics: root-mean-square of successive RR intervals differences ([RMSSD]; vagal tone), (high-frequency [HF]), low-frequency (LF)/HF (sympathovagal balance), and standard deviation of RR intervals ([SDNN]; global variability).ResultsPatients showed severe autonomic dysfunction with reduced vagal tone (RMSSD: 18.6 ms vs 36.7 ms, P < .001) and global variability (SDNN: 21.3 ms vs 50.9 ms, P < .001). Left frontal lesions exacerbate sympathovagal imbalance (LF/HF ↑2.40, P < .05). Left DLPFC iTBS selectively enhanced vagal modulation (ΔHF%: +2.73, P < .01; ΔLF/HF: -1.60, P < .001), confirming lateralized hub function, while patients exhibited attenuated HRV responses (ΔRMSSD: 0.50 ms vs 3.34 ms in controls, P < .01).ConclusionThe dual-modality iTBS-HRV framework provides an effective approach for mapping FVN dysfunction and targeting the left DLPFC hub for neuromodulation after brain injury.

Keywords: autonomic dysfunction; brain injury; frontal–vagal network; heart rate variability; intermittent theta-burst stimulation; left dorsolateral prefrontal cortex.