Post-brain injury autonomic dysfunction, mediated by frontal–vagal network (FVN) dysregulation, lacks noninvasive tools for functional mapping and targeted neuromodulation.
Objective
To 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.
Methods
This 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).
Results
Patients 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).
Conclusion
The dual-modality iTBS–HRV framework provides an effective approach for mapping FVN dysfunction and targeting the left DLPFC hub for neuromodulation after brain injury.
BaguleyIJSlewa-YounanSHeriseanuRENottMTMudaliarYNayyarV. The incidence of dysautonomia and its relationship with autonomic arousal following traumatic brain injury. Brain Inj. 2007;21(11):1175-1181. doi:10.1080/02699050701687375
2.
GoldbergerJJAroraRBuckleyUShivkumarK. Autonomic nervous system dysfunction. J Am Coll Cardiol. 2019;73(10):1189-1206. doi:10.1016/j.jacc.2018.12.064
3.
MercierLJBatyckyJCampbellCSchneiderKSmirlJDebertCT. Autonomic dysfunction in adults following mild traumatic brain injury: a systematic review. NeuroRehabilitation. 2022;50(1):3-32. doi:10.3233/NRE-210243
4.
PurkayasthaSStokesMBellKR. Autonomic nervous system dysfunction in mild traumatic brain injury: a review of related pathophysiology and symptoms. Brain Inj. 2019;33(9):1129-1136. doi:10.1080/02699052.2019.1631488
5.
Fernandez-OrtegaJFPrieto-PalominoMAGarcia-CaballeroMGaleas-LopezJLQuesada-GarciaGBaguleyIJ. Paroxysmal sympathetic hyperactivity after traumatic brain injury: clinical and prognostic implications. J Neurotrauma. 2012;29(7):1364-1370. doi:10.1089/neu.2011.2033
6.
Jimenez-RuizARacostaJMKimpinskiKHilzMJSposatoLA. Cardiovascular autonomic dysfunction after stroke. Neurol Sci. 2021;42(5):1751-1758. doi:10.1007/s10072-021-05128-y
CritchleyHDMathiasCJJosephsO, et al. Human cingulate cortex and autonomic control: converging neuroimaging and clinical evidence. Brain. 2003;126(10):2139-2152. doi:10.1093/brain/awg216
HowardLDumkriegerGChongCDRossKBerishaVSchwedtTJ. Symptoms of autonomic dysfunction among those with persistent posttraumatic headache attributed to mild traumatic brain injury: a comparison to migraine and healthy controls. Headache J Head Face Pain. 2018;58(9):1397-1407. doi:10.1111/head.13396
11.
ThayerJFHansenALSaus-RoseEJohnsenBH. Heart rate variability, prefrontal neural function, and cognitive performance: the neurovisceral integration perspective on self-regulation, adaptation, and health. Ann Behav Med. 2009;37(2):141-153. doi:10.1007/s12160-009-9101-z
12.
Mizuno-MatsumotoYInoguchiYCarpelsSMAMuramatsuAYamamotoY. Cerebral cortex and autonomic nervous system responses during emotional memory processing. PLoS ONE. 2020;15(3):e0229890. doi:10.1371/journal.pone.0229890
13.
RomaniukMXiaYFisherG, et al. The relationship between chronic PTSD, cortical volumetry and white matter microstructure among Australian combat veterans. Mil Med Res. 2022;9(1):50. doi:10.1186/s40779-022-00413-z
14.
ParkJKangYHanKM, et al. Association between the C4 binding protein level and white matter integrity in major depressive disorder. Psychiatry Investig. 2022;19(9):703-711. doi:10.30773/pi.2022.0100
15.
IsegerTAvan BuerenNERKenemansJLGevirtzRArnsM. A frontal-vagal network theory for Major Depressive Disorder: implications for optimizing neuromodulation techniques. Brain Stimulat. 2020;13(1):1-9. doi:10.1016/j.brs.2019.10.006
16.
HuangYZEdwardsMJRounisEBhatiaKPRothwellJC. Theta burst stimulation of the human motor cortex. Neuron. 2005;45(2):201-206. doi:10.1016/j.neuron.2004.12.033
17.
HuangCCLiangCSChuHTChangHAYehTC. Intermittent theta burst stimulation for the treatment of autonomic dysfunction and depressive symptoms in dementia with Lewy bodies. Asian J Psychiatry. 2022;75:103212. doi:10.1016/j.ajp.2022.103212
18.
PoppaTde WitteSVanderhasseltMABecharaABaekenC. Theta-burst stimulation and frontotemporal regulation of cardiovascular autonomic outputs: the role of state anxiety. Int J Psychophysiol. 2020;149:25-34. doi:10.1016/j.ijpsycho.2019.12.011
19.
QuintanaDSAlvaresGAHeathersJAJ. Guidelines for Reporting Articles on Psychiatry and Heart rate variability (GRAPH): recommendations to advance research communication. Transl Psychiatry. 2016;6(5):e803. doi:10.1038/tp.2016.73
20.
RiganelloFLarroqueSKBahriMA, et al. A heartbeat away from consciousness: heart rate variability entropy can discriminate disorders of consciousness and is correlated with resting-state fMRI brain connectivity of the central autonomic network. Front Neurol. 2018;9:769. doi:10.3389/fneur.2018.00769
21.
BlankeEHolmesGBeseckerE. Altered physiology of gastrointestinal vagal afferents following neurotrauma. Neural Regen Res. 2021;16(2):254. doi:10.4103/1673-5374.290883
22.
KriegerJPSkibickaKP. From physiology to psychiatry: key role of vagal interoceptive pathways in emotional control. Biol Psychiatry. 2025;98(6):466-475. doi:10.1016/j.biopsych.2025.04.012
23.
ÖngürDFerryATPriceJL. Architectonic subdivision of the human orbital and medial prefrontal cortex. J Comp Neurol. 2003;460(3):425-449. doi:10.1002/cne.10609
24.
HiserJKoenigsM. The multifaceted role of ventromedial prefrontal cortex in emotion, decision-making, social cognition, and psychopathology. Biol Psychiatry. 2018;83(8):638-647. doi:10.1016/j.biopsych.2017.10.030
25.
SaperCB. The central autonomic nervous system: conscious visceral perception and autonomic pattern generation. Annu Rev Neurosci. 2002;25:433-469. doi:10.1146/annurev.neuro.25.032502.111311
26.
BakerJRBourneKMLamotteG. Recent updates in autonomic research: a focus on new technologies with high-resolution procedures to study sympathetic nerve activity, plasma proteomic profiling in POTS, and non-invasive neuromodulation with focused ultrasound. Clin Auton Res. 2023;33(1):11-14. doi:10.1007/s10286-023-00924-2
27.
MatusikPSZhongCMatusikPTAlomarOSteinPK. Neuroimaging studies of the neural correlates of heart rate variability: a systematic review. J Clin Med. 2023;12(3):1016. doi:10.3390/jcm12031016
28.
TrifilioEShortellDOlshanS, et al. Impact of transcutaneous vagus nerve stimulation on healthy cognitive and brain aging. Front Neurosci. 2023;17:1184051. doi:10.3389/fnins.2023.1184051
29.
KhanNKaurSKnuthCMJeschkeMG. CNS-spleen axis - a close interplay in mediating inflammatory responses in burn patients and a key to novel burn therapeutics. Front Immunol. 2021;12:720221. doi:10.3389/fimmu.2021.720221
30.
KrickSKoobJLLatarnikS, et al. Neuroanatomy of post-stroke depression: the association between symptom clusters and lesion location. Brain Commun. 2023;5(5):fcad275. doi:10.1093/braincomms/fcad275
31.
TinneyEMAiMEspaña-IrlaGHillmanCHMorrisTP. Physical activity and frontoparietal network connectivity in traumatic brain injury. Brain Behav. 2024;14(9):e70022. doi:10.1002/brb3.70022
32.
StolicynAHarrisMADe NooijL, et al. Disrupted limbic-prefrontal effective connectivity in response to fearful faces in lifetime depression. J Affect Disord. 2024;351:983-993. doi:10.1016/j.jad.2024.01.038
33.
OzdenHCGurelSCOzerNDemirB. Bidirectionality of LF when the movie makes you sad: effects of negative emotions on heart rate variability among patients with major depression. J Psychosom Res. 2024;184:111855. doi:10.1016/j.jpsychores.2024.111855
34.
GalinSKerenH. The predictive potential of heart rate variability for depression. Neuroscience. 2024;546:88-103. doi:10.1016/j.neuroscience.2024.03.013
35.
StöhrmannPGodbersenGMReedMB, et al. Effects of bilateral sequential theta-burst stimulation on functional connectivity in treatment-resistant depression: first results. J Affect Disord. 2023;324:660-669. doi:10.1016/j.jad.2022.12.088
36.
GreiciusMDFloresBHMenonV, et al. Resting-state functional connectivity in major depression: abnormally increased contributions from subgenual cingulate cortex and thalamus. Biol Psychiatry. 2007;62(5):429-437. doi:10.1016/j.biopsych.2006.09.020
37.
BadkeCMMarsillioLECarrollMSWeese-MayerDESanchez-PintoLN. Development of a heart rate variability risk score to predict organ dysfunction and death in critically ill children. Pediatr Crit Care Med. 2021;22(8):e437-e447. doi:10.1097/PCC.0000000000002707
38.
NorrisPROzdasACaoH, et al. Cardiac uncoupling and heart rate variability stratify ICU patients by mortality: a study of 2088 trauma patients. Ann Surg. 2006;243(6):804-814. doi:10.1097/01.sla.0000219642.92637.fd
39.
NorrisPRSteinPKMorrisJA. Reduced heart rate multiscale entropy predicts death in critical illness: a study of physiologic complexity in 285 trauma patients. J Crit Care. 2008;23(3):399-405. doi:10.1016/j.jcrc.2007.08.001
