{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T13:07:13Z","timestamp":1788959233339,"version":"build-2803163510"},"reference-count":368,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"AFMU New Talent Program","award":["2025-89"],"award-info":[{"award-number":["2025-89"]}]},{"name":"Military Medicine Key-Technology Tackling Program Project of AFMU","award":["2025JSKY27"],"award-info":[{"award-number":["2025JSKY27"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Brain fatigue is a debilitating condition whose molecular complexity\u2014neurotransmitter imbalance, neuroinflammation, and metabolic failure\u2014has long defied effective intervention. Conventional open-loop neuromodulation offers fixed stimulation, but fatigue fluctuates. Closed-loop neuromodulation, adjusting stimulation in real time, holds real promise. Yet its delivery hinges on a single, unresolved bottleneck: the sensing\u2013decision chain. In this review, we deconstruct closed-loop systems into sensing, decision, and intervention, and argue that the true challenge is not technological but informational\u2014how to integrate fast electrophysiological signals with slow molecular biomarkers (inflammatory cytokines, neurotrophic factors, adenosine) into a unified control framework. We show that a \u201cfast-slow variable\u201d architecture offers a practical path forward: fast signals guide immediate responses, slow variables set baselines and thresholds, and their integration enables predictive, pre-emptive intervention. We also examine the molecular correlates of neuromodulation\u2014synaptic plasticity, anti-inflammatory signaling, and neurotrophic regulation\u2014as the mechanistic foundation for therapeutic effect. Finally, we confront the translational triad of causality, inter-individual variability, and the information\u2013energy\u2013time trade-off. We conclude that realizing effective closed-loop neuromodulation for brain fatigue will require parallel advances in both stimulation hardware\u2014improving spatial targeting, dose precision, and modality versatility\u2014and individualized sensing\u2013decision algorithms capable of reliably translating multi-modal biomarkers into timely, safe interventions. Both areas remain active fronts of development, and neither can be neglected in clinical translation.<\/jats:p>","DOI":"10.3390\/ijms27177970","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T13:53:28Z","timestamp":1788789208000},"page":"7970","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Closed-Loop Neuromodulation for Brain Fatigue: From Real-Time Biomarkers to Adaptive Intervention"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2757-1471","authenticated-orcid":false,"given":"Hongliang","family":"Lu","sequence":"first","affiliation":[{"name":"Department of Military Medical Psychology, Air Force Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yajuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Military Medical Psychology, Air Force Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengjun","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Military Medical Psychology, Air Force Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danmin","family":"Miao","sequence":"additional","affiliation":[{"name":"Department of Military Medical Psychology, Air Force Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e00068","DOI":"10.1097\/IN9.0000000000000068","article-title":"Metabolic neuroimaging of myalgic encephalomyelitis\/chronic fatigue syndrome and Long-COVID","volume":"7","author":"Zhu","year":"2025","journal-title":"Immunometabolism"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1191\/1352458503ms904oa","article-title":"Fatigue associated with multiple sclerosis: Diagnosis, impact and management","volume":"9","author":"Bakshi","year":"2003","journal-title":"Mult. 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