Evidence tier key (experimental interventions only)

• [Tier 1] Human data in a target population (TBI or post-viral)

• [Tier 2] Human data in a related condition (stroke, aging, chronic fatigue syndrome) or human physiology only

• [Tier 3] Mechanism or animal data only

UNDERSTANDING NEUROFATIGUE / WHY IS IT HAPPENING?

Fuel: glucose metabolism and brain energy (mitochondria/ATP)

• Siqueira IFB, et al. "Metabolic Brain Changes in Post-Acute COVID-19: Systematic Review and Meta-Analysis of [18F]-FDG-PET Findings." Brain Structure and Function, 2025. (post-viral)

• Manganotti P, et al. "Mapping Brain Changes in Post-COVID-19 Cognitive Decline via FDG-PET Hypometabolism and EEG Slowing." Scientific Reports, 2025. (post-viral)

• Weber-Fahr W, et al. "Reduced Adenosine Triphosphate-to-Phosphocreatine Ratios in Neuropsychiatric Post-Covid Condition: Evidence From 31P Magnetic Resonance Spectroscopy." Biological Psychiatry, 2026. (post-viral)

• Godlewska BR, et al. "Brain and Muscle Chemistry in Myalgic Encephalitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID: A 7T Magnetic Resonance Spectroscopy Study." Molecular Psychiatry, 2025. (post-viral, ME/CFS)

• Peper CJ, et al. "Tracing the Path of Disruption: 13C Isotope Applications in Traumatic Brain Injury-Induced Metabolic Dysfunction." CNS Neuroscience & Therapeutics, 2024. (TBI)

• Oft HC, Simon DW, Sun D. "New Insights into Metabolism Dysregulation after TBI." Journal of Neuroinflammation, 2024. (TBI)

• Di Pietro V, et al. "Fusion or Fission: The Destiny of Mitochondria in Traumatic Brain Injury of Different Severities." Scientific Reports, 2017. (TBI, animal)

Lingering inflammation (microglia, cytokines, synapse loss)

• Gerhard A. "Does Microglial Activation Lead to Cognitive Changes After COVID-19 Infection?" JAMA Psychiatry, 2023. (post-viral)

• Davis HE, McCorkell L, Vogel JM, Topol EJ. "Long COVID: Major Findings, Mechanisms and Recommendations." Nature Reviews Microbiology, 2023. (post-viral)

• Witcher KG, et al. "Traumatic Brain Injury Causes Chronic Cortical Inflammation and Neuronal Dysfunction Mediated by Microglia." Journal of Neuroscience, 2021. (TBI, animal)

• Alawieh A, et al. "Complement Drives Synaptic Degeneration and Progressive Cognitive Decline in the Chronic Phase After Traumatic Brain Injury." Journal of Neuroscience, 2021. (TBI, animal)

• Bray CE, et al. "Chronic Cortical Inflammation, Cognitive Impairment, and Immune Reactivity Associated With Diffuse Brain Injury Are Ameliorated by Forced Turnover of Microglia." Journal of Neuroscience, 2022. (TBI, animal)

• Wangler LM, Godbout JP. "Microglia Moonlighting After Traumatic Brain Injury: Aging and Interferons Influence Chronic Microglia Reactivity." Trends in Neurosciences, 2023. (TBI, animal)

• Li N, et al. "Microglia in Post-Traumatic Brain Injury (TBI) Cognitive Impairment: From Pathological Changes to Therapeutic Approaches." CNS Neuroscience & Therapeutics, 2025. (TBI, review)

Blood flow and oxygen delivery (perfusion, neurovascular coupling)

• Novak P, et al. "Shared Autonomic Phenotype of Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome." PLoS One, 2025. (post-viral, ME/CFS)

• Morris G, Maes M. "Mitochondrial Dysfunctions in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Explained by Activated Immuno-Inflammatory, Oxidative and Nitrosative Stress Pathways." Metabolic Brain Disease, 2014. (ME/CFS)

• Baker TL, et al. "Targeting the Cerebrovascular System: Next-Generation Biomarkers and Treatment for Mild Traumatic Brain Injury." The Neuroscientist, 2022. (TBI)

• Magyar-Sumegi ZD, et al. "Chronic Impairment of Neurovascular Coupling and Cognitive Decline in Young Survivors of Severe Traumatic Brain Injury." GeroScience, 2025. (TBI)

• Kim D, et al. "Comparative Evaluation of Resting-State and CO2-Induced Cerebrovascular Reactivity in Patients with Traumatic Brain Injury." Journal of Neurotrauma, 2026. (TBI)

• Mayer AR, et al. "Multifaceted Neural and Vascular Pathologies after Pediatric Mild Traumatic Brain Injury." Journal of Cerebral Blood Flow & Metabolism, 2024. (TBI, pediatric)

The effort gauge: dopamine and effort versus reward

• Heine J, et al. "Structural Brain Changes in Patients With Post-Covid Fatigue: A Prospective Observational Study." EClinicalMedicine, 2023. (post-viral)

• Walitt B, et al. "Deep Phenotyping of Post-Infectious Myalgic Encephalomyelitis/Chronic Fatigue Syndrome." Nature Communications, 2024. (post-viral ME/CFS)

• Inderyas M, et al. "Distinct Functional Connectivity Patterns in Myalgic Encephalomyelitis and Long COVID Patients During Cognitive Fatigue: A 7 Tesla Task-fMRI Study." Journal of Translational Medicine, 2026. (post-viral, ME/CFS)

• Kuppuswamy A, et al. "Mechanisms of Post-Stroke Fatigue: A Follow-Up From the Third Stroke Recovery and Rehabilitation Roundtable." Neurorehabilitation and Neural Repair, 2024. (post-stroke)

• Womack KB, et al. "123I-Ioflupane Single-Photon Emission Computed Tomography as an Imaging Biomarker of Pre-Synaptic Dopaminergic System after Moderate-to-Severe Traumatic Brain Injury." Journal of Neurotrauma, 2020. (TBI)

• Wylie GR, et al. "Cognitive Fatigue in Individuals with Traumatic Brain Injury Is Associated with Caudate Activation." Scientific Reports, 2017. (TBI)

Shared model across conditions

• Morris G, Berk M, Walder K, Maes M. "Central Pathways Causing Fatigue in Neuro-Inflammatory and Autoimmune Illnesses." BMC Medicine, 2015.

• Liu IH, et al. "Dynamic Prevalence of and Factors Associated With Fatigue Following Traumatic Brain Injury: A Systematic Review and Meta-Analysis of Observational Studies." Journal of Head Trauma Rehabilitation, 2024. (TBI)

• Andelic N, et al. "Frequency of Fatigue and Its Changes in the First 6 Months After Traumatic Brain Injury: Results From the CENTER-TBI Study." Journal of Neurology, 2021. (TBI)

• Saksvik SB, et al. "The Prevalence and Stability of Sleep-Wake Disturbance and Fatigue Throughout the First Year After Mild Traumatic Brain Injury." Journal of Neurotrauma, 2020. (TBI)

MANAGING IT: PACING AND EXERCISE

• Senior HE, Leung JH, Meehan B, et al. "Interventions for Fatigue Management After Traumatic Brain Injury." Cochrane Database of Systematic Reviews, 2026. (TBI; pacing, exercise, methylphenidate)

• Davis HE, McCorkell L, Vogel JM, Topol EJ. "Long COVID: Major Findings, Mechanisms and Recommendations." Nature Reviews Microbiology, 2023. (post-exertional malaise; supports the "crash 12-48 hours later" box)

BEFORE YOU ASSUME IT IS NEUROFATIGUE (screening)

• Kelestimur F, Agha A, Ioachimescu AG, et al. "Approach to the Patient With Traumatic Brain Injury-Induced Pituitary Dysfunction." Journal of Clinical Endocrinology & Metabolism, 2026. (TBI; about 15% prevalence, growth hormone deficiency most common, often missed)

• Tan CL, Alavi SA, Baldeweg SE, et al. "The Screening and Management of Pituitary Dysfunction Following Traumatic Brain Injury in Adults: British Neurotrauma Group Guidance." Journal of Neurology, Neurosurgery & Psychiatry, 2017. (TBI; screening guidance)

• Zhang CD, Ioachimescu AG. "Clinical Manifestations and Treatment of Hypopituitarism Due to Traumatic Brain Injury." Best Practice & Research Clinical Endocrinology & Metabolism, 2025. (TBI)

• Schneider HJ, Kreitschmann-Andermahr I, Ghigo E, Stalla GK, Agha A. "Hypothalamopituitary Dysfunction Following Traumatic Brain Injury and Aneurysmal Subarachnoid Hemorrhage: A Systematic Review." JAMA, 2007. (TBI)

• Mercier LJ, et al. "Growth Hormone Deficiency Testing and Treatment Following Mild Traumatic Brain Injury." Scientific Reports, 2021. (mild TBI; growth hormone deficiency symptoms overlap with persistent post-concussion symptoms)

• Novak P, et al. "Shared Autonomic Phenotype of Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome." PLoS One, 2025. (orthostatic intolerance/POTS)

THERE'S MORE? EXPERIMENTAL INTERVENTIONS

Ketosis and ketones [Tier 1, very limited]

• Feinberg C, Dickerson Mayes K, Jarvis RC, Carr C, Mannix R. "Nutritional Supplement and Dietary Interventions as a Prophylaxis or Treatment of Sub-Concussive Repetitive Head Impact and Mild Traumatic Brain Injury: A Systematic Review." Journal of Neurotrauma, 2023. (TBI; ketogenic diet, n = 14)

• Craig C. "Mitoprotective Dietary Approaches for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Caloric Restriction, Fasting, and Ketogenic Diets." Medical Hypotheses, 2015. (ME/CFS; mechanistic hypothesis, mitochondrial rationale)

• Godlewska BR, et al. "Brain and Muscle Chemistry in ME/CFS and Long COVID: A 7T Magnetic Resonance Spectroscopy Study." Molecular Psychiatry, 2025. (post-viral, ME/CFS; notes fatigue reduction on ketone diet and inefficient oxidative respiration as rationale)

• Bolesławska I, Kowalówka M, Bolesławska-Król N, Przysławski J. "Ketogenic Diet and Ketone Bodies as Clinical Support for the Treatment of SARS-CoV-2: Review of the Evidence." Viruses, 2023. (post-viral; mechanism, improved mitochondrial function)

• Bradshaw PC, Seeds WA, Miller AC, Mahajan VR, Curtis WM. "COVID-19: Proposing a Ketone-Based Metabolic Therapy as a Treatment to Blunt the Cytokine Storm." Oxidative Medicine and Cellular Longevity, 2020. (mechanism; beta-hydroxybutyrate, anti-inflammatory)

• Karagiannis F, et al. "Impaired Ketogenesis Ties Metabolism to T Cell Dysfunction in COVID-19." Nature, 2022. (mechanism; BHB restores oxidative phosphorylation)

Red light / transcranial photobiomodulation [Tier 1]

• Lee TL, et al. "Transcranial Photobiomodulation Improves Cognitive Function, Post-Concussion, and PTSD Symptoms in Mild Traumatic Brain Injury." Journal of Neurotrauma, 2025. (TBI; sham-controlled crossover RCT)

• Zeng J, Wang C, Chai Y, Lei D, Wang Q. "Can Transcranial Photobiomodulation Improve Cognitive Function in TBI Patients? A Systematic Review." Frontiers in Psychology, 2024. (TBI)

• Naeser MA, et al. "Significant Improvements in Cognitive Performance Post-Transcranial, Red/Near-Infrared Light-Emitting Diode Treatments in Chronic, Mild Traumatic Brain Injury: Open-Protocol Study." Journal of Neurotrauma, 2014. (TBI; open-label)

• Lim L, Hosseinkhah N, Van Buskirk M, et al. "Photobiomodulation for Cognitive Dysfunction (Brain Fog) in Post-COVID-19 Condition: A Randomized Double-Blind Sham-Controlled Pilot Trial." EClinicalMedicine, 2026. (post-viral; intranasal + transcranial PBM, Vielight device, objective cognition improved in adults under 45)

• Telles-Araujo GT, et al. "Photobiomodulation in the Management of Persistent Olfactory and Gustatory Dysfunction Post-COVID-19: A Systematic Review." Lasers in Medical Science, 2025. (post-viral; neurosensory recovery, mechanism)

Methylene blue [Tier 2-3]

• Singh N, MacNicol E, DiPasquale O, et al. "The Effects of Acute Methylene Blue Administration on Cerebral Blood Flow and Metabolism in Humans and Rats." Journal of Cerebral Blood Flow & Metabolism, 2023. (human physiology; no fatigue outcome)

• Genrikhs EE, Stelmashook EV, Voronkov DN, et al. "The Single Intravenous Administration of Methylene Blue After Traumatic Brain Injury Diminishes Neurological Deficit, Blood-Brain Barrier Disruption and Decrease in the Expression of S100 Protein in Rats." Brain Research, 2020. (TBI, animal)

• Isaev NK, Genrikhs EE, Stelmashook EV. "Methylene Blue and Its Potential in the Treatment of Traumatic Brain Injury, Brain Ischemia, and Alzheimer's Disease." Reviews in the Neurosciences, 2024. (review)

• Tucker D, Lu Y, Zhang Q. "From Mitochondrial Function to Neuroprotection: An Emerging Role for Methylene Blue." Molecular Neurobiology, 2018. (mechanism)

Hyperbaric oxygen therapy (HBOT) [Tier 1]

• Harch PG. "Systematic Review and Dosage Analysis: Hyperbaric Oxygen Therapy Efficacy in Mild Traumatic Brain Injury Persistent Postconcussion Syndrome." Frontiers in Neurology, 2022. (TBI)

• Boussi-Gross R, et al. "Hyperbaric Oxygen Therapy Can Improve Post Concussion Syndrome Years After Mild Traumatic Brain Injury: Randomized Prospective Trial." PLoS One, 2013. (TBI; crossover RCT)

• Weaver LK, Ziemnik R, Deru K, Russo AA. "A Double-Blind Randomized Trial of Hyperbaric Oxygen for Persistent Symptoms After Brain Injury." Scientific Reports, 2025. (TBI; sham-controlled)

• Hadanny A, et al. "Hyperbaric Oxygen Therapy in Children with Post-Concussion Syndrome Improves Cognitive and Behavioral Function: A Randomized Controlled Trial." Scientific Reports, 2022. (TBI, pediatric)

• Zilberman-Itskovich S, Catalogna M, Sasson E, et al. "Hyperbaric Oxygen Therapy Improves Neurocognitive Functions and Symptoms of Post-COVID Condition: Randomized Controlled Trial." Scientific Reports, 2022. (post-viral; sham-controlled RCT, n = 73, improved energy, cognition, sleep, pain, with MRI perfusion changes)

• Hadanny A, Zilberman-Itskovich S, Catalogna M, et al. "Long Term Outcomes of Hyperbaric Oxygen Therapy in Post COVID Condition: Longitudinal Follow-Up of a Randomized Controlled Trial." Scientific Reports, 2024. (post-viral; benefits persisted at 1 year)

• Kim L, Cammà G, Peters CK, et al. "Hyperbaric Oxygen Therapy Improves Clinical Symptoms and Functional Capacity and Modulates Thalamic Connectivity in ME/CFS: A Prospective Cohort Study." Journal of Translational Medicine, 2026. (ME/CFS; n = 30, improved physical function, fatigue, pain, processing speed)

• van Berkel J, Lalieu RC, Joseph D, Hellemons M, Lansdorp CA. "Hyperbaric Oxygen Therapy for Long COVID: A Prospective Registry." Scientific Reports, 2025. (post-viral; registry)

Low-dose naltrexone (LDN) [Tier 1, observational only]

• Seo YB, Choi YJ, Seo JW, et al. "Therapeutic Options for the Treatment of Post-Acute Sequelae of COVID-19: A Scoping Review." BMC Infectious Diseases, 2025. (post-viral; observational improvement in fatigue, pain, and cognition)

• Gouda AHK, Aitcheson NEC, Steadman KJ. "Low-Dose Naltrexone: What Is the Evidence? A Narrative Review." Advances in Therapy, 2026. (chronic fatigue syndrome cohort, n = 218)

• Naik H, Cooke E, Boulter T, et al. "Low-Dose Naltrexone for Post-Covid Fatigue Syndrome: A Study Protocol for a Double-Blind, Randomised Trial in British Columbia." BMJ Open, 2024. (post-viral; RCT in progress)

• Gillan A, Peace M, Quinn D, Levenson J, Thant T. "Resource Document on the Neuropsychiatric Symptoms of Subacute and Chronic Long COVID." American Psychiatric Association, 2024. (post-viral)

• No human TBI fatigue trial was identified.

Fish oil (omega-3) [Tier 1]

• Hajimohammadebrahim-Ketabforoush M, et al. "Immunonutrition for Modifying Inflammatory Markers and Improving Clinical Outcomes Following Traumatic Brain Injury: A Systematic Review and Meta-Analysis." BMC Neurology, 2025. (TBI)

• Feinberg C, et al. "Nutritional Supplement and Dietary Interventions... Mild Traumatic Brain Injury: A Systematic Review." Journal of Neurotrauma, 2023. (TBI; omega-3, 4 studies, n = 150)

• Yang CP, Chang CM, Yang CC, Pariante CM, Su KP. "Long COVID and Long Chain Fatty Acids (LCFAs): Psychoneuroimmunity Implication of Omega-3 LCFAs in Delayed Consequences of COVID-19." Brain, Behavior, and Immunity, 2022. (post-viral; mechanism, pro-resolving mediators)

• Liu TH, Ho CH, Chen DT, et al. "Omega-3 Polyunsaturated Fatty Acids and the Psychiatric Post-Acute Sequelae of COVID-19: A One-Year Retrospective Cohort Analysis of 33,908 Patients." Brain, Behavior, and Immunity, 2023. (post-viral; large cohort, reduced depression/anxiety/insomnia, no significant effect on fatigue or cognition)

• Bradbury J, Wilkinson S, Schloss J. "Nutritional Support During Long COVID: A Systematic Scoping Review." Journal of Integrative and Complementary Medicine, 2023. (post-viral; identifies omega-3 as a research gap)

Creatine [Tier 1]

• Candow DG, Forbes SC, Ostojic SM, et al. "'Heads Up' for Creatine Supplementation and Its Potential Applications for Brain Health and Function." Sports Medicine, 2023. (TBI; pediatric open-label RCT plus animal data)

• Senior HE, et al. "Interventions for Fatigue Management After Traumatic Brain Injury." Cochrane Database of Systematic Reviews, 2026. (TBI)

• Ostojic SM, Candow DG, Tarnopolsky MA. "Creatine and Post-Viral Fatigue Syndrome: An Update." Journal of the International Society of Sports Nutrition, 2025. (post-viral; narrative review, impaired creatine metabolism as target)

• Slankamenac J, Ranisavljev M, Todorovic N, et al. "Eight-Week Creatine-Glucose Supplementation Alleviates Clinical Features of Long COVID." Journal of Nutritional Science and Vitaminology, 2024. (post-viral; RCT, n = 15, reduced body aches, concentration difficulty, headache; raised brain creatine)

• Godlewska BR, et al. "Brain and Muscle Chemistry in ME/CFS and Long COVID: A 7T Magnetic Resonance Spectroscopy Study." Molecular Psychiatry, 2025. (post-viral, ME/CFS; reduced brain creatine as rationale)

• Williams NB, Hurley RB, Cevallos ME. "Creatine Supplementation and Acute Sleep Deprivation: A Systematic Review of Cognitive, Psychomotor, and Mood Outcomes." Journal of Integrative and Complementary Medicine, 2026. (related context; reduced fatigue and increased vigor under stress)

Peptides

• Cerebrolysin [Tier 1, short-lived benefit]: Feinberg C, et al. "Nutritional Supplement and Dietary Interventions... Mild Traumatic Brain Injury: A Systematic Review." Journal of Neurotrauma, 2023. (TBI; n = 745, benefit at day 10, not day 30)

• Semax [Tier 2-3]:

  • Dolotov OV, Karpenko EA, Seredenina TS, et al. "Semax, an Analogue of Adrenocorticotropin (4-10), Binds Specifically and Increases Levels of Brain-Derived Neurotrophic Factor Protein in Rat Basal Forebrain." Journal of Neurochemistry, 2006. (animal; BDNF)

  • Filippenkov IB, Stavchansky VV, Denisova AE, et al. "Novel Insights Into the Protective Properties of ACTH(4-7)PGP (Semax) Peptide at the Transcriptome Level Following Cerebral Ischaemia-Reperfusion in Rats." Genes (Basel), 2020. (animal; ischemia)

  • Liu R, Chen Y, Huang H, et al. "Semax Peptide Targets the Mu Opioid Receptor Gene Oprm1 to Promote Deubiquitination and Functional Recovery After Spinal Cord Injury in Female Mice." British Journal of Pharmacology, 2025. (animal; spinal cord injury)

  • Mavrych V, Shypilova I, Bolgova O. "Therapeutic Peptides in Gerontology: Mechanisms and Applications for Healthy Aging." Frontiers in Aging, 2026. (review; includes stroke clinical data)

Prescription comparator (not in the handout, but useful context)

• Senior HE, et al. "Interventions for Fatigue Management After Traumatic Brain Injury." Cochrane Database of Systematic Reviews, 2026. (TBI; methylphenidate reduced fatigue, modafinil results mixed)