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NeurologyPEM-relevant

Neuroinflammation

171 studies in the atlas

Neuroinflammation has emerged as a significant area of ME/CFS research, supported by PET imaging studies showing elevated microglial activation in patients relative to healthy controls. Brain imaging, including MRI and functional connectivity studies, has documented structural and functional abnormalities in multiple brain regions. Central nervous system involvement may help explain cognitive impairment, sensory sensitivity, and the characteristic post-exertional symptom worsening seen in ME/CFS. Research in this area explores the relationship between peripheral immune dysfunction, central nervous system inflammation, and the neurological symptom profile of the illness.

What we know

  • PET imaging studies have detected microglial activation in some ME/CFS patients, particularly in regions associated with cognition and autonomic function
  • Reduced cerebral blood flow during upright posture has been replicated across multiple studies
  • Cognitive dysfunction (brain fog) is one of the most commonly reported symptoms and correlates with functional impairment
  • Neurological symptoms including sensory sensitivity, headache, and poor concentration are reported by a majority of patients

What remains uncertain

  • Whether microglial activation is a primary driver or a downstream consequence of systemic inflammation
  • Peripheral immune signals may cross the blood-brain barrier and trigger central neuroinflammation
  • Small fiber neuropathy, found in a subset of patients, may contribute to both neurological and autonomic symptoms
  • Whether neuroimaging findings correlate with symptom severity remains unclear — sample sizes have been small

What is emerging

  • The precise mechanisms linking systemic immune activation to CNS inflammation
  • Whether anti-neuroinflammatory treatments could benefit ME/CFS patients
  • The relationship between neuroinflammation and cognitive impairment at the cellular level
  • Whether neuroinflammation patterns differ between post-infectious and gradual-onset ME/CFS

Start here

E0 ConsensusPEM requiredPreliminary

Potential application of brain-gut axis-based treatments in Long COVID and ME/CFS: a case-based systematic review.

Kim, Do-Young, Youn, Jaeyoung, Kang, Naeun et al.·Journal of translational medicine·2026

This study looked at how treating the connection between the brain and gut might help people with ME/CFS and Long COVID. Researchers reviewed eight previous studies testing different treatments—including special nerve stimulation and probiotics—and also followed one patient who improved with a type of needle stimulation. Many of these treatments showed promise in reducing fatigue and post-exertional malaise, possibly by helping restore healthy gut bacteria and reduce brain inflammation.

Research Momentum

171 publications over 28 years. Recent trend: steady (15/year over the last 3 years).

All Studies

171 studies, sorted by review status and evidence level

E0 ConsensusPEM unclearModerate confidenceReview-NarrativeEditor reviewed

Cognitive Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-Aetiology and Potential Treatments.

Bansal, Amolak Singh, Seton, Katharine A, Brooks, Jonathan C W et al.·International journal of molecular sciences·2025

Many ME/CFS patients experience brain fog and difficulty concentrating, which can be as disabling as physical symptoms. This review examined how ongoing low-level inflammation and viral activity in the body may damage thinking and memory by affecting blood flow and nerve function in the brain. The researchers suggest that treating inflammation, controlling viral reactivation, and improving how cells produce energy could potentially help restore cognitive function.

NeuroinflammationImmune System
E0 ConsensusPEM requiredModerate confidenceReview-NarrativeEditor reviewed

Insights into the Complex Biological Network Underlying Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Dudova, Dobrina, Bozhkova, Martina, Petrov, Steliyan et al.·International journal of molecular sciences·2025

This review brings together research showing that ME/CFS involves multiple body systems going wrong at the same time—including problems with the immune system, energy production in cells, hormone balance, and gut health. These problems appear to feed into each other, creating a cycle that keeps the illness going. The findings suggest ME/CFS is not just one thing breaking down, but rather many interconnected systems all struggling together.

NeuroinflammationEnergy MetabolismImmune SystemPost-Exertional Malaise
E0 ConsensusPEM unclearPreliminaryReview-NarrativeEditor reviewed

The microbiota-gut-brain axis in myalgic encephalomyelitis/chronic fatigue syndrome: a narrative review of an emerging field.

El-Sehrawy, Amr Ali Mohamed Abdelgawwad, Ayoub, Ibtihal Ibrahim, Uthirapathy, Subasini et al.·European journal of translational myology·2025

This review examines how bacteria in your gut may be connected to ME/CFS symptoms like fatigue and brain fog. Researchers looked at studies from 1995 to 2025 about how gut bacteria communicate with the brain and immune system. The review suggests that fixing imbalances in gut bacteria might help treat ME/CFS, though more research is needed to confirm this.

NeuroinflammationImmune System
E0 ConsensusPEM unclearModerate confidenceSystematic-ReviewEditor reviewed

Brain-regional characteristics and neuroinflammation in ME/CFS patients from neuroimaging: A systematic review and meta-analysis.

Lee, Jin-Seok, Sato, Wakiro, Son, Chang-Gue·Autoimmunity reviews·2024

Researchers combined results from 65 brain imaging studies involving over 1,500 ME/CFS patients to look for signs of inflammation in the brain. They used four different types of brain scans and found that specific brain regions—particularly the insular and thalamic regions that help process emotions and manage body functions—showed reduced activity in ME/CFS patients compared to healthy controls. These findings suggest that problems in how these brain regions communicate may help explain why ME/CFS causes fatigue and other characteristic symptoms.

Neuroinflammation
E0 ConsensusPEM unclearPreliminaryReview-NarrativeEditor reviewed

Microglia and Sleep Disorders.

Picard, Katherine, Dolhan, Kira, Watters, Jyoti J et al.·Advances in neurobiology·2024

This review examines how microglia—immune cells in the brain and spinal cord—affect sleep and sleep disorders. The authors discuss how sleep problems and lack of sleep can harm brain health and potentially lead to diseases like Alzheimer's and Parkinson's. They specifically look at how microglia may be involved in ME/CFS and other sleep disorders, and what happens to these immune cells when people don't get enough sleep.

NeuroinflammationImmune System
E0 ConsensusPEM unclearPreliminaryReview-NarrativeEditor reviewed

Could the kynurenine pathway be the key missing piece of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) complex puzzle?

Kavyani, Bahar, Lidbury, Brett A, Schloeffel, Richard et al.·Cellular and molecular life sciences : CMLS·2022

This review explores whether problems with how your body processes an amino acid called tryptophan might explain ME/CFS symptoms. The kynurenine pathway is a biochemical process that helps your cells make energy and affects immune function and brain inflammation. The authors suggest that abnormalities in this pathway could be a missing piece in understanding why ME/CFS develops.

NeuroinflammationBiomarkers
E0 ConsensusPEM unclearPreliminaryReview-NarrativeEditor reviewed

Animal Models for Neuroinflammation and Potential Treatment Methods.

Tamura, Yasuhisa, Yamato, Masanori, Kataoka, Yosky·Frontiers in neurology·2022

This review looked at how ME/CFS may be caused by inflammation in the brain and examined animal studies testing anti-inflammatory treatments. Researchers found that brain inflammation is connected to how severe ME/CFS symptoms are, and that certain compounds with anti-inflammatory properties showed promise in reducing these inflammatory responses in animal models. This suggests that anti-inflammatory medicines might help improve symptoms in ME/CFS patients.

NeuroinflammationImmune System
E0 ConsensusPEM unclearPreliminarySystematic-ReviewEditor reviewed

Brainstem Abnormalities in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Scoping Review and Evaluation of Magnetic Resonance Imaging Findings.

Nelson, Todd, Zhang, Lan-Xin, Guo, Hui et al.·Frontiers in neurology·2021

This review examined brain imaging studies to understand how ME/CFS affects the brainstem, which is the part of the brain that controls vital functions like heart rate, breathing, and sleep. Researchers found that people with ME/CFS often show changes in the brain's structure and how different brain regions communicate with each other. These findings suggest that problems in the brainstem might explain many ME/CFS symptoms, though more research is needed to fully understand the connections.

Neuroinflammation
E0 ConsensusPEM not requiredPreliminaryMeta-AnalysisEditor reviewed

Meta analysis of Chronic Fatigue Syndrome through integration of clinical, gene expression, SNP and proteomic data.

Pihur, Vasyl, Datta, Somnath, Datta, Susmita·Bioinformation·2011

Researchers combined multiple types of biological data from ME/CFS patients and healthy controls to identify genes that may contribute to ME/CFS and its severity. They found 11 genes of potential importance, with one gene called WASF3 standing out as possibly influencing fatigue through a specific cellular pathway in the brain.

NeuroinflammationImmune System
E0 ConsensusPEM not requiredModerate confidenceReview-NarrativeEditor reviewed

Cognitive dysfunction in post-COVID-19 condition: Mechanisms, management, and rehabilitation.

Möller, Marika, Borg, Kristian, Janson, Christer et al.·Journal of internal medicine·2023

Many people experience brain fog and memory problems long after COVID-19 infection, affecting thinking, attention, and processing speed. This review found that 17–28% of people have these cognitive problems more than 3 months after infection, and some experience them for years. Treatment approaches include cognitive training, memory aids, lifestyle adjustments, and education about managing these symptoms.

NeuroinflammationPost-Exertional Malaise
E0 ConsensusPEM unclearPreliminaryReview-NarrativeEditor reviewed

The Neurological Manifestations of Post-Acute Sequelae of SARS-CoV-2 infection.

Moghimi, Narges, Di Napoli, Mario, Biller, José et al.·Current neurology and neuroscience reports·2021

This review examined what we know about how COVID-19 can affect the nervous system in people who experience long-term symptoms after infection (called PASC or long COVID). The researchers looked at published studies to understand how common these neurological problems are, who is most at risk, why they happen, and how they might be treated. They found that long COVID can range from mild to severely disabling symptoms that last weeks or longer, and that multiple factors—including lingering inflammation, immune system problems, and possible viral effects on the brain—may play a role.

NeuroinflammationImmune System
E0 ConsensusPEM requiredPreliminarySystematic-ReviewEditor reviewed

Potential application of brain-gut axis-based treatments in Long COVID and ME/CFS: a case-based systematic review.

Kim, Do-Young, Youn, Jaeyoung, Kang, Naeun et al.·Journal of translational medicine·2026

This study looked at how treating the connection between the brain and gut might help people with ME/CFS and Long COVID. Researchers reviewed eight previous studies testing different treatments—including special nerve stimulation and probiotics—and also followed one patient who improved with a type of needle stimulation. Many of these treatments showed promise in reducing fatigue and post-exertional malaise, possibly by helping restore healthy gut bacteria and reduce brain inflammation.

NeuroinflammationPost-Exertional Malaise
E0 ConsensusPEM unclearModerate confidenceReview-NarrativeEditor reviewed

Causes of symptoms and symptom persistence in long COVID and myalgic encephalomyelitis/chronic fatigue syndrome.

Komaroff, Anthony L, Dantzer, Robert·Cell reports. Medicine·2025

This review examines why long COVID and ME/CFS cause such severe, lasting symptoms. Researchers found that both conditions share similar biological problems, including immune system misbehavior, problems with blood vessel function, and issues with how cells produce energy. The study suggests that symptoms may come from both these biological problems and from ancient survival responses in the brain that were meant to protect us during serious illness.

NeuroinflammationSevere MEGut Microbiome
E0 ConsensusPEM unclearModerate confidenceSystematic-ReviewEditor reviewed

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): diagnosis and management.

Fan, Jin, Jiao, Jiao, Chang, Hai-Qing et al.·Journal of translational medicine·2025

This comprehensive review examines how ME/CFS is diagnosed and treated based on current medical knowledge. The authors found that ME/CFS is caused by problems with the immune system, energy production in cells, and brain inflammation, but there are currently no definitive blood tests to confirm the disease. Treatment options include both medication approaches (targeting immune dysfunction and cell energy) and non-medication strategies like activity pacing and cognitive behavioral therapy, though doctors now recognize that exercise programs can actually harm some patients.

NeuroinflammationBiomarkersImmune System
E0 ConsensusPEM requiredModerate confidenceSystematic-ReviewEditor reviewed

Applicability and adaptation of cognitive behavior therapy for long COVID neuropsychiatric symptoms: a review with insights from ME/CFS.

Takamatsu, Naoki, Kuga, Hironori·BMC infectious diseases·2025

This review examined whether cognitive behavior therapy (CBT)—a talking therapy that helps address thought patterns and behaviors—might help patients with long COVID who experience brain fog, fatigue, and mood problems. The authors compared long COVID to ME/CFS, noting they share many features, and found that while CBT may help some patients feel less tired and think more clearly, it works best when tailored to each person's energy limits and combined with other treatments. Importantly, the authors stress that suggesting CBT does not mean these illnesses are 'all in your head'—they have real physical causes.

NeuroinflammationImmune SystemPost-Exertional Malaise
E0 ConsensusPEM unclearPreliminaryReview-NarrativeEditor reviewed

Metabolic neuroimaging of myalgic encephalomyelitis/chronic fatigue syndrome and Long-COVID.

Zhu, Yijuan, Quan, Patrick, Yamazaki, Tadahiro et al.·Immunometabolism (Cobham, Surrey)·2025

This review examines brain imaging studies that look at how the brains of people with ME/CFS and Long-COVID process energy and nutrients differently. Researchers used advanced scanning techniques to measure glucose and oxygen use in the brain, finding that both conditions show similar patterns of disrupted brain energy metabolism and inflammation. The findings suggest these brain changes might explain why patients experience persistent fatigue, thinking problems, and worsening after physical activity.

NeuroinflammationBiomarkersPost-Exertional Malaise
E0 ConsensusPEM unclearPreliminaryReview-NarrativeEditor reviewed

Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders.

Cohen, Jessica, Mathew, Annette, Dourvetakis, Kirk D et al.·Cells·2024

This review examines how inflammation in the brain and nervous system contributes to several chronic diseases, including ME/CFS and Gulf War Illness. The authors discuss how immune cells and inflammatory molecules can damage the brain and cause persistent symptoms. They highlight promising new laboratory techniques using human stem cells to create brain cells for testing potential treatments.

NeuroinflammationImmune System
E0 ConsensusPEM unclearPreliminarySystematic-ReviewEditor reviewed

[Long COVID - neurological or somatoform disease?].

Tényi, Dalma, Tényi, Tamás, Janszky, József·Ideggyogyaszati szemle·2024

This study reviews research on long COVID to understand what causes its main symptoms like extreme fatigue, pain, and brain fog. Doctors are still debating whether long COVID is primarily a brain/nerve disease, a whole-body illness affecting multiple systems, or a condition where the brain becomes overly sensitive to signals. The researchers found that long COVID shares many similarities with ME/CFS and other hard-to-diagnose conditions, but no single test currently exists to confirm long COVID diagnosis.

NeuroinflammationPost-Exertional Malaise
E0 ConsensusPEM not requiredModerate confidenceReview-NarrativeEditor reviewed

Understanding the kynurenine pathway: A narrative review on its impact across chronic pain conditions.

Hazrati, Ebrahim, Eftekhar, Seyed Parsa, Mosaed, Reza et al.·Molecular pain·2024

This review examined how a specific pathway in the body that breaks down the amino acid tryptophan might contribute to chronic pain, including in ME/CFS patients. The review looked at research across various pain conditions and depression, finding that certain chemicals produced along this pathway can either protect or damage nerve cells. The authors suggest that targeting this pathway could lead to new, non-opioid treatments for chronic pain.

NeuroinflammationEnergy Metabolism
E0 ConsensusPEM requiredModerate confidenceReview-NarrativeEditor reviewed

Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome.

Paul, Bindu D, Lemle, Marian D, Komaroff, Anthony L et al.·Proceedings of the National Academy of Sciences of the United States of America·2021

This review examines how COVID-19 and ME/CFS may share similar biological problems, particularly an imbalance in how the body handles harmful molecules called free radicals. Both conditions appear to involve problems with inflammation, energy production in cells, and a slowed metabolism. While this research shows these biological abnormalities exist in both illnesses, more studies are needed to understand exactly how they work together and how to treat them.

NeuroinflammationPost-Exertional Malaise
E0 ConsensusPEM not requiredModerate confidenceReview-NarrativeEditor reviewed

Shared microglial mechanisms underpinning depression and chronic fatigue syndrome and their comorbidities.

Chaves-Filho, Adriano José Maia, Macedo, Danielle S, de Lucena, David Freitas et al.·Behavioural brain research·2019

This review examined how depression and ME/CFS might share common causes in the brain, specifically through immune cells called microglia. Researchers found that when these brain immune cells become overactive, they may trigger both depression and the fatigue characteristic of ME/CFS. The study suggests that reducing this immune activation could potentially help treat both conditions.

NeuroinflammationImmune System
E0 ConsensusPEM not requiredPreliminaryReview-NarrativeEditor reviewed

The inflammatory hypothesis of mood spectrum broadened to fibromyalgia and chronic fatigue syndrome.

Dell'Osso, Liliana, Bazzichi, Laura, Baroni, Stefano et al.·Clinical and experimental rheumatology·2015

This review examined whether ME/CFS, fibromyalgia, and mood disorders like depression might share similar root causes involving inflammation and immune system dysfunction. Researchers looked at scientific papers from 2000-2014 and found striking similarities in how these conditions affect the brain, nervous system, and immune system. The findings suggest these seemingly different conditions may be connected through common biological mechanisms rather than being completely separate diseases.

NeuroinflammationImmune System
E0 ConsensusPEM unclearModerate confidenceReview-NarrativeEditor reviewed

An intriguing and hitherto unexplained co-occurrence: Depression and chronic fatigue syndrome are manifestations of shared inflammatory, oxidative and nitrosative (IO&NS) pathways.

Maes, Michael·Progress in neuro-psychopharmacology & biological psychiatry·2011

Depression and ME/CFS often occur together, and this study suggests they share common biological root causes involving inflammation and oxidative stress (damage to cells). While depression and ME/CFS look different clinically, they appear to involve similar underlying problems with the immune system, energy production, and antioxidant defenses. The authors argue these should be considered connected disorders rather than two separate conditions that happen to co-occur.

NeuroinflammationImmune System
E0 ConsensusPEM not requiredPreliminaryReview-NarrativeEditor reviewed

Autoantibodies associated with psychiatric disorders.

Margutti, Paola, Delunardo, Federica, Ortona, Elena·Current neurovascular research·2006

This review examines evidence that the immune system can sometimes produce antibodies that attack the brain and blood vessels, potentially causing psychiatric symptoms like depression, anxiety, and psychosis. The authors discuss how this autoimmune mechanism may occur in several conditions, including chronic fatigue syndrome, and review what we know about antibodies in psychiatric disorders including schizophrenia and autism.

Neuroinflammation
E0 ConsensusPEM not requiredModerate confidenceReview-NarrativeEditor reviewed

The microbiota-gut-brain axis in mental and neurodegenerative disorders: opportunities for prevention and intervention.

Yassin, Lidya K, Skrabulyte-Barbulescu, Jurga, Alshamsi, Shamsa H et al.·Frontiers in aging neuroscience·2025

Your gut bacteria communicate with your brain through multiple pathways, and when this communication breaks down (called dysbiosis), it may contribute to several conditions including ME/CFS, depression, and neurological diseases. This review found that people with these conditions often have fewer types of bacteria, lower levels of beneficial short-chain fatty acids, and more inflammatory bacteria. Treatment approaches like dietary changes, probiotics, and fecal microbiota transplantation show promise in helping restore this gut-brain communication and reduce symptoms.

Neuroinflammation
E1 ReplicatedPEM not requiredModerate confidenceRCTEditor reviewed

Effect of Milnacipran Treatment on Ventricular Lactate in Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled Trial.

Natelson, Benjamin H, Vu, Diana, Mao, Xiangling et al.·The journal of pain·2015

This study tested whether a medication called milnacipran could reduce brain inflammation and pain in fibromyalgia patients. Researchers measured a chemical called lactate in the brain using a special MRI scan and found that fibromyalgia patients had higher levels than healthy people. After 8 weeks of treatment, patients taking milnacipran showed lower lactate levels and less pain compared to those taking placebo, suggesting the medication may work by reducing brain inflammation.

NeuroinflammationBiomarkers
E2 ModeratePEM unclearModerate confidenceCross-SectionalEditor reviewed

Evidence of White Matter Neuroinflammation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Diffusion-Based Neuroinflammation Imaging Study.

Yu, Qiang, Kothe, Kiana, Kwiatek, Richard A et al.·Human brain mapping·2026

This study used advanced brain imaging to look for signs of inflammation in the white matter (the brain's communication cables) of ME/CFS patients compared to healthy people. Researchers found several differences in how water moves through brain tissue in ME/CFS patients, suggesting there may be swelling, immune cell activity, and changes to nerve fibers. These imaging markers could potentially help doctors identify and track ME/CFS in the future.

Neuroinflammation
E2 ModeratePEM requiredModerate confidenceCase-ControlEditor reviewed

Development and validation of blood-based diagnostic biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) using EpiSwitch® 3-dimensional genomic regulatory immuno-genetic profiling.

Hunter, Ewan, Alshaker, Heba, Bundock, Oliver et al.·Journal of translational medicine·2025

Researchers developed a new blood test called EpiSwitch®CFS that may help diagnose ME/CFS by detecting specific patterns in how DNA is organized in blood cells. When tested on stored blood samples from 47 ME/CFS patients and 61 healthy people, the test correctly identified 92% of ME/CFS patients and correctly ruled out 98% of healthy controls. This could potentially help doctors diagnose ME/CFS more reliably, since there is currently no standard blood test for the condition.

NeuroinflammationBiomarkersImmune System
E2 ModeratePEM unclearPreliminaryCross-SectionalEditor reviewed

Free-water-corrected diffusion and adrenergic/muscarinic antibodies in myalgic encephalomyelitis/chronic fatigue syndrome.

Kimura, Yukio, Sato, Wakiro, Maikusa, Norihide et al.·Journal of neuroimaging : official journal of the American Society of Neuroimaging·2023

Researchers used a specialized brain imaging technique to look for signs of inflammation in the brains of ME/CFS patients and compared these findings to levels of harmful antibodies (immune proteins) in their blood. They found that certain antibodies were linked to visible changes in a specific brain region called the right frontal operculum, and that longer disease duration was associated with more brain changes. These findings suggest that ME/CFS may involve both immune system dysfunction and measurable changes in brain structure.

Neuroinflammation
E2 ModeratePEM unclearPreliminaryObservationalEditor reviewed

Oral Minocycline Therapy Improves Symptoms of Myalgic Encephalomyelitis, Especially in the Initial Disease Stage.

Miwa, Kunihisa·Internal medicine (Tokyo, Japan)·2021

Researchers tested whether minocycline, an antibiotic that may reduce brain inflammation, could help ME/CFS patients. About 27% of 100 patients taking minocycline for 6 weeks experienced meaningful symptom improvement, particularly those who had been sick for less than 3 years. However, 38% of patients had to stop taking it early due to side effects like nausea and dizziness.

Neuroinflammation
E2 ModeratePEM unclearPreliminaryCross-SectionalEditor reviewed

Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy.

Mueller, Christina, Lin, Joanne C, Sheriff, Sulaiman et al.·Brain imaging and behavior·2020

Researchers used advanced brain imaging to measure chemical substances in the brains of ME/CFS patients and compared them to healthy people. They found several differences in brain chemistry and temperature in ME/CFS patients, particularly in areas involved in processing pain and regulating energy. These changes suggest that inflammation in the brain may contribute to ME/CFS symptoms.

Neuroinflammation
E2 ModeratePEM not requiredModerate confidenceCross-SectionalEditor reviewed

Hyperintense sensorimotor T1 spin echo MRI is associated with brainstem abnormality in chronic fatigue syndrome.

Barnden, Leighton R, Shan, Zack Y, Staines, Donald R et al.·NeuroImage. Clinical·2018

Researchers used advanced MRI scans to compare the brains of 43 people with ME/CFS and 27 healthy people. They found that people with ME/CFS had different patterns in their brainstem (the base of the brain that controls basic functions) and in the sensorimotor areas (parts that control movement and sensation). The study suggests that the body may be compensating for problems in the brainstem by increasing protective coating around nerve fibers in motor control areas.

Neuroinflammation
E2 ModeratePEM unclearPreliminaryReview-NarrativeEditor reviewed

The neuroinflammatory hypothesis of chronic fatigue syndrome/myalgic encephalomyelitis: an update

Jarred W. Younger, Linda Yan, Sean Mackey·Journal of Neuroinflammation·2014·n=18

Using thermography and brain temperature imaging at Stanford, this study found evidence consistent with neuroinflammation — specifically elevated brain temperature — in ME/CFS patients compared to healthy controls. Brain regions associated with pain and fatigue showed the strongest signal.

Neuroinflammation
E2 ModeratePEM unclearPreliminaryMechanisticEditor reviewed

Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

Yasuhito Nakatomi, Kei Mizuno, Akira Ishii et al.·Brain, Behavior, and Immunity·2014·n=9

Japanese researchers used PET imaging with a neuroinflammation tracer (PK11195) in 9 ME/CFS patients and healthy controls. They found significantly elevated neuroinflammation signals across multiple brain regions in ME/CFS patients, particularly in the cingulate cortex, thalamus, and brainstem — areas regulating fatigue and cognition.

Neuroinflammation
E2 ModeratePEM unclearModerate confidenceCase-ControlEditor reviewed

In myalgic encephalomyelitis/chronic fatigue syndrome, increased autoimmune activity against 5-HT is associated with immuno-inflammatory pathways and bacterial translocation.

Maes, Michael, Ringel, Karl, Kubera, Marta et al.·Journal of affective disorders·2013

This study found that people with ME/CFS often develop antibodies (immune proteins) against serotonin, a chemical messenger in the brain. These antibodies were linked to higher levels of inflammation, signs of bacteria leaking from the gut, and worse symptoms including pain, fatigue, brain fog, and mood changes. The findings suggest ME/CFS involves immune system problems that may contribute to the condition's core symptoms.

NeuroinflammationImmune System
E2 ModeratePEM not requiredPreliminaryCross-SectionalEditor reviewed

Spinal fluid abnormalities in patients with chronic fatigue syndrome.

Natelson, Benjamin H, Weaver, Shelley A, Tseng, Chin-Lin et al.·Clinical and diagnostic laboratory immunology·2005

Researchers performed spinal taps on 44 ME/CFS patients and 13 healthy people to look for signs of brain inflammation. They found that 30% of ME/CFS patients had abnormal levels of white blood cells or proteins in their spinal fluid, compared to none in the healthy group. They also found that certain immune molecules were different in ME/CFS patients, particularly in those with sudden flu-like symptom onset. These results suggest that ME/CFS may involve real physical changes in the nervous system, not just psychological factors.

NeuroinflammationImmune System
E2 ModeratePEM not requiredModerate confidenceCross-SectionalEditor reviewed

Increased galanin-galanin receptor 1 signaling, inflammation, and insulin resistance are associated with affective symptoms and chronic fatigue syndrome due to long COVID.

Al Masoodi, Wasim Talib Mahdi, Radhi, Sami Waheed, Abdalsada, Habiba Khdair et al.·PloS one·2025

This study looked at 90 people, some with Long COVID and some without, to understand why Long COVID patients develop depression, anxiety, and chronic fatigue. Researchers measured several substances in the blood related to inflammation and metabolism. They found that people with Long COVID had higher levels of inflammatory markers and abnormal insulin function, and these changes were linked to their mood and fatigue symptoms.

NeuroinflammationEnergy MetabolismImmune System
E2 ModeratePEM not requiredModerate confidenceCross-SectionalEditor reviewed

Chronic Fatigue, Depression and Anxiety Symptoms in Long COVID Are Strongly Predicted by Neuroimmune and Neuro-Oxidative Pathways Which Are Caused by the Inflammation during Acute Infection.

Al-Hakeim, Hussein Kadhem, Al-Rubaye, Haneen Tahseen, Almulla, Abbas F et al.·Journal of clinical medicine·2023

This study examined whether severe COVID-19 infection—particularly high fever and low oxygen levels—can trigger lasting fatigue, depression, and anxiety through inflammation and oxidative stress in the body. Researchers compared 86 long COVID patients with 39 healthy controls and found that about one-third of long COVID patients had very high signs of immune activation and cellular damage. The study suggests that the severity of initial COVID infection may predict who develops long-term symptoms through measurable changes in inflammatory markers.

NeuroinflammationImmune System
E2 ModeratePEM unclearModerate confidenceCross-SectionalEditor reviewed

Lowered Quality of Life in Long COVID Is Predicted by Affective Symptoms, Chronic Fatigue Syndrome, Inflammation and Neuroimmunotoxic Pathways.

Maes, Michael, Al-Rubaye, Haneen Tahseen, Almulla, Abbas F et al.·International journal of environmental research and public health·2022

This study found that Long COVID patients have significantly lower quality of life compared to healthy people, and this decline is mostly explained by three factors: mood and pain-related symptoms (like depression, anxiety, and fatigue), signs of ongoing inflammation in the body, and problems with how the body processes calcium. The severity of the initial infection—measured by high fever and low oxygen levels—also plays a role by triggering these inflammatory and immune problems that persist afterward.

NeuroinflammationImmune System
E2 ModeratePEM unclearPreliminaryCross-SectionalEditor reviewed

Imbalanced Brain Neurochemicals in Long COVID and ME/CFS: A Preliminary Study Using MRI.

Thapaliya, Kiran, Marshall-Gradisnik, Sonya, Eaton-Fitch, Natalie et al.·The American journal of medicine·2025

Researchers used advanced brain imaging to measure chemical imbalances in ME/CFS and long COVID patients compared to healthy people. They found that two important brain chemicals—glutamate and N-acetyl-aspartate—were significantly higher in patients with both conditions. These chemical imbalances were connected to how severe patients' symptoms were, suggesting that abnormal brain chemistry may play a role in the exhaustion and other symptoms these patients experience.

Neuroinflammation
E2 ModeratePEM unclearModerate confidenceCross-SectionalEditor reviewed

Brain-targeted autoimmunity is strongly associated with Long COVID and its chronic fatigue syndrome as well as its affective symptoms.

Almulla, Abbas F, Maes, Michael, Zhou, Bo et al.·Journal of advanced research·2025

This study found that people with Long COVID have unusual immune responses targeting the brain and nerve cells. Researchers measured antibodies (immune proteins) in people with Long COVID and healthy controls, discovering that Long COVID patients have significantly higher levels of antibodies attacking several brain proteins. These brain-targeted immune responses were strongly linked to fatigue severity and mood symptoms like depression and anxiety.

Neuroinflammation
E2 ModeratePEM not requiredModerate confidenceCross-SectionalEditor reviewed

In Schizophrenia, Chronic Fatigue Syndrome- and Fibromyalgia-Like Symptoms are Driven by Breakdown of the Paracellular Pathway with Increased Zonulin and Immune Activation-Associated Neurotoxicity.

Maes, Michael, Andrés-Rodríguez, Laura, Vojdani, Aristo et al.·CNS & neurological disorders drug targets·2023

This study looked at people with schizophrenia who also experience fatigue and pain symptoms similar to ME/CFS and fibromyalgia. Researchers found that these symptoms may be caused by a breakdown in the intestinal barrier (the paracellular pathway), which allows harmful substances into the bloodstream and triggers immune system activation. This immune activation then produces neurotoxic byproducts that may cause the fatigue and pain symptoms.

NeuroinflammationImmune System
E2 ModeratePEM unclearPreliminaryCross-SectionalEditor reviewed

Exercise modifies glutamate and other metabolic biomarkers in cerebrospinal fluid from Gulf War Illness and Myalgic encephalomyelitis / Chronic Fatigue Syndrome.

Baraniuk, James N, Kern, Grant, Narayan, Vaishnavi et al.·PloS one·2021

Researchers studied the fluid around the brain and spinal cord in people with ME/CFS and Gulf War Illness to see how exercise affects certain chemicals in the body. They found that glutamate (a brain chemical) levels changed differently depending on whether someone had exercised and how their body responded, and that some fat-related molecules were different between the two conditions. This suggests that ME/CFS and Gulf War Illness may involve different problems with how the body uses energy and processes fats.

NeuroinflammationBiomarkersPost-Exertional Malaise
E2 ModeratePEM unclearModerate confidenceCross-SectionalEditor reviewed

Kynurenine metabolites and ratios differ between Chronic Fatigue Syndrome, Fibromyalgia, and healthy controls.

Groven, Nina, Reitan, Solveig Klæbo, Fors, Egil Andreas et al.·Psychoneuroendocrinology·2021

This study examined a specific metabolic pathway in the blood called the kynurenine pathway, which affects how the brain functions. Researchers compared blood samples from people with ME/CFS, people with fibromyalgia, and healthy people to see if the chemical breakdown products in this pathway differed. They found that the balance of certain chemicals was different in people with these conditions, and these differences may relate to fatigue and pain symptoms.

NeuroinflammationEnergy Metabolism
E2 ModeratePEM unclearPreliminaryCase-ControlEditor reviewed

Using Plasma Autoantibodies of Central Nervous System Proteins to Distinguish Veterans with Gulf War Illness from Healthy and Symptomatic Controls.

Abou-Donia, Mohamed B, Lapadula, Elizabeth S, Krengel, Maxine H et al.·Brain sciences·2020

Researchers tested blood samples from Gulf War veterans with Gulf War Illness (GWI) and compared them to healthy veterans and people with ME/CFS or irritable bowel syndrome. They found that GWI veterans had higher levels of autoantibodies—proteins the immune system makes that mistakenly attack the brain and nervous system—compared to all three control groups. This suggests that a blood test measuring these autoantibodies could potentially help doctors diagnose Gulf War Illness objectively.

NeuroinflammationBiomarkers
E2 ModeratePEM unclearPreliminaryCross-SectionalEditor reviewed

Distinct cerebrospinal fluid proteomes differentiate post-treatment lyme disease from chronic fatigue syndrome.

Schutzer, Steven E, Angel, Thomas E, Liu, Tao et al.·PloS one·2011

This study examined spinal fluid from people with post-treatment Lyme disease and ME/CFS to see if these two conditions are different. Using advanced laboratory techniques, researchers found that each condition has a unique pattern of proteins in the spinal fluid, meaning they appear to be distinct diseases rather than the same illness. This discovery could eventually help doctors tell these conditions apart and develop better treatments for each.

Neuroinflammation
E2 ModeratePEM not requiredModerate confidenceCase-ControlEditor reviewed

In transfusion-dependent thalassemia, neuronal damage biomarkers are associated with affective and chronic fatigue symptoms.

Ridhaa, Maha Abdul Saheb, Al-Hakeim, Hussein Kadhem, Kahlol, Mohammed K et al.·Scientific reports·2025

This study looked at children with thalassemia, a blood disorder requiring frequent transfusions, to see if brain damage and inflammation might cause depression, anxiety, and chronic fatigue. Researchers measured specific markers of brain injury and inflammation in the blood and found that children with thalassemia had higher levels of these markers and more fatigue and mood symptoms than healthy children. The study suggests that iron buildup from transfusions may damage nerve cells in the brain, leading to these symptoms.

Neuroinflammation
E2 ModeratePEM not requiredModerate confidenceCase-ControlEditor reviewed

Affective and chronic fatigue symptoms are associated with serum neuronal damage markers in Parkinson's disease.

Al-Hakeim, Hussein Kadhem, Khudhair, Hayder Naji, Ranaei-Siadat, Sayed-Omid et al.·Scientific reports·2025

This study looked at people with Parkinson's disease who also experienced depression and extreme fatigue, similar to ME/CFS. Researchers found that certain proteins in the blood that signal brain cell damage were elevated in these patients, and these proteins were connected to inflammation, blood sugar problems, and the mood and fatigue symptoms they experienced.

NeuroinflammationImmune System
E2 ModeratePEM not requiredModerate confidenceCase-ControlEditor reviewed

[Association of inflammation and chronic fatigue syndrome in patients with Parkinson's disease].

Nikitina, M A, Bragina, E Yu, Ivanova, S A et al.·Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova·2024

This study looked at severe tiredness (chronic fatigue syndrome) in people with Parkinson's disease. Researchers found that about two-thirds of Parkinson's patients experience this kind of fatigue, and it tends to occur alongside other symptoms like mood problems, memory difficulties, and pain. Blood tests showed that people with this fatigue had higher levels of inflammation markers, suggesting that inflammation may play a role in causing the tiredness.

Neuroinflammation
E2 ModeratePEM not requiredPreliminaryCross-SectionalEditor reviewed

In Schizophrenia, Depression, Anxiety, and Physiosomatic Symptoms Are Strongly Related to Psychotic Symptoms and Excitation, Impairments in Episodic Memory, and Increased Production of Neurotoxic Tryptophan Catabolites: a Multivariate and Machine Learning Study.

Kanchanatawan, Buranee, Thika, Supaksorn, Sirivichayakul, Sunee et al.·Neurotoxicity research·2018

This study examined 80 people with schizophrenia and 40 healthy controls to understand why schizophrenia patients often experience depression, anxiety, and physical symptoms like those seen in chronic fatigue. The researchers found that these symptoms were linked to changes in how the body breaks down tryptophan (an amino acid), problems with memory, and the severity of psychotic symptoms. The findings suggest that toxic byproducts from tryptophan metabolism may contribute to depression, anxiety, and physical symptoms in schizophrenia.

Neuroinflammation
E3 PreliminaryPEM unclearPreliminaryCross-SectionalEditor reviewed

Proteomic signatures in cerebrospinal fluid and their clinical associations in patients with ME/CFS.

Bragée, Björn, Li, Peng, Meadows, Danielle et al.·Scientific reports·2026

Researchers analyzed fluid from the spinal cords of 31 ME/CFS patients to study 902 different proteins and understand what might be happening in their bodies. They found that patients with certain heart-related symptoms (POTS) had different protein patterns, and those with more severe ME/CFS had changes in immune system and blood clotting proteins. These protein patterns suggest several biological processes may be involved in ME/CFS, providing clues for future research.

NeuroinflammationImmune System
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

Immunosenescence-Driven Hemodynamic Dysregulation and Cognitive Impairment in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Integrative Perspective.

Xu, Huimin, Luo, Yingzhe, Wu, Xi·Comprehensive Physiology·2026

This review examines how ME/CFS may involve aging of the immune system that affects blood flow to the brain, causing cognitive problems like 'brain fog.' The researchers propose that this immune aging triggers chronic inflammation, reduces oxygen delivery to brain cells, and damages the protective barrier around the brain, leading to memory and thinking difficulties. The authors suggest that treatments targeting inflammation, improving blood vessel function, and modulating immune responses could help improve cognition in ME/CFS patients.

Neuroinflammation
E3 PreliminaryPEM not requiredPreliminaryMechanisticEditor reviewed

Chronic fatigue syndrome induced by environmental toxic exposure: Effects of polyhexamethyleneguanidine phosphate exposure on mitochondrial function and neural health.

Yang, Hyo-Seon, Lee, Jin-Seok, Kang, Mi-Hyun et al.·Environmental research·2026

This study found that exposure to humidifier disinfectants—cleaning chemicals used in humidifiers—may trigger ME/CFS by damaging the energy-producing structures (mitochondria) inside our cells and disrupting communication in the brain. Researchers compared patients with ME/CFS who had been exposed to these chemicals to laboratory mice exposed to the same chemicals, and both showed similar problems with mitochondrial function and brain health. The findings suggest that environmental toxins could be a trigger for ME/CFS in some people.

Neuroinflammation
E3 PreliminaryPEM not requiredPreliminaryMechanisticEditor reviewed

Immunomodulatory and locomotor regulations via Diosgenin treatment in lipopolysaccharide-induced chronic fatigue syndrome (CFS)/ depressive despair symptom: an in vivo assessment.

Shirole, Rahul Lotan, Khalane, Mohan Rajendra, Nage, Vijayeta Pralhad et al.·Naunyn-Schmiedeberg's archives of pharmacology·2026

This study tested a natural compound called diosgenin (found in fenugreek) to see if it could help with fatigue and depression-like symptoms in mice given a substance that triggered an immune response similar to what happens in ME/CFS. Mice treated with diosgenin showed improvements in activity levels, reduced fatigue-like behavior, and their brains had less inflammation and stress. The results suggest diosgenin might be worth investigating further as a potential treatment.

NeuroinflammationImmune System
E3 PreliminaryPEM not requiredPreliminaryMechanisticEditor reviewed

PKM2 accelerated the progression of chronic fatigue syndrome via promoting the H4K12la/ NF-κB induced neuroinflammation and mitochondrial damage.

Sun, Meng, Zhang, Xinwen, Feng, Xinli et al.·Scientific reports·2025

This study in mice explored how a protein called PKM2 may contribute to ME/CFS by increasing inflammation in the brain and damaging energy-producing structures inside cells (mitochondria). Researchers found that when PKM2 levels increased, cognitive problems worsened and brain cells showed more damage, while reducing PKM2 improved these outcomes. The mechanism involves lactate buildup and activation of inflammatory pathways in the brain.

Neuroinflammation
E3 PreliminaryPEM requiredPreliminaryMechanisticEditor reviewed

Inactivation of ATG13 stimulates chronic demyelinating pathologies in muscle-serving nerves and spinal cord.

Drosen, Molly E, Bulbule, Sarojini, Gottschalk, Gunnar et al.·Immunologic research·2025

Researchers gave mice a drug that overactivates a protein called mTOR and found it triggered muscle weakness, nerve damage, and worsening fatigue after exercise—similar to post-exertional malaise (PEM) in ME/CFS. The drug blocked a cellular cleanup system called autophagy, which led to inflammation and damage to the nerves controlling muscles. Mice engineered to have impaired autophagy showed similar problems, suggesting that broken autophagy may be involved in ME/CFS fatigue and exercise intolerance.

NeuroinflammationPost-Exertional Malaise
E3 PreliminaryPEM not requiredPreliminaryMechanisticEditor reviewed

Effect of electroacupuncture on behavior and hippocampal inflammatory factors in rats with chronic fatigue syndrome.

Qu, Yuan-Yuan, Feng, Chu-Wen, Sun, Zhong-Ren et al.·Zhen ci yan jiu = Acupuncture research·2024

Researchers tested whether electroacupuncture—a traditional needle-based treatment—could help rats with experimentally-induced fatigue syndrome. The treated rats showed improved physical endurance, better memory, and reduced anxiety compared to untreated sick rats. The researchers also found that treatment reduced inflammatory markers in the brain and blood that were elevated in sick rats.

NeuroinflammationImmune System
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

Whole-body cryotherapy as a treatment for chronic medical conditions?

Tabisz, Hanna, Modlinska, Aleksandra, Kujawski, Sławomir et al.·British medical bulletin·2023

This review article examines whole-body cryotherapy (WBC)—exposing your entire body to very cold temperatures—as a possible treatment for various chronic conditions, including ME/CFS. The authors suggest that because WBC appears to reduce inflammation in the body, it might help conditions involving persistent inflammation. However, they emphasize that current research quality is low and that proper clinical trials are needed before we can know if WBC actually works.

NeuroinflammationImmune System
E3 PreliminaryPEM not requiredPreliminaryReview-NarrativeEditor reviewed

Research progress on central mechanism of acupuncture treatment for chronic fatigue syndrome.

Li, Bin-Bin, Feng, Chu-Wen, Qu, Yuan-Yuan et al.·World journal of acupuncture-moxibustion·2023

This review examined how ME/CFS affects the brain and nervous system by looking at laboratory tests and brain imaging studies. Researchers found that people with ME/CFS have changes in brain structure, abnormal inflammation, and problems with chemical messengers in the brain. The study also explored how acupuncture might help correct some of these brain abnormalities in animal models of the condition.

Neuroinflammation
E3 PreliminaryPEM not requiredPreliminaryMechanisticEditor reviewed

[Effect of transcutaneous electrical acupoint stimulation on learning and memory ability of chronic fatigue syndrome rats and its mechanisms].

Zhong, Xiao-Ling, Tong, Bo-Ying, Yang, Yi-Han et al.·Zhen ci yan jiu = Acupuncture research·2023

This study tested whether a non-invasive electrical stimulation treatment applied to specific acupuncture points could help rats with chronic fatigue improve their memory and learning. Researchers found that the treatment reduced fatigue symptoms and improved memory performance in fatigued rats, possibly by protecting brain cells in the memory center of the brain.

Neuroinflammation
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

Inflammation From Peripheral Organs to the Brain: How Does Systemic Inflammation Cause Neuroinflammation?

Sun, Yuanjie, Koyama, Yoshihisa, Shimada, Shoichi·Frontiers in aging neuroscience·2022

This review explores how inflammation in the body's organs—like the gut, lungs, or joints—can trigger inflammation in the brain. The authors describe several pathways by which this happens, including damage to the protective barrier around the brain, activation of immune cells in the brain, and communication through nerves connecting organs to the brain. ME/CFS is highlighted as one disease where this peripheral-to-brain inflammation mechanism may be important.

NeuroinflammationImmune System
E3 PreliminaryPEM requiredPreliminaryMechanisticEditor reviewed

Exosome-associated mitochondrial DNA from patients with myalgic encephalomyelitis/chronic fatigue syndrome stimulates human microglia to release IL-1β.

Tsilioni, Irene, Natelson, Benjamin, Theoharides, Theoharis C·The European journal of neuroscience·2022

This study found that after exercise, patients with ME/CFS have more pieces of DNA from their mitochondria (the energy-producing parts of cells) floating in their blood inside tiny particles called exosomes. When researchers tested these exosomes on immune cells in the lab, they triggered the release of IL-1β, a chemical that causes inflammation in the brain. This suggests that exercise might trigger a chain reaction involving these DNA-carrying particles that could contribute to ME/CFS symptoms.

NeuroinflammationImmune SystemPost-Exertional Malaise
E3 PreliminaryPEM unclearPreliminaryMechanisticEditor reviewed

Elevated ATG13 in serum of patients with ME/CFS stimulates oxidative stress response in microglial cells via activation of receptor for advanced glycation end products (RAGE).

Gottschalk, Gunnar, Peterson, Daniel, Knox, Konstance et al.·Molecular and cellular neurosciences·2022

Researchers found that people with ME/CFS have higher levels of a protein called ATG13 in their blood compared to healthy people. When they tested this protein on brain immune cells in the lab, it triggered the production of harmful molecules called free radicals (oxidative stress). This suggests that a breakdown in the body's cellular recycling system (autophagy) might contribute to the inflammation and stress response seen in ME/CFS.

NeuroinflammationImmune System
E3 PreliminaryPEM unclearPreliminaryMechanisticEditor reviewed

Aberrations in the Cross-Talks Among Redox, Nuclear Factor-κB, and Wnt/β-Catenin Pathway Signaling Underpin Myalgic Encephalomyelitis and Chronic Fatigue Syndrome.

Maes, Michael, Kubera, Marta, Kotańska, Magdalena·Frontiers in psychiatry·2022

This study examined proteins and metabolites in ME/CFS patients to understand how the disease works at a molecular level. Researchers found that ME/CFS involves problems with three interconnected cellular systems: how cells handle harmful oxidative stress, how the immune system responds through inflammation, and how cells communicate through a pathway called Wnt/β-catenin. The study suggests ME/CFS may be triggered by various causes—like infections or toxic exposures—but they all damage these same three systems.

NeuroinflammationImmune System
E3 PreliminaryPEM unclearPreliminaryMechanisticEditor reviewed

Tissue specific signature of HHV-6 infection in ME/CFS.

Kasimir, Francesca, Toomey, Danny, Liu, Zheng et al.·Frontiers in molecular biosciences·2022

This study looked for signs of active HHV-6 virus (a common herpesvirus) in brain and spinal cord tissue from ME/CFS patients after death, compared to people without ME/CFS. Using a special detection technique, researchers found markers of active viral infection in the nervous tissue of ME/CFS patients but not in the control group. This suggests that HHV-6 may be reactivating specifically in the brain and nervous system in ME/CFS, rather than in the blood where it's usually tested.

Neuroinflammation
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

Mucosal Immunity and the Gut-Microbiota-Brain-Axis in Neuroimmune Disease.

Sterling, Kathryn G, Dodd, Griffin Kutler, Alhamdi, Shatha et al.·International journal of molecular sciences·2022

This review article examines the connection between gut bacteria, immunity, and the brain in diseases like ME/CFS. The authors explain that the bacteria in our gut can communicate with our brain through chemical signals and nerves, but this communication can be disrupted in certain illnesses. They focus on how the immune system in the gut lining controls which bacteria thrive there, and how changes in these bacterial communities might contribute to neuroimmune diseases.

NeuroinflammationGut MicrobiomeImmune System
E3 PreliminaryPEM not requiredPreliminaryMechanisticEditor reviewed

Differential Impacts of HHV-6A versus HHV-6B Infection in Differentiated Human Neural Stem Cells.

Bahramian, Elham, Furr, Mercede, Wu, Jerry T et al.·Frontiers in immunology·2022

This study examined how two closely related viruses called HHV-6A and HHV-6B infect different types of nerve cells in the brain. Researchers found that both viruses can infect certain brain cells that use glutamate and dopamine (chemical messengers), but neither virus infected a third type of brain cell that uses GABA. Importantly, HHV-6A appeared to cause more damage to infected cells than HHV-6B, suggesting it may be more harmful to nerve tissue.

Neuroinflammation
E3 PreliminaryPEM not requiredPreliminaryMechanisticEditor reviewed

Improvement Effects of Myelophil on Symptoms of Chronic Fatigue Syndrome in a Reserpine-Induced Mouse Model.

Song, Ji-Hye, Won, Seul-Ki, Eom, Geun-Hyang et al.·International journal of molecular sciences·2021

Researchers tested a herbal mixture called myelophil (made from two traditional medicinal plants) in mice engineered to show ME/CFS-like symptoms including fatigue, pain, and depression. The treatment improved all three symptoms and appeared to work by increasing important brain chemicals like dopamine and serotonin, reducing inflammation, and protecting against cell damage. While these results are encouraging, this study was only in mice, so it's too early to know if the same benefits would occur in people with ME/CFS.

Neuroinflammation
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

[Intestinal flora and neurological disorders].

Tang, Qianqian, Cao, Lihua·Sheng wu gong cheng xue bao = Chinese journal of biotechnology·2021

Your gut bacteria (microbiome) communicate with your brain through multiple pathways, including immune signals and nerve connections. When this gut-brain communication goes wrong, it may contribute to various neurological conditions, including chronic fatigue syndrome. This review summarizes what scientists know about how imbalanced gut bacteria might affect the nervous system and cause disease.

Neuroinflammation
E3 PreliminaryPEM not requiredPreliminaryMechanisticEditor reviewed

[Electroacupuncture improves cognitive function by inhibiting NF-κB activity in rats with chronic fatigue syndrome].

Feng, Chu-Wen, Qu, Yuan-Yuan, Sun, Zhong-Ren et al.·Zhen ci yan jiu = Acupuncture research·2021

This study tested whether electroacupuncture (a form of acupuncture with electrical stimulation) could help rats with chronic fatigue syndrome recover cognitive abilities like memory and learning. The researchers found that electroacupuncture reduced inflammation in the brain's memory center (hippocampus) and improved the rats' ability to learn and remember, likely by blocking a inflammatory protein called NF-κB.

Neuroinflammation
E3 PreliminaryPEM not requiredPreliminaryReview-NarrativeEditor reviewed

[Imaging and Manipulation of Stem and Progenitor Cells for Revealing the Novel Mechanism of Local Tissue Maintenance in the Brain].

Kataoka, Yosky·Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan·2021

This study examined special cells in the brain called glial progenitor cells that help maintain healthy brain tissue and manage inflammation. Researchers used imaging technology to track these cells and discovered that when these cells are removed, the brain develops harmful inflammation and immune activation. The findings suggest these cells may play a protective role and could be targeted to treat conditions associated with brain inflammation, including chronic fatigue syndrome.

Neuroinflammation
E3 PreliminaryPEM not requiredPreliminaryMechanisticEditor reviewed

An Adrenalectomy Mouse Model Reflecting Clinical Features for Chronic Fatigue Syndrome.

Lee, Jin-Seok, Jeon, Yoo-Jin, Park, Samuel-Young et al.·Biomolecules·2020

Researchers tested three different mouse models to find the best one for studying ME/CFS. They found that removing the adrenal glands (small organs that produce stress hormones) in mice created fatigue and pain symptoms most similar to ME/CFS, while other common models mainly produced depression-like behaviors. The adrenal-removed mice also showed specific brain changes involving inflammation and stress hormone pathways.

Neuroinflammation
E3 PreliminaryPEM unclearPreliminaryMechanisticEditor reviewed

Epstein-Barr Virus dUTPase Induces Neuroinflammatory Mediators: Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Williams PhD, Marshall V, Cox, Brandon, Lafuse PhD, William P et al.·Clinical therapeutics·2019

This study explores whether a protein from the Epstein-Barr virus (EBV) may trigger brain inflammation in ME/CFS patients. Researchers found that this viral protein can change how brain cells function and alter important chemical pathways involved in energy, mood, and pain processing. The findings suggest that in some ME/CFS patients, this viral protein might contribute to fatigue, pain, and thinking difficulties.

NeuroinflammationImmune System
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

Myalgic encephalomyelitis or chronic fatigue syndrome: how could the illness develop?

Morris, Gerwyn, Maes, Michael, Berk, Michael et al.·Metabolic brain disease·2019

This study proposes a theory for how ME/CFS might develop, starting with an infection that triggers lasting problems in the body's immune system and stress response. The authors suggest that in genetically vulnerable people, this leads to a chain of events: increased inflammation, intestinal problems that allow bacteria-related substances to enter the bloodstream, nervous system dysfunction, and eventually a state where the immune system becomes exhausted and less able to fight back. This model tries to explain why ME/CFS patients have the specific symptoms and lab abnormalities doctors observe.

NeuroinflammationImmune System
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

Myalgia and chronic fatigue syndrome following immunization: macrophagic myofasciitis and animal studies support linkage to aluminum adjuvant persistency and diffusion in the immune system.

Gherardi, Romain K, Crépeaux, Guillemette, Authier, François-Jérome·Autoimmunity reviews·2019

This review examines whether ME/CFS could be triggered by aluminum-containing substances in certain vaccines. The authors present evidence that aluminum particles may persist in immune cells and travel to the brain, potentially causing the cognitive problems, muscle pain, and fatigue seen in ME/CFS. They argue this condition represents a broader category of vaccine-related adverse effects called ASIA.

NeuroinflammationImmune System
E3 PreliminaryPEM not requiredPreliminaryMechanisticEditor reviewed

Hyperactivation of proprioceptors induces microglia-mediated long-lasting pain in a rat model of chronic fatigue syndrome.

Yasui, Masaya, Menjyo, Yuki, Tokizane, Kyohei et al.·Journal of neuroinflammation·2019

This study used rats exposed to chronic stress to understand why ME/CFS patients experience widespread pain without obvious tissue damage. Researchers found that stress caused sensory nerve fibers (proprioceptors) that detect body position to become overactive, which then triggered immune cells in the spinal cord called microglia to activate and cause pain. When they immobilized the ankle to reduce proprioceptor signaling, both the immune activation and pain behavior decreased.

Neuroinflammation
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

[Immunopathogenesis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)].

Yamamura, Takashi, Ono, Hirohiko, Sato, Wakiro·Brain and nerve = Shinkei kenkyu no shinpo·2018

This study found that people with ME/CFS have unusual patterns of immune system chemicals (cytokines) in their blood and spinal fluid, and some patients have antibodies that attack their own bodies. When researchers treated some ME/CFS patients with a medication that removes certain immune cells called B cells, patients improved. This suggests that ME/CFS may be caused by the immune system mistakenly attacking the body.

NeuroinflammationImmune System
E3 PreliminaryPEM unclearPreliminaryObservationalEditor reviewed

[Neuroinflammation in the Brain of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome].

Nakatomi, Yasuhito, Kuratsune, Hirohiko, Watanabe, Yasuyoshi·Brain and nerve = Shinkei kenkyu no shinpo·2018

Researchers used a special imaging scan called PET to look at the brains of people with ME/CFS and found signs of inflammation (immune system activation) throughout several brain regions. This inflammation was connected to how severe patients' symptoms were, including problems with thinking and memory, as well as widespread pain. This discovery suggests that ME/CFS involves measurable changes in the brain that could eventually lead to better ways to diagnose and treat the condition.

NeuroinflammationBiomarkers
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

[History of Researches on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome].

Watanabe, Yasuyoshi, Kuratsune, Hirohiko·Brain and nerve = Shinkei kenkyu no shinpo·2018

This review summarizes research on ME/CFS conducted in Japan since the disease was first identified there in 1990. Scientists have been searching for objective biological markers to help diagnose ME/CFS and understand what causes it. Recent brain imaging studies found evidence of immune cell activation in the brains of ME/CFS patients, which may be linked to the severity of their symptoms.

NeuroinflammationBiomarkers
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-Metabolic Disease or Disturbed Homeostasis due to Focal Inflammation in the Hypothalamus?

Hatziagelaki, Erifili, Adamaki, Maria, Tsilioni, Irene et al.·The Journal of pharmacology and experimental therapeutics·2018

This study proposes that ME/CFS may be caused by inflammation in a small brain region called the hypothalamus, triggered by problems with how cells produce energy. The researchers suggest that when mitochondria (the energy factories in cells) malfunction, they may release harmful substances that activate immune cells in the brain, creating a chain reaction that leads to ME/CFS symptoms. If this theory is correct, it could open new doors for treating the condition by targeting this brain inflammation.

Neuroinflammation
E3 PreliminaryPEM requiredModerate confidenceReview-NarrativeEditor reviewed

Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods.

VanElzakker, Michael B, Brumfield, Sydney A, Lara Mejia, Paula S·Frontiers in neurology·2018

This review examines different methods scientists use to look for signs of brain inflammation in ME/CFS, including specialized brain scans and blood tests. The authors found that while these techniques show promise, many studies have used inconsistent methods that make it hard to compare results across different research teams. They argue that scientists need better techniques and more careful standardization if we want to find reliable biological markers that could help diagnose ME/CFS.

NeuroinflammationBiomarkers
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

Tetramethoxyluteolin for the Treatment of Neurodegenerative Diseases.

Theoharides, Theoharis C, Tsilioni, Irene·Current topics in medicinal chemistry·2018

This review examines how certain molecules in the brain called cytokines and neuropeptides may trigger inflammation in specific brain areas (the hypothalamus and amygdala) in people with ME/CFS. The authors propose that a natural compound called tetramethoxyluteolin (a modified form of a plant-derived substance called luteolin) might help reduce this inflammation and improve symptoms. The study suggests this compound could be delivered directly into the nasal passages to reach the brain more effectively.

Neuroinflammation
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

[Brain Science on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome].

Watanabe, Yasuyoshi·Brain and nerve = Shinkei kenkyu no shinpo·2018

This study examined the brains of people with ME/CFS using three types of imaging technology (PET scans, MRI, and MEG) to look for physical differences compared to healthy people. Researchers found that people with ME/CFS have reduced blood flow and energy use in certain brain areas, decreased levels of important chemical messengers, and inflammation in the brain that appears connected to symptom severity. These findings suggest ME/CFS involves real, measurable brain changes rather than being purely psychological.

Neuroinflammation
E3 PreliminaryPEM not requiredPreliminaryReview-NarrativeEditor reviewed

Glial Activation and Expression of the Serotonin Transporter in Chronic Fatigue Syndrome.

Noda, Mami, Ifuku, Masataka, Hossain, Md Shamim et al.·Frontiers in psychiatry·2018

This review examines how brain inflammation might cause ME/CFS symptoms. When the body fights off a viral infection, special immune cells in the brain called microglia and astrocytes can become overactive and trigger a chain of events that reduces serotonin levels—a chemical important for mood and energy. Understanding this pathway could help researchers develop new treatments for ME/CFS.

Neuroinflammation
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

The Neuroinflammatory Etiopathology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

Glassford, Julian A G·Frontiers in physiology·2017

This article reviews research suggesting that ME/CFS may result from problems in how the nervous system and immune system interact. The author discusses how physical strain on the spine and nerves, combined with prolonged infections and immune activation, may trigger a chain reaction of inflammation in the brain and throughout the body. This inflammation can affect energy production, hormone balance, and how the body processes pain.

Neuroinflammation
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

Nitrosative Stress, Hypernitrosylation, and Autoimmune Responses to Nitrosylated Proteins: New Pathways in Neuroprogressive Disorders Including Depression and Chronic Fatigue Syndrome.

Morris, Gerwyn, Berk, Michael, Klein, Hans et al.·Molecular neurobiology·2017

This study proposes that ME/CFS may be caused by a harmful process called 'hypernitrosylation,' where a molecule called nitric oxide damages proteins in cells, particularly those responsible for producing energy and fighting infections. When this damage becomes chronic, it can disable the body's natural repair systems and trigger the immune system to attack the body's own proteins. The researchers suggest this process could explain many ME/CFS symptoms, including fatigue, cognitive problems, and how bacterial toxins may trigger or worsen the disease.

NeuroinflammationImmune System
E3 PreliminaryPEM not requiredPreliminaryCase-ControlEditor reviewed

CNS findings in chronic fatigue syndrome and a neuropathological case report.

Ferrero, Kimberly, Silver, Mitchell, Cocchetto, Alan et al.·Journal of investigative medicine : the official publication of the American Federation for Clinical Research·2017

This study examines brain tissue from one person who had ME/CFS and died, looking for physical changes that might explain the illness. Researchers found several abnormalities in the brain including areas of damaged nerve fibers, tangles similar to those seen in Alzheimer's disease, and deposits of a protein called amyloid. These findings suggest that ME/CFS may involve damage to the brain's structure and deserve further investigation.

Neuroinflammation
E3 PreliminaryPEM not requiredPreliminaryMechanisticEditor reviewed

NLRP3 inflammasome activation mediates fatigue-like behaviors in mice via neuroinflammation.

Zhang, Ziteng, Ma, Xiujuan, Xia, Zhenna et al.·Neuroscience·2017

This study explored whether a specific immune system protein called NLRP3 might be involved in causing fatigue in mice. Researchers stressed mice with repeated swimming tests and found that stressed mice had higher levels of an inflammatory chemical (IL-1β) in their brains and showed fatigue-like behaviors. When they removed the NLRP3 protein in mice, the fatigue behaviors were reduced and inflammatory levels decreased, suggesting this protein may play a role in fatigue.

NeuroinflammationImmune System
E3 PreliminaryPEM unclearPreliminaryEditorialEditor reviewed

The role of the hippocampus in the pathogenesis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

Saury, Jean-Michel·Medical hypotheses·2016

This study proposes that a brain structure called the hippocampus—which helps control memory, stress responses, and pain perception—may play a key role in ME/CFS. The researcher suggests that whatever triggers ME/CFS damages the hippocampus, leading to problems with thinking, sleep, and pain regulation, which then causes people to become less active. This reduced activity further damages the hippocampus, creating a harmful cycle that keeps the illness going.

Neuroinflammation
E3 PreliminaryPEM unclearModerate confidenceReview-NarrativeEditor reviewed

The Neuro-Immune Pathophysiology of Central and Peripheral Fatigue in Systemic Immune-Inflammatory and Neuro-Immune Diseases.

Morris, Gerwyn, Berk, Michael, Galecki, Piotr et al.·Molecular neurobiology·2016

This review examines why people with ME/CFS and similar immune-based illnesses experience severe, disabling fatigue. The authors identify multiple biological pathways that may contribute to this fatigue, including excessive inflammation, problems with how cells produce energy, and chemical imbalances in the brain and muscles. The fatigue appears to result from a complex interaction between the immune system, energy production, and brain function rather than a single cause.

NeuroinflammationImmune System
E3 PreliminaryPEM not requiredPreliminaryMechanisticEditor reviewed

Moxibustion upregulates hippocampal progranulin expression.

Yi, Tao, Qi, Li, Li, Ji et al.·Neural regeneration research·2016

This study tested whether moxibustion, a traditional Chinese medicine technique using heat from burning herbs, could help rats with chronic fatigue syndrome. Researchers found that moxibustion reduced stress hormone levels and increased a protective protein in the brain called progranulin, which appeared to improve the rats' symptoms of fatigue and low mood.

Neuroinflammation
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

The Deleterious Effects of Oxidative and Nitrosative Stress on Palmitoylation, Membrane Lipid Rafts and Lipid-Based Cellular Signalling: New Drug Targets in Neuroimmune Disorders.

Morris, Gerwyn, Walder, Ken, Puri, Basant K et al.·Molecular neurobiology·2016

This review explains how harmful molecules called oxidative and nitrosative stress damage specific fatty structures in cells that are important for cell communication and brain function. These damaged structures may contribute to ME/CFS, along with other conditions affecting the brain and immune system. The authors suggest that omega-3 fatty acid supplements might help restore these damaged cellular structures.

NeuroinflammationEnergy MetabolismImmune System
E3 PreliminaryPEM not requiredPreliminaryMechanisticEditor reviewed

Activation of the NLRP3 inflammasome in lipopolysaccharide-induced mouse fatigue and its relevance to chronic fatigue syndrome.

Zhang, Zi-Teng, Du, Xiu-Ming, Ma, Xiu-Juan et al.·Journal of neuroinflammation·2016

Researchers created a mouse model of fatigue by exposing mice to immune stress (a bacterial compound) combined with physical stress. They found that a specific immune protein called NLRP3 becomes active in the brain during fatigue, and that blocking this protein reduced fatigue symptoms. This suggests that controlling this immune pathway might help treat fatigue in conditions like ME/CFS.

NeuroinflammationImmune System
E3 PreliminaryPEM not requiredPreliminaryReview-NarrativeEditor reviewed

The Role of Microbiota and Intestinal Permeability in the Pathophysiology of Autoimmune and Neuroimmune Processes with an Emphasis on Inflammatory Bowel Disease Type 1 Diabetes and Chronic Fatigue Syndrome.

Morris, Gerwyn, Berk, Michael, Carvalho, André F et al.·Current pharmaceutical design·2016

This review explores how problems with the gut barrier and changes in gut bacteria may trigger widespread immune activation and brain inflammation in ME/CFS and other autoimmune diseases. When the intestinal lining becomes more permeable (leaky), bacteria and their products can enter the bloodstream, potentially causing the fatigue, brain fog, and other symptoms characteristic of ME/CFS.

NeuroinflammationImmune System
E3 PreliminaryPEM not requiredPreliminaryReview-NarrativeEditor reviewed

The Many Neuroprogressive Actions of Tryptophan Catabolites (TRYCATs) that may be Associated with the Pathophysiology of Neuro-Immune Disorders.

Morris, Gerwyn, Carvalho, André F, Anderson, George et al.·Current pharmaceutical design·2016

When the body has chronic inflammation and immune activation, it breaks down an amino acid called tryptophan differently than usual, creating byproducts called TRYCATs. Some of these byproducts can damage nerve cells and mitochondria (the energy factories in cells), while others may protect the brain but at the cost of causing brain fog and emotional problems. This review examines how this abnormal tryptophan breakdown might contribute to ME/CFS and other neurological conditions.

NeuroinflammationEnergy MetabolismImmune System
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

The Role of Toll-Like Receptors in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: A New Promising Therapeutic Approach?

Gambuzza, Maria Elsa, Salmeri, Francesca Maria, Soraci, Luca et al.·CNS & neurological disorders drug targets·2015

This review examines how certain immune system sensors called Toll-like receptors (TLRs) may contribute to ME/CFS. These receptors sit on cells in the gut and detect bacteria and other microbes, triggering inflammation that may spread to the brain and cause fatigue and other symptoms. The researchers suggest that targeting these TLRs with new medications might help reduce inflammation and improve symptoms.

NeuroinflammationGut MicrobiomeImmune System
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

Central pathways causing fatigue in neuro-inflammatory and autoimmune illnesses.

Morris, Gerwyn, Berk, Michael, Walder, Ken et al.·BMC medicine·2015

This review proposes that ME/CFS fatigue may be caused by ongoing inflammation and immune system activation in the body, which then damages the brain's support cells (astrocytes) and energy-producing structures (mitochondria). The authors suggest that ME/CFS shares similar biological mechanisms with other inflammatory diseases like multiple sclerosis and lupus, and recommend that ME/CFS patients be tested for immune activation and receive specific brain imaging to look for evidence of inflammation.

NeuroinflammationImmune System
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

Oxidative and Nitrosative Stress and Immune-Inflammatory Pathways in Patients with Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS).

Morris, Gerwyn, Maes, Michael·Current neuropharmacology·2014

This study proposes that ME/CFS involves a harmful cycle where the body's immune system becomes overactive and produces damaging molecules called oxidative stress. These problems can be triggered by infections, gut bacteria leaking into the bloodstream, or problems with the energy-producing parts of cells called mitochondria. Once started, this cycle feeds on itself, causing brain inflammation, reduced blood flow to the brain, and damage to cells throughout the body.

NeuroinflammationImmune System
E3 PreliminaryPEM unclearPreliminaryCross-SectionalEditor reviewed

Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An ¹¹C-(R)-PK11195 PET Study.

Nakatomi, Yasuhito, Mizuno, Kei, Ishii, Akira et al.·Journal of nuclear medicine : official publication, Society of Nuclear Medicine·2014

This study used a special brain imaging technique called PET scans to look for signs of inflammation in the brains of ME/CFS patients. Researchers found that people with ME/CFS had higher levels of brain inflammation markers in several key brain regions compared to healthy controls. The amount of inflammation was linked to how severe patients' cognitive problems, pain, and depression were.

Neuroinflammation
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

The glutathione system: a new drug target in neuroimmune disorders.

Morris, Gerwyn, Anderson, George, Dean, Olivia et al.·Molecular neurobiology·2014

This review examines glutathione (GSH), a naturally occurring substance in our cells that protects against damage and helps our immune system work properly. When glutathione levels drop, cells become more stressed and inflamed, which may contribute to ME/CFS and other conditions affecting the brain and immune system. The authors suggest several potential treatments—including supplements like N-acetyl cysteine and natural compounds like curcumin—that might help restore glutathione levels.

NeuroinflammationImmune System
E3 PreliminaryPEM not requiredPreliminaryMechanisticEditor reviewed

A chronic fatigue syndrome model demonstrates mechanical allodynia and muscular hyperalgesia via spinal microglial activation.

Yasui, Masaya, Yoshimura, Takashi, Takeuchi, So et al.·Glia·2014

This study used rats exposed to continuous stress to model ME/CFS and fibromyalgia, finding that stress caused pain sensitivity without any actual tissue damage or infection. The researchers discovered that immune cells in the spinal cord called microglia became activated in stressed animals, and blocking this activation with a drug called minocycline reduced their pain. This suggests that abnormal pain in ME/CFS may stem from brain and spinal cord inflammation rather than damage to muscles or skin.

Neuroinflammation
E3 PreliminaryPEM not requiredPreliminaryMechanisticEditor reviewed

Induction of interleukin-1β by activated microglia is a prerequisite for immunologically induced fatigue.

Ifuku, Masataka, Hossain, Shamim M, Noda, Mami et al.·The European journal of neuroscience·2014

This study used rats to understand how an immune trigger (a synthetic viral mimic) causes prolonged fatigue. Researchers found that when this trigger activates immune cells in the brain called microglia, they release a chemical messenger called IL-1β that affects how the brain handles serotonin, leading to reduced activity and fatigue-like behavior.

NeuroinflammationImmune System
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

The gut microbiome and the brain.

Galland, Leo·Journal of medicinal food·2014

Your gut bacteria can communicate with your brain in several ways: they produce substances that trigger your immune system, create chemicals that affect your mood and sleep, and send signals directly to your brain through a major nerve called the vagus nerve. When the balance of gut bacteria is disrupted, this communication can go wrong and may contribute to problems like chronic fatigue, brain fog, and mood changes.

NeuroinflammationGut MicrobiomeImmune System
E3 PreliminaryPEM requiredPreliminaryReview-NarrativeEditor reviewed

A neuro-immune model of Myalgic Encephalomyelitis/Chronic fatigue syndrome.

Morris, Gerwyn, Maes, Michael·Metabolic brain disease·2013

This study proposes a theory about how ME/CFS develops and persists. The researchers suggest that an initial infection triggers the immune system, which then gets stuck in an overactive state even after the infection is cleared. This causes ongoing inflammation, energy problems in cells, and damage to the nervous system, leading to the characteristic symptoms including post-exertional malaise (feeling worse after activity).

NeuroinflammationAutonomic Nervous SystemImmune SystemPost-Exertional Malaise
E3 PreliminaryPEM unclearPreliminaryMechanisticEditor reviewed

Plasmacytoid dendritic cells in the duodenum of individuals diagnosed with myalgic encephalomyelitis are uniquely immunoreactive to antibodies to human endogenous retroviral proteins.

De Meirleir, Kenny L, Khaiboullina, Svetlana F, Frémont, Marc et al.·In vivo (Athens, Greece)·2013

Researchers found that a specific type of immune cell in the gut (called plasmacytoid dendritic cells) reacts to remnants of ancient viral DNA in 8 out of 12 ME/CFS patients, but not in healthy controls. These cells appear to be displaying signs of viral proteins on their surface, which suggests the gut may be involved in triggering immune problems seen in ME/CFS.

NeuroinflammationImmune System
E3 PreliminaryPEM not requiredPreliminaryCross-SectionalEditor reviewed

Reduction of [11C](+)3-MPB binding in brain of chronic fatigue syndrome with serum autoantibody against muscarinic cholinergic receptor.

Yamamoto, Shigeyuki, Ouchi, Yasuomi, Nakatsuka, Daisaku et al.·PloS one·2012

Some people with ME/CFS have antibodies in their blood that target a chemical receptor in the brain called the muscarinic cholinergic receptor. This study used brain imaging (PET scans) to compare the brains of ME/CFS patients with and without these antibodies. Patients with these antibodies showed lower levels of these receptors in their brains, but this difference did not affect their thinking or memory performance.

Neuroinflammation
E3 PreliminaryPEM unclearPreliminaryMechanisticEditor reviewed

An Etiological Model for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Jason, Leonard A, Sorenson, Matthew, Porter, Nicole et al.·Neuroscience and medicine·2011

This study proposes that ME/CFS may develop through a process called 'kindling,' where the brain becomes increasingly sensitive to stress after repeated infections or injuries. Think of it like a fire alarm that has been triggered so many times it stays in an oversensitive state. Once this happens, the brain's stress system stays highly activated even without new triggers, which could explain why ME/CFS patients have such persistent symptoms.

Neuroinflammation
E3 PreliminaryPEM unclearPreliminaryEditorialEditor reviewed

Chronic fatigue syndrome--a neuroimmunological model.

Arnett, S V, Alleva, L M, Korossy-Horwood, R et al.·Medical hypotheses·2011

This review suggests that ME/CFS may develop when the body has trouble controlling infections early on, leading to long-term inflammation in the brain. The authors propose that this inflammatory process—involving both the immune system and the nervous system—could explain many ME/CFS symptoms and why more women are affected than men. They also suggest that anti-inflammatory treatments targeting a protein called TNF might help patients.

NeuroinflammationImmune System
E3 PreliminaryPEM not requiredPreliminaryMechanisticEditor reviewed

Resveratrol improves hippocampal atrophy in chronic fatigue mice by enhancing neurogenesis and inhibiting apoptosis of granular cells.

Moriya, Junji, Chen, Rui, Yamakawa, Jun-ichi et al.·Biological & pharmaceutical bulletin·2011

Researchers created mice with chronic fatigue by repeatedly exposing them to a bacterial antigen, which caused them to move less and their brains to shrink in a region called the hippocampus. When they gave these mice resveratrol (a compound found in red grapes), the mice became more active and their hippocampus enlarged. The treatment appeared to work by reducing brain cell death and promoting the growth of new brain cells.

Neuroinflammation
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

Kindling and Oxidative Stress as Contributors to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Jason, L A, Porter, N, Herrington, J et al.·Journal of behavioral and neuroscience research·2009

ME/CFS is a complex illness that often starts suddenly, sometimes after a viral infection, and affects multiple body systems including the immune system, nervous system, and heart. This study proposes that two processes—'kindling' (where repeated small stresses build up over time) and oxidative stress (cellular damage from harmful molecules)—may help explain why different ME/CFS patients have such different symptoms and test results.

NeuroinflammationImmune System
E3 PreliminaryPEM not requiredPreliminaryMechanisticEditor reviewed

Lymphatic drainage of the neuraxis in chronic fatigue syndrome: a hypothetical model for the cranial rhythmic impulse.

Perrin, Raymond N·The Journal of the American Osteopathic Association·2007

This study proposes that ME/CFS may be connected to problems with how fluid drains from the brain and spinal cord. The author suggests that the cranial rhythmic impulse—a subtle body rhythm that practitioners can feel—reflects cerebrospinal fluid drainage and lymphatic system activity controlled by the nervous system. When this drainage process becomes disrupted, the author argues it could cause the fatigue and other symptoms of ME/CFS.

Neuroinflammation
E3 PreliminaryPEM not requiredPreliminaryEditorialEditor reviewed

Pain in patients with chronic fatigue syndrome: does nitric oxide trigger central sensitisation?

Nijs, Jo, Van de Velde, Bart, De Meirleir, Kenny·Medical hypotheses·2005

This study proposes a theory about why ME/CFS patients experience widespread pain. The researchers suggest that a molecule called nitric oxide may cause the central nervous system (the brain and spinal cord) to become overly sensitive, amplifying pain signals throughout the body. They propose that viral infections or other pathogens associated with ME/CFS may trigger this chain reaction, and that behaviors like catastrophizing or avoiding activity may either contribute to or result from this heightened sensitivity.

Neuroinflammation
E3 PreliminaryPEM not requiredPreliminaryReview-NarrativeEditor reviewed

Chronic fatigue syndrome: neurological findings may be related to blood--brain barrier permeability.

Bested, A C, Saunders, P R, Logan, A C·Medical hypotheses·2001

This study proposes that ME/CFS symptoms may be caused by a breakdown in the blood-brain barrier (BBB), a protective layer that normally keeps harmful substances out of the brain. The researchers reviewed scientific literature to identify factors that could damage this barrier in ME/CFS patients, including viral infections, stress, and certain chemical imbalances. They suggest that if this protective barrier becomes leaky, it could allow harmful substances into the brain and disrupt normal nerve function, potentially explaining many ME/CFS symptoms.

Neuroinflammation
E3 PreliminaryPEM unclearPreliminaryEditorialEditor reviewed

Raphe nucleus encephalopathy (myalgic encephalomyelitis, epidemic neuromyasthenia).

Maurizi, C P·Medical hypotheses·1985

This 1985 paper proposes that ME/CFS may be caused by damage to a specific brain region called the dorsal raphe nucleus, potentially triggered by Coxsackie B viruses. The symptoms of ME/CFS match what doctors would expect to see if serotonin levels were too low in this area of the brain. The authors suggest that stress and nutritional deficiencies in tryptophan (a building block for serotonin) may make the condition more likely to develop.

Neuroinflammation
E3 PreliminaryPEM not requiredPreliminaryReview-NarrativeEditor reviewed

[Post-COVID neurological sequelae, proposed mechanisms and therapeutic approaches].

Slama Schwok, Anny·Medecine sciences : M/S·2026

This review examines the long-term neurological effects that some people experience after COVID-19 infection, affecting about 5% of patients. The symptoms include brain fog, chronic fatigue, anxiety, depression, and nerve inflammation, which significantly impact daily life. The authors examine the underlying biological mechanisms—such as brain inflammation, disrupted brain chemistry, immune dysfunction, and blood vessel problems—that may cause these symptoms to help guide future treatments.

Neuroinflammation
E3 PreliminaryPEM unclearPreliminaryCross-SectionalEditor reviewed

Upregulation of olfactory receptors and neuronal-associated genes highlights complex immune and neuronal dysregulation in Long COVID patients.

Shahbaz, Shima, Rezaeifar, Maryam, Syed, Hussein et al.·Brain, behavior, and immunity·2025

Researchers studied blood samples from Long COVID patients with ME/CFS-like symptoms and compared them to healthy controls. They found that certain genes related to immune function and brain health were turned on in the patients, while others were turned off. The study also discovered unusual activation of smell-related genes and changes in immune cell types, suggesting the body remains in a state of ongoing inflammation and stress.

NeuroinflammationBiomarkersImmune System
E3 PreliminaryPEM not requiredPreliminaryReview-NarrativeEditor reviewed

Role of Tau protein in long COVID and potential therapeutic targets.

Marwaha, Bharat·Frontiers in cellular and infection microbiology·2023

Long COVID causes ongoing fatigue, breathing problems, brain fog, and other symptoms that can last months or years. This review suggests that a protein called tau—which is known to damage the brain in other diseases—may also be involved in Long COVID. The authors propose that future research should look for tau damage in Long COVID patients and that treatments designed to stop tau buildup might help.

NeuroinflammationBiomarkers
E3 PreliminaryPEM not requiredPreliminaryCase-ControlEditor reviewed

Stellate ganglion block reduces symptoms of Long COVID: A case series.

Liu, Luke D, Duricka, Deborah L·Journal of neuroimmunology·2022

This small study looked at a procedure called a stellate ganglion block, which uses local anesthetic to temporarily quiet the nerve signals in the neck that control your 'fight or flight' response. Two Long COVID patients received this procedure, and their symptoms—including fatigue, brain fog, and dizziness upon standing—improved. The authors suggest that an imbalance in the autonomic nervous system (the system that controls automatic body functions) may be contributing to Long COVID symptoms.

Neuroinflammation
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

Dissecting the Molecular Mechanisms Surrounding Post-COVID-19 Syndrome and Neurological Features.

Mohamed, Mohamed S, Johansson, Anton, Jonsson, Jörgen et al.·International journal of molecular sciences·2022

This study reviews how the virus that causes COVID-19 may damage the nervous system and brain, leading to long-term symptoms similar to those seen in other coronavirus outbreaks. The authors identify specific brain mechanisms—involving inflammation, nerve cell communication problems, and hormone regulation—that could explain why some people develop persistent neurological symptoms after COVID-19. These findings suggest potential targets for future treatments.

Neuroinflammation
E3 PreliminaryPEM unclearPreliminaryEditorialEditor reviewed

Postural Orthostatic Tachycardia Syndrome, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID as Neuroimmune Disorders.

Blitshteyn, Svetlana, Doherty, Taylor A, Steinman, Lawrence·ImmunoTargets and therapy·2026

This editorial argues that three related conditions—POTS, ME/CFS, and Long COVID—should be understood and studied together as disorders affecting both the nervous system and immune system. The authors identify several common problems in these conditions, including heart rate abnormalities when standing, immune system dysfunction, and reduced blood flow to the brain. They believe treating these as a single category of disease could improve how doctors train, research, and care for patients with these serious illnesses.

NeuroinflammationImmune System
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

The Gut-Brain-Immune Axis in Environmental Sensitivity Illnesses: Microbiome-Centered Narrative Review of Fibromyalgia Syndrome, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, and Multiple Chemical Sensitivity.

Watai, Kentaro, Taniguchi, Masami, Azuma, Kenichi·International journal of molecular sciences·2025

This review examines how changes in gut bacteria may contribute to ME/CFS, fibromyalgia, and multiple chemical sensitivity—three conditions that share similar symptoms like fatigue, pain, and sensitivity to environmental triggers. The researchers found that people with these conditions tend to have fewer helpful bacteria and more harmful bacteria in their gut, which may affect how their immune system and brain work. The review suggests that treatments targeting the microbiome—such as probiotics or other interventions—might help, though more research is needed to confirm this.

NeuroinflammationEnergy MetabolismImmune System
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

Proposed Mechanistic Axis of Infections and mTOR Hyperactivation: A Multidisciplinary Review of Immune, Rheumatologic, and Psychiatric Links.

Fronticelli Baldelli, Giovanni, Buonsenso, Danilo·Children (Basel, Switzerland)·2025

This review proposes that a protein called mTOR may be the key link between infections and the long-lasting symptoms seen in ME/CFS and similar post-infection illnesses. The authors suggest that when mTOR stays overactive after an infection, it can damage the barrier that protects the brain, allow immune cells to enter brain tissue, and cause ongoing inflammation that affects how the brain works. They outline a step-by-step pathway explaining how this might happen and suggest that targeting mTOR could be a new treatment approach.

NeuroinflammationImmune System
E3 PreliminaryPEM requiredPreliminaryReview-NarrativeEditor reviewed

Mechanistic Insights Into Long Covid: Viral Persistence, Immune Dysregulation, and Multi-Organ Dysfunction.

Gupta, Gautam, Buonsenso, Danilo, Wood, John et al.·Comprehensive Physiology·2025

This review examines how Long Covid causes persistent symptoms affecting multiple body systems. The research suggests that SARS-CoV-2 virus may hide in body tissues, trigger ongoing immune problems, and damage how cells produce energy, which could explain fatigue and post-exertion crashes. These mechanisms appear similar to ME/CFS, suggesting the two conditions may share common biological pathways.

NeuroinflammationImmune SystemPost-Exertional Malaise
E3 PreliminaryPEM not requiredPreliminaryReview-NarrativeEditor reviewed

Management of Fibromyalgia: Novel Nutraceutical Therapies Beyond Traditional Pharmaceuticals.

Antonelli, Antonella, Bianchi, Marzia, Fear, Elizabeth Jane et al.·Nutrients·2025

This review examines how natural plant-based compounds, particularly polyphenols, might help manage fibromyalgia pain without the side effects of traditional medications. Fibromyalgia and ME/CFS are related conditions that involve abnormal pain signaling in the nervous system, persistent fatigue, and sleep problems. The authors suggest that natural products could be safer alternatives to current drugs like antidepressants and anticonvulsants, which can cause dependence and tolerance over time.

Neuroinflammation
E3 PreliminaryPEM not requiredPreliminaryEditorialEditor reviewed

Post infectious fatigue and circadian rhythm disruption in long-COVID and other infections: a need for further research.

Livieratos, Achilleas, Lockley, Steven W, Tsiodras, Sotirios·EClinicalMedicine·2025

This article discusses how infections like COVID-19 can disrupt the body's internal 24-hour clock, leading to persistent fatigue and sleep problems. The authors explain that viral infections may damage the genes and cellular machinery that control our daily rhythms, trigger inflammation in the brain, and harm energy-producing structures in our cells. Understanding these mechanisms could help doctors develop better treatments for Long COVID and chronic fatigue syndrome.

Neuroinflammation
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

A Narrative Review on Gut Microbiome Disturbances and Microbial Preparations in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Implications for Long COVID.

Jurek, Joanna Michalina, Castro-Marrero, Jesus·Nutrients·2024

This review examines how changes in gut bacteria may contribute to ME/CFS and long COVID symptoms, and whether taking probiotics or similar microbial preparations might help. The authors looked at existing research to understand the connection between gut health and the brain-immune system, and whether restoring healthy gut bacteria could reduce fatigue, inflammation, and other symptoms in these conditions.

NeuroinflammationImmune SystemPost-Exertional Malaise
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

Conceptual foundations of acetylcarnitine supplementation in neuropsychiatric long COVID syndrome: a narrative review.

Helbing, Dario Lucas, Dommaschk, Eva-Maria, Danyeli, Lena Vera et al.·European archives of psychiatry and clinical neuroscience·2024

This review examines whether a natural supplement called acetylcarnitine might help treat long COVID symptoms like fatigue, brain fog, and depression. Acetylcarnitine is a substance your body normally makes that helps cells produce energy. The authors looked at research showing this supplement has helped some people with similar illnesses like ME/CFS and depression, and they propose studying whether it could help long COVID patients too.

Neuroinflammation
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

Current update on the neurological manifestations of long COVID: more questions than answers.

Stefanou, Maria-Ioanna, Panagiotopoulos, Evangelos, Palaiodimou, Lina et al.·EXCLI journal·2024

This review examines the nerve and brain-related symptoms that can persist after COVID-19 infection, which doctors call long COVID. About one-third of COVID-19 survivors experience lasting neurological problems such as fatigue, brain fog, sleep issues, and problems with smell or taste that can last at least 12 months. The authors discuss what we currently know about why these symptoms happen and what treatments might help.

NeuroinflammationPost-Exertional Malaise
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

The molecular fingerprint of neuroinflammation in COVID-19: A comprehensive discussion on molecular mechanisms of neuroinflammation due to SARS-COV2 antigens.

Zayeri, Zeinab Deris, Torabizadeh, Mehdi, Kargar, Masoud et al.·Behavioural brain research·2024

This study explains how COVID-19 can damage the brain and nervous system, causing inflammation and injury. The researchers found that about half of people recovering from COVID-19 develop ME/CFS symptoms, and brain scans show reduced activity in key areas that control memory, movement, and mood. The study focuses on the biological mechanisms—essentially how viruses trigger harmful immune responses in the brain that can lead to long-term neurological problems.

Neuroinflammation
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

Mast cells in the autonomic nervous system and potential role in disorders with dysautonomia and neuroinflammation.

Theoharides, Theoharis C, Twahir, Assma, Kempuraj, Duraisamy·Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology·2024

This study examines mast cells, which are immune cells found throughout the body, and how they may be involved in conditions like ME/CFS that affect the nervous system and cause abnormal heart rate and blood pressure responses. Mast cells sit near nerve endings and important organs, where they can release chemicals that affect how the body regulates basic functions like temperature and blood pressure. The researchers suggest that controlling mast cell activation might help treat these conditions, though currently there are no proven treatments.

NeuroinflammationImmune System
E3 PreliminaryPEM not requiredPreliminaryMechanisticEditor reviewed

Repeated cold stress, an animal model for fibromyalgia, elicits proprioceptor-induced chronic pain with microglial activation in mice.

Wakatsuki, Koji, Kiryu-Seo, Sumiko, Yasui, Masaya et al.·Journal of neuroinflammation·2024

Researchers used mice exposed to repeated cold stress to study how chronic pain develops, similar to fibromyalgia. They found that sensory nerve cells (proprioceptors) become overactive and trigger immune cells in the nervous system called microglia to become inflamed. When they reduced microglial activity with a drug, the pain improved, suggesting that this immune activation along nerve pathways may be a key driver of long-lasting pain.

Neuroinflammation
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

Chronic inflammation, neuroglial dysfunction, and plasmalogen deficiency as a new pathobiological hypothesis addressing the overlap between post-COVID-19 symptoms and myalgic encephalomyelitis/chronic fatigue syndrome.

Chaves-Filho, Adriano Maia, Braniff, Olivia, Angelova, Angelina et al.·Brain research bulletin·2023

This study examines how long COVID and ME/CFS may share similar problems in the body, particularly chronic inflammation (ongoing swelling and immune activation) and low levels of plasmalogens, which are protective fats found in cell membranes. The researchers propose that restoring plasmalogen levels through dietary supplements could potentially help reduce symptoms like fatigue, brain fog, and post-exertional malaise in both conditions.

NeuroinflammationPost-Exertional Malaise
E3 PreliminaryPEM requiredPreliminaryReview-NarrativeEditor reviewed

A review of cytokine-based pathophysiology of Long COVID symptoms.

Low, Russell N, Low, Ryan J, Akrami, Athena·Frontiers in medicine·2023

This review examines how Long COVID may develop through a chain reaction of immune system problems. When the virus infects the body, it can trigger ongoing inflammation that affects both the immune system and the brain, potentially causing blood clots in small vessels. This combination may explain symptoms like fatigue, brain fog, and pain that Long COVID and ME/CFS patients experience.

NeuroinflammationPost-Exertional Malaise
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

Towards a Better Understanding of the Complexities of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID.

Tate, Warren P, Walker, Max O M, Peppercorn, Katie et al.·International journal of molecular sciences·2023

ME/CFS is a complex illness that typically starts after a viral infection, though other stressful events can also trigger it. This review explains that different patients experience different combinations of symptoms and respond differently to treatments—what helps one person may not help another. The authors discuss how the immune system may shift from a temporary response to a lasting problem, and how the brain's immune system may cause the neurological symptoms people experience.

NeuroinflammationImmune SystemPost-Exertional Malaise
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

Hypothetical framework for post-COVID 19 condition based on a fibromyalgia pathogenetic model.

Martínez-Lavín, Manuel, Miguel-Álvarez, Adriana·Clinical rheumatology·2023

This study compares three conditions that share similar symptoms: fibromyalgia, ME/CFS, and long COVID. All three cause fatigue, brain fog, and widespread pain. Researchers propose that these conditions may work through the same biological mechanism—specifically, problems with nerve fiber communication in the body—and suggest that long COVID may develop through the same pathway as fibromyalgia.

Neuroinflammation
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

Perioperative opioid-minimization approach as a useful protocol in the management of patients with Ehlers-Danlos syndrome-hypermobility type, craniocervical instability and severe chronic pain who are to undergo occipito-cervical fixation.

Ramírez-Paesano, Carlos, Rodiera Clarens, Claudia, Sharp Segovia, Allan et al.·Orphanet journal of rare diseases·2023

Some people with Ehlers-Danlos syndrome (a connective tissue disorder) develop neck instability that causes severe pain and fatigue similar to ME/CFS. This review examines how doctors can better manage pain during and after neck surgery in these patients by using less opioid medication and combining multiple pain-relief strategies instead, because opioids often don't work well and can actually make pain worse in these cases.

Neuroinflammation
E3 PreliminaryPEM requiredPreliminaryReview-NarrativeEditor reviewed

The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure.

Renz-Polster, Herbert, Tremblay, Marie-Eve, Bienzle, Dorothee et al.·Frontiers in cellular neuroscience·2022

This study suggests that ME/CFS might be caused by problems with certain support cells in the brain called glia, which help protect and maintain nerve cells. The researchers reviewed existing research on two key ME/CFS symptoms—feeling worse after activity and reduced blood flow to the brain—and found evidence that brain cell dysfunction could explain many of the different problems seen in ME/CFS.

NeuroinflammationPost-Exertional Malaise
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

At the Root of 3 "Long" Diseases: Persistent Antigens Inflicting Chronic Damage on the Brain and Other Organs in Gulf War Illness, Long-COVID-19, and Chronic Fatigue Syndrome.

James, Lisa M, Georgopoulos, Apostolos P·Neuroscience insights·2022

This review explores why some people develop long-lasting illnesses after exposure to viruses or bacteria, while others recover normally. The researchers propose that certain infections may persist in the body longer in people with specific immune system markers (HLA types), potentially causing ongoing damage to the brain and other organs. They suggest this mechanism might explain symptoms seen in ME/CFS, long-COVID, and Gulf War Illness.

NeuroinflammationImmune System
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

Molecular Mechanisms of Neuroinflammation in ME/CFS and Long COVID to Sustain Disease and Promote Relapses.

Tate, Warren, Walker, Max, Sweetman, Eiren et al.·Frontiers in neurology·2022

This study explores why ME/CFS and Long COVID symptoms persist and come and go in cycles. The researchers propose that after an initial trigger—like a viral infection, chemical exposure, or major stress—inflammation spreads to the brain through damaged blood vessels, causing ongoing brain inflammation that keeps the illness cycling. They suggest that similar mechanisms may explain why both ME/CFS (from various causes) and Long COVID (from COVID-19) produce remarkably similar symptoms despite different starting triggers.

NeuroinflammationImmune SystemPost-Exertional Malaise
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The Role of Neuro-Immune Interaction in Chronic Pain Conditions; Functional Somatic Syndrome, Neurogenic Inflammation, and Peripheral Neuropathy.

Meade, Elaine, Garvey, Mary·International journal of molecular sciences·2022

This review article examines how the nervous and immune systems interact to cause chronic pain and fatigue in conditions like ME/CFS, fibromyalgia, and IBS. The authors explain that childhood trauma and ongoing stress can permanently change how the body's stress response system works, leading to long-term symptoms. They discuss how these systems become dysregulated and contribute to the wide range of symptoms people with these conditions experience.

NeuroinflammationImmune System
E3 PreliminaryPEM not requiredPreliminaryCross-SectionalEditor reviewed

No Signs of Neuroinflammation in Women With Chronic Fatigue Syndrome or Q Fever Fatigue Syndrome Using the TSPO Ligand [11C]-PK11195.

Raijmakers, Ruud, Roerink, Megan, Keijmel, Stephan et al.·Neurology(R) neuroimmunology & neuroinflammation·2022

Researchers used a specialized brain scan to look for signs of inflammation in the brains of women with ME/CFS and Q fever fatigue syndrome, compared to healthy women. The scan didn't find evidence of the type of brain inflammation they were looking for, which contradicts some earlier research suggesting inflammation might play a role in these conditions.

NeuroinflammationBiomarkersImmune System
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Dorsal root ganglia: fibromyalgia pain factory?

Martínez-Lavín, Manuel·Clinical rheumatology·2021

This article explores whether structures called dorsal root ganglia (DRG)—small nerve clusters along the spine—might be the main source of pain in fibromyalgia. These ganglia contain pain-sensing nerve cells and immune molecules that can become overactive. Recent evidence suggests that in some fibromyalgia patients, these nerve clusters show signs of damage and increased pain signaling.

Neuroinflammation
E3 PreliminaryPEM requiredPreliminaryEditorialEditor reviewed

A Paradigm for Post-Covid-19 Fatigue Syndrome Analogous to ME/CFS.

Mackay, Angus·Frontiers in neurology·2021

This study proposes that long-term fatigue following COVID-19 works similarly to ME/CFS—both may result from severe infection triggering dysfunction in a brain region called the hypothalamic paraventricular nucleus (PVN). In people genetically susceptible to this condition, the stress from COVID-19 infection could overwhelm this brain center, making it oversensitive to everyday stressors and causing the fatigue, post-exertional malaise, and other symptoms characteristic of ME/CFS.

NeuroinflammationPost-Exertional Malaise
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COVID-19 and chronic fatigue syndrome: Is the worst yet to come?

Wostyn, Peter·Medical hypotheses·2021

This paper proposes a theory about why some people develop prolonged fatigue after COVID-19 that resembles ME/CFS. The author suggests that COVID-19 may damage nerve cells in the nose, which could reduce the brain's ability to clear out waste products, leading to toxic buildup and fatigue. The paper calls for research to test whether treatments that help drain fluid from around the brain might help patients with post-COVID fatigue.

Neuroinflammation
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Persistent Brainstem Dysfunction in Long-COVID: A Hypothesis.

Yong, Shin Jie·ACS chemical neuroscience·2021

This paper suggests that long-COVID symptoms may be caused by damage to the brainstem, a part of the brain that controls basic functions like breathing, heart rate, and digestion. The authors propose that the coronavirus may directly infect the brainstem or cause inflammation there, and because brain cells heal slowly, this damage could persist long after the initial infection. This theory could help explain why long-COVID patients experience lasting fatigue, breathing problems, and other widespread symptoms.

Neuroinflammation
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Historical Insight into Infections and Disorders Associated with Neurological and Psychiatric Sequelae Similar to Long COVID.

Stefano, George B·Medical science monitor : international medical journal of experimental and clinical research·2021

This review examines how long COVID causes long-term symptoms similar to those seen after other viral infections throughout history, particularly focusing on 'brain fog' and difficulty thinking clearly. By looking at past pandemics like the 1918 flu and other viral illnesses, researchers found that many infections can cause similar cognitive problems and fatigue that persist long after the initial infection. The study suggests that viruses may damage the brain's energy-producing structures (mitochondria), leading to reduced oxygen in the brain and chronic symptoms like those seen in ME/CFS and long COVID.

Neuroinflammation
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

Neuroinflammation disorders exacerbated by environmental stressors.

O'Callaghan, James P, Miller, Diane B·Metabolism: clinical and experimental·2019

This review examines how inflammation in the brain and nervous system may be involved in ME/CFS and similar conditions. The authors suggest that various environmental stressors—like infections or other physical demands—can trigger or worsen this brain inflammation, leading to symptoms like fatigue, muscle pain, and brain fog. They propose that stress affects a key hormone system in the body (the HPA axis), which may play a role in how long these symptoms persist.

Neuroinflammation
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

Neuroimmunology: What Role for Autoimmunity, Neuroinflammation, and Small Fiber Neuropathy in Fibromyalgia, Chronic Fatigue Syndrome, and Adverse Events after Human Papillomavirus Vaccination?

Ryabkova, Varvara A, Churilov, Leonid P, Shoenfeld, Yehuda·International journal of molecular sciences·2019

This review explores three interconnected biological processes that may cause fibromyalgia and chronic fatigue syndrome (ME/CFS): the immune system attacking the body's own tissues, inflammation in the nervous system, and damage to small nerve fibers. The authors propose that these three mechanisms work together and may explain why patients experience widespread pain, extreme fatigue, and other symptoms like brain fog and sleep problems. They also examine whether similar mechanisms might explain some adverse reactions to HPV vaccination.

NeuroinflammationImmune System
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A Comparison of Neuroimaging Abnormalities in Multiple Sclerosis, Major Depression and Chronic Fatigue Syndrome (Myalgic Encephalomyelitis): is There a Common Cause?

Morris, Gerwyn, Berk, Michael, Puri, Basant K·Molecular neurobiology·2018

This review compared brain imaging findings across three conditions—multiple sclerosis, depression, and ME/CFS—looking for similarities that might suggest a common underlying cause. The researchers found that all three conditions show similar patterns of brain abnormalities, including problems with blood flow to the brain and changes in brain structure. They suggest that inflammation and immune cell dysfunction in the brain may explain why patients with these different diagnoses have comparable brain imaging problems.

Neuroinflammation
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

Stress, inflammation and natural treatments.

Theoharides, T C, Kavalioti, M·Journal of biological regulators and homeostatic agents·2018

This study explores how stress and inflammation work together to cause several conditions including ME/CFS, fibromyalgia, and others. The researchers found that immune cells called mast cells and brain cells called microglia may communicate in ways that trigger inflammation during stress. They suggest that a natural supplement combining luteolin and Ashwagandha might help reduce this inflammation and benefit patients with these conditions.

NeuroinflammationImmune System
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

Brain "fog," inflammation and obesity: key aspects of neuropsychiatric disorders improved by luteolin.

Theoharides, Theoharis C, Stewart, Julia M, Hatziagelaki, Erifili et al.·Frontiers in neuroscience·2015

This review discusses 'brain fog'—trouble thinking clearly, concentrating, and remembering—which affects people with ME/CFS and other conditions. Researchers suggest brain fog may be caused by inflammation and immune cells releasing harmful chemicals in the brain. A natural compound called luteolin, which has anti-inflammatory properties, shows promise in early studies for reducing brain fog symptoms.

Neuroinflammation
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Clinical features in patients with long-lasting macrophagic myofasciitis.

Rigolet, Muriel, Aouizerate, Jessie, Couette, Maryline et al.·Frontiers in neurology·2014

This study describes macrophagic myofasciitis (MMF), a condition where aluminum from vaccines persists in muscle tissue and causes long-lasting symptoms similar to ME/CFS, including widespread pain, severe fatigue, and significant problems with thinking and memory. Patients show patterns of brain abnormalities on imaging scans, and their cognitive problems appear to be caused by brain dysfunction rather than just pain or depression. The researchers found that standard treatments don't work well for these patients, making their condition particularly disabling.

Neuroinflammation
E3 PreliminaryPEM unclearPreliminaryEditorialEditor reviewed

New developments in the diagnosis and treatment of chronic prostatitis/chronic pelvic pain syndrome.

Pontari, Michel, Giusto, Laura·Current opinion in urology·2013

This article discusses how chronic prostatitis and chronic pelvic pain syndrome in men can present differently—some men have pain localized to the pelvic area, while others experience widespread body symptoms similar to other chronic conditions. The authors review new treatment options including physical therapy, acupuncture, psychological support, and medications, and note that these conditions often occur alongside other chronic pain disorders like fibromyalgia and chronic fatigue syndrome.

Neuroinflammation
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

Depression's multiple comorbidities explained by (neuro)inflammatory and oxidative & nitrosative stress pathways.

Maes, Michael, Kubera, Marta, Obuchowiczwa, Ewa et al.·Neuro endocrinology letters·2011

This review explains why depression often occurs alongside many other diseases, including ME/CFS, autoimmune conditions, heart disease, and neurodegenerative disorders. The common link appears to be activation of inflammatory and oxidative stress pathways in both the brain and body. These pathways may act like a 'warning system' that produces depression symptoms such as fatigue, anxiety, and physical discomfort when the body detects a threat.

NeuroinflammationImmune System
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Perspectives on fatigue from the study of chronic fatigue syndrome and related conditions.

Clauw, Daniel J·PM & R : the journal of injury, function, and rehabilitation·2010

This article explains that ME/CFS is a complex illness with roots in both the body and brain, involving several connected problems at the same time. Researchers have found that ME/CFS shares similar patterns with other conditions like fibromyalgia and irritable bowel syndrome, and involves issues with sleep, pain, cognitive problems, and extreme tiredness after activity. The article describes how inflammation, infection, problems with stress hormones, and nerve signal problems may all contribute to ME/CFS, though we don't yet know which problems matter most.

NeuroinflammationPost-Exertional Malaise
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Postulated vasoactive neuropeptide immunopathology affecting the blood-brain/blood-spinal barrier in certain neuropsychiatric fatigue-related conditions: A role for phosphodiesterase inhibitors in treatment?

Staines, Donald R, Brenu, Ekua W, Marshall-Gradisnik, Sonya·Neuropsychiatric disease and treatment·2009

This paper proposes that ME/CFS, along with MS, Parkinson's disease, and ALS, may involve immune system problems affecting the protective barriers around the brain and spinal cord. Specifically, the authors suggest that certain signaling molecules called PACAP and VIP, which normally help maintain these barriers, may become targets of autoimmune attack. They propose that a class of drugs called phosphodiesterase inhibitors might help restore normal function by boosting protective immune responses.

NeuroinflammationImmune System
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A Chronic Fatigue Syndrome - related proteome in human cerebrospinal fluid.

Baraniuk, James N, Casado, Begona, Maibach, Hilda et al.·BMC neurology·2005

Researchers examined fluid from around the spine (cerebrospinal fluid) in people with ME/CFS and found specific proteins that were present in patients but absent in healthy people. Using advanced laboratory techniques, they identified a set of 5 key proteins that could correctly identify ME/CFS in 80% of cases. These findings suggest ME/CFS may involve immune system and brain inflammation, offering hope for an objective test in the future.

NeuroinflammationBiomarkers
E3 PreliminaryPEM not requiredPreliminaryReview-NarrativeEditor reviewed

The neurological significance of abnormal natural killer cell activity in chronic toxigenic mold exposures.

Anyanwu, Ebere, Campbell, Andrew W, Jones, Joseph et al.·TheScientificWorldJournal·2003

This review examines how toxic molds found in homes and buildings can damage the immune system, specifically affecting natural killer cells—white blood cells that help fight infections. When people are exposed to these molds over time, their natural killer cells may stop working normally, which could contribute to symptoms like fatigue, memory problems, sleep trouble, depression, headaches, and fevers that resemble ME/CFS.

NeuroinflammationImmune System
E3 PreliminaryPEM not requiredModerate confidenceReview-NarrativeEditor reviewed

Connecting cytokines and brain: a review of current issues.

Quan, N, Herkenham, M·Histology and histopathology·2002

This review examines how immune molecules called cytokines communicate with the brain and affect how it works. Scientists have found that cytokines can trigger fatigue, changes in mood and behavior, and problems with the nervous system. The authors suggest that cytokines may play a role in several brain-related conditions, including chronic fatigue syndrome.

NeuroinflammationImmune System
E3 PreliminaryPEM not requiredPreliminaryReview-NarrativeEditor reviewed

Are cytokines associated with neuropsychiatric syndromes in humans?

Hickie, I, Lloyd, A·International journal of immunopharmacology·1995

This paper suggests that immune molecules called cytokines—which your body produces during infections or inflammation—may affect your brain and behavior in ways that look like psychiatric symptoms such as depression, fatigue, loss of appetite, and difficulty thinking clearly. The authors review evidence from various illnesses where these immune-related behavioral changes happen together, including ME/CFS, and propose that cytokines may be the biological link between immune activation and these symptoms.

NeuroinflammationImmune System
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

Stealth viruses as neuropathogens.

Martin, W J·CAP today·1994

This article suggests that certain stealth viruses may damage the nervous system and contribute to various brain-related conditions, including ME/CFS. The authors note that diseases like ME/CFS, fibromyalgia, depression, and autism share overlapping symptoms—such as pain, mood changes, and cognitive problems—which may reflect a common underlying problem in how the brain responds to different triggers.

Neuroinflammation
E3 PreliminaryPEM not requiredPreliminaryReview-NarrativeEditor reviewed

Role of infection and neurologic dysfunction in chronic fatigue syndrome.

Komaroff, Anthony L, Cho, Tracey A·Seminars in neurology·2011

This review examines the connection between infections and ME/CFS, looking at decades of cases where people developed long-lasting fatigue after infections. The authors found evidence that certain viruses and bacteria can cause persistent infections that trigger and maintain ME/CFS symptoms by affecting the nervous system and triggering ongoing immune responses. While no single infection has been proven to cause ME/CFS in all cases, the pattern suggests that chronic infections may be important triggers in some people with the illness.

Neuroinflammation
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Moderate, intermittent voluntary exercise in a model of Gulf War Illness improves cognitive and mood function with alleviation of activated microglia and astrocytes, and enhanced neurogenesis in the hippocampus.

Kodali, Maheedhar, Mishra, Vikas, Hattiangady, Bharathi et al.·Brain, behavior, and immunity·2021

Researchers tested whether moderate exercise three times a week could help rats with a Gulf War Illness-like condition improve their memory, mood, and thinking skills. After 13 weeks, the exercising rats showed better memory and less anxiety, and their brains showed less inflammation and more growth of new brain cells. This suggests that gentle, part-time exercise might help people with similar conditions improve brain function.

NeuroinflammationPost-Exertional Malaise
E3 PreliminaryPEM not requiredPreliminaryMechanisticEditor reviewed

Non-linear dose-response of aluminium hydroxide adjuvant particles: Selective low dose neurotoxicity.

Crépeaux, Guillemette, Eidi, Housam, David, Marie-Odile et al.·Toxicology·2017

This study gave mice different amounts of aluminum hydroxide (a substance used in vaccines) injected into muscle and then checked their brains 6 months later. Surprisingly, the mice that received the lowest dose showed cognitive and movement changes, increased immune cell activity in the brain, and accumulated more aluminum in their brains—while the mice given higher doses did not. This unusual pattern suggests that aluminum's harmful effects may not simply follow the traditional "more dose = more harm" rule.

NeuroinflammationImmune System
E3 PreliminaryPEM not requiredPreliminaryMechanisticEditor reviewed

Hepatitis C virus enters human peripheral neuroblastoma cells - evidence for extra-hepatic cells sustaining hepatitis C virus penetration.

Bürgel, B, Friesland, M, Koch, A et al.·Journal of viral hepatitis·2011

This study investigated whether hepatitis C virus (HCV) can infect and replicate in nerve cells, since some HCV patients experience fatigue, depression, and memory problems. Researchers tested whether HCV could enter and survive in different types of brain and nerve cells in the laboratory. They found that HCV could enter one type of peripheral nerve cell, but could not replicate in any of the brain or nerve cell types tested.

Neuroinflammation
E3 PreliminaryPEM unclearPreliminaryReview-NarrativeEditor reviewed

[Possible mechanisms of chronic fatigue syndrome in multiple sclerosis].

Kasatkin, D S, Spirin, N N·Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova·2006

This review describes how fatigue in multiple sclerosis (MS) can happen in different ways: tiredness even at rest, exhaustion during activity, and fatigue linked to MS flare-ups. The authors explain that fatigue likely involves both brain-based and body-based mechanisms, and often occurs alongside depression and sleep problems, suggesting these conditions may share common biological causes related to brain chemicals like serotonin.

NeuroinflammationPost-Exertional Malaise
E3 PreliminaryPEM not requiredPreliminaryCross-SectionalEditor reviewed

Neuropathology in rhinosinusitis.

Baraniuk, James N, Petrie, Kristina Naranch, Le, Uyenphuong et al.·American journal of respiratory and critical care medicine·2005

Researchers tested how the nasal passages of people with ME/CFS, sinusitis, allergies, and healthy controls responded to salt water spray. They found that people with ME/CFS experienced unusual nerve sensitivity (feeling more pain) but their mucus-producing glands didn't respond normally to the stimulus. This suggests that ME/CFS involves a different pattern of how nerves and mucus glands work in the nose compared to other nasal conditions.

Neuroinflammation
E3 PreliminaryPEM unclearPreliminaryObservationalEditor reviewed

Chronic fatigue syndrome differs from fibromyalgia. No evidence for elevated substance P levels in cerebrospinal fluid of patients with chronic fatigue syndrome.

Evengard, B, Nilsson, C G, Lindh, G et al.·Pain·1998

Researchers measured a pain-signaling chemical called substance P in the spinal fluid of 15 people with ME/CFS. They found that all the ME/CFS patients had normal levels of this chemical. This is important because fibromyalgia—a condition with similar symptoms—typically shows elevated substance P levels. This finding suggests that ME/CFS and fibromyalgia may be caused by different biological problems, even though patients experience some overlapping symptoms.

Neuroinflammation
E0 ConsensusPEM unclearPreliminaryReview-NarrativeMachine-drafted

Nutritional modulation of the intestinal microbiota; future opportunities for the prevention and treatment of neuroimmune and neuroinflammatory disease.

Lombardi, Vincent C, De Meirleir, Kenny L, Subramanian, Krishnamurthy et al.·The Journal of nutritional biochemistry·2018

Your gut bacteria and brain communicate constantly with each other in ways that affect your immune system and inflammation levels. This review looks at how diet and nutrition can change your gut bacteria in ways that might help prevent or treat brain-related diseases that involve immune problems. The authors suggest that maintaining healthy gut bacteria through food choices could be an important treatment strategy.

NeuroinflammationImmune System
E2 ModeratePEM not requiredModerate confidenceCross-SectionalMachine-drafted

The physio-affective phenome of major depression is strongly associated with biomarkers of astroglial and neuronal projection toxicity which in turn are associated with peripheral inflammation, insulin resistance and lowered calcium.

Al-Hakeim, Hussein Kadhem, Al-Naqeeb, Tabarek Hadi, Almulla, Abbas F et al.·Journal of affective disorders·2023

This study examined whether brain and nerve damage markers in the blood are connected to depression symptoms and other physical complaints. Researchers measured several proteins in the blood of people with depression and compared them to healthy controls, finding that markers of brain cell and nerve damage—along with inflammation and insulin resistance—together explained about 61% of the severity of depression, anxiety, fatigue, and physical symptoms.

NeuroinflammationBiomarkers
E3 PreliminaryPEM not requiredPreliminaryReview-NarrativeMachine-drafted

From Fork to Brain: The Role of AGE-RAGE Signaling and the Western Diet in Neurodegenerative Disease.

Pomroy, Haylie J, Mote, Arjun, Mathew, Simeon et al.·NeuroSci·2025

This review examines how certain compounds called AGEs (advanced glycation end products) form in food and in our bodies, and how they may contribute to brain damage and disease. AGEs are created when food is cooked at high temperatures or processed, and when they build up in the body, they can trigger inflammation and harm cells. The authors suggest that limiting AGEs in the diet might help prevent or slow down brain diseases, though more research is needed to confirm this.

Neuroinflammation

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