Evidence browser

NeuroinflammationBiomarkers

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.

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.

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.

NeuroinflammationEnergy Metabolism

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.

NeuroinflammationBiomarkersPost-Exertional Malaise

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.

E2 ModerateCohortPEM unclearObservational

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.

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.

E2 ModerateCohortPEM unclearCase-Control

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

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.

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.

E2 ModerateMechanismPEM unclearMechanistic

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.

E2 ModerateReviewPEM unclearReview-Narrative

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.

E2 ModerateCohortPEM unclearCase-Control

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.

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.

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.

E3 PreliminaryMechanismPEM not requiredMechanistic

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.

E3 PreliminaryMechanismPEM unclearCross-Sectional

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.

E3 PreliminaryReviewPEM not requiredReview-Narrative

[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.

E3 PreliminaryMechanismPEM not requiredMechanistic

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.

E3 PreliminaryReviewPEM unclearReview-Narrative

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.