Evidence browser

BiomarkersCognitive ImpairmentLong COVID OverlapPost-Exertional Malaise

Central noradrenergic deficiency in post-infectious chronic fatigue: neurobehavioral correlates.

Aregawi, Lillian, Walitt, Brian, Sullivan, Patti et al.·Brain communications·2026

Researchers measured levels of norepinephrine (a brain chemical) in cerebrospinal fluid from people with ME/CFS, Long COVID, and Parkinson's disease, comparing them to healthy volunteers. They observed that norepinephrine pathway activity was lower in all three patient groups, and in Long COVID patients with post-exertional malaise, this reduction was particularly pronounced. This is one study in a small sample, and it remains unclear whether these findings fully explain fatigue and brain fog or apply directly to ME/CFS.

BiomarkersAutonomic Nervous SystemImmune SystemCognitive Impairment

Involvement of autoantibodies against G protein-coupled receptors in post-COVID condition and Chronic Fatigue Syndrome.

Azcue, N, Prada, A, Del Pino, R et al.·Scientific reports·2026

Researchers compared immune markers called autoantibodies in people with post-COVID condition, ME/CFS, and healthy controls. They found that people with ME/CFS had higher levels of antibodies against certain nerve receptors (β2 adrenergic), and these antibodies were associated with autonomic nervous system problems and memory changes. However, this is a single cross-sectional study, and autoimmunity remains one of several proposed mechanisms—it is not yet clear whether these antibodies are a cause or a consequence of ME/CFS.

E2 ModerateBehavioralPEM not requiredCross-Sectional

Disentangling comorbidity: symptom dimensions of internalizing and functional disorders in a large general population sample.

Saini, Urvi, Aggen, Steven H, Oldehinkel, Albertine J et al.·BMC psychiatry·2026

This study looked at how symptoms of depression, anxiety, ME/CFS, fibromyalgia, and irritable bowel syndrome overlap in over 100,000 people. Researchers found that these conditions share common symptoms like fatigue, sleep problems, and difficulty concentrating—which they call 'general malaise'—rather than being completely separate diseases. Understanding these shared symptoms may help explain why people often have multiple conditions at the same time.

Pain and SensitizationCognitive Impairment

E2 ModerateCohortPEM not requiredLongitudinal

Long COVID longitudinal symptoms burden clusters within a national community-based cohort.

Shen, Yanhan, Shahn, Zach, Robertson, McKaylee M et al.·BMC infectious diseases·2026

This study followed over 500 people with long COVID for up to a year, tracking their symptoms over time. Researchers identified three groups based on symptom burden: one with persistent severe symptoms (including fatigue, brain fog, post-exertional malaise, and pain), one with moderate symptoms that improved, and one with minimal symptoms. The findings are preliminary and based on self-reported data, so the stability and generalisability of these groups to other long COVID populations remain to be confirmed.

Pain and SensitizationSleepAutonomic Nervous SystemCognitive Impairment

E2 ModerateCohortPEM unclearLongitudinal

Validation of the Wood Mental Fatigue Inventory in adolescents with myalgic encephalomyelitis/chronic fatigue syndrome.

Welch, David C, Edwards, Charles C, Broussard, Camille A et al.·Brain, behavior, & immunity - health·2026

This study tested whether a questionnaire called the Wood Mental Fatigue Inventory (WMFI) works well for measuring brain fog and cognitive problems in teenagers with ME/CFS. Researchers compared it to another commonly used teen fatigue scale and found that both questionnaires measured mental fatigue similarly and could track changes over time as teenagers received treatment.

Assessment of dynamic cerebral blood flow changes during cognitive tasks in patients with post-COVID-19 syndrome.

Kutz, Dieter F, Garbsch, René, Mooren, Frank C et al.·Brain communications·2026

This study looked at how blood flow in the brain changes when people with post-COVID-19 syndrome try to do mental tasks. Researchers used special infrared cameras to watch blood flow in the thinking part of the brain while patients did concentration exercises. They found that people with post-COVID-19 had unusual, less flexible blood flow patterns compared to healthy people, which may help explain why they feel mentally tired and have trouble concentrating.

BiomarkersDiagnosticsCognitive Impairment

3D Virtual Reality Performance Metrics as a Future Fatigue Biomarker in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

Ladek, Anja-Maria, Priebe, Leonie, Harrer, Thomas et al.·Biomedicines·2026

Researchers tested how quickly 60 ME/CFS patients and 60 healthy controls could react to visual tasks presented in 3D virtual reality. ME/CFS patients showed slower reaction times across all difficulty levels, and they improved less with practice than controls did. The study reports an association between ME/CFS and prolonged reaction times, though the findings are preliminary and whether this could become a reliable test for fatigue severity requires further validation.

E2 ModerateCohortPEM not requiredObservational

Identifying commonalities and differences between EHR representations of PASC and ME/CFS in the RECOVER EHR cohort.

Powers, John P, McIntee, Tomas J, Bhatia, Abhishek et al.·Communications medicine·2025

Researchers compared medical records from millions of patients to see how Long COVID (PASC) and ME/CFS are similar and different. They found that both conditions share common symptoms like fatigue, breathing difficulties, and trouble concentrating, but Long COVID tends to have more heart and lung problems, while ME/CFS more often involves pain and sleep issues. These similarities suggest that some treatment approaches might help both conditions.

Pain and SensitizationSleepCognitive Impairment

The impact of APOE4 on neurological symptoms after exposure to K. brevis neurotoxin.

Aldrich, Gregory J, Nkiliza, Aurore, Ferguson, Scott et al.·Environmental toxicology and pharmacology·2025

Researchers studied whether a genetic variant called APOE4 makes people more vulnerable to neurological problems from brevetoxins—toxic chemicals released by harmful algae blooms in coastal Florida waters. They found that people carrying the APOE4 gene variant reported more memory problems and fatigue during red tide events compared to those without this variant. This suggests that certain genetic factors may increase how vulnerable someone's brain is to environmental toxins.

Hippocampal subfield volume alterations and associations with severity measures in long COVID and ME/CFS: A 7T MRI study.

Thapaliya, Kiran, Marshall-Gradisnik, Sonya, Eaton-Fitch, Natalie et al.·PloS one·2025

Researchers used advanced brain imaging to compare a part of the brain called the hippocampus in long COVID patients, ME/CFS patients, and healthy people. They found that certain areas of the hippocampus were larger in both patient groups compared to healthy controls, and these size differences were linked to how severe symptoms like fatigue, pain, and memory problems were. This suggests that changes in brain structure might explain some of the cognitive difficulties these patients experience.

Autonomic Nervous SystemCognitive Impairment

Characterization of Postural Orthostatic Tachycardia Syndrome in Long COVID: Self-reported Data From the LISTEN Study.

Al Mouslmani, Mohammad, Sawano, Mitsuaki, Arun, Adith S et al.·JACC. Advances·2025

This study looked at people with long COVID who also developed POTS (a condition where the heart rate spikes when standing up). Among nearly 600 long COVID patients, about 29% reported having POTS. People with both conditions reported significantly more symptoms—including dizziness, chest pain, extreme fatigue, difficulty exercising, and brain fog—and experienced worse overall health and quality of life compared to those with long COVID alone.

E2 ModerateCohortPEM unclearLongitudinal

Functional olfactory impairment and fatigue in post-COVID-19 syndrome including ME/CFS - a longitudinal prospective observational study.

Meyer-Arndt, Lil, Pierchalla, Greta, Mödl, Lukas et al.·Brain, behavior, & immunity - health·2025

This study followed 45 long-COVID patients over 28 months to understand the connection between smell problems and fatigue, including those who developed ME/CFS. Researchers tested how well patients could smell (detecting scent strength, telling scents apart, and identifying them) and measured their fatigue, thinking ability, and physical strength. Most patients' smell improved over time, but problems with identifying specific smells lasted the longest, and patients with better smell discrimination at the start tended to feel better and function better after 20 months.

Cognitive functioning in patients with chronic fatigue syndrome: Slowed information processing or a deficit in attentional selectivity?

Banovic, Ingrid, Šaban, Iva, Ayad, Adel et al.·Neuropsychology·2025

This study tested whether people with ME/CFS have trouble focusing their attention or simply process information more slowly. Researchers gave 83 ME/CFS patients and 83 healthy people a simple attention test (the Stroop task) where they had to name colors while ignoring conflicting words. The results showed that ME/CFS patients were slower overall, but their difficulty wasn't due to problems with attention—it was purely because their brains processed information more slowly.

E2 ModerateCohortPEM unclearObservational

Absence of BOLD adaptation in chronic fatigue syndrome revealed by task functional MRI.

Schönberg, Laura, Mohamed, Abdalla Z, Yu, Qiang et al.·Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism·2025

This study looked at how the brain responds when people with ME/CFS do mental tasks, using brain imaging to measure blood flow. Researchers found that while healthy people's brains become more efficient with repeated effort (showing less activation over time), people with ME/CFS showed the opposite pattern—their brains actually increased activity with each repetition. This suggests that ME/CFS may involve a fundamental difference in how the brain adapts to mental work, potentially explaining why cognitive tasks feel so exhausting.

E2 ModerateCohortPEM not required

Two neurocognitive domains identified for patients with myalgic encephalomyelitis/chronic fatigue syndrome and post-acute sequelae of COVID-19.

Sandoval, Ariadna, Li, Mingqi, Jason, Leonard A·Frontiers in neurology·2025

This study looked at brain-related symptoms in over 2,600 people with ME/CFS and COVID long-haul (PASC), finding that their cognitive problems fall into two main categories. The first group includes classic memory and concentration difficulties, while the second group involves being overwhelmed by sensory input like loud noises or bright lights. The research suggests that doctors and researchers should pay more attention to sensory overload as an important part of cognitive problems in these conditions.

E2 ModerateBehavioralPEM not requiredCross-Sectional

Network structure of functional somatic symptoms.

Litzenburger, Alexandra, Rothacher, Yannick, Hanusch, Kay-Uwe et al.·Journal of psychosomatic research·2025

This study looked at how symptoms cluster together in people with functional somatic syndromes (like ME/CFS, fibromyalgia, and others). Researchers surveyed over 3,000 young adults and used network analysis to map which symptoms tend to appear together. They found that fatigue and depression are particularly important symptoms that connect different symptom groups, and identified ten distinct clusters of related symptoms.

Pain and SensitizationCognitive Impairment

E2 ModerateCohortPEM requiredCross-Sectional

Exploratory study on autoantibodies to arginine-rich human peptides mimicking Epstein-Barr virus in women with post-COVID and myalgic encephalomyelitis/chronic fatigue syndrome.

Hoheisel, Friederike, Fleischer, Kathrin Maria, Rubarth, Kerstin et al.·Frontiers in immunology·2025

This study looked for certain antibodies in the blood of women with post-COVID and ME/CFS that might mistakenly attack the body's own proteins. The researchers found that patients with these conditions had more of these problematic antibodies than healthy people, and these antibodies were linked to common ME/CFS symptoms like fatigue, brain fog, pain, and autonomic problems. The results suggest that a virus (EBV) may trigger the immune system to attack human proteins that look similar to viral proteins.

Pain and SensitizationAutonomic Nervous SystemCognitive Impairment

Comparative Study Between Cognitive Phenotypes of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Multiple Sclerosis.

Aoun Sebaiti, Mehdi, Oubaya, Nadia, Gounden, Yannick et al.·Diagnostics (Basel, Switzerland)·2025

This study compared thinking and memory problems in ME/CFS patients with those in multiple sclerosis (MS) patients, since both conditions can cause similar cognitive issues, fatigue, and pain. Researchers tested 40 people with ME/CFS and 40 with MS using standard memory and attention tests. They found that ME/CFS patients have a specific pattern of cognitive difficulties, particularly problems with consolidating (storing) new information in memory, which is distinct from MS.

Prevalence and severity of neurologic symptoms in Long-COVID and the role of pre-existing conditions, hospitalization, and mental health.

Huff, Hanalise V, Roberts, Henry, Bartrum, Elizabeth et al.·Frontiers in neurology·2025

This study looked at neurological symptoms in 213 people with Long-COVID, examined 8 months after infection. Researchers found that fatigue, brain fog, unrefreshed sleep, and word-finding difficulties were very common and often severe. Importantly, these symptoms appeared to be caused by the virus itself rather than by pre-existing health conditions or how sick people were during acute infection.