Search Results (488)

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a worldwide challenge. There are an estimated 17–24 million patients worldwide, with an estimated 60 percent or more who have not been diagnosed. Without a known cure, no specific curative medication, disability lasting years to being life-long, and disagreement among healthcare providers as to how to most appropriately treat these patients, ME/CFS patients are in need of assistance. Appropriate healthcare provider education would increase the percentage of patients diagnosed and treated; however, in-school healthcare provider education is limited. To address the latter issue, the New Jersey Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Association (NJME/CFSA) has developed an independent, incentive-driven, learning program for students of the health professions. NJME/CFSA offers a yearly scholarship program in which applicants write a scholarly paper on an ME/CFS-related topic. The efficacy of the program is demonstrated by the 2024–2025 first place scholarship winner’s essay, which addresses the biological basis of ME/CFS and how the healthcare provider can improve the quality of life of ME/CFS patients. For the reader, the essay provides an update on what is known regarding the biological underpinnings of ME/CFS, as well as a medical student’s perspective as to how the clinician can provide care and support for ME/CFS patients. The original essay has been slightly modified to demonstrate that ME/CFS is a worldwide problem and for publication. Full article

Background: Emerging evidence indicates that some individuals recovering from COVID-19 develop persistent symptoms, including fatigue, pain, cognitive difficulties, and psychological distress, commonly known as Long COVID. These symptoms often overlap with those seen in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME), underscoring the need for integrative, non-pharmacological interventions. This Phase II controlled trial aimed to evaluate the feasibility and preliminary efficacy of Heart Rate Variability Biofeedback (HRV-BF) in individuals with Long COVID who meet the diagnostic criteria for CFS/ME. Specific objectives included assessing feasibility indicators (drop-out rates, side effects, participant satisfaction) and changes in fatigue, depression, anxiety, pain, and health-related quality of life. Methods: Participants were assigned alternately and consecutively to the HRV-BF intervention or Treatment-as-usual (TAU), in a predefined 1:1 sequence (quasirandom assignment). The intervention consisted of 10 HRV-BF sessions, held twice weekly over 5 weeks, with each session including a 10 min respiratory preparation and 40 min of active training. Results: The overall drop-out rate was low (5.56%), and participants reported a generally high level of satisfaction. Regarding side effects, the mean total Simulator Sickness Questionnaire score was 24.31 (SD = 35.42), decreasing to 12.82 (SD = 15.24) after excluding an outlier. A significantly greater improvement in severe fatigue was observed in the experimental group (H = 4.083, p = 0.043). When considering all outcomes collectively, a tendency toward improvement was detected in the experimental group (binomial test, p < 0.0001). Conclusions: HRV-BF appears feasible and well tolerated. Findings support the need for Phase III trials to confirm its potential in mitigating fatigue in Long COVID. Full article

Chronic inflammatory response syndrome (CIRS) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) are debilitating multisystem illnesses that share overlapping symptoms and molecular patterns, including immune dysregulation, mitochondrial impairment, and vascular dysfunction. This review provides a chronological synthesis of biomarker development in CIRS, tracing its evolution from early functional tests such as visual contrast sensitivity (VCS) to advanced transcriptomic profiling. Drawing on peer-reviewed studies spanning two decades, we examine the layered integration of neuroendocrine, immunologic, metabolic, and genomic markers that collectively support a multisystem model of innate immune activation specific to environmentally acquired illness. Particular focus is given to the Gene Expression: Inflammation Explained (GENIE) platform’s use of transcriptomics to classify disease stages and distinguish CIRS from other fatiguing conditions. While ME/CFS research continues to explore overlapping pathophysiologic features, it has yet to establish a unified diagnostic model with validated biomarkers or exposure-linked mechanisms. As a result, many patients labeled with ME/CFS may, in fact, represent unrecognized CIRS cases. This review underscores the importance of structured biomarker timelines in improving differential diagnosis and guiding treatment in complex chronic illness and highlights the reproducibility of the CIRS framework in contrast to the diagnostic ambiguity surrounding ME/CFS. Full article

Background/Objectives: Fibromyalgia syndrome (FMS) is a chronic pain condition in which executive function (EF) alterations have been reported, though strikingly, relationships between simple executive functions (EFs) (updating, inhibition, and mental flexibility) and high-order ones, such as planning and problem-solving, have not been addressed yet in this population. This research aimed to firstly explore how low-level EFs play a role in planning and problem-solving performances. Methods: Thirty FMS patients and thirty healthy participants completed a series of neuropsychological tests evaluating low- and high-order EFs. Clinical and emotional symptoms were assessed with self-report questionnaires, while pain and fatigue levels were measured with numerical scales. Importantly, specific drug restrictions were accounted for. Results: Patients scored lower in most neurocognitive tests, with statistical significance noted only for visuospatial working memory (WM) and two planning and problem-solving tests. Pain, fatigue, and sleep disturbances showed important effects on most of the cognitive outcomes. Multiple regression analyses reflected that planning and problem-solving were successfully and partially predicted by updating, inhibition, and mental flexibility (though differences emerged between tasks). Conclusions: Our study confirms the presence of cognitive impairments in FMS, especially in high-order EFs, supporting patients’ complaints. Clinical symptoms play a role in FMS dyscognition but do not explain it completely. For the first time, as far as the authors know, simple EF influences on planning and problem-solving tests have been described for FMS patients. These results might help in unraveling the dysexecutive profile in FMS to design more adjusted treatment options. Full article

This narrative review examines the effects of caffeine on brain health in older adults, with particular attention to its potential for dependence—an often-overlooked issue in geriatric care. Caffeine acts on central adenosine, dopamine, and glutamate systems, producing both stimulating and rewarding effects that can foster tolerance and habitual use. Age-related pharmacokinetic and pharmacodynamic changes prolong caffeine’s half-life and increase physiological sensitivity in the elderly. While moderate consumption may enhance alertness, attention, and possibly offer neuroprotective effects—especially in Parkinson’s disease and Lewy body dementia—excessive or prolonged use may lead to anxiety, sleep disturbances, and cognitive or motor impairment. Chronic exposure induces neuroadaptive changes, such as adenosine receptor down-regulation, resulting in tolerance and withdrawal symptoms, including headache, irritability, and fatigue. These symptoms, often mistaken for typical aging complaints, may reflect a substance use disorder yet remain under-recognized due to caffeine’s cultural acceptance. The review explores caffeine’s mixed role in neurological disorders, being beneficial in some and potentially harmful in others, such as restless legs syndrome and frontotemporal dementia. Given the variability in individual responses and the underestimated risk of dependence, personalized caffeine intake guidelines are warranted. Future research should focus on the long-term cognitive effects and the clinical significance of caffeine use disorder in older populations. Full article

Post-viral conditions, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID (LC), share > 95% of their symptoms, but the connection between disturbances in their underlying molecular biology is unclear. This study investigates DNA methylation patterns in peripheral blood mononuclear cells (PBMC) from patients with ME/CFS, LC, and healthy controls (HC). Reduced Representation Bisulphite Sequencing (RRBS) was applied to the DNA of age- and sex-matched cohorts: ME/CFS (n = 5), LC (n = 5), and HC (n = 5). The global DNA methylomes of the three cohorts were similar and spread equally across all chromosomes, except the sex chromosomes, but there were distinct minor changes in the exons of the disease cohorts towards more hypermethylation. A principal component analysis (PCA) analysing significant methylation changes (p < 0.05) separated the ME/CFS, LC, and HC cohorts into three distinct clusters. Analysis with a limit of >10% methylation difference and at p < 0.05 identified 214 Differentially Methylated Fragments (DMF) in ME/CFS, and 429 in LC compared to HC. Of these, 118 DMFs were common to both cohorts. Those in promoters and exons were mainly hypermethylated, with a minority hypomethylated. There were rarer examples with either no change in methylation in ME/CFS but a change in LC, or a methylation change in ME/CFS but in the opposite direction in LC. The differential methylation in a number of fragments was significantly greater in the LC cohort than in the ME/CFS cohort. Our data reveal a generally shared epigenetic makeup between ME/CFS and LC but with specific, distinct changes. Differences between the two cohorts likely reflect the stage of the disease from onset (LC 1 year vs. ME/CFS 12 years), but specific changes imposed by the SARS-CoV-2 virus in the case of the LC patients cannot be discounted. These findings provide a foundation for further studies with larger cohorts at the same disease stage and for functional analyses to establish clinical relevance. Full article

Background/Objectives: The main objective of the present study is to assess the short-term effects of Forest Bathing (FB) conducted in a Mediterranean forest on individuals with fibromyalgia (FM) and/or chronic fatigue syndrome/myalgia encephalomyelitis (CFS/ME) on perceived pain, fatigue, state anxiety, positive and negative affect, mood states, and state mindfulness. Methods: A total of 44 participants with FM and/or CSF/ME agreed to participate in this study. The FB session consisted of a 3 km silent walk, lasting three hours and guided by a specialized psychologist and a mountain guide to guarantee the safety of the activity. Paired-sample t-tests were used to analyze the pre–post changes in perceived pain, fatigue, state anxiety, positive and negative affect, mood states, and mindfulness. Results: All reported variables but self-reported pain showed statistically significant pre–post variations after the FB session. Particularly, large-to-very-large improvements in positive and negative affect, state anxiety, tension, depression, anger, and vigor were found. Small-to-moderate effect sizes for fatigue, friendliness, and state mindfulness were also reported. Conclusions: This study provides preliminary evidence of the short-term benefits of FB in individuals with FM and/or CFS/ME, especially on state anxiety and negative affect. Full article

Background/Objectives: Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may report abnormalities in voice and speech; however, no formal research has been conducted in this area. Methods: An online mixed-methods survey was completed by 685 people with ME/CFS. A total of 302 respondents completed the qualitative component (44.09%). Questions assessed disease experience with ME/CFS and post-exertional malaise without prompting on specific symptoms. Within the qualitative results, a search of the terms “speech, voice,” “words,” and “speak” was conducted. Results: Excluding neurocognitive associations, colloquial phrases, and “speech therapy,” there were 38 mentions of the terms in the context of voice or speech changes across 28 unique qualitative survey responses (9.27%). Conclusions: A notable portion of respondents reported voice or speech changes when responding to open-ended qualitative questions about their disease experience. More research is needed regarding the implications of voice and speech anomalies in ME/CFS pathology and disease monitoring. Full article

Background: The gut microbiome is a key modulator of the gut–brain axis and may contribute to the pathophysiology of both gastrointestinal and systemic disorders. This study aimed to evaluate gut microbiota composition and tryptophan/phenylalanine metabolism in women with unclassified irritable bowel syndrome (IBS-U), with or without coexisting chronic fatigue syndrome (CFS). Methods: Eighty women were enrolled and divided into two groups: IBS-U without CFS (Group I, n = 40) and IBS-U with coexisting CFS (Group II, n = 40). Microbial composition and diversity were assessed using the GA-map™ Dysbiosis Test, including the dysbiosis index (DI) and Shannon Diversity Index (SDI). Hydrogen and methane levels were measured in breath samples. Urinary concentrations of selected microbial and neuroactive metabolites—homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), kynurenine (KYN), kynurenic acid (KYNA), xanthurenic acid (XA), quinolinic acid (QA), hydroxyphenylacetic acid (HPA), and 3-indoxyl sulfate (3-IS)—were quantified using LC-MS/MS. Fatigue severity was assessed using the Chalder Fatigue Questionnaire (CFQ-11) and the fatigue severity scale (FSS). Results: Compared to Group I, patients with IBS-CFS showed significantly greater microbial diversity, higher breath methane levels, and elevated urinary concentrations of QA, XA, 3-IS, and HVA, alongside lower concentrations of 5-HIAA and KYN. Fatigue severity was positively correlated with urinary XA and QA levels. Conclusions: Women with IBS and coexisting CFS exhibit distinct gut microbiota and tryptophan metabolite profiles compared to those without fatigue. The observed metabolite–symptom associations, particularly involving neuroactive kynurenine derivatives, warrant further investigation. These preliminary findings should be interpreted as hypothesis-generating and require validation through high-resolution microbiome analyses, functional pathway profiling, and longitudinal or interventional studies to clarify causality and clinical significance. Full article

The COVID-19 pandemic has revealed the profound and lasting impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the nervous system. Beyond acute infection, SARS-CoV-2 acts as a potent immunomodulatory agent, disrupting immune homeostasis and contributing to persistent inflammation, autoimmunity, and neurodegeneration. Long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC), is characterized by a spectrum of neurological symptoms, including cognitive dysfunction, fatigue, neuropathy, and mood disturbances. These are linked to immune dysregulation involving cytokine imbalance, blood–brain barrier (BBB) disruption, glial activation, and T-cell exhaustion. Key biomarkers such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NFL) correlate with disease severity and chronicity. This narrative review examines the immunopathological mechanisms underpinning the neurological sequelae of long COVID, focusing on neuroinflammation, endothelial dysfunction, and molecular mimicry. We also assess the role of viral variants in shaping neuroimmune outcomes and explore emerging diagnostic and therapeutic strategies, including biomarker-guided and immune-targeted interventions. By delineating how SARS-CoV-2 reshapes neuroimmune interactions, this review aims to support the development of precision-based diagnostics and targeted therapies for long COVID-related neurological dysfunction. Emerging approaches include immune-modulatory agents (e.g., anti-IL-6), neuroprotective drugs, and strategies for repurposing antiviral or anti-inflammatory compounds in neuro-COVID. Given the high prevalence of comorbidities, personalized therapies guided by biomarkers and patient-specific immune profiles may be essential. Advancements in vaccine technologies and targeted biologics may also hold promise for prevention and disease modification. Finally, continued interdisciplinary research is needed to clarify the complex virus–immune–brain axis in long COVID and inform effective clinical management. Full article

While there are many postulates for the etiology of post-viral chronic fatigue and other symptomatology, little is known. We draw on our past experience of these syndromes to devise means which can expose the primary players of this malady in terms of a panoply participating biomolecules and the state of the stool microbiome. Using databases established from a large dataset of patients at risk of colorectal cancer who were followed longitudinally over 3 decades, and a smaller database dedicated to building a Long PASC cohort (Post-Acute Sequelae of COVID-19), we were able to ascertain factors that predisposed patients to (and resulted in) significant changes in various biomarkers, i.e., the stool microbiome and serum cytokine levels, which we verified by collecting stool and serum samples. There were significant changes in the stool microbiome with an inversion from the usual Bacillota and Bacteroidota species. Serum cytokines showed significant differences in MIP-1β versus TARC (CC chemokine ligand 17) in patients with either PASC or COVID-19 (p < 0.02); IL10 versus IL-12p70a (p < 0.02); IL-1b versus IL-6 (p < 0.01); MCP1 versus TARC (p < 0.03); IL-8 versus TARC (p < 0.002); and Eotaxin3 versus TARC (p < 0.004) in PASC. Some changes were seen solely in COVID-19, including MDC versus MIP-1α (p < 0.01); TNF-α versus IL-1-β (p < 0.06); MCP4 versus TARC (p < 0.0001). We also show correlates with chronic fatigue where an etiology was not identified. These findings in patients with positive criteria for PASC show profound changes in the microbiome and serum cytokine expression. Patients with chronic fatigue without clear viral etiologies also have common associations, including a history of tonsillectomy, which evokes a likely immune etiology. Full article

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID are complex multisystem conditions that pose significant challenges in healthcare. Accumulated research evidence suggests that ME/CFS and Long COVID exhibit overlapping metabolic symptoms, indicating potential shared metabolic dysfunctions. This study aims to systematically explore shared metabolic disturbances in the muscle tissue of patients. Utilizing genome-wide metabolic modeling, we identified key metabolic irregularities in the muscle of patients with ME/CFS, notably the downregulation of the alanine and aspartate metabolism pathway and the arginine and proline metabolism pathway. Further, in silico knockout analyses suggested that supplementation with aspartate (ASP) or asparagine (ASN) could potentially ameliorate these metabolic deficiencies. In addition, assessments of metabolomic levels in Long COVID patients also showed the significant downregulation of ASP during post-exertional malaise (PEM) in both muscle and blood. Consequently, we propose that a combination of l-ornithine and l-aspartate (LOLA) is a potential candidate to alleviate metabolic symptoms in ME/CFS and Long COVID for future clinical trials. Full article

Systemic autoimmune rheumatic diseases (SARDs), such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjögren’s syndrome (SS), are traditionally characterized by chronic inflammation and immune-mediated damage to joints and other tissues. However, many patients also experience symptoms such as widespread pain, persistent fatigue, cognitive dysfunction, and autonomic disturbances that cannot be attributed directly or entirely to peripheral inflammation or structural pathology. These conditions suggest the involvement of interactions between the nervous and immune systems, which probably include both peripheral and central components. This review summarizes the current knowledge of neurological and neuroimmune mechanisms that may contribute to these symptoms in SARDs. Glial cell activation and neuroinflammation within the central nervous system (CNS), small-fiber neuropathy (SFN) affecting peripheral nociceptive pathways, central pain sensitization, and autonomic nervous system dysfunction will be discussed. In addition, the role of molecular mediators, including cytokines, neuropeptides, and microRNAs, that could potentially modulate neuroimmune signaling will be highlighted. Integrating findings from pathology, immunology, and neuroscience, this review seeks to provide a useful framework for understanding neuroimmune dysregulation in SARDs. It also highlights the clinical relevance of these mechanisms and summarizes new directions for diagnosis and treatment. Full article

Fibromyalgia is a syndrome that causes chronic musculoskeletal pain accompanied by symptoms such as fatigue, sleep disorders, headaches, anxiety, and depression. People diagnosed with fibromyalgia usually have higher levels of reactive oxygen species and lower antioxidant capacity compared to healthy individuals. This condition can contribute to elevated oxidative stress in the body, especially within the lipid-rich nervous system. Treatment with antioxidants through diet or supplements is one method being investigated to reduce the symptoms of fibromyalgia. This narrative review focuses on the latest research, specifically peer-reviewed publications within the last 10 years, on potential antioxidant treatments for patients with fibromyalgia. Relevant micronutrients, such as vitamin B12, vitamin D, and iron, and supplements such as melatonin, coenzyme Q, alpha-lipoic acid, and palmitoylethanolamide are discussed. Based on the current evidence, many of these antioxidants show potential for the management of fibromyalgia symptoms as standalone treatments or in combination with other antioxidants or pharmacological agents. More clinical research is required to understand the long-term efficacy and safety of these micronutrients and supplements, as well as their overall health impact. Full article

Background/Objectives: The aetiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a chronic and severe debilitating disease with a complex phenotype, remains elusive. Associations with infectious diseases and autoimmune and neuropsychiatric disorders have been observed, without the identification of mechanisms. Previous studies suggest that genetic predisposition plays a role, but results are difficult to replicate, with Genome-Wide Association Studies of ME/CFS being challenging due to the relative rareness and heterogeneity of the disorder. Methods: We studied a well-defined Australian patient cohort diagnosed via the International Consensus Criteria, recruited by a specialist ME/CFS clinic. The whole-exome sequences of 77 patients were contrasted against genome variation in the 1000 Genome Project’s genome-matched population. Results: Significant associations with ME/CFS were harboured in genes that belong to the Neuroblastoma Breakpoint Family encoding Olduvai (DUF1220) domains, namely NBPF1 (rs3897177, p-value = 3.15 × 10⁻⁸), NBPF10 (rs1553120233, p-value = 9.262 × 10⁻¹³), and NBPF16 (rs200632836, p-value = 1.04 × 10⁻⁶). Other significantly associated variants were detected in the ATR, RSPH10B, ADGRE5-CD97, and NTRK2 genes, among others. Replication of these results was attempted via a GWAS on raw data from a US cohort, which confirmed shared significant associations with variation identified in the PTPRD, CSMD3, RAPGEF5, DCC, ALDH18A1, GALNT16, UNC79, and NCOA3 genes. Conclusions: These genes are involved in cortical neurogenesis, brain evolution, and neuroblastoma, and have been implicated by several studies in schizophrenia and autism. The sharing of these associations by the two cohorts supports their validity and grants the necessity of future studies to evaluate the implications for ME/CFS aetiology. Full article