Tag: fatigue

NIH study offers new clues into the causes of post-infectious ME/CFS

Press Release:

In a detailed clinical study, researchers at the National Institutes of Health have found differences in the brains and immune systems of people with post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS). They also found distinct differences between men and women with the disease. The findings were published in Nature Communications.

“People with ME/CFS have very real and disabling symptoms, but uncovering their biological basis has been extremely difficult,” said Walter Koroshetz, M.D., director of NIH’s National Institute of Neurological Disorders and Stroke (NINDS). “This in-depth study of a small group of people found a number of factors that likely contribute to their ME/CFS. Now researchers can test whether these findings apply to a larger patient group and move towards identifying treatments that target core drivers of the disease.”

A team of multidisciplinary researchers discovered how feelings of fatigue are processed in the brains of people with ME/CFS. Results from functional magnetic resonance imaging (fMRI) brain scans showed that people with ME/CFS had lower activity in a brain region called the temporal-parietal junction (TPJ), which may cause fatigue by disrupting the way the brain decides how to exert effort.

They also analyzed spinal fluid collected from participants and found abnormally low levels of catecholamines and other molecules that help regulate the nervous system in people with ME/CFS compared to healthy controls. Reduced levels of certain catecholamines were associated with worse motor performance, effort-related behaviors, and cognitive symptoms. These findings, for the first time, suggest a link between specific abnormalities or imbalances in the brain and ME/CFS.

“We think that the immune activation is affecting the brain in various ways, causing biochemical changes and downstream effects like motor, autonomic, and cardiorespiratory dysfunction,” said Avindra Nath, M.D., clinical director at NINDS and senior author of the study.

Immune testing revealed that the ME/CFS group had higher levels of naive B cells and lower levels of switched memory B cells—cells that help the immune system fight off pathogens—in blood compared to healthy controls. Naive B cells are always present in the body and activate when they encounter any given antigen, a foreign substance that triggers the immune system. Memory B cells respond to a specific antigen and help maintain adaptive or acquired immunity. More studies are needed to determine how these immune markers relate to brain dysfunction and fatigue in ME/CFS.

To study fatigue, Dr. Nath and his team asked participants to make risk-based decisions about exerting physical effort. This allowed them to assess the cognitive aspects of fatigue, or how an individual decides how much effort to exert when given a choice. People with ME/CFS had difficulties with the effort choice task and with sustaining effort. The motor cortex, a brain region in charge of telling the body to move, also remained abnormally active during fatiguing tasks. There were no signs of muscle fatigue. This suggests that fatigue in ME/CFS could be caused by a dysfunction of brain regions that drive the motor cortex, such as the TPJ.

“We may have identified a physiological focal point for fatigue in this population,” said Brian Walitt, M.D., M.P.H., associate research physician at NINDS and first author of the study. “Rather than physical exhaustion or a lack of motivation, fatigue may arise from a mismatch between what someone thinks they can achieve and what their bodies perform.”

Deeper analyses revealed differences between men and women in gene expression patterns, immune cell populations, and metabolic markers. Males had altered T cell activation, as well as markers of innate immunity, while females had abnormal B cell and white blood cell growth patterns. Men and women also had distinct markers of inflammation.

“Men and women were quite divergent in their data, and that tells you that ME/CFS is not one-size-fits-all,” said Dr. Nath. “Considering male and female immune differences in ME/CFS, the results may open up new avenues of research that could provide insight into other infection-associated chronic diseases.”

The study, which was conducted at the NIH Clinical Center, took a comprehensive look at ME/CFS that developed after a viral or bacterial infection. The team used state-of-the-art techniques to examine 17 people with PI-ME/CFS who had been sick for less than five years and 21 healthy controls. Participants were screened and medically evaluated for ME/CFS over several days and underwent extensive tests, including clinical exams, fMRI brain imaging, physical and cognitive performance tests, autonomic function tests, skin and muscle biopsies, and advanced analyses of blood and spinal fluid. Participants also spent time in metabolic chambers where, under controlled conditions, their diet, energy consumption, metabolism, sleep patterns, and gut microbiome were evaluated. During a second visit, they completed a cardiopulmonary exercise test to measure the body’s response to exercise.

Many studies have identified immune, microbiome, and other abnormalities in ME/CFS, but the results tend to be inconsistent and exactly how these markers relate to or cause fatigue and other symptoms is unknown. By using a rigorous phenotyping approach to pull out meaningful differences, this study helps validate prior results and may identify new ways to target the brain or immune system therapeutically.

The highly collaborative project involved 75 investigators across 15 institutes and centers in the NIH Intramural Research Program, and at national and international institutions. Dr. Nath and his colleagues plan to publish additional findings from the data that was collected during this study.

The study was supported in part by the Intramural Research Program at the NIH.

Article:

Walitt, B., et al. “Deep phenotyping of Post-infectious Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.” Nature Communications. February 21, 2024. DOI: 10.1038/s41467-024-45107-3

NINDS is the nation’s leading funder of research on the brain and nervous system. The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.

Brain FADE syndrome: the final common pathway of chronic inflammation in neurological disease

Abstract:

Importance: While the understanding of inflammation in the pathogenesis of many neurological diseases is now accepted, this special commentary addresses the need to study chronic inflammation in the propagation of cognitive Fog, Asthenia, and Depression Related to Inflammation which we name Brain FADE syndrome. Patients with Brain FADE syndrome fall in the void between neurology and psychiatry because the depression, fatigue, and fog seen in these patients are not idiopathic, but instead due to organic, inflammation involved in neurological disease initiation.

Observations: A review of randomized clinical trials in stroke, multiple sclerosis, Parkinson’s disease, COVID, traumatic brain injury, and Alzheimer’s disease reveal a paucity of studies with any component of Brain FADE syndrome as a primary endpoint. Furthermore, despite the relatively well-accepted notion that inflammation is a critical driving factor in these disease pathologies, none have connected chronic inflammation to depression, fatigue, or fog despite over half of the patients suffering from them.

Conclusions and relevance: Brain FADE Syndrome is important and prevalent in the neurological diseases we examined. Classical “psychiatric medications” are insufficient to address Brain FADE Syndrome and a novel approach that utilizes sequential targeting of innate and adaptive immune responses should be studied.

Source: Khalid A. Hanafy, Tudor G. Jovin. Brain FADE syndrome: the final common pathway of chronic inflammation in neurological disease. Front. Immunol., 17 January 2024, Sec. Inflammation, Volume 15 – 2024 | https://doi.org/10.3389/fimmu.2024.1332776 https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1332776/full (Full text)

The role of clinical neurophysiology in the definition and assessment of fatigue and fatigability

Highlights:

  • Though a common symptom, fatigue is difficult to define and investigate, and occurs in a wide variety of disorders, with differing pathological causes.
  • This review aims to guide clinicians in how to approach fatigue and to suggest that neurophysiological tests may allow an understanding of its origin and severity.
  • The effectiveness of neurophysiological tests as cost-effective objective biomarkers for the assessment of fatigue has been summarised.

Abstract

Though a common symptom, fatigue is difficult to define and investigate, occurs in a wide variety of neurological and systemic disorders, with differing pathological causes. It is also often accompanied by a psychological component. As a symptom of long-term COVID-19 it has gained more attention.

In this review, we begin by differentiating fatigue, a perception, from fatigability, quantifiable through biomarkers. Central and peripheral nervous system and muscle disorders associated with these are summarised. We provide a comprehensive and objective framework to help identify potential causes of fatigue and fatigability in a given disease condition. It also considers the effectiveness of neurophysiological tests as objective biomarkers for its assessment. Among these, twitch interpolation, motor cortex stimulation, electroencephalography and magnetencephalography, and readiness potentials will be described for the assessment of central fatigability, and surface and needle electromyography (EMG), single fibre EMG and nerve conduction studies for the assessment of peripheral fatigability.

The purpose of this review is to guide clinicians in how to approach fatigue, and fatigability, and to suggest that neurophysiological tests may allow an understanding of their origin and interactions. In this way, their differing types and origins, and hence their possible differing treatments, may also be defined more clearly.

Source: Tankisi H, Versace V, Kuppuswamy A, Cole J. The role of clinical neurophysiology in the definition and assessment of fatigue and fatigability. Clin Neurophysiol Pract. 2023 Dec 18;9:39-50. doi: 10.1016/j.cnp.2023.12.004. PMID: 38274859; PMCID: PMC10808861. https://www.sciencedirect.com/science/article/pii/S2467981X23000367 (Full text)

A randomized open-label clinical trial on the effect of Amantadine on post Covid 19 fatigue

Abstract:

Many COVID-19 survivors experience lingering post-COVID-19 symptoms, notably chronic fatigue persisting for months after the acute phase. Despite its prevalence, limited research has explored effective treatments for post-COVID-19 fatigue. This randomized controlled clinical trial assessed the impact of Amantadine on patients with post-COVID-19 fatigue.

The intervention group received Amantadine for two weeks, while the control group received no treatment. Fatigue levels were assessed using the Visual Analog Fatigue Scale (VAFS) and Fatigue Severity Scale (FSS) questionnaires before and after the trial. At the study’s onset, VAFS mean scores were 7.90 ± 0.60 in the intervention group and 7.34 ± 0.58 in the control group (P-value = 0.087). After two weeks, intervention group scores dropped to 3.37 ± 0.44, significantly lower than the control group’s 5.97 ± 0.29 (P-value < 0.001). Similarly, FSS mean scores at the trial’s commencement were 53.10 ± 5.96 in the intervention group and 50.38 ± 4.88 in the control group (P-value = 0.053). At the trial’s end, intervention group scores decreased to 28.40 ± 2.42, markedly lower than the control group’s 42.59 ± 1.50 (P-value < 0.001).

In this study, we report the safety, tolerability, and substantial fatigue-relieving effects of Amantadine in post-COVID-19 fatigue. The intervention demonstrates a statistically significant reduction in fatigue levels, suggesting Amantadine’s potential as an effective treatment for this persistent condition.

Source: Harandi, A.A., Pakdaman, H., Medghalchi, A. et al. A randomized open-label clinical trial on the effect of Amantadine on post Covid 19 fatigue. Sci Rep 14, 1343 (2024). https://doi.org/10.1038/s41598-024-51904-z https://www.nature.com/articles/s41598-024-51904-z (Full text)

Frequency and characteristics of chronic fatigue syndrome in multiple sclerosis patients at a university hospital in Eastern Saudi Arabia

Abstract:

BACKGROUND: Multiple sclerosis (MS) is a chronic, inflammatory demyelinating disease that affects various parts of the central nervous system. Fatigue, a common symptom, transient, prolonged, or chronic experienced by individuals with MS, can significantly impact daily functioning. It can be associated with underlying pathological processes or can have an idiopathic cause, such as chronic fatigue syndrome (CFS). The study aimed to assess the presence and etiology of fatigue in MS patients and its relationship with CFS.

MATERIALS AND METHODS: This cross-sectional study was conducted in the Eastern Province of Saudi Arabia. Data were collected using a questionnaire from a sample of 225 MS patients receiving care at our university hospital. The questionnaire included the Centers for Disease Control and Prevention (CDC) criteria for diagnosing CFS and the Expanded Disability Status Scale to evaluate fatigue in MS patients.

RESULTS: Of the total of 225 MS patients who participated in this study, 87.1% were diagnosed with relapsing-remitting MS, 6.7% with primary progressive MS, 3.6% with clinically isolated syndrome, and 2.7% with secondary progressive MS. About 53% had experienced fatigue that persisted for over 6 months. Analysis of CFS diagnosis revealed that 7.3% of patients met both CDC criteria and self-reported answers while 17.5% reported having CFS despite not meeting the CDC criteria. These findings highlight a significant lack of agreement between patient-reported diagnoses and established criteria, indicating poor agreement (P = 0.028).

CONCLUSION: The study found an association between CFS and MS, and a significant impact on daily functioning. The study revealed lack of agreement between patient-reported diagnoses and established criteria for CFS. This emphasizes the need for a standardized approach to diagnosis and evaluation of fatigue in MS patients.

Source: AlAmri, Abdullah S.; AlShamrani, Foziah J.; AlMohish, Noor M.; Zafar, Azra S.; Alnaaim, Saud A.1; Alazman, Hatem A.; Al-Ghanimi, Ibrahim A.2; AlNahdi, Abdullah A.; AlDawsari, Fahad A.; AlMatrafi, Shahad B.3; Alzahrani, Ghaida R.3; Alnamlah, Muna S.; Alkhalifa, Rawan A.. Frequency and characteristics of chronic fatigue syndrome in multiple sclerosis patients at a university hospital in Eastern Saudi Arabia. Journal of Family and Community Medicine 31(1):p 63-70, Jan–Mar 2024. | DOI: 10.4103/jfcm.jfcm_73_23 https://journals.lww.com/jfcm/fulltext/2024/31010/frequency_and_characteristics_of_chronic_fatigue.9.aspx (Full text)

Acupoint massage at Shenque (CV 8) for chronic fatigue syndrome: a randomized controlled trial

Abstract:

in English, Chinese

Objectives: To observe the clinical efficacy of acupoint massage at Shenque (CV 8) for chronic fatigue syndrome (CFS).

Methods: A total of 71 patients with CFS were randomized into an observation group (36 cases, 2 cases were eliminated, 3 cases dropped out) and a control group (35 cases). Using a specially made massage instrument, acupoint massage was adopted at the the five points of Shenque (CV 8), i.e. the center and the upper, lower, left, and right parts of the inner wall. The manipulation was given 10 min a time, once every 2 days, 3 times a week for 4 weeks continuously. No intervention was delivered in the control group. Before and after treatment, the scores of fatigue scale-14 (FS-14) and Pittsburgh sleep quality index (PSQI) were observed, and the clinical efficacy was evaluated in the both groups.

Results: After treatment, the physical fatigue and mental fatigue scores, as well as the total score of FS-14 were decreased compared with those before treatment in the observation group (P<0.001); the above scores in the observation group were lower than those in the control group (P<0.001). After treatment, excepted for the sleep time and hypnotic scores, the remaining item scores and the total score of PSQI were decreased compared with those before treatment in the observation group (P<0.05); the each item score and the total score of PSQI were lower than those in the control group (P<0.05). The total effective rate in the observation group was superior to that in the control group (P<0.01).

Conclusions: Acupoint massage at Shenque (CV 8) can effectively improve the fatigue state and sleep quality in patients with chronic fatigue syndrome.

Source: Li Z, Ji R, Yan C, Chen Y, Cao Z, Wang J. Acupoint massage at Shenque (CV 8) for chronic fatigue syndrome: a randomized controlled trial. Zhongguo Zhen Jiu. 2023 Jan 12;44(1):67-70. English, Chinese. doi: 10.13703/j.0255-2930.20230307-0002. PMID: 38191162. https://pubmed.ncbi.nlm.nih.gov/38191162/

Post Viral Pain, Fatigue, and Sleep Disturbance Syndromes: Current knowledge and Future Directions

Abstract:

Post-viral pain syndrome, also known as post-viral syndrome (PVS), is a complex condition characterized by persistent pain, fatigue, musculoskeletal pain, neuropathic pain, neurocognitive difficulties, and sleep disturbances1,2 that can occur after an individual has recovered from a viral infection. Much remains unknown regarding the pathophysiology of post-viral syndromes and few studies have provided a comprehensive summary of the condition, agents that cause it, and successful treatment modalities.

With the COVID-19 pandemic continuing to affect millions of people worldwide, the need for understanding the etiology of post-viral illness and how to help individuals cope with the sequalae is paramount.2 This narrative review provides a summary of the sequelae of post-viral syndromes, viral agents that cause it, the pathophysiology, treatment, and future considerations for research and targeted therapies.

Source: Caleb Tackey, P. Maxwell Slepian, Hance Clarke & Nimish Mittal (2023) Post Viral Pain, Fatigue, and Sleep Disturbance Syndromes: Current knowledge and Future Directions, Canadian Journal of Pain, DOI: 10.1080/24740527.2023.2272999 https://www.tandfonline.com/doi/full/10.1080/24740527.2023.2272999 (Full text)

Integrated ‘omics analysis for the gut microbiota response to moxibustion in a rat model of chronic fatigue syndrome

Abstract:

Objective: To observe the efficacy of moxibustion in the treatment of chronic fatigue syndrome (CFS) and explore the effects on gut microbiota and metabolic profiles.

Methods: Forty-eight male Sprague-Dawley rats were randomly assigned to control group (Con), CFS model group (Mod, established by multiple chronic stress for 35 d), MoxA group (CFS model with moxibustion Shenque (CV8) and Guanyuan (CV4), 10 min/d, 28 d) and MoxB group (CFS model with moxibustion Zusanli (ST36), 10 min/d, 28 d).

Open-field test (OFT) and Morris-water-maze test (MWMT) were determined for assessment the CFS model and the therapeutic effects of moxibustion.16S rRNA gene sequencing analysis based gut microbiota integrated untargeted liquid chromatograph-mass spectrometer (LC-MS) based fecal metabolomics were executed, as well as Spearman correlation analysis, was utilized to uncover the functional relevance between the potential metabolites and gut microbiota.

Results: The results of our behavioral tests showed that moxibustion improved the performance of CFS rats in the OFT and the MWMT. Microbiome profiling analysis revealed that the gut microbiomes of CFS rats were less diverse with altered composition, including increases in pro-inflammatory species (such as Proteobacteria) and decreases in anti-inflammatory species (such as Bacteroides, Lactobacillus, Ruminococcus, and Prevotella). Moxibustion partially normalized these changes in the gut microbiota.

Furthermore, CFS was associated with metabolic disorders, which were effectively ameliorated by moxibustion. This was demonstrated by the normalization of 33 microbiota-related metabolites, including mannose (P = 0.001), aspartic acid (P = 0.009), alanine (P = 0.007), serine (P = 0.000), threonine (P = 0.027), methionine (P = 0.023), 5-hydroxytryptamine (P = 0.008), alpha-linolenic acid (P = 0.003), eicosapentaenoic acid (P = 0.006), hypoxanthine (P = 0.000), vitamin B6 (P = 0.000), cholic acid (P = 0.013), and taurocholate (P = 0.002).

Correlation analysis showed a significant association between the perturbed fecal microbiota and metabolite levels, with a notable negative relationship between LCA and Bacteroides.

Conclusions: In this study, we demonstrated that moxibustion has an antifatigue-like effect. The results from the 16S rRNA gene sequencing and metabolomics analysis suggest that the therapeutic effects of moxibustion on CFS are related to the regulation of gut microorganisms and their metabolites. The increase in Bacteroides and decrease in LCA may be key targets for the moxibustion treatment of CFS.

Source: Chaoran LI, Yan Y, Chuwen F, Heng LI, Yuanyuan QU, Yulin W, Delong W, Qingyong W, Jing G, Tianyu S, Xiaowei S, Xue W, Yunlong H, Zhongren S, Tiansong Y. Integrated ‘omics analysis for the gut microbiota response to moxibustion in a rat model of chronic fatigue syndrome. J Tradit Chin Med. 2023 Oct;43(6):1176-1189. doi: 10.19852/j.cnki.jtcm.20231018.004. PMID: 37946480; PMCID: PMC10623263. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10623263/ (Full text)

Fatigue in post COVID-19 patients: the P4O2 COVID-19 study

Abstract:

Background: Some patients do not fully recover after COVID-19 and have symptoms occurring 3 months after acute illness, lasting for >2 months, defined as post COVID-19. Fatigue seems most present in post COVID-19 and part of the patients might develop symptoms similar to chronic fatigue syndrome.

Aim: To determine the occurrence of fatigue and other symptoms in post COVID-19 patients.

Methods: In the prospective P4O2 COVID-19 cohort, post COVID-19 patients aged 40-65 years were recruited from outpatient post-COVID clinics in 5 Dutch hospitals between May 2021-September 2022. At 3-6 months post-COVID, patients completed the Fatigue Severity Scale (FSS). If the FSS score was ≥4 (the cut-off for severe fatigue), patients also completed the DePaul Symptom Questionnaire version 2 (DSQ-2). The FSS ranges from 1-7 and a higher score means more fatigued. The DSQ-2 rates frequency and severity of 79 symptoms on a 5-point Likert scale. Binary thresholds (if scored ≥2 on both severity and frequency, the threshold is met and the symptom is present) were calculated.

Results: The mean age of the 78 included patients was 53.9±6.2 and 51.7% were male. Median (IQR) FSS score was 5.6 (4.2-6.3) and 66 patients (84.6%) had a score ≥4. According to the DSQ-2 (n=61), patients reported a median (IQR) of 16 (8-23) symptoms. The majority of the patients experienced fatigue (85%). Furthermore, post-exertional malaise (PEM) (40%), sleep-related problems (37%), pain (21%) and neurocognitive problems (23%) were frequently reported.

Conclusion: The occurrence of severe fatigue 3-6 months after COVID-19 was 84.6% in our cohort. Patients with severe fatigue also frequently reported PEM, sleep related problems, pain and neurocognitive problems.

Source: Merel E.B. Cornelissen, Lizan D. Bloemsma, Nadia Baalbaki, Somayeh Bazdar, Jelle M. Blankestijn, Inés Beekers, Rosanne J.H.C.G. Beijers, Joop P. Van Den Bergh, Debbie Gach, J.J. Miranda Geelhoed, Sebastiaan Holverda, Laura Houweling, John J. Jacobs, Renée Jonker, Ivo Van Der Lee, Paulien M.A. Linders, Lieke C.E. Noij, Esther J. Nossent, Marianne A. Van De Pol, Daphne W. Schaminee, Annemie M.W.J. Schols, Lisanne T. Schuurman, Brigitte Sondermeijer, Anouk W. Vaes, Els J.M. Weersink, Yolanda De Wit-Van Wijck, Martijn A. Spruit, Anke H. Maitland-Van Der Zee. Fatigue in post COVID-19 patients: the P4O2 COVID-19 study. European Respiratory Journal 2023 62: PA4574; DOI: 10.1183/13993003.congress-2023.PA4574 https://erj.ersjournals.com/content/62/suppl_67/PA4574.abstract

Fatigue, chronic fatigue syndrome and migraine: Intersecting the lines through a cross-sectional study in patients with episodic and chronic migraine

Abstract:

Objectives: Fatigue is a common symptom occurring in a variety of disorders. Chronic fatigue syndrome (CFS) is characterized by debilitating fatigue as the core symptom. The risk of CFS is nearly 1.5 times higher in migraine while headaches have been reported in 59% of cases with CFS. However, details of its occurrence and severity remain largely unexplored.

The primary objective of our study was to determine the occurrence and severity of fatigue and CFS in patients with episodic and chronic migraine. The secondary objectives were to define their relationship with other common comorbidities.

Materials and methods: 60 migraine patients (30 each, episodic [EM] and chronic migraine [CM]) were recruited from Neurology Outpatient Department, GIPMER a tertiary referral center in New Delhi, India. Patients’ headache severity was analyzed using the Headache impact test-6 (HIT-6) score while fatigue and other migraine accompaniments were assessed using Fatigue severity scale (FSS), Chalder fatigue scale, CDC diagnostic criteria for CFS, American College of Rheumatology Diagnostic Criteria for fibromyalgia, Hamilton Depression Scale, the Generalized Anxiety Disorder 7-Item Scale, and Epworth sleepiness Scale (ESS). Comparative analysis was further done among migraine patients with and without fatigue and CFS.

Results: The mean HIT-6 score was significantly higher in CM versus EM. The CM group had a higher mean FSS score (47.87 vs. 37.3 in EM; P = 0.004), a percentage of patients with severe fatigue (60% vs. 20% in EM; P = 0.004), and a higher percentage of patients with pathological fatigue (83.3% vs. 63.3% in EM; P = 0.04). Around 23.33% of CM patients fulfilled the criteria of CFS. Fatigue correlated positively with severity, frequency, attack duration and chronicity of the migraine episodes, along with depression, anxiety, and excessive daytime sleepiness.

Conclusion: Fatigue and related comorbid disorders are significantly more common in CM than in EM, expanding the morbidity of the condition and underscores the need to address these accompanying symptoms for devising a holistic treatment plan.

Source: Kumar H, Dhamija K, Duggal A, Khwaja GA, Roshan S. Fatigue, chronic fatigue syndrome and migraine: Intersecting the lines through a cross-sectional study in patients with episodic and chronic migraine. J Neurosci Rural Pract. 2023 Jul-Sep;14(3):424-431. doi: 10.25259/JNRP_63_2022. Epub 2023 Apr 20. PMID: 37692810; PMCID: PMC10483198. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10483198/ (Full text)