Intra brainstem connectivity is impaired in chronic fatigue syndrome, by Leighton R Barnden, Zack Y Shan, Donald R Staines, Sonya Marshall-Gradisnik, Kevin Finegan, Timothy Ireland, Sandeep Bhuta, inNeuroImage: Clinical Vol 24, 2019, [https://doi.org/10.1016/j.nicl.2019.102045]
Research highlights:
RAS connectivity was detected in HC and CFS groups both during rest and task.
Strong connections were active for CFS from hippocampus to midbrain and medulla.
RAS connectivity was diminished in CFS in the brainstem and to the hippocampus.
RAS nuclei generate oscillatory signals which facilitate thalamocortical signal coherence.
Impaired RAS affects cortical coherence necessary for attention, memory and problem solving.
Research abstract:
Brain stem highlighted
In myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), abnormal MRI correlations with symptom severity and autonomic measures have suggested impaired nerve signal conduction within the brainstem.
Here we analyse fMRI correlations to directly test connectivity within and from the brainstem. Resting and task functional MRI (fMRI) were acquired for 45 ME/CFS (Fukuda criteria) and 27 healthy controls (HC).
We selected limited brainstem reticular activation system (RAS) regions-of-interest (ROIs) based on previous structural MRI findings in a different ME/CFS cohort (bilateral rostral medulla and midbrain cuneiform nucleus), the dorsal Raphe nucleus, and two subcortical ROIs (hippocampus subiculum and thalamus intralaminar nucleus) reported to have rich brainstem connections.
When HC and ME/CFS were analysed separately, significant correlations were detected for both groups during both rest and task, with stronger correlations during task than rest. Strong hippocampal connections with midbrain and medulla nuclei were detected for ME/CFS. When corresponding correlations from HC and ME/CFS were compared, ME/CFS connectivity deficits were detected within the brainstem between the medulla and cuneiform nucleus and between the brainstem and hippocampus and intralaminar thalamus, but only during task.
In CFS/ME, weaker connectivity between some RAS nuclei was associated with increased symptom severity. RAS neuron oscillatory signals facilitate coherence in thalamo-cortical oscillations.
Brainstem RAS connectivity deficits can explain autonomic changes and diminish cortical oscillatory coherence which can impair attention, memory, cognitive function, sleep quality and muscle tone, all symptoms of ME/CFS.
Myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) are controversial chronic illnesses with a myriad of debilitating symptoms. This study aimed to explore physician referrals to psychiatrists or psychologists, perceived stigma, and estrangement for patients with ME and CFS.
Findings indicate that patients who have been referred to psychiatrists are likely to perceive illness stigma and feel estranged from others due to their illness. These relationships are moderated by the country of residence, the United States and the United Kingdom. The implications of physician referrals for people with ME and CFS are discussed.
Discussion:
The present findings indicate that patients with ME and CFS who have been referred to psychiatrists are likely to perceive illness stigma and feel estranged from others due to their illness. As previous studies have shown a high propensity of patients with ME and CFS to be misdiagnosed with a psychiatric condition (Deale & Wessely, 2000), these referrals are likely a cause of anxiety and stigma for the patient receiving them. The relationship between psychiatric referral and estrangement was mediated by perceived stigma, yet the impact was stronger for the British sample than the American sample.
Despite the different mediation model outcomes due to the moderation effect of country, all three variables correlate with one another for individuals from both countries. These findings corroborate the qualitative accounts that have been reported in previous literature (Åsbring & Närvänen, 2002; Dickson et al., 2007; Jason, Taylor, Plioplys, Stepanek, & Shlaes, 2002), which suggest that physician attitudes related to stigma and estrangement of individuals with ME and CFS.
Findings indicated that patients are at risk for estrangement and high stigma. Stigma can impair help-seeking and predict mental health challenges (Clement et al., 2015; McManimen et al., 2018). Estrangement is also a risk factor for patients because socially isolated individuals may experience loneliness, and loneliness predicts subsequent depression (Cacioppo, Hawkley, & Thisted, 2010; Matthews et al., 2016). Thus, individuals with chronic illness who feel estranged may be at risk for depression (Cacioppo et al., 2010), as well as early mortality (Smith, Jackson, Kobayashi, & Steptoe, 2018).
The differences between the American and British models may, in part, be explained by different illness profiles and cultural differences. British individuals experience more severe symptomology than Americans across several indicators (Zdunek et al., 2015), which may impact their experiences with healthcare providers and peers. It is possible that a patient with more severe symptoms may be treated more negatively by physicians than someone with less severe symptoms, especially if the physician upholds a stigmatizing view of the illness.
Another possibility may be due to differences in diagnostic and treatment guidelines between the two countries. In the United Kingdom, the National Institute for Health and Care Excellence (NICE) guidelines for ME and CFS stipulate the cognitive behavioural therapy (CBT) and graded exercise treatment (GET) should be part of the treatment program for patients with ME and CFS (https://www.nice.org.uk/guidance/cg53/chapter/1-Guidance#diagnosis)…
While this has positive outcomes for patients with depression, patients report that GET often exacerbate symptoms and leaves them feeling more fatigued and more ill than before (Wilshire et al., 2018; Maes & Twisk, 2010). CBT has had more mixed findings, but it has been demonstrated that CBT’s effectiveness is directly tied to patient comorbid diagnosis of depression (Sunnquist & Jason, 2018).
While these guidelines are in place for U.K. practitioners, the Institute of Medicine in the U.S. does not have specific guidelines for treating ME or CFS. Attitudes toward the illness and treatment likely differ in Britain compared to America due to these nuanced sets of differences, as has been demonstrated with attitudes toward the cause of ME and CFS (Zdunek et al., 2015). These outcomes highlight the importance of co-production in patient healthcare, as stigmatization in patient healthcare can be reduced through the involvement of patients in planning and implementing their treatment and outcome options (Turakhia & Combs, 2017).
Community psychologists can use these findings to identify patients who may be at risk for further social and family estrangement due to false positive referrals, and to help administer proper therapies aimed at reintegration into social settings that negate perceived stigma.
In summation, physician treatment, societal stigma, and the social estrangement of individuals with ME and CFS are interconnected in our two samples of patients. Findings indicate that referral to psychiatric treatment can be damaging when prescribed to someone as a means of dismissing physical complaints. Physicians can utilize a shared decision making treatment model to treat patients with ME and CFS (Bieber et al., 2008). This method involves mutual exchange of information between the doctor and patient, as the doctor holds medical knowledge and the patient holds knowledge about individual health experiences. This model has been effective for those with chronic invisible illnesses and may better allow physicians to aid patients who feel their symptoms are physical and not psychological (Bieber et al., 2008). By remaining sensitive, physicians, friends, and family can aim to improve the lives of those with ME and CFS.
a) there is a strong co-occurrence between major depression and chronic fatigue syndrome (CFS), with fatigue and physio-somatic symptoms being key symptoms of depression, and depressive symptoms appearing during the course of CFS; and
b) the comorbidity between both disorders may in part be explained by activated immune-inflammatory pathways, including increased translocation of Gram-negative bacteria and increased levels of pro-inflammatory cytokines, such as interleukin (IL)-1.
Nevertheless, the possible involvement of activated microglia in this comorbidity has remained unclear. This paper aims to review microglial disturbances in major depression, CFS and their comorbidity.
A comprehensive literature search was conducted using the PubMed / MEDLINE database to identify studies, which are relevant to this current review. Depressed patients present neuroinflammatory alterations, probably related to microglial activation, while animal models show that a microglial response to immune challenges including lipopolysaccharides is accompanied by depressive-like behaviors.
Recent evidence from preclinical studies indicates that activated microglia have a key role in the onset of fatigue. In chronic inflammatory conditions, such as infections and senescence, microglia orchestrate an inflammatory microenvironment thereby causing fatigue.
In conclusion, based on our review we may posit that shared immune-inflammatory pathways and especially activated microglia underpin comorbid depression and CFS. As such, microglial activation and neuro-inflammation may be promising targets to treat the overlapping manifestations of both depression and CFS.
Fibromyalgia is a disorder characterized by chronic widespread pain and non-pain symptoms, such as fatigue, dysautonomia, and cognitive and sleep disturbances. Its pathogenesis and treatment continue to be the subject of debate.
We highlight the role of three mechanisms—autoimmunity, neuroinflammation, and small fiber neuropathy—in the pathogenesis of the disease. These mechanisms are shown to be closely interlinked (also on a molecular level), and the review considers the implementation of this relationship in the search for therapeutic options.
Hypothalamus in brain
We also pay attention to chronic fatigue syndrome, which overlaps with fibromyalgia, and propose a concept of “autoimmune hypothalamopathy” for its pathogenesis.
Finally, we analyze the molecular mechanisms underlying the neuroinflammatory background in the development of adverse events following HPV vaccination and suggesting neuroinflammation, which could exacerbate the development of symptoms following HPV vaccination (though this is hotly debated), as a model for fibromyalgia pathogenesis.
Open trial of Vitamin B12 nasal drops in adults with Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome: comparison of responders and non-responders, by C (Linda) MC van Campen, Klaas Riepma and Frans C Visser in Frontiers in Pharmacology, 20 September 2019 [ https://doi.org/10.3389/fphar.2019.01102]
Research abstract:
Introduction:
A recent study reported a favorable effect of vitamin B12 injections/oral folic acid support in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients. Recently, vitamin B12 nasal drops were developed as an alternative to the vitamin B12 injections. As no data are available on efficacy of this formulation, we studied vitamin B12 serum levels, the physical activity scale of the RAND-36, the number of steps on an activity meter, and the fatigue and concentration scales of the CIS20r questionnaires, before and after 3 months of treatment in ME/CFS patients.
Methods and Results:
Fifty-one patients completed all measurements. Forty-four were female. Mean age was 42 years, and mean disease duration was 16 years. Median vitamin B12 levels before treatment were 328 (244–429) pmol/l, and 973 (476–1,476) pmol/l after treatment. Thirty-four patients reported a favorable response to treatment. In the non-responders, only a small but significant increase in vitamin B12 levels was observed. In contrast, in responders, the number of steps, the physical activity scale of the RAND-36, and the vitamin B12 serum levels increased significantly. The CIS20r fatigue scale decreased significantly, and the CIS20r concentration scale was unchanged.
Conclusions:
Nasal drop vitamin B12 administration resulted in a significant increase in vitamin B12 serum levels and therefore may be effective. This pilot study suggest that the nasal drops may be used as an alternative to injections because two thirds of ME/CFS patients reported a positive effect, accompanied by an increased number of steps, improvement of the RAND-36 physical functioning scale and the CIS20r fatigue scale, and a significant increase in serum vitamin B12 levels.
There is a strong demand for therapeutics to treat chronic fatigue syndrome (CFS), although there are limitations. Myelophil, which is a combination of extracts from Astragali Radix and Salviae Miltiorrhizae Radix, has been clinically used to treat fatigue-related disorders in South Korea. We conducted a randomized controlled clinical trial of Myelophil in patients with CFS and evaluated its efficacy and safety in two hospitals.
Methods:
We enrolled 98 participants (M: 38, F: 60) with CFS in a phase 2 trial of oral Myelophil (2 g daily) or placebo for 12 weeks. The primary end point was a change in the Chalder fatigue scale, as scored by a numeric rating scale (NRS). The secondary end points included changes in the visual analogue scale, fatigue severity scale (FSS), and 36-item short-form health survey (SF-36). Biomarkers of oxidative stress and cytokines were evaluated by blood tests.
Results:
Ninety-seven participants (48 in the Myelophil group and 49 in the placebo group) completed the trial. An analysis of all participants showed that Myelophil slightly improved fatigue symptoms compared with those of the placebo, but this effect was not statistically significant (p > 0.05 for the NRS, VAS, FSS, and SF-36). By contrast, an analysis of the subpopulation (53 participants, M: 24, F: 29) with severe symptoms (≥63, median NRS value of total participants) showed a statistically significant improvement in fatigue symptoms in the Myelophil group compared with the placebo (p < 0.05 for NRS, FSS, and SF-36). There were no significant changes in the biomarkers for oxidative stress and cytokines before or after the treatment. No Myelophil-related adverse response was observed during the trial.
Conclusion:
These results support the hypothesis that Myelophil can be a therapeutic candidate to manage CFS and provide the rationale for its progression to a phase 3 clinical trial.
WAMES statement: The revised Cochrane review on exercise therapy for ME & CFS has taken positive steps to acknowledge the limitations of the research into exercise therapy that they previously promoted, and especially the lack of research into potential harms. We welcome the decision to produce a full update and review of the protocol but we are concerned that the interim review still concludes that GET “probably has a positive effect on fatigue in adults with CFS compared to usual care or passive therapies.” Research into the effect of exercise on people with ME clearly shows scientifically measurable adverse effects on many of the body’s systems. To deliver a conclusion without taking into account this research is negligent and misleading.
Exercise therapy for chronic fatigue syndrome, by Lillebeth Larun, Kjetil G Brurberg, Jan Odgaard‐Jensen, Jonathan R Price inThe Cochrane Database of Systematic Reviews, 2 Oct 2019
Research abstract
Background:
Chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME) is a serious disorder characterised by persistent postexertional fatigue and substantial symptoms related to cognitive, immune and autonomous dysfunction. There is no specific diagnostic test, therefore diagnostic criteria are used to diagnose CFS.
The prevalence of CFS varies by type of diagnostic criteria used. Existing treatment strategies primarily aim to relieve symptoms and improve function. One treatment option is exercise therapy.
Objectives:
The objective of this review was to determine the effects of exercise therapy for adults with CFS compared with any other intervention or control on fatigue, adverse outcomes, pain, physical functioning, quality of life, mood disorders, sleep, self‐perceived changes in overall health, health service resources use and dropout.
Search methods:
We searched the Cochrane Common Mental Disorders Group controlled trials register, CENTRAL, and SPORTDiscus up to May 2014, using a comprehensive list of free‐text terms for CFS and exercise. We located unpublished and ongoing studies through the World Health Organization International Clinical Trials Registry Platform up to May 2014. We screened reference lists of retrieved articles and contacted experts in the field for additional studies.
Selection criteria:
We included randomised controlled trials (RCTs) about adults with a primary diagnosis of CFS, from all diagnostic criteria, who were able to participate in exercise therapy.
Data collection and analysis:
Two review authors independently performed study selection, ‘Risk of bias’ assessments and data extraction. We combined continuous measures of outcomes using mean differences (MDs) or standardised mean differences (SMDs). To facilitate interpretation of SMDs, we re‐expressed SMD estimates as MDs on more common measurement scales. We combined dichotomous outcomes using risk ratios (RRs). We assessed the certainty of evidence using GRADE.
Main results:
We included eight RCTs with data from 1518 participants.
Exercise therapy lasted from 12 weeks to 26 weeks. The studies measured effect at the end of the treatment and at long‐term follow‐up, after 50 weeks or 72 weeks.
Seven studies used aerobic exercise therapies such as walking, swimming, cycling or dancing, provided at mixed levels in terms of intensity of the aerobic exercise from very low to quite rigorous, and one study used anaerobic exercise. Control groups consisted of passive control, including treatment as usual, relaxation or flexibility (eight studies); cognitive behavioural therapy (CBT) (two studies); cognitive therapy (one study); supportive listening (one study); pacing (one study); pharmacological treatment (one study) and combination treatment (one study).
Most studies had a low risk of selection bias. All had a high risk of performance and detection bias.
Exercise therapy compared with ‘passive’ control:
Exercise therapy probably reduces fatigue at end of treatment (SMD −0.66, 95% CI −1.01 to −0.31; 7 studies, 840 participants; moderate‐certainty evidence; re‐expressed MD −3.4, 95% CI −5.3 to −1.6; scale 0 to 33). We are uncertain if fatigue is reduced in the long term because the certainty of the evidence is very low (SMD −0.62, 95 % CI −1.32 to 0.07; 4 studies, 670 participants; re‐expressed MD −3.2, 95% CI −6.9 to 0.4; scale 0 to 33).
We are uncertain about the risk of serious adverse reactions because the certainty of the evidence is very low (RR 0.99, 95% CI 0.14 to 6.97; 1 study, 319 participants).
Exercise therapy may moderately improve physical functioning at end of treatment, but the long‐term effect is uncertain because the certainty of the evidence is very low. Exercise therapy may also slightly improve sleep at end of treatment and at long term. The effect of exercise therapy on pain, quality of life and depression is uncertain because evidence is missing or of very low certainty.
Exercise therapy compared with CBT:
Exercise therapy may make little or no difference to fatigue at end of treatment (MD 0.20, 95% CI ‐1.49 to 1.89; 1 study, 298 participants; low‐certainty evidence), or at long‐term follow‐up (SMD 0.07, 95% CI −0.13 to 0.28; 2 studies, 351 participants; moderate‐certainty evidence).
We are uncertain about the risk of serious adverse reactions because the certainty of the evidence is very low (RR 0.67, 95% CI 0.11 to 3.96; 1 study, 321 participants).
The available evidence suggests that there may be little or no difference between exercise therapy and CBT in physical functioning or sleep (low‐certainty evidence) and probably little or no difference in the effect on depression (moderate‐certainty evidence). We are uncertain if exercise therapy compared to CBT improves quality of life or reduces pain because the evidence is of very low certainty.
Exercise therapy compared with adaptive pacing:
Exercise therapy may slightly reduce fatigue at end of treatment (MD −2.00, 95% CI −3.57 to −0.43; scale 0 to 33; 1 study, 305 participants; low‐certainty evidence) and at long‐term follow‐up (MD −2.50, 95% CI −4.16 to −0.84; scale 0 to 33; 1 study, 307 participants; low‐certainty evidence).
We are uncertain about the risk of serious adverse reactions (RR 0.99, 95% CI 0.14 to 6..97; 1 study, 319 participants; very low‐certainty evidence).
The available evidence suggests that exercise therapy may slightly improve physical functioning, depression and sleep compared to adaptive pacing (low‐certainty evidence). No studies reported quality of life or pain.
Exercise therapy compared with antidepressants:
We are uncertain if exercise therapy, alone or in combination with antidepressants, reduces fatigue and depression more than antidepressant alone, as the certainty of the evidence is very low. The one included study did not report on adverse reactions, pain, physical functioning, quality of life, sleep or long‐term results.
Why is this review important?
Exercise therapy is recommended by treatment guidelines and often used as treatment for people with chronic fatigue syndrome. People with chronic fatigue syndrome should have the opportunity to make informed decisions about their care and treatment based on robust research evidence and whether exercise therapy is effective, either as a stand‐alone intervention or as part of a treatment plan.
It is important to note that the evidence in this review is from people diagnosed with 1994 criteria of the Centers for Disease Control and Prevention or the Oxford criteria. People diagnosed using other criteria may experience different effects.
Today, Cochrane publishes an amended version of the Review, ‘Exercise therapy for chronic fatigue syndrome.’ In the last nine months, this Cochrane Review has been modified by the review’s authors and evaluated by independent peer reviewers and editors. It now places more emphasis on the limited applicability of the evidence to definitions of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) used in the included studies, the long-term effects of exercise on symptoms of fatigue, and acknowledges the limitations of the evidence about harms that may occur….
‘We have decided… that a new approach to the publication of evidence in this area is needed; and, today we are committing to the production of a full update of this Cochrane Review, beginning with a comprehensive review of the protocol, which will be developed in consultation with an independent advisory group that we intend to convene. This group will involve partners from patient-advocacy groups from different parts of the world who will help us to embed a patient-focused, contemporary perspective on the review question, methods and findings.’
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome leads to severe functional impairment and work disability in a considerable number of patients. The majority of patients who manage to continue or return to work, work part-time instead of full time in a physically less demanding job. The prognosis in terms of returning to work is poor if patients have been on long-term sick leave for more than two to three years. Being older and more ill when falling ill are associated with a worse employment outcome.
Cognitive behavioural therapy and graded exercise therapy do not restore the ability to work. Consequently, many patients will eventually be medically retired depending on the requirements of the retirement policy, the progress that has been made since they have fallen ill in combination with the severity of their impairments compared to the sort of work they do or are offered to do.
However, there is one thing that occupational health physicians and other doctors can do to try and prevent chronic and severe incapacity in the absence of effective treatments. Patients who are given a period of enforced rest from the onset, have the best prognosis. Moreover, those who work or go back to work should not be forced to do more than they can to try and prevent relapses, long-term sick leave and medical retirement.
The historical infectious disease Myalgic encephalomyelitis (ME) also erroneously known as chronic fatigue Syndrome (CFS) termed “ME/CFS” represents a complex area of difficulty for the modern medical profession where it is commonly held that no empirical diagnostic tests exist to solve its mystery. Confusion surrounding ME/CFS has frequently led to unfounded psychiatric interpretations and application of associated treatments including graded exercise therapy (GET)which is harmful to patients (Twisk & Maes, 2009).
The Nightingale Research Foundation (NRF) led by Dr. Byron Hyde have developed an empirically testable and non-falsifiable ME/CFS criteria defined by a) SPECT (Single Positron Emission Computed Tomography) demonstrating diffuse vascular hypoperfusion over key areas of cerebral cortex and b) persisting enteroviral presence in the gut measured with immunoperoxidase staining (Hyde, 2017, Chia et al, 2009). NRF’s data strongly support that both poliomyelitis and ME/CFS represent enteroviral central nervous system pathologies secondary to insufficient blood supply caused by vascular cuffing.
The present study was conducted to independently assess NRF SPECT findings using qEEG (Quantitative Electroencephalography) coupled with sLORETA (Standardized Low-Resolution Electromagnetic Tomography) software.
Forty-five adult volunteers (aged 18 or over) with a medical diagnosis of ME/CFS were recruited. An aggregate brain representing 675 minutes of eyes-closed data was assembled from the group and compared to the sLORETA BRL normative database in the frequency range between 1.5-35Hz.
Results show 13 source localizations significant (z= 3.085, p= 0.001) overlap with key NRF SPECT findings. NRF SPECT findings can be independently confirmed with qEEG coupled with sLORETA and neuroanatomically support signs and symptoms of the disease first documented in 1934.
SPECT and qEEG should be immediately taken up by the scientific and medical professions as definitive standards for measuring ME/CFS.
Biomarker discovery applied to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a disabling disease of inconclusive aetiology, has identified several cytokines to potentially fulfil a role as a quantitative blood/serum marker for laboratory diagnosis, with activin B a recent addition.
We explored further the potential of serum activin B as a ME/CFS biomarker, alone and in combination with a range of routine test results obtained from pathology laboratories.
Previous pilot study results showed that activin B was significantly elevated for the ME/CFS participants compared to healthy (control) participants. All the participants were recruited via CFS Discovery and assessed via the Canadian/International Consensus Criteria.
A significant difference for serum activin B was also detected for ME/CFS and control cohorts recruited for this study, but median levels were significantly lower for the ME/CFS cohort. Random Forest (RF) modelling identified five routine pathology blood test markers that collectively predicted ME/CFS at ≥62% when compared via weighted standing time (WST) severity classes.
A closer analysis revealed that the inclusion of activin B to the panel of pathology markers improved the prediction of mild to moderate ME/CFS cases. Applying correct WST class prediction from RFA modelling, new reference intervals were calculated for activin B and associated pathology markers, where 24-h urinary creatinine clearance, serum urea and serum activin B showed the best potential as diagnostic markers.
While the serum activin B results remained statistically significant for the new participant cohorts, activin B was found to also have utility in enhancing the prediction of symptom severity, as represented by WST class.
Australian researchers explored a potentially effective method of identifying ME/CFS by using a combination of cytokines. By grouping activin B with 24-hour urinary creatinine clearance and serum urea together for analysis, the results show good potential for use in diagnosing ME/CFS. Activin B is a complex protein found to have biological effects in numerous bodily functions.
A previous pilot study showed a significant increase of activin B in ME/CFS patients as compared to healthy controls. The researchers found that including activin B in the panel of pathology markers improved prediction rates for mild and moderate cases of ME/CFS. Additionally, activin B was also found to help with the prediction of symptom severity as represented by weighted standing time tests.
**This paper is from the Emerge Australia sponsored issue of Diagnostics
