Using structural & functional MRI as a neuroimaging technique to investigate CFS/ME: a systematic review

Posted on 09/05/2020 by wames

Using structural and functional MRI as a neuroimaging technique to investigate chronic fatigue syndrome/myalgic encephalopathy: a systematic review, by in BMJ Open Vol 10, #8, p e031672, August 30, 2020 [doi.org/10.1136/bmjopen-2019-031672]

 

Strengths and limitations of this study

  • To the best of our knowledge, this is the first systematic review of neuroimaging studies that have investigated chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) using MRI.
  • We reviewed both structural MRI and functional MRI (fMRI) studies of CFS/ME.
  • We identified common limitations across the neuroimaging studies and make recommendations for future research.
  • We were unable to find conclusive evidence for neural biomarkers of CFS/ME.
  • The main limitation of the current systematic review is that a meta-analysis was not possible because of the different methodologies across the studies, such as fMRI studies using a variety of tasks to assess different cognitive functions.

Research abstract

Objective
This systematic review aims to synthesise and evaluate structural MRI (sMRI) and functional MRI (fMRI) studies in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME).

Methods
We systematically searched Medline and Ovid and included articles from 1991 (date of Oxford diagnostic criteria for CFS/ME) to first April 2019. Studies were selected by predefined inclusion and exclusion criteria. Two reviewers independently reviewed the titles and abstracts to determine articles for inclusion, full text and quality assessment
for risk of bias.

Results
sMRI studies report differences in CFS/ME brain anatomy in grey and white matter volume, ventricular enlargement and hyperintensities. Three studies report no neuroanatomical differences between CFS/ME and healthy controls. Task-based fMRI investigated working memory, attention, reward and motivation, sensory information processing and emotional conflict. The most consistent finding was CFS/ME exhibited increased activations and recruited additional brain regions. Tasks with increasing load or
complexity produced decreased activation in task-specific brain regions.

Conclusions
There were insufficient data to define a unique neural profile or biomarker of CFS/ME. This may be due to inconsistencies in finding neuroanatomical differences in CFS/ME and the variety of different tasks employed by fMRI studies. But there are also limitations with
neuroimaging. All brain region specific volumetric differences in CFS/ME were derived from voxel-based statistics that are biased towards group differences that are highly localised in space. fMRI studies demonstrated both increases and decreases in activation patterns in CFS/ME, this may be related to task demand. However, fMRI signal cannot
differentiate between neural excitation and inhibition or function-specific neural processing.

Many studies have small sample sizes and did not control for the heterogeneity of this clinical population. We suggest that with robust study design, subgrouping and
larger sample sizes, future neuroimaging studies could potentially lead to a breakthrough in our understanding of the disease.

[NB a broad definition of CFS was used – the patients are not homogeneous.]

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Neuroimaging characteristics of ME/CFS: a systematic review

Posted on 09/02/2020 by wames

Neuroimaging characteristics of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a systematic review, by Zack Y. Shan, Leighton R Barnden, Richard A Kwiatek, Sandeep Bhuta, Daniel F Hermens, Jim Lagopoulos in Journal of Translational Medicine Vol 18, #335 Sep 1 2020

 

Review abstract: 

Background

Since the 1990s, neuroimaging has been utilised to study Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS), a debilitating illness with unknown aetiology. While brain abnormalities in ME/CFS have been identified, relatively little is known regarding which specific abnormalities are consistently observed across research groups and to what extent the observed abnormalities are reproducible.

Method

To identify consistent and inconsistent neuroimaging observations in ME/CFS, this retrospective and systematic review searched for studies in which neuroimaging was used to investigate brain abnormalities in ME/CFS in Ovid MEDLINE, PubMed (NCBI), and Scopus from January 1988 to July 2018. A qualitative synthesis of observations was performed to identify brain abnormalities that were consistently and inconsistently reported.

Results

63 full-text articles were included in the synthesis of results from 291 identified papers. Additional brain area recruitment for cognitive tasks and abnormalities in the brain stem are frequent observations in 11 and 9 studies using different modalities from different research teams respectively. Also, sluggish blood oxygenation level-dependent (BOLD) signal responses to tasks, reduced serotonin transporters, and regional hypometabolism are consistent observations by more than two research teams. Single observations include abnormal brain tissue properties, regional metabolic abnormalities, and association of brain measures with ME/CFS symptoms. Reduced resting cerebral blood flow and volumetric brain changes are inconsistent observations across different studies.

Conclusion

Neuroimaging studies of ME/CFS have frequently observed additional brain area recruitment during cognitive tasks and abnormalities in the brain stem. The frequent observation of additional brain area recruitment and consistent observation of sluggish fMRI signal response suggest abnormal neurovascular coupling in ME/CFS.

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Machine Learning detects pattern of differences in fMRI data between CFS & Gulf War Illness

Posted on 08/30/2020 by wames

Machine Learning detects pattern of differences in Functional Magnetic Resonance Imaging (fMRI) data between Chronic Fatigue Syndrome (CFS) and Gulf War Illness (GWI), by Destie Provenzano, Stuart D Washington, Yuan J Rao, Murray Loew and James Baraniuk in Brain Sci. 2020, 10(7), 456; [doi.org/10.3390/brainsci10070456] 17 July 2020

 

Research abstract:

Background:

Gulf War Illness (GWI) and Chronic Fatigue Syndrome (CFS) are two debilitating disorders that share similar symptoms of chronic pain, fatigue, and exertional exhaustion after exercise. Many physicians continue to believe that both are psychosomatic disorders and to date no underlying etiology has been discovered. As such, uncovering objective biomarkers is important to lend credibility to criteria for diagnosis and to help differentiate the two disorders.

Methods:

We assessed cognitive differences in 80 subjects with GWI and 38 with CFS by comparing corresponding fMRI scans during 2-back working memory tasks before and after exercise to model brain activation during normal activity and after exertional exhaustion, respectively. Voxels were grouped by the count of total activity into the Automated Anatomical Labeling (AAL) atlas and used in an “ensemble” series of machine learning algorithms to assess if a multi-regional pattern of differences in the fMRI scans could be detected.

Results:

A K-Nearest Neighbor (70%/81%), Linear Support Vector Machine (SVM) (70%/77%), Decision Tree (82%/82%), Random Forest (77%/78%), AdaBoost (69%/81%), Naïve Bayes (74%/78%), Quadratic Discriminant Analysis (QDA) (73%/75%), Logistic Regression model (82%/82%), and Neural Net (76%/77%) were able to differentiate CFS from GWI before and after exercise with an average of 75% accuracy in predictions across all models before exercise and 79% after exercise.

An iterative feature selection and removal process based on Recursive Feature Elimination (RFE) and Random Forest importance selected 30 regions before exercise and 33 regions after exercise that differentiated CFS from GWI across all models, and produced the ultimate best accuracies of 82% before exercise and 82% after exercise by Logistic Regression or Decision Tree by a single model, and 100% before and after exercise when selected by any six or more models.

Differential activation on both days included the right anterior insula, left putamen, and bilateral orbital frontal, ventrolateral prefrontal cortex, superior, inferior, and precuneus (medial) parietal, and lateral temporal regions. Day 2 had the cerebellum, left supplementary motor area and bilateral pre- and post-central gyri. Changes between days included the right Rolandic operculum switching to the left on Day 2, and the bilateral midcingulum switching to the left anterior cingulum.

Conclusion:

We concluded that CFS and GWI are significantly differentiable using a pattern of fMRI activity based on an ensemble machine learning model.

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Associations of physical & psychiatric conditions with CFS in Germany

Posted on 08/27/2020 by wames

Associations of physical and psychiatric conditions with chronic fatigue syndrome in Germany: an exploratory case-control study, by Louis Jacob, Josep Maria Haro and Karel Kostev in Psychological Medicine, 1-7, 2020 [doi.org/10.1017/S0033291720002470]

 

Research abstract:

Background:

Only a few studies have analyzed the effects of physical and psychiatric conditions on the risk of chronic fatigue syndrome (CFS). Therefore, the goal of this exploratory case-control study was to investigate the associations of physical and psychiatric conditions with CFS in almost 19 800 adults from Germany.

Methods:

This study included patients diagnosed for the first time with CFS in one of 1238 general practices in Germany between 2010 and 2017 (index date). Controls without CFS were matched (1:1) to cases with CFS by sex, age, index year, and practice. Physical and psychiatric conditions diagnosed in the year prior to the index date were included if they were present in at least 3% of patients with CFS. Associations between physical and psychiatric conditions (33 potential independent variables) and CFS (dependent variable) were analyzed in an adjusted conditional logistic regression model, and physical and psychiatric disorders were included in the model using forward stepwise selection.

Results:

This study included 9896 cases with CFS and 9896 controls without CFS [65.1% women; mean (standard deviation) age 49.5 (18.3) years]. Seven conditions were associated with CFS in the adjusted regression model. The disorders displaying the strongest relationship with CFS were cancer [odds ratio (OR) = 2.57, 95% confidence interval (CI) = 2.24–2.95], sleep disorders (OR = 1.88, 95% CI = 1.66–2.12) and depression (OR = 1.77, 95% CI = 1.61–1.95).

Conclusions:

Cancer, sleep disorders, and depression were strongly and positively associated with CFS. Additional studies are needed to gain a better understanding of the mechanisms underlying these relationships.

Read full paper

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DecodeME is recruiting more study participants

Posted on 08/27/2020 by wames

Dear DecodeME Friend,

We have been blown away by the response we have had since we announced funding for the study. Over 25,000 people have signed up to receive updates, with nearly 20,000 people in the UK indicating they are over 16 years of age and interested in participating.

We have secured funding for a very large study to analyse DNA from the saliva of people with ME/CFS to see whether the disease is partly genetic and if so, help pinpoint what causes it. The study should help us understand the disease and ultimately find treatments.

This is a fantastic start but we have a huge amount to do before we open recruitment. We’re aiming for 40,000 sign-ups by the time recruitment begins in March 2021 to give us the best chance of having at least 20,000 people taking part in the study.

Over the last few months, we have been working hard in preparation for the project officially starting next month. You can find out more

Funding announcement gets a big response

We will continue to provide regular updates over the next few months and appreciate all your amazing support in helping us get as many people signed up to receive updates as possible!

Bye for now,

DecodeME Team      www.decodeme.org.uk

The ME/CFS Biomedical Partnership
42 Temple Street,
Keynsham,
BS31 1EH

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Activity measurement in pediatric CFS

Posted on 08/26/2020 by wames

Activity measurement in pediatric chronic fatigue syndrome, by Bernardo Loiacono, Madison Sunnquist, Laura Nicholson, Leonard A Jason in Chronic Illness, August 17, 2020 [doi.org/10.1177/1742395320949613]

 

Research abstract:

Objectives:
Individuals with myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) experience debilitating symptoms, including post-exertional malaise, an intensification of symptoms after physical or cognitive exertion.

Previous studies found differences in the activity levels and patterns of activity among individuals with ME and CFS, compared to healthy controls; however, limited research exists on the activity levels of pediatric patients. The objective of this study was to examine differences in activity between healthy children and youth with ME and CFS.

Methods:
The present study examines the objective (i.e., ActiGraphy) and self-reported levels of activity among children (ages 5 to 17) enrolled in a community-based study of pediatric CFS.

Results:
Children with ME and CFS evidenced lower activity levels than healthy control children. Moreover, participants with ME and CFS evidenced increased night time activity and delayed initiation of daytime activity. Participants’ self-reported activity data significantly correlated with their ActiGraph data, suggesting that children with ME and CFS are able to accurately describe their activity level.

Discussion:
This study highlights differences in activity level and diurnal/nocturnal activity patterns between healthy children and those with ME and CFS. These differences should be considered in identifying appropriate supports and accommodations for children with ME and CFS.

Read full paper

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How ME/CFS progresses: the natural history of ME/CFS

Posted on 08/25/2020 by wames

How Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) progresses: the natural history of ME/CFS, by Luis Nacul,  Shennae O’Boyle,  Luigi Palla,  Flavio E Nacul,  Kathleen Mudie,  Caroline C Kingdon,  Jacqueline M Cliff,  Taane G Clark,  Hazel M Dockrell and  Eliana M Lacerda in Front. Neurol. 11 August 2020 [doi.org/10.3389/fneur.2020.00826]

 

Article abstract:

We propose a framework for understanding and interpreting the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) that considers wider determinants of health and long-term temporal variation in pathophysiological features and disease phenotype throughout the natural history of the disease.

Dr Luis Nacul

As in other chronic diseases, ME/CFS evolves through different stages, from asymptomatic predisposition, progressing to a prodromal stage, and then to symptomatic disease. Disease incidence depends on genetic makeup and environment factors, the exposure to singular or repeated insults, and the nature of the host response.

In people who develop ME/CFS, normal homeostatic processes in response to adverse insults may be replaced by aberrant responses leading to dysfunctional states. Thus, the predominantly neuro-immune manifestations, underlined by a hyper-metabolic state, that characterize early disease, may be followed by various processes leading to multi-systemic abnormalities and related symptoms.

This abnormal state and the effects of a range of mediators such as products of oxidative and nitrosamine stress, may lead to progressive cell and metabolic dysfunction culminating in a hypometabolic state with low energy production. These processes do not seem to happen uniformly; although a spiraling of progressive inter-related and self-sustaining abnormalities may ensue, reversion to states of milder abnormalities is possible if the host is able to restate responses to improve homeostatic equilibrium.

With time variation in disease presentation, no single ME/CFS case description, set of diagnostic criteria, or molecular feature is currently representative of all patients at different disease stages. While acknowledging its limitations due to the incomplete research evidence, we suggest the proposed framework may support future research design and health care interventions for people with ME/CFS.

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Hemodynamics during the 10-minute NASA Lean Test: evidence of circulatory decompensation in a subset of ME/CFS patients

Posted on 08/24/2020 by wames

Hemodynamics during the 10-minute NASA Lean Test: evidence of circulatory decompensation in a subset of ME/CFS patients by Jihyun Lee, Suzanne D Vernon, Patricia Jeys, Weam Ali, Andrea Campos, Derya Unutmaz, Brayden Yellman, Lucinda Bateman in J Transl Med. 2020 Aug 15;18(1):314 [doi: 10.1186/s12967-020-02481-y]

 

Research abstract:

Background:

Lightheadedness, fatigue, weakness, heart palpitations, cognitive dysfunction, muscle pain, and exercise intolerance are some of the symptoms of orthostatic intolerance (OI). There is substantial comorbidity of OI in ME/CFS (Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome). The 10-minute NASA Lean Test (NLT) is a simple, point-of-care method that can aid ME/CFS diagnosis and guide management and treatment of OI. The objective of this study was to understand the hemodynamic changes that occur in ME/CFS patients during the 10-minute NLT.

Methods:

A total of 150 ME/CFS patients and 75 age, gender and race matched healthy controls (HCs) were enrolled. We recruited 75 ME/CFS patients who had been sick for less than 4 years (< 4 ME/CFS) and 75 ME/CFS patients sick for more than 10 years (> 10 ME/CFS). The 10-minute NLT involves measurement of blood pressure and heart rate while resting supine and every minute for 10 min while standing with shoulder-blades on the wall for a relaxed stance. Spontaneously reported symptoms are recorded during the test. ANOVA and regression analysis were used to test for differences and relationships in hemodynamics, symptoms and upright activity between groups.

Results:

At least 5 min of the 10-minute NLT were required to detect hemodynamic changes. The < 4 ME/CFS group had significantly higher heart rate and abnormally narrowed pulse pressure compared to > 10 ME/CFS and HCs. The < 4 ME/CFS group experienced significantly more OI symptoms compared to > 10 ME/CFS and HCs. The circulatory decompensation observed in the < 4 ME/CFS group was not related to age or medication use.

Conclusions:

Circulatory decompensation characterized by increased heart rate and abnormally narrow pulse pressure was identified in a subgroup of ME/CFS patients who have been sick for < 4 years. This suggests inadequate ventricular filling from low venous pressure. The 10-minute NLT can be used to diagnose and treat the circulatory decompensation in this newly recognized subgroup of ME/CFS patients.

The > 10 ME/CFS group had less pronounced hemodynamic changes during the NLT possibly from adaptation and compensation that occurs over time. The 10-minute NLT is a simple and clinically useful point-of-care method that can be used for early diagnosis of ME/CFS and help guide OI treatment.

 

Excerpt

While it isn’t entirely clear why the > 10 ME/CFS group appear to tolerate the orthostatic stress better than < 4 ME/CFS in terms of a dramatic drop in pulse pressure, that does not prove they aren’t experiencing a drop in cerebral perfusion. It is possible that after many years of ME/CFS illness there is gradual adaptation of the circulatory stress response to upright posture. That may also explain why the > 10 ME/CFS had the highest rise in SBP during the 10-minute NLT. There is also an age difference between the < 4 and > 10 ME/CFS groups of about 5–6 years which might also explain the higher SBP response in the > 10 ME/CFS subgroup. A very important recently published study demonstrated that cerebral blood flow is reduced in ME/CFS during head-up tilt testing even in the absence of hypotension or tachycardia [22]. This is consistent with our findings and may explain why ME/CFS patients were not much more likely to meet standard criteria for POTS or OH than the HCs, even though they still became more symptomatic during the 10-minute NLT.

Health Rising blog post: NASA Lean test, an easy way to diagnose Orthostatic Intolerance in ME/CFS, Fibromyalgia and POTS, by Cort Johnson

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ME/CFS in Europe – EMEC factsheets

Posted on 08/24/2020 by wames

European ME Coalition fact sheets

 

The European ME Coalition (EMEC) presents three new fact sheets about Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). The documents briefly summarize key facts about the economic and societal impact of ME/CFS in Europe and the recent efforts made by ME/CFS advocates including the petition submitted by Evelien Van Den Brink. The fact sheets will help to inform politicians and key policymakers about the need for biomedical research on ME/CFS in Europe.

The three fact sheets focus on separate topics.

One longer document provides basic information in a plain text format and is supported by ample scientific references. It forms an ideal starting point for anyone who wants to learn more about ME/CFS in Europe.

A second document is shorter and focuses on key figures. With its simple formatting and pictograms, it will be most helpful to those who want a brief overview (or who are simply bad at memorizing numbers).

A third document focuses on recommendations to Member States made in the recently adopted European ME/CFS resolution.

Find out more

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Validation of the severity of ME/CFS by other measures than history

Posted on 08/21/2020 by wames

Validation of the severity of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome by other measures than history: activity bracelet, Cardiopulmonary Exercise Testing and a validated activity, Questionnaire: SF-36, by by C (Linda) M C van Campen, Peter C Rowe and Frans C Visser in Healthcare 2020, 8(3), 273; [doi.org/10.3390/healthcare8030273]

 

Research abstract:

Introduction:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe and disabling chronic disease. Grading patient’s symptom and disease severity for comparison and therapeutic decision-making is necessary. Clinical grading that depends on patient self-report is subject to inter-individual variability. Having more objective measures to grade and confirm clinical grading would be desirable.

Therefore, the aim of this study was to validate the clinical severity grading that has been proposed by the authors of the ME International Consensus Criteria (ICC) using more standardized measures like questionnaires, and objective measures such as physical activity tracking and cardiopulmonary exercise testing.

Methods and results:

The clinical database of a subspecialty ME/CFS clinic was searched for patients who had completed the SF 36 questionnaire, worn a SensewearTM armband for five days, and undergone a cardiopulmonary exercise test. Only patients who completed all three investigations within 3 months from each other—to improve the likelihood of stable disease—were included in the analysis. Two-hundred-eighty-nine patients were analyzed: 121 were graded as mild, 98 as moderate and 70 as having severe disease.

The mean (SD) physical activity subscale of the SF-36 was 70 (11) for mild, 43 (8) for moderate and 15 (10) for severe ME/CFS patients. The mean (SD) number of steps per day was 8235 (1004) for mild, 5195 (1231) for moderate and 2031 (824) for severe disease. The mean (SD) percent predicted oxygen consumption at the ventilatory threshold was 47 (11)% for mild, 38 (7)% for moderate and 30 (7)% for severe disease. The percent peak oxygen consumption was 90 (14)% for mild, 64 (8)% for moderate and 48 (9)% for severe disease. All comparisons were p < 0.0001.

Conclusion:

This study confirms the validity of the ICC severity grading. Grading assigned by clinicians on the basis of patient self-report created groups that differed significantly on measures of activity using the SF-36 physical function subscale and objective measures of steps per day and exercise capacity. There was variability in function within severity grading groups, so grading based on self-report can be strengthened by the use of these supplementary measures.

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