Neurology – Page 9 – American ME and CFS Society

Autonomic Phenotypes in Chronic Fatigue Syndrome (CFS) Are Associated with Illness Severity: A Cluster Analysis

Abstract:

In this study we set out to define the characteristics of autonomic subgroups of patients with Chronic Fatigue Syndrome (CFS). The study included 131 patients with CFS (Fukuda criteria). Participants completed the following screening symptom assessment tools: Chalder Fatigue Scale, Fatigue Impact Scale, Fatigue Severity Scale, Epworth Sleepiness Scales, the self-reported Composite Autonomic Symptom Scale. Autonomic parameters were measured at rest with a Task Force Monitor (CNS Systems) and arterial stiffness using an Arteriograph (TensioMed Kft.).

Principal axis factor analysis yielded four factors: fatigue, subjective and objective autonomic dysfunction and arterial stiffness. Using cluster analyses, these factors were grouped in four autonomic profiles: 34% of patients had sympathetic symptoms with dysautonomia, 5% sympathetic alone, 21% parasympathetic and 40% had issues with sympathovagal balance.

Those with a sympathetic-dysautonomia phenotype were associated with more severe disease, reported greater subjective autonomic symptoms with sympathetic over-modulation and had the lowest quality of life. The highest quality of life was observed in the balance subtype where subjects were the youngest, had lower levels of fatigue and the lowest values for arterial stiffness. Future studies will aim to design autonomic profile-specific treatment interventions to determine links between autonomic phenotypes CFS and a specific treatment.

Source: Słomko J, Estévez-López F, Kujawski S, et al. Autonomic Phenotypes in Chronic Fatigue Syndrome (CFS) Are Associated with Illness Severity: A Cluster Analysis. J Clin Med. 2020;9(8):E2531. Published 2020 Aug 5. doi:10.3390/jcm9082531 https://www.mdpi.com/2077-0383/9/8/2531 (Full text)

Exercise alters brain activation in Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Gulf War Illness affects 25–30% of American veterans deployed to the 1990–91 Persian Gulf War and is characterized by cognitive post-exertional malaise following physical effort. Gulf War Illness remains controversial since cognitive post-exertional malaise is also present in the more common Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. An objective dissociation between neural substrates for cognitive post-exertional malaise in Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome would represent a biological basis for diagnostically distinguishing these two illnesses.

Here, we used functional magnetic resonance imaging to measure neural activity in healthy controls and patients with Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome during an N-back working memory task both before and after exercise. Whole brain activation during working memory (2-Back > 0-Back) was equal between groups prior to exercise. Exercise had no effect on neural activity in healthy controls yet caused deactivation within dorsal midbrain and cerebellar vermis in Gulf War Illness relative to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients.

Further, exercise caused increased activation among Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients within the dorsal midbrain, left operculo-insular cortex (Rolandic operculum) and right middle insula. These regions-of-interest underlie threat assessment, pain, interoception, negative emotion and vigilant attention. As they only emerge post-exercise, these regional differences likely represent neural substrates of cognitive post-exertional malaise useful for developing distinct diagnostic criteria for Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Source: Stuart D Washington, Rakib U Rayhan, Richard Garner, Destie Provenzano, Kristina Zajur, Florencia Martinez Addiego, John W VanMeter, James N Baraniuk, Exercise alters brain activation in Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Brain Communications, Volume 2, Issue 2, 2020, fcaa070, https://doi.org/10.1093/braincomms/fcaa070 https://academic.oup.com/braincomms/article/2/2/fcaa070/5885074 (Full text)

Attentional Processing and Interpretative Bias in Functional Neurological Disorder

Abstract:

Objective: Altered attentional processing (automatically attending to negative or illness-relevant information) and interpretative biases (interpreting ambiguous information as negative or illness-relevant) may be mechanistically involved in functional neurological disorder (FND). Common mechanisms between FND and chronic fatigue syndrome (CFS) have been proposed but not compared experimentally.

Methods: We compared cognitive task performance of FND, CFS and healthy control (HC) groups. Tasks assessed attentional bias towards illness-relevant stimuli (visual probe task), attentional control (attention network task) and somatic interpretations (interpretative bias task), alongside self-reported depression, anxiety, fatigue and general health.

Results: Thirty-seven participants diagnosed with FND, 52 participants diagnosed with CFS and 51 HC participants were included. Whilst participants with CFS showed attentional bias for illness-relevant stimuli relative to HC (t = -3.13 p = 0.002, d = 0.624), individuals with FND did not (t = -1.59, p = 0.118, d = 0.379). Both FND (t = 3.08, p = 0.003, d = 0.759) and CFS (t = 2.74, p = 0.007, d = 0.548) groups displayed worse attentional control than HC. Similarly, FND (t = 3.63, p < 0.001, d = 0.801) and CFS groups (t = 4.58, p < 0.001, d = 0.909) showed more somatic interpretative bias than HC.

Conclusions: Similar attentional control deficits and somatic interpretative bias in individuals with FND and CFS support potential shared mechanisms underlying symptoms. Interpretative bias towards somatic and illness-relevant stimuli in functional disorders may prove a therapeutic target.

Source: Keynejad RC, Fenby E, Pick S, et al. Attentional processing and interpretative bias in functional neurological disorder [published online ahead of print, 2020 Jun 12]. Psychosom Med. 2020;10.1097/PSY.0000000000000821. doi:10.1097/PSY.0000000000000821 https://pubmed.ncbi.nlm.nih.gov/32541544/

A systematic review of neurological impairments in myalgic encephalomyelitis/ chronic fatigue syndrome using neuroimaging techniques

Abstract:

BACKGROUND: Myalgic encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) is a multi-system illness characterised by a diverse range of debilitating symptoms including autonomic and cognitive dysfunction. The pathomechanism remains elusive, however, neurological and cognitive aberrations are consistently described. This systematic review is the first to collect and appraise the literature related to the structural and functional neurological changes in ME/CFS patients as measured by neuroimaging techniques and to investigate how these changes may influence onset, symptom presentation and severity of the illness.

METHODS: A systematic search of databases Pubmed, Embase, MEDLINE (via EBSCOhost) and Web of Science (via Clarivate Analytics) was performed for articles dating between December 1994 and August 2019. Included publications report on neurological differences in ME/CFS patients compared with healthy controls identified using neuroimaging techniques such as magnetic resonance imaging, positron emission tomography and electroencephalography. Article selection was further refined based on specific inclusion and exclusion criteria. A quality assessment of included publications was completed using the Joanna Briggs Institute checklist.

RESULTS: A total of 55 studies were included in this review. All papers assessed neurological or cognitive differences in adult ME/CFS patients compared with healthy controls using neuroimaging techniques. The outcomes from the articles include changes in gray and white matter volumes, cerebral blood flow, brain structure, sleep, EEG activity, functional connectivity and cognitive function. Secondary measures including symptom severity were also reported in most studies.

CONCLUSIONS: The results suggest widespread disruption of the autonomic nervous system network including morphological changes, white matter abnormalities and aberrations in functional connectivity. However, these findings are not consistent across studies and the origins of these anomalies remain unknown. Future studies are required confirm the potential neurological contribution to the pathology of ME/CFS.

Source: Maksoud R, du Preez S, Eaton-Fitch N, Thapaliya K, Barnden L, Cabanas H, Staines D, Marshall-Gradisnik S. A systematic review of neurological impairments in myalgic encephalomyelitis/ chronic fatigue syndrome using neuroimaging techniques. PLoS One. 2020 Apr 30;15(4):e0232475. doi: 10.1371/journal.pone.0232475. eCollection 2020. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232475

A Machine Learning Approach to the Differentiation of Functional Magnetic Resonance Imaging Data of Chronic Fatigue Syndrome (CFS) From a Sedentary Control

Abstract:

Chronic Fatigue Syndrome (CFS) is a debilitating condition estimated to impact at least 1 million individuals in the United States, however there persists controversy about its existence. Machine learning algorithms have become a powerful methodology for evaluating multi-regional areas of fMRI activation that can classify disease phenotype from sedentary control. Uncovering objective biomarkers such as an fMRI pattern is important for lending credibility to diagnosis of CFS.

fMRI scans were evaluated for 69 patients (38 CFS and 31 Control) taken before (Day 1) and after (Day 2) a submaximal exercise test while undergoing the n-back memory paradigm. A predictive model was created by grouping fMRI voxels into the Automated Anatomical Labeling (AAL) atlas, splitting the data into a training and testing dataset, and feeding these inputs into a logistic regression to evaluate differences between CFS and control. Model results were cross-validated 10 times to ensure accuracy. Model results were able to differentiate CFS from sedentary controls at a 80% accuracy on Day 1 and 76% accuracy on Day 2 (Table 3).

Recursive features selection identified 29 ROI’s that significantly distinguished CFS from control on Day 1 and 28 ROI’s on Day 2 with 10 regions of overlap shared with Day 1 (Figure 3). These 10 shared regions included the putamen, inferior frontal gyrus, orbital (F3O), supramarginal gyrus (SMG), temporal pole; superior temporal gyrus (T1P) and caudate ROIs. This study was able to uncover a pattern of activated neurological regions that differentiated CFS from Control.

This pattern provides a first step toward developing fMRI as a diagnostic biomarker and suggests this methodology could be emulated for other disorders. We concluded that a logistic regression model performed on fMRI data significantly differentiated CFS from Control.

Source: Provenzano D, Washington SD, Baraniuk JN. A Machine Learning Approach to the Differentiation of Functional Magnetic Resonance Imaging Data of Chronic Fatigue Syndrome (CFS) From a Sedentary Control. Front Comput Neurosci. 2020 Jan 29;14:2. doi: 10.3389/fncom.2020.00002. eCollection 2020. https://www.ncbi.nlm.nih.gov/pubmed/32063839

Circulating levels of GDF15 in patients with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition characterised by fatigue and post-exertional malaise. Its pathogenesis is poorly understood. GDF15 is a circulating protein secreted by cells in response to a variety of stressors. The receptor for GDF15 is expressed in the brain, where its activation results in a range of responses. Among the conditions in which circulating GDF15 levels are highly elevated are mitochondrial disorders, where early skeletal muscle fatigue is a key symptom. We hypothesised that GDF15 may represent a marker of cellular stress in ME/CFS.

METHODS: GDF15 was measured in serum from patients with ME/CFS (n = 150; 100 with mild/moderate and 50 with severe symptoms), “healthy volunteers” (n = 150) and a cohort of patients with multiple sclerosis (n = 50).

RESULTS: Circulating GDF15 remained stable in a subset of ME/CFS patients when sampled on two occasions ~ 7 months (IQR 6.7-8.8) apart, 720 pg/ml (95% CI 625-816) vs 670 pg/ml (95% CI 598-796), P = 0.5. GDF15 levels were 491 pg/ml in controls (95% CI 429-553), 546 pg/ml (95% CI 478-614) in MS patients, 560 pg/ml (95% CI 502-617) in mild/moderate ME/CFS patients and 602 pg/ml (95% CI 531-674) in severely affected ME/CFS patients. Accounting for potential confounders, severely affected ME/CFS patients had GDF15 concentrations that were significantly increased compared to healthy controls (P = 0.01). GDF15 levels were positively correlated (P = 0.026) with fatigue scores in ME/CFS.

CONCLUSIONS: Severe ME/CFS is associated with increased levels of GDF15, a circulating biomarker of cellular stress that appears which stable over several months.

Source: Melvin A, Lacerda E, Dockrell HM, O’Rahilly S, Nacul L. Circulating levels of GDF15 in patients with myalgic encephalomyelitis/chronic fatigue syndrome. J Transl Med. 2019 Dec 4;17(1):409. doi: 10.1186/s12967-019-02153-6. https://www.ncbi.nlm.nih.gov/pubmed/31801546

Intra brainstem connectivity is impaired in chronic fatigue syndrome

Abstract:

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. In ME/CFS, connections were absent between medulla and midbrain nuclei, although hippocampal connections with these nuclei were enhanced.

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.

Source: Barnden LR, Shan ZY, Staines DR, Marshall-Gradisnik S, Finegan K, Ireland T, Bhuta S. Intra brainstem connectivity is impaired in chronic fatigue syndrome. Neuroimage Clin. 2019 Oct 19;24:102045. doi: 10.1016/j.nicl.2019.102045. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31671321

Brain studies show chronic fatigue syndrome and Gulf War illness are distinct conditions

CHICAGO (October 23, 2019) — Gulf War Illness (GWI) and chronic fatigue syndrome (CFS) share symptoms of disabling fatigue, pain, systemic hyperalgesia (tenderness), negative emotion, sleep and cognitive dysfunction that are made worse after mild exertion (postexertional malaise). Now, neuroscientists at Georgetown University Medical Center have evidence, derived from human brain studies, that GWI and CFS are two distinct disorders that affect the brain in opposing ways.

The findings, presented in two related studies at the annual meeting of the Society for Neuroscience (SFN) in Chicago, offer a new perspective on neurotoxicity and suggest that methods to effectively diagnose and treat these disorders could be developed, says the studies’ senior author, James Baraniuk, MD, a Georgetown professor of medicine.

GWI affects veterans of the 1990-1991 Persian Gulf War who were exposed to a toxic environment of nerve agents, pesticides and other neurotoxins, while the etiology of CFS is unknown. The overlapping symptoms suggest they may share some common mechanisms of disease.

Baraniuk was first to find unique physical changes in the brains of patients with GWI, and he and his colleagues have also found changes in brain chemistry between GWI and CFS. “This new work further emphasizes that chronic fatigue syndrome and Gulf War Illness are two very real, and very distinct, diseases of the brain,” he says.

The two SFN studies were led by investigators in Baraniuk’s lab. One, being presented by neuroscientist Stuart Washington, PhD, details how specific areas in the brain are affected by the disorders, and the second, led by student Haris Pepermintwala, MS, takes a deep dive into one of those areas, the brain stem, to illustrate the degree to which these conditions have differing effects.

Chronic fatigue syndrome/myalgic encephalomyelitis affects between 836,000 and 2.5 million Americans, according to a 2015 report by the National Academy of Medicine. Gulf War Illness developed in about one-third of the 697,000 veterans deployed to the 1990-1991 Persian Gulf War. Baraniuk says that during Operation Desert Storm, these veterans were exposed to combinations of nerve agents, pesticides and other toxic chemicals that may have triggered the chronic pain and cognitive and gastrointestinal problems.

Both GWI and CFS share common features: cognitive dysfunction, pain and fatigue primarily following physical exercise. To determine how these conditions affect brain function, investigators studied neuronal activation using functional MRI (fMRI) during a cognitive task a day before and a day after bicycle exercise stress tests in their different groups: 38 CFS patients, 80 GWI patients, and a control group of 23 healthy sedentary volunteers. Brain activation during a working memory task was compared between the pre- and post-exercise fMRI studies, and between CFS and GWI groups.

Before exercise, brain activation was similar between groups. However, after exercise the CFS group showed significantly increased activation of the midbrain, while GWI had the opposite effect, with decreased activation in this vital region of the arousal network. CFS also had increased activation in the insula. In contrast, GWI, but not CFS, had a decrease in activation of the cerebellum after exercise. The findings show that specific brain regions acted in opposing ways, representing a differentiation between GWI and CFS.

While these areas are involved in pain perception, among their many other tasks, “this doesn’t mean more or less activity is directly related to pain,” says Washington. “What it does show is that the two conditions are distinct from each other and involve different cellular/molecular mechanisms.”

The second study, led by Pepermintwala, looked more closely at specific regions within the brain stem and confirmed that CFS had significantly increased activation during the cognitive task after the exercise provocations, while GWI had significantly reduced activation.

These regions are involved in vital functions for instantaneous assessments of threats, predator-prey decisions, arousal, modulation of chronic pain, sleep and other neurobehavioral functions, Pepermintwala says. But after exercise, the CFS group had significantly increased activity in the majority of regions evaluated, while the GWI patients experienced significantly decreased activation.

The results support other research, conducted post-mortem in veterans with PTSD, suggesting that the brain stem in these veterans may have physical abnormalities, such as a loss of neurons, Pepermintwala says. “The midbrain is affected by the exercise and cognitive challenges, but CFS and GWI react in opposite ways, showing that they are related, but distinctly different disorders.”

For the study led by Washington, additional co-authors include Rakib Rahan, Richard Garner, Destie Provenzano, Kristina Zajur, Florencia Martinez Addiego, John VanMeter and Baraniuk.

For the study led by Pepermintwala, additional co-authors include Washington, Addiego, Rayhan and Baraniuk.

The authors report having no personal financial interests related to the studies.

These studies were supported by funding from The Sergeant Sullivan Circle, Barbara Cottone, Dean Clarke Bridge Prize, Department of Defense Congressionally Directed Medical Research Program (W81XWH-15-1-0679 and W81-XWH-09-1-0526), and the National Institute of Neurological Disorders and Stroke (R21NS088138 and RO1NS085131). The project has been funded in whole or in part with federal funds (UL1TR000101 previously UL1RR031975) from the National Center for Advancing Translational Sciences, National Institutes of Health, through the Clinical and Translational Science Awards Program.

Brain Responses in CFS and TMD to Autonomic Challenges: An Exploratory fMRI Study

Abstract:

INTRODUCTION: Dysfunction of the autonomic nervous system (ANS) is seen in chronic fatigue syndrome (CFS) and temporomandibular disorders (TMDs). Both conditions have poorly understood pathophysiology. Several brain structures that play a role in pain and fatigue, such as the insular cortex and basal ganglia, are also implicated in autonomic function.

OBJECTIVES: ANS dysfunction may point to common neurophysiologic mechanisms underlying the predominant symptoms for CFS and TMD. No studies to date have investigated the combination of both conditions. Thus, our aim was to test whether patients with CFS with or without TMD show differences in brain responses to autonomic challenges.

METHODS: In this exploratory functional imaging study, patients with CFS who screened positive for TMD (n = 26), patients who screened negative for TMD (n = 16), and age-matched control participants (n = 10) performed the Valsalva maneuver while in a 3-T magnetic resonance imaging scanner. This maneuver is known to activate the ANS.

RESULTS: For all 3 groups, whole-brain F test showed increased brain activation during the maneuver in the superior and inferior frontal gyri, the left and right putamen and thalamus, and the insular cortex. Furthermore, group contrasts with small-volume correction showed that patients with CFS who screened positive for TMD showed greater activity in the left insular cortex as compared with patients who screened negative and in the left caudate nucleus as compared with controls.

CONCLUSION: Our results suggest that increased activity in the cortical and subcortical regions observed during autonomic challenges may be modulated by fatigue and pain. ANS dysfunction may be a contributing factor to these findings, and further work is required to tease apart the complex relationship among CFS, TMD, and autonomic functions.

KNOWLEDGE TRANSFER STATEMENT: Brain activity related to activation of the autonomic nervous system in patients with chronic fatigue syndrome who screened positive for painful temporomandibular disorder was greater than in patients who screened negative; activity was seen in brain regions associated with autonomic functions and pain. These findings suggest that autonomic dysfunction may play a role in the pathophysiology of both conditions, explain some of the apparent comorbidity between them, and offer avenues to help with treatment.

Source: Vuong QC, Allison JR, Finkelmeyer A, Newton J, Durham J. Brain Responses in CFS and TMD to Autonomic Challenges: An Exploratory fMRI Study. JDR Clin Trans Res. 2019 Aug 28:2380084419872135. doi: 10.1177/2380084419872135. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31461628

Autonomic dysfunction in myalgic encephalomyelitis and chronic fatigue syndrome: comparing self-report and objective measures

Myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) have debilitating impacts on affected individuals. Core symptoms include post-exertional malaise, neurocognitive challenges, and sleep dysfunction [1]. Additionally, a significant minority of patients experience autonomic symptoms, including orthostatic intolerance, gastrointestinal disturbances, and circulation issues [2].

Several case definitions for ME and CFS require the presence of autonomic dysfunction for diagnosis [2], while other researchers have proposed an “autonomic dysfunction” subtype of ME and CFS [3]. Identifying the appropriate measures of autonomic symptomatology for individuals with ME and CFS will further contribute to understanding the role of the autonomic system in this illness.

Read the rest of this article here.

Source: Kemp J, Sunnquist M, Jason LA, Newton JL. Autonomic dysfunction in myalgic encephalomyelitis and chronic fatigue syndrome: comparing self-report and objective measures. Clin Auton Res. 2019 May 21. doi: 10.1007/s10286-019-00615-x. [Epub ahead of print] https://sci-hub.se/10.1007/s10286-019-00615-x (Full article)