Newton – Page 2 – American ME and CFS Society

The Impact of a Structured Exercise Programme upon Cognitive Function in Chronic Fatigue Syndrome Patients

[Editor’s Note: The dropout rate for this study was 50%. After false discovery rate (FDR) correction, none the results achieved statistical significance.]

Abstract:

BACKGROUND: Cognitive function disturbance is a frequently described symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In this study, the effects of a structured exercise programme (SEP) upon cognitive function in ME/CFS patients was examined.

METHODS: Out of the 53 ME/CFS patients initiating SEP 34 (64%) completed the 16 week programme. Cognitive function was assessed using a computerized battery test consisting of a Simple Reaction Time (SRT) (repeated three times) and Choice Reaction Time (CRT) measurements, a Visual Attention Test (VAT) and a Delayed Matching to Sample (DMS) assessment.

RESULTS: Statistically significant improvement was noted in the third attempt to SRT in reaction time for correct answers, p = 0.045, r = 0.24. Moreover, significant improvement was noted in VAT reaction time, number of correct answers and errors committed, p = 0.02, omega = 0.03, p = 0.007, r = 0.34 and p = 0.004, r = 0.35, respectively. Non-significant changes were noted in other cognitive tests.

CONCLUSIONS: A substantial number of participants were unwilling or unable to complete the exercise programme. ME/CFS patients able to complete the SEP showed improved visual attention both in terms of reaction time and correctness of responses and processing speed of simple visual stimuli.

Source: Zalewski P1, Kujawski S1, Tudorowska M2, Morten K3, Tafil-Klawe M4, Klawe JJ1, Strong J3, Estévez-López F5, Murovska M6, Newton JL7, The European Network On Me/Cfs Euromene. The Impact of a Structured Exercise Programme upon Cognitive Function in Chronic Fatigue Syndrome Patients. Brain Sci. 2019 Dec 19;10(1). pii: E4. doi: 10.3390/brainsci10010004. https://www.mdpi.com/2076-3425/10/1/4 (Full study)

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

Assessing cellular energy dysfunction in CFS/ME using a commercially available laboratory test

Abstract:

The mitochondrial energy score (MES) protocol, developed by the Myhill group, is marketed as a diagnostic test for chronic fatigue syndrome/Myalgic Encephalomyelitis (CFS/ME). This study assessed the reliability and reproducibility of the test, currently provided by private clinics, to assess its potential to be developed as an NHS accredited laboratory test.

We replicated the MES protocol using neutrophils and peripheral blood mononuclear cells (PBMCs) from CFS/ME patients (10) and healthy controls (13). The protocol was then repeated in PBMCs and neutrophils from healthy controls to investigate the effect of delayed sample processing time used by the Myhill group.

Experiments using the established protocol showed no differences between CFS/ME patients and healthy controls in any of the components of the MES (p ≥ 0.059). Delaying blood sample processing by 24 hours (well within the 72 hour time frame quoted by the Myhill group) significantly altered many of the parameters used to calculate the MES in both neutrophils and PBMCs. The MES test does not have the reliability and reproducibility required of a diagnostic test and therefore should not currently be offered as a diagnostic test for CFS/ME. The differences observed by the Myhill group may be down to differences in sample processing time between cohorts.

Source: Tomas C, Lodge TA, Potter M, Elson JL, Newton JL, Morten KJ. Assessing cellular energy dysfunction in CFS/ME using a commercially available laboratory test. Sci Rep. 2019 Aug 7;9(1):11464. doi: 10.1038/s41598-019-47966-z. https://www.ncbi.nlm.nih.gov/pubmed/31391529

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.

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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)

Network structure underpinning (dys)homeostasis in chronic fatigue syndrome; Preliminary findings

Abstract:

INTRODUCTION: A large body of evidence has established a pattern of altered functioning in the immune system, autonomic nervous system and hypothalamic pituitary adrenal axis in chronic fatigue syndrome. However, the relationship between components within and between these systems is unclear. In this paper we investigated the underlying network structure of the autonomic system in patients and controls, and a larger network comprising all three systems in patients alone.

METHODS: In a sample of patients and controls we took several measures of autonomic nervous system output during 10 minutes of supine rest covering tests of blood pressure variability, heart rate variability and cardiac output. Awakening salivary cortisol was measured on each of two days with participants receiving 0.5mg dexamethasone during the afternoon of the first day. Basal plasma cytokine levels and the in vitro cytokine response to dexamethasone were also measured. Symptom outcome measures used were the fatigue impact scale and cognitive failures questionnaire. Mutual information criteria were used to construct networks describing the dependency amongst variables. Data from 42 patients and 9 controls were used in constructing autonomic networks, and 15 patients in constructing the combined network.

RESULTS: The autonomic network in patients showed a more uneven distribution of information, with two distinct modules emerging dominated by systolic blood pressure during active stand and end diastolic volume and stroke volume respectively. The combined network revealed strong links between elements of each of the three regulatory systems, characterised by three higher modules the centres of which were systolic blood pressure during active stand, stroke volume and ejection fraction respectively.

CONCLUSIONS: CFS is a complex condition affecting physiological systems. It is important that novel analytical techniques are used to understand the abnormalities that lead to CFS. The underlying network structure of the autonomic system is significantly different to that of controls, with a small number of individual nodes being highly influential. The combined network suggests links across regulatory systems which shows how alterations in single nodes might spread throughout the network to produce alterations in other, even distant, nodes. Replication in a larger cohort is warranted.

Source: Clark JE, Ng WF, Rushton S, Watson S, Newton JL. Network structure underpinning (dys)homeostasis in chronic fatigue syndrome; Preliminary findings. PLoS One. 2019 Mar 25;14(3):e0213724. doi: 10.1371/journal.pone.0213724. eCollection 2019. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0213724 (Full article)

Prevalence and characteristics of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) in Poland: a cross-sectional study

Abstract:

OBJECTIVES: The aim of this study was to estimate the prevalence of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) and describe illness characteristics in a community population in Poland.

DESIGN: cross-sectional study.

SETTING: Poland.

PARTICIPANTS: Of the cohort of 1400 who self-presented with fatigue only 69 subsequently were confirmed as having CFS/ME using the Fukuda criteria.

MAIN OUTCOME MEASURES: Participants completed the following screening symptom assessment tools: Chalder Fatigue Scale, Hospital Anxiety and Depression Scale (HADS), Epworth Sleepiness Scale (ESS), Composite Autonomic Symptom Score 31 (COMPASS 31), Quality of Life Scale (QOLS). Haemodynamic and autonomic parameters were automatically measured at rest with a Task Force Monitor.

RESULTS: In 1308, from 1400 (93%) individuals who identified themselves as fatigued, recognised chronic conditions were identified, for example, neurological (n=280, 21.5%), neurodegenerative (n=200, 15%), psychiatric (n=654, 50%) and immunologic (n=174, 13.5%) disorders. The remaining 69 participants (mean age 38.3±8.5) met the Fukuda defintion for CFS/ME and had baseline objective assessment. The majority had experienced symptoms for over 2 years with 37% having symptoms for 2-5 years and 21.7% for more than 10 years. The COMPASS 31 indicated that 50% have symptoms consistent with orthostatic intolerance. About 43/69 (62%) had Epworth sleepiness scores ≥10, ie, consistent with excessive daytime sleepiness, 26/69 (38%) had significant anxiety and 22/69 (32%) depression measured by HADS A & D. Quality of life is significantly impaired in those with Fukuda criteria CFS (QLS score 64±11) with significant negative relationships between quality of life and fatigue (p<0.0001), anxiety (p=0.0009), depression (p<0.0001) and autonomic symptoms (p=0.04).

CONCLUSION: This is the first study to summarise illness characteristics of Polish CFS/ME patients. Our study has confirmed that fatigue is a common and under-recognised symptom affecting the Polish population.

Source: Słomko J, Newton JL, Kujawski S, Tafil-Klawe M, Klawe J, Staines D, Marshall-Gradisnik S, Zalewski P. Prevalence and characteristics of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) in Poland: a cross-sectional study. BMJ Open. 2019 Mar 7;9(3):e023955. doi: 10.1136/bmjopen-2018-023955. https://bmjopen.bmj.com/content/9/3/e023955.long (Full study)

Mitochondrial complex activity in permeabilised cells of chronic fatigue syndrome patients using two cell types

Abstract:

Abnormalities in mitochondrial function have previously been shown in chronic fatigue syndrome (CFS) patients, implying that mitochondrial dysfunction may contribute to the pathogenesis of disease. This study builds on previous work showing that mitochondrial respiratory parameters are impaired in whole cells from CFS patients by investigating the activity of individual mitochondrial respiratory chain complexes.

Two different cell types were used in these studies in order to assess individual complex activity locally in the skeletal muscle (myotubes) (n = 6) and systemically (peripheral blood mononuclear cells (PBMCs)) (control n = 6; CFS n = 13). Complex I, II and IV activity and respiratory activitysupported by fatty acid oxidation and glutaminolysis were measured usingextracellular flux analysis. Cells were permeabilised and combinations of substrates and inhibitors were added throughout the assays to allow states of mitochondrial respiration to be calculated and the activity of specific aspects of respiratory activity to be measured.

Results showed there to be no significant differences in individual mitochondrial complex activity or respiratory activity supported by fatty acid oxidation or glutaminolysis between healthy control and CFS cohorts in either skeletal muscle (p ≥ 0.190) or PBMCs (p ≥ 0.065).

This is the first study to use extracellular flux analysisto investigate individual mitochondrial complex activity in permeabilised cells in the context of CFS. The lack of difference in complex activity in CFS PBMCs suggests that the previously observed mitochondrial dysfunction in whole PBMCs is due to causes upstream of the mitochondrial respiratory chain.

Source: Tomas C, Brown AE, Newton JL, Elson JL. Mitochondrial complex activity in permeabilised cells of chronic fatigue syndrome patients using two cell types. PeerJ. 2019 Mar 1;7:e6500. doi: 10.7717/peerj.6500. eCollection 2019. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398432/ (Full article)

MtDNA population variation in Myalgic encephalomyelitis/Chronic fatigue syndrome in two populations: a study of mildly deleterious variants

Abstract:

Myalgic Encephalomyelitis (ME), also known as Chronic Fatigue Syndrome (CFS) is a debilitating condition. There is growing interest in a possible etiologic or pathogenic role of mitochondrial dysfunction and mitochondrial DNA (mtDNA) variation in ME/CFS. Supporting such a link, fatigue is common and often severe in patients with mitochondrial disease.

We investigate the role of mtDNA variation in ME/CFS. No proven pathogenic mtDNA mutations were found. We then investigated population variation. Two cohorts were analysed, one from the UK (n = 89 moderately affected; 29 severely affected) and the other from South Africa (n = 143 moderately affected). For both cohorts, ME/CFS patients had an excess of individuals without a mildly deleterious population variant. The differences in population variation might reflect a mechanism important to the pathophysiology of ME/CFS.

Source: Venter M, Tomas C, Pienaar IS, Strassheim V, Erasmus E, Ng WF, Howell N, Newton JL, Van der Westhuizen FH, Elson JL. MtDNA population variation in Myalgic encephalomyelitis/Chronic fatigue syndrome in two populations: a study of mildly deleterious variants. Sci Rep. 2019 Feb 27;9(1):2914. doi: 10.1038/s41598-019-39060-1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393470/ (Full article)

Impairments in cognitive performance in chronic fatigue syndrome are common, not related to co-morbid depression but do associate with autonomic dysfunction

Abstract:

OBJECTIVES: To explore cognitive performance in chronic fatigue syndrome (CFS) examining two cohorts. To establish findings associated with CFS and those related to co-morbid depression or autonomic dysfunction.

METHODS: Identification and recruitment of participants was identical in both phases, all CFS patients fulfilled Fukuda criteria. In Phase 1 (n = 48) we explored cognitive function in a heterogeneous cohort of CFS patients, investigating links with depressive symptoms (HADS). In phase 2 (n = 51 CFS & n = 20 controls) participants with co-morbid major depression were excluded (SCID). Furthermore, we investigated relationships between cognitive performance and heart rate variability (HRV).

RESULTS: Cognitive performance in unselected CFS patients is in average range on most measures. However, 0-23% of the CFS sample fell below the 5th percentile. Negative correlations occurred between depressive symptoms (HAD-S) with Digit-Symbol-Coding (r = -.507, p = .006) and TMT-A (r = -.382, p = .049). In CFS without depression, impairments of cognitive performance remained with significant differences in indices of psychomotor speed (TMT-A: p = 0.027; digit-symbol substitution: p = 0.004; digit-symbol copy: p = 0.007; scanning: p = .034) Stroop test suggested differences due to processing speed rather than inhibition. Both cohorts confirmed relationships between cognitive performance and HRV (digit-symbol copy (r = .330, p = .018), digit-symbol substitution (r = .313, p = .025), colour-naming trials Stroop task (r = .279, p = .050).

CONCLUSION: Cognitive difficulties in CFS may not be as broad as suggested and may be restricted to slowing in basic processing speed. While depressive symptoms can be associated with impairments, co-morbidity with major depression is not itself responsible for reductions in cognitive performance. Impaired autonomic control of heart-rate associates with reductions in basic processing speed.

Source: Robinson LJ, Gallagher P, Watson S, Pearce R, Finkelmeyer A, Maclachlan L, Newton JL. Impairments in cognitive performance in chronic fatigue syndrome are common, not related to co-morbid depression but do associate with autonomic dysfunction. PLoS One. 2019 Feb 5;14(2):e0210394. doi: 10.1371/journal.pone.0210394. eCollection 2019. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0210394 (Full article)

Defining the prevalence and symptom burden of those with self-reported severe chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a two-phase community pilot study in the North East of England

Abstract:

OBJECTIVES:
To define the prevalence of severe chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) and its clinical characteristics in a geographically defined area of Northern England. To understand the feasibility of a community-based research study in the severely affected CFS/ME group.

DESIGN: A two-phase clinical cohort study to pilot a series of investigations in participants own homes.

SETTING: Participants were community living from the area defined by the Northern clinical network of the UK.

PARTICIPANTS: Adults with either a medical or a self-reported diagnosis of CFS/ME. Phase 1 involved the creation of a database. Phase 2: five participants were selected from database, dependent on their proximity to Newcastle.

INTERVENTIONS: The De Paul fatigue questionnaire itemised symptoms of CFS/ME, the Barthel Functional Outcome Measure and demographic questions were collected via postal return. For phase 2, five participants were subsequently invited to participate in the pilot study.

RESULTS: 483 questionnaire packs were requested, 63 were returned in various stages of completion. 56 De Paul fatigue questionnaires were returned: all but 12 met one of the CFS/ME criteria, but 12 or 22% of individuals did not fulfil the Fukuda nor the Clinical Canadian Criteria CFS/ME diagnostic criteria but 6 of them indicated that their fatigue was related to other causes and they barely had any symptoms. The five pilot participants completed 60% of the planned visits.

CONCLUSIONS: Severely affected CFS/ME individuals are keen to participate in research, however, their symptom burden is great and quality of life is poor. These factors must be considered when planning research and methods of engaging with such a cohort.

Source: Strassheim VJ, Sunnquist M, Jason LA, Newton JL. Defining the prevalence and symptom burden of those with self-reported severe chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a two-phase community pilot study in the North East of England. BMJ Open. 2018 Sep 19;8(9):e020775. doi: 10.1136/bmjopen-2017-020775. https://bmjopen.bmj.com/content/8/9/e020775.long (Full article)