Low putamen activity associated with poor reward sensitivity in childhood chronic fatigue syndrome

Abstract:

Motivational signals influence a wide variety of cognitive processes and components of behavioral performance. Cognitive dysfunction in patients with childhood chronic fatigue syndrome (CCFS) may be closely associated with a low motivation to learn induced by impaired neural reward processing. However, the extent to which reward processing is impaired in CCFS patients is unclear.

The aim of the present functional magnetic resonance imaging (fMRI) study was to determine whether brain activity in regions related to reward sensitivity is impaired in CCFS patients. fMRI data were collected from 13 CCFS patients (mean age, 13.6 ± 1.0 years) and 13 healthy children and adolescents (HCA) (mean age, 13.7 ± 1.3 years) performing a monetary reward task. Neural activity in high- and low-monetary-reward conditions was compared between CCFS and HCA groups. Severity of fatigue and the reward obtained from learning in daily life were evaluated by questionnaires.

Activity of the putamen was lower in the CCFS group than in the HCA group in the low-reward condition, but not in the high-reward condition. Activity of the putamen in the low-reward condition in CCFS patients was negatively and positively correlated with severity of fatigue and the reward from learning in daily life, respectively.

We previously revealed that motivation to learn was correlated with striatal activity, particularly the neural activity in the putamen. This suggests that in CCFS patients low putamen activity, associated with altered dopaminergic function, decreases reward sensitivity and lowers motivation to learn.

 

Source: Mizuno K, Kawatani J, Tajima K, Sasaki AT, Yoneda T, Komi M, Hirai T, Tomoda A, Joudoi T, Watanabe Y. Low putamen activity associated with poor reward sensitivity in childhood chronic fatigue syndrome. Neuroimage Clin. 2016 Sep 26;12:600-606. eCollection 2016. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5043413/ (Full article)

 

Postural orthostatic tachycardia is not a useful diagnostic marker for chronic fatigue syndrome

Abstract:

BACKGROUND: Postural orthostatic tachycardia syndrome (POTS) is considered a diagnostic marker for chronic fatigue syndrome (CFS).

OBJECTIVES: The aims of this study were to (i) compare POTS prevalence in a CFS cohort with fatigued patients not meeting CFS criteria, and (ii) assess activity, impairment and response to cognitive behavioural therapy (CBT) in CFS patients with POTS (POTS-CFS) and without POTS (non-POTS-CFS).

METHODS: Prospective cohort study at the Radboud University Medical Centre in the Netherlands. Between June 2013 and December 2014, 863 consecutive patients with persistent fatigue were screened. Patients underwent an active standing test, filled out questionnaires and wore an activity-sensing device for a period of 12 days.

RESULTS: A total of 419 patients with CFS and 341 non-CFS fatigued patients were included in the study. POTS prevalence in adult patients with CFS was 5.7% vs. 6.9% in non-CFS adults (P = 0.54). In adolescents, prevalence rates were 18.2% and 17.4%, respectively (P = 0.93). Adult patients with POTS-CFS were younger (30 ± 12 vs. 40 ± 13 years, P = 0.001) and had a higher supine heart rate (71 ± 11 vs. 65 ± 9 beats per min, P = 0.009) compared with non-POTS-CFS patients. Severity and activity patterns did not differ between groups. In patients with CFS, criteria for Systemic Exertion Intolerance Disease (SEID) were met in 76% of adults and 67% of adolescents. In these patients with CFS fulfilling the SEID criteria, the prevalence of POTS was not different from that in the overall CFS population. POTS-CFS adolescents had less clinically significant improvement after CBT than non-POTS-CFS adolescents (58% vs. 88%, P = 0.017).

CONCLUSION: In adults with CFS, the prevalence of POTS was low, was not different from the rate in non-CFS fatigued patients and was not related to disease severity or treatment outcome. In POTS-CFS adolescents, CBT was less successful than in non-POTS-CFS patients. The evaluation of POTS appears to be of limited value for the diagnosis of CFS.

© 2016 The Association for the Publication of the Journal of Internal Medicine.

 

Source: Roerink ME, Lenders JW, Schmits IC, Pistorius AM, Smit JW, Knoop H, van der Meer JW. Postural orthostatic tachycardia is not a useful diagnostic marker for chronic fatigue syndrome. J Intern Med. 2017 Feb;281(2):179-188. doi: 10.1111/joim.12564. Epub 2016 Oct 2. https://www.ncbi.nlm.nih.gov/pubmed/27696568

 

Static and dynamic functional connectivity in patients with chronic fatigue syndrome: use of arterial spin labelling fMRI

Abstract:

Studies using arterial spin labelling (ASL) have shown that individuals with chronic fatigue syndrome (CFS) have decreased regional cerebral blood flow, which may be associated with changes in functional neural networks.

Indeed, recent studies indicate disruptions in functional connectivity (FC) at rest in chronically fatigued patients including perturbations in static FC (sFC), that is average FC at rest between several brain regions subserving neurocognitive, motor and affect-related networks.

Whereas sFC often provides information of functional network reorganization in chronic illnesses, investigations of temporal changes in functional connectivity between multiple brain areas may shed light on the dynamic characteristics of brain network activation associated with such maladies.

We used ASL fMRI in 19 patients with CFS and 15 healthy controls (HC) to examine both static and dynamic changes in FC among several a priori selected brain regions during a fatiguing cognitive task. HC showed greater increases than CFS in static FC (sFC) between insula and temporo-occipital structures and between precuneus and thalamus/striatum.

Furthermore, inferior frontal gyrus connectivity to cerebellum, occipital and temporal structures declined in HC but increased in CFS. Patients also showed lower dynamic FC (dFC) between hippocampus and right superior parietal lobule. Both sFC and dFC correlated with task-related fatigue increases.

These data provide the first evidence that perturbations in static and dynamic FC may underlie chronically fatigued patients’ report of task-induced fatigue. Further research will determine whether such changes in sFC and dFC are also characteristic for other fatigued individuals, including patients with chronic pain, cancer and multiple sclerosis.

© 2016 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.

 

Source: Boissoneault J, Letzen J, Lai S, Robinson ME, Staud R. Static and dynamic functional connectivity in patients with chronic fatigue syndrome: use of arterial spin labelling fMRI. Clin Physiol Funct Imaging. 2016 Sep 28. doi: 10.1111/cpf.12393. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/27678090

 

 

Bottom-up proteomics suggests an association between differential expression of mitochondrial proteins and chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is a debilitating and complex disorder characterized by unexplained fatigue not improved by rest. An area of investigation is the likely connection of CFS with defective mitochondrial function.

In a previous work, we investigated the proteomic salivary profile in a couple of monozygotic twins discordant for CFS. Following this work, we analyzed mitochondrial proteins in the same couple of twins. Nano-liquid chromatography electrospray ionization mass spectrometry (nano-LC-MS) was used to study the mitochondria extracted from platelets of the twins. Subsequently, we selected three proteins that were validated using western blot analysis in a big cohort of subjects (n=45 CFS; n=45 healthy), using whole saliva (WS). The selected proteins were as follows: aconitate hydratase (ACON), ATP synthase subunit beta (ATPB) and malate dehydrogenase (MDHM).

Results for ATPB and ACON confirmed their upregulation in CFS. However, the MDHM alteration was not confirmed. Thereafter, seeing the great variability of clinical features of CFS patients, we decided to analyze the expression of our proteins after splitting patients according to clinical parameters. For each marker, the values were actually higher in the group of patients who had clinical features similar to the ill twin.

In conclusion, these results suggest that our potential markers could be one of the criteria to be taken into account for helping in diagnosis. Furthermore, the identification of biomarkers present in particular subgroups of CFS patients may help in shedding light upon the complex entity of CFS. Moreover, it could help in developing tailored treatments.

 

Source: Ciregia F, Kollipara L, Giusti L, Zahedi RP, Giacomelli C, Mazzoni MR, Giannaccini G, Scarpellini P, Urbani A, Sickmann A, Lucacchini A, Bazzichi L. Bottom-up proteomics suggests an association between differential expression of mitochondrial proteins and chronic fatigue syndrome. Transl Psychiatry. 2016 Sep 27;6(9):e904. doi: 10.1038/tp.2016.184. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5048217/ (Full article)

 

Obesity in adolescents with chronic fatigue syndrome: an observational study

Abstract:

OBJECTIVE: Identify the prevalence of obesity in patients with chronic fatigue syndrome (CFS) compared with healthy adolescents, and those identified with CFS in a population cohort.

DESIGN: Cross-sectional analysis of multiple imputed data.

SETTING: Data from UK paediatric CFS/myalgic encephalomyelitis (CFS/ME) services compared with data collected at two time points in the Avon Longitudinal Study of Parents and Children (ALSPAC).

PATIENTS: 1685 adolescents who attended a CFS/ME specialist service between 2004 and 2014 and 13 978 adolescents aged approximately 13 years and 16 years participating in the ALSPAC study.

MAIN OUTCOME MEASURES: Body mass index (BMI) (kg/m2), sex-specific and age-specific BMI Z-scores (relative to the International Obesity Task Force cut-offs) and prevalence of obesity (%).

RESULTS: Adolescents who had attended specialist CFS/ME services had a higher prevalence of obesity (age 13 years: 9.28%; age 16 years: 16.43%) compared with both adolescents classified as CFS/ME in ALSPAC (age 13 years: 3.72%; age 16 years: 5.46%) and those non-CFS in ALSPAC (age 13 years: 4.18%; age 16 years: 4.46%). The increased odds of obesity in those who attended specialist services (relative to non-CFS in ALSPAC) was apparent at both 13 years (OR: 2.31 (1.54 to 3.48)) and 16 years, with a greater likelihood observed at 16 years (OR: 4.07 (2.04 to 8.11)).

CONCLUSIONS: We observed an increased prevalence of obesity in adolescents who were affected severely enough to be referred to a specialist CFS/ME service. Further longitudinal research is required in order to identify the temporal relationship between the two conditions.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

 

Source: Norris T, Hawton K, Hamilton-Shield J, Crawley E. Obesity in adolescents with chronic fatigue syndrome: an observational study. Arch Dis Child. 2017 Jan;102(1):35-39. doi: 10.1136/archdischild-2016-311293. Epub 2016 Sep 21. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5256402/ (Full article)

 

Emotional conflict processing in adolescent chronic fatigue syndrome: A pilot study using functional magnetic resonance imaging

Abstract:

INTRODUCTION: Studies of neurocognition suggest that abnormalities in cognitive control contribute to the pathophysiology of chronic fatigue syndrome (CFS) in adolescents, yet these abnormalities remain poorly understood at the neurobiological level. Reports indicate that adolescents with CFS are significantly impaired in conflict processing, a primary element of cognitive control.

METHOD: In this study, we examine whether emotional conflict processing is altered on behavioral and neural levels in adolescents with CFS and a healthy comparison group. Fifteen adolescent patients with CFS and 24 healthy adolescent participants underwent functional magnetic resonance imaging (fMRI) while performing an emotional conflict task that involved categorizing facial affect while ignoring overlaid affect labeled words.

RESULTS: Adolescent CFS patients were less able to engage the left amygdala and left midposterior insula (mpINS) in response to conflict than the healthy comparison group. An association between accuracy interference and conflict-related reactivity in the amygdala was observed in CFS patients. A relationship between response time interference and conflict-related reactivity in the mpINS was also reported. Neural responses in the amygdala and mpINS were specific to fatigue severity.

CONCLUSIONS: These data demonstrate that adolescent CFS patients displayed deficits in emotional conflict processing. Our results suggest abnormalities in affective and cognitive functioning of the salience network, which might underlie the pathophysiology of adolescent CFS.

 

Source: Wortinger LA, Endestad T, Melinder AM, Øie MG, Sulheim D, Fagermoen E, Wyller VB. Emotional conflict processing in adolescent chronic fatigue syndrome: A pilot study using functional magnetic resonance imaging. J Clin Exp Neuropsychol. 2016 Sep 20:1-14. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/27647312

 

Cognitive behavioural therapy in the treatment of chronic fatigue syndrome: A narrative review on efficacy and informed consent

Abstract:

Cognitive behavioural therapy is increasingly promoted as a treatment for chronic fatigue syndrome. There is limited research on informed consent using cognitive behavioural therapy in chronic fatigue syndrome. We undertook a narrative review to explore efficacy and to identify the salient information that should be disclosed to patients.

We found a complex theoretical model underlying the rationale for psychotherapy in chronic fatigue syndrome. Cognitive behavioural therapy may bring about changes in self-reported fatigue for some patients in the short term, however there is a lack of evidence for long-term benefit or for improving physical function and cognitive behavioural therapy may cause distress if inappropriately prescribed. Therapist effects and placebo effects are important outcome factors.

© The Author(s) 2016.

 

Source: Geraghty KJ, Blease C. Cognitive behavioural therapy in the treatment of chronic fatigue syndrome: A narrative review on efficacy and informed consent. J Health Psychol. 2016 Sep 15. pii: 1359105316667798. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/27634687

 

The Role of Microbiota and Intestinal Permeability in the Pathophysiology of Autoimmune and Neuroimmune Processes with an Emphasis on Inflammatory Bowel Disease Type 1 Diabetes and Chronic Fatigue Syndrome

Abstract:

BACKGROUND: In steady state conditions intestinal immune homeostasis is maintained by a sophisticated bidirectional dialogue between the microbiota and the intestinal immune system. This “cross talk” is enabled by the presence of highly adapted secretory cells, sampling cells and pattern recognition receptors in the gastric epithelium.

METHODS: Herein we discuss the mechanisms involved in the breakdown of intestinal homeostasis and the development of systemic immune activation and neuroinflammation with a view to discussing the importance of these processes, in tandem with genetic and environmental factors, in the pathophysiology of (auto)immune diseases.Data is presented explaining how immune tolerance is maintained and how it may breakdown.

CONCLUSION: The breakdown of immune homeostasis following the development of gut inflammation, caused for example by gut dysbiosis, and the consequent increased intestinal permeability, is increasingly considered to be the ultimate source of the systemic immune activation and T helper 17/T regulatory cell imbalances, and maybe neurological disturbances, seen in autoimmune diseases such as Type 1 diabetes and inflammatory bowel disease. Increased intestinal permeability and translocation of commensal antigens into the systemic circulation is also a likely cause of the severe fatigue and an almost bewildering range of neurocognitive, neuroimaging and overall symptom presentations seen in patients with a diagnosis of Chronic Fatigue Syndrome.

 

Source: Morris G, Berk M, Carvalho AF, Caso JR, Sanz Y, Maes M. The Role of Microbiota and Intestinal Permeability in the Pathophysiology of Autoimmune and Neuroimmune Processes with an Emphasis on Inflammatory Bowel Disease Type 1 Diabetes and Chronic Fatigue Syndrome. Curr Pharm Des. 2016;22(40):6058-6075. https://www.ncbi.nlm.nih.gov/pubmed/27634186

 

The utility of patient-reported outcome measures among patients with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

PURPOSE: Debilitating fatigue is a core symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS); however, the utility of patient-reported symptom outcome measures of fatigue for ME/CFS patients is problematic due to ceiling effects and issues with reliability and validity. We sought to evaluate the performance of three patient-reported symptom measures in a sample of ME/CFS patients and matched controls.

METHODS: Two hundred and forty ME/CFS patients and 88 age, sex, race, and zip code matched controls participated in the study. Participants completed the Multidimensional Fatigue Inventory-20, DePaul Symptom Questionnaire, and RAND SF-36.

RESULTS: The general and physical fatigue subscales on Multidimensional Fatigue Inventory-20, as well as the role of physical health on the RAND SF-36, demonstrated questionable or unacceptable internal consistency and problematic ceiling effects. The DePaul Symptom Questionnaire demonstrated excellent internal reliability, and less than 5 % of participants were at the ceiling on each subscale. The post-exertional malaise subscale on the DePaul Symptom Questionnaire demonstrated excellent clinical utility as it was able to differentiate between ME/CFS patients and controls (OR 1.23, p < .001) and predicted ceiling effects on other patient-reported outcome subscales. A score of 20 on the post-exertional malaise subscale of the DePaul Symptom Questionnaire optimally differentiated between patients and controls.

CONCLUSIONS: Significant ceiling effects and concerns with reliability and validity were observed among Multidimensional Fatigue Inventory-20 and RAND SF-36 subscales for ME/CFS patients. The DePaul Symptom Questionnaire addresses a number of concerns typically identified when using patient-reported outcome measures with ME/CFS patients; however, an improved multidimensional patient-reported outcome tool for measuring ME/CFS-related symptoms is warranted.

 

Source: Murdock KW, Wang XS, Shi Q, Cleeland CS, Fagundes CP, Vernon SD. The utility of patient-reported outcome measures among patients with myalgic encephalomyelitis/chronic fatigue syndrome. Qual Life Res. 2016 Sep 6. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/27600520

 

Dysregulation of Protein Kinase Gene Expression in NK Cells from Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients

Abstract:

BACKGROUND: The etiology and pathomechanism of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) are unknown. However, natural killer (NK) cell dysfunction, in particular reduced NK cytotoxic activity, is a consistent finding in CFS/ME patients. Previous research has reported significant changes in intracellular mitogen-activated protein kinase pathways from isolated NK cells. The purpose of this present investigation was to examine whether protein kinase genes have a role in abnormal NK cell intracellular signaling in CFS/ME.

METHOD: Messenger RNA (mRNA) expression of 528 protein kinase genes in isolated NK cells was analyzed (nCounter GX Human Kinase Kit v2 (XT); NanoString Technologies) from moderate (n = 11; age, 54.9 ± 10.3 years) and severe (n = 12; age, 47.5 ± 8.0 years) CFS/ME patients (classified by the 2011 International Consensus Criteria) and nonfatigued controls (n = 11; age, 50.0 ± 12.3 years).

RESULTS: The expression of 92 protein kinase genes was significantly different in the severe CFS/ME group compared with nonfatigued controls. Among these, 37 genes were significantly upregulated and 55 genes were significantly downregulated in severe CFS/ME patients compared with nonfatigued controls.

CONCLUSIONS: In severe CFS/ME patients, dysfunction in protein kinase genes may contribute to impairments in NK cell intracellular signaling and effector function. Similar changes in protein kinase genes may be present in other cells, potentially contributing to the pathomechanism of this illness.

 

Source: Chacko A, Staines DR, Johnston SC, Marshall-Gradisnik SM. Dysregulation of Protein Kinase Gene Expression in NK Cells from Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients. Gene Regul Syst Bio. 2016 Aug 28;10:85-93. doi: 10.4137/GRSB.S40036. ECollection 2016. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5003121/ (Full article)