TGI Friday! Our weekly update of recently published research abstracts | 26 February 2016

From British Medical Bulletin, published online on 12 February 2016.

The aetiopathogenesis of fatigue: unpredictable, complex and persistent

James E. Clark(†), W. Fai Ng(‡), Stuart Watson(†) and Julia L. Newton(‡,§,*).
†) Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK
‡) Faculty of Medical Sciences, Institute of Cellular Medicine, Newcastle University, Clinical Academic Office, 3rd Floor, William Leech Building, Newcastle upon Tyne NE2 4HH, UK
§) Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
*Correspondence address. E-mail:;



Chronic fatigue syndrome is a common condition characterized by severe fatigue with post-exertional malaise, impaired cognitive ability, poor sleep quality, muscle pain, multi-joint pain, tender lymph nodes, sore throat or headache. Its defining symptom, fatigue is common to several diseases.


Research has established a broad picture of impairment across autonomic, endocrine and inflammatory systems though progress seems to have reached an impasse.


The absence of a clear consensus view of the pathophysiology of fatigue suggests the need to switch from a focus on abnormalities in one system to an experimental and clinical approach which integrates findings across multiple systems and their constituent parts and to consider multiple environmental factors.


We discuss this with reference to three key factors, non-determinism, non-reductionism and self-organization and suggest that an approach based on these principles may afford a coherent explanatory framework for much of the observed phenomena in fatigue and offers promising avenues for future research.


By adopting this approach, the field can examine issues regarding aetiopathogenesis and treatment, with relevance for future research and clinical practice.

From Neurologia. published online on 11 February 2016.

Chronic fatigue syndrome and sleep disorders: clinical associations and diagnostic difficulties.
[Article in English, Spanish]

Ferré A
Unidad del Sueño, Servicio Neurofisiología Clínica, Hospital Quirón, Barcelona, España. Electronic address:



Chronic fatigue syndrome (CFS) is characterised by the presence of intractable fatigue and non-restorative sleep, symptoms which are also very prevalent in multiple diseases and appear as side effects of different drugs. Numerous studies have shown a high prevalence of sleep disorders in patients with CFS. However, non-restorative sleep and fatigue are frequently symptoms of the sleep disorders themselves, so primary sleep disorders have to be ruled out in many cases of CFS.

This review was performed using a structured search of the MeSH terms ([Sleep]+[Chronic fatigue syndrome]) in the PubMed database.


Identifying primary sleep disorders in patients meeting diagnostic criteria for CFS will allow for a more comprehensive treatment approach involving new diagnostic and therapeutic strategies that may improve quality of life for these patients.

From the Journal of Psychosomatic Research, 16 February 2016.

Treatment expectations influence the outcome of multidisciplinary rehabilitation treatment in patients with CFS

D.C.W.M. Vos-Vromans(1), I.P.J. Huijnen(2), L.J.M. Rijnders(1), B. Winkens(3), J.A. Knottnerus(4), R.J.E.M. Smeets(3)
1) Revant Rehabilitation Centre Breda, Brabantlaan 1, 4817 JW Breda, The Netherlands
2) Department of Rehabilitation Medicine, Research School CAPHRI Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands
3) Department of Methodology and Statistics, Research School CAPHRI, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands
4) Department of General Practice, Research School CAPHRI, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands


• Expectancy influenced the severity of fatigue and the physical component of the health-related quality of life after multidisciplinary rehabilitation treatment for patients with chronic fatigue syndrome.
• Credibility did not significantly influence the outcomes in multidisciplinary rehabilitation treatment or in cognitive behavioural therapy.
• Expectancy was not significantly influenced by baseline factors age, symptoms of depression, duration of illness, or treatment allocation, but was influenced by centre of treatment.
• For future research it is important to study how to increase expectations in order to increase the effectiveness of treatment.



To improve the effectiveness of treatment in patients with chronic fatigue syndrome it is worthwhile studying factors influencing outcomes. The aims of this study were (1) to assess the association of expectancy and credibility on treatment outcomes, and (2) to identify baseline variables associated with treatment expectancy and credibility.


122 patients were included in a randomized controlled trial of whom 60 received cognitive behavioural therapy (CBT) and 62 multidisciplinary rehabilitation treatment (MRT). Expectancy and credibility were measured with the credibility and expectancy questionnaire. Outcomes of treatment, fatigue, and quality of life (QoL), were measured at baseline and post-treatment. Multiple linear regressions were performed to analyse associations.


In explaining fatigue and the physical component of the QoL, the effect of expectancy was significant for MRT, whereas in CBT no such associations were found. The main effect of expectancy on the mental component of QoL was not significant. For credibility, the overall effect on fatigue and the physical component of QoL was not significant. In explaining the mental component of QoL, the interaction between treatment and credibility was significant. However, the effects within each group were not significant.

In the regression model with expectancy as dependent variable, only treatment centre appeared significantly associated. In explaining credibility, treatment centre, treatment allocation and depression contributed significantly.


For clinical practice it seems important to check the expectations of the patient, since expectations influence the outcome after MRT.

From Scientific Reports, published online on 19 February 2016 (open access).

Basal ganglia correlates of fatigue in young adults

Seishu Nakagawa(1,2), Hikaru Takeuchi(3), Yasuyuki Taki(3,4, 5), Rui Nouchi(6,7), Yuka Kotozaki(7), Takamitsu Shinada(2), Tsukasa Maruyama(2), Atsushi Sekiguchi(2,4,7,8), Kunio Iizuka(2,9), Ryoichi Yokoyama(2, 10), Yuki Yamamoto(2), Sugiko Hanawa(2), Tsuyoshi Araki(7), Carlos Makoto Miyauchi(2,11), Daniele Magistro(2, 10), Kohei Sakaki(2), Hyeonjeong Jeong(2, 10), Yukako Sasaki(2) & Ryuta Kawashima(2,3,7)
1) Department of Psychiatry, Tohoku Pharmaceutical University, Sendai, Japan
2) Department of Functional Brain Imaging, Institute of Development, Ageing and Cancer, Tohoku University, Sendai, Japan
3) Division of Developmental Cognitive Neuroscience, Institute of Development, Ageing and Cancer, Tohoku University, Sendai, Japan
4) Division of Medical Neuroimaging Analysis, Department of Community Medical Supports, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
5) Department of Nuclear Medicine and Radiology, Institute of Development, Ageing and Cancer, Tohoku University, Sendai, Japan
6)Human and Social Response Research Division, International Research Institute of Disaster Science, Tohoku University, Sendai, Japan
7) Smart Ageing International Research Center, Institute of Development, Ageing and Cancer, Tohoku University, Sendai, Japan
8) Department of Adult Mental Health, National Institute of Mental Health, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan
9) Department of Psychiatry, Tohoku University Graduate School of Medicine, Sendai, Japan
10) Japan Society for the Promotion of Science, Tokyo, Japan
11) Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, Japan


Although the prevalence of chronic fatigue is approximately 20% in healthy individuals, there are no studies of brain structure that elucidate the neural correlates of fatigue outside of clinical subjects.

We hypothesized that fatigue without evidence of disease might be related to changes in the basal ganglia and prefrontal cortex and be implicated in fatigue with disease. We aimed to identify the white matter structures of fatigue in young subjects without disease using magnetic resonance imaging (MRI).

Healthy young adults (n = 883; 489 males and 394 females) were recruited. As expected, the degrees of fatigue and motivation were associated with larger mean diffusivity (MD) in the right putamen, pallidus and caudate. Furthermore, the degree of physical activity was associated with a larger MD only in the right putamen.

Accordingly, motivation was the best candidate for widespread basal ganglia, whereas physical activity might be the best candidate for the putamen. A plausible mechanism of fatigue may involve abnormal function of the motor system, as well as areas of the dopaminergic system in the basal ganglia that are associated with motivation and reward.

From Applied Psychophysiology and Biofeedback, published online 11 February 2016.

Intrinsic Functional Hypoconnectivity in Core Neurocognitive Networks Suggests Central Nervous System Pathology in Patients with Myalgic Encephalomyelitis: A Pilot Study

Marcie L. Zinn , Mark A. Zinn, Leonard A. Jason


Exact low resolution electromagnetic tomography (eLORETA) was recorded from nineteen EEG channels in nine patients with myalgic encephalomyelitis (ME) and 9 healthy controls to assess current source density and functional connectivity, a physiological measure of similarity between pairs of distributed regions of interest, between groups. Current source density and functional connectivity were measured using eLORETA software.

We found significantly decreased eLORETA source analysis oscillations in the occipital, parietal, posterior cingulate, and posterior temporal lobes in Alpha and Alpha-2. For connectivity analysis, we assessed functional connectivity within Menon triple network model of neuropathology. We found support for all three networks of the triple network model, namely the central executive network (CEN), salience network (SN), and the default mode network (DMN) indicating hypo-connectivity in the Delta, Alpha, and Alpha-2 frequency bands in patients with ME compared to controls.

In addition to the current source density resting state dysfunction in the occipital, parietal, posterior temporal and posterior cingulate, the disrupted connectivity of the CEN, SN, and DMN appears to be involved in cognitive impairment for patients with ME.

This research suggests that disruptions in these regions and networks could be a neurobiological feature of the disorder, representing underlying neural dysfunction.

From Diagnostics, 5 February 2016 (open access).

Discussion paper: Replacing Myalgic Encephalomyelitis and Chronic Fatigue Syndrome with Systemic Exercise Intolerance Disease Is Not the Way forward

Frank N.M. Twisk
ME-de-patiënten Foundation, Zonnedauw 15, 1906 HB Limmen, The Netherlands;;


Myalgic encephalomyelitis (ME), described in the medical literature since 1938, is characterized by distinctive muscular symptoms, neurological symptoms, and signs of circulatory impairment. The only mandatory feature of chronic fatigue syndrome (CFS), introduced in 1988 and redefined in 1994, is chronic fatigue, which should be accompanied by at least four or more out of eight “additional” symptoms.

The use of the abstract, polythetic criteria of CFS, which define a heterogeneous patient population, and self-report has hampered both scientific progress and accurate diagnosis. To resolve the “diagnostic impasse” the Institute of Medicine proposes that a new clinical entity, systemic exercise intolerance disease (SEID), should replace the clinical entities ME and CFS. However, adopting SEID and its defining symptoms, does not resolve methodological and diagnostic issues.

Firstly, a new diagnostic entity cannot replace two distinct, partially overlapping, clinical entities such as ME and CFS. Secondly, due to the nature of the diagnostic criteria, the employment of self-report, and the lack of criteria to exclude patients with other conditions, the SEID criteria seem to select an even more heterogeneous patient population, causing additional diagnostic confusion.

This article discusses methodological and diagnostic issues related to SEID and proposes a methodological solution for the current “diagnostic impasse”.

From Comprehensive Psychiatry, published online 9 February 2016.

Neurocognitive improvements after best-practice intervention for chronic fatigue syndrome: Preliminary evidence of divergence between objective indices and subjective perceptions

Erin Cvejice(1), Andrew R. Lloyd(2), Uté Vollmer-Conna(1)
1) School of Psychiatry, University of New South Wales, Australia
2) Inflammation and Infection Research Centre, School of Medical Sciences, University of New South Wales, Australia



Neurocognitive difficulties are commonly reported by patients suffering from chronic fatigue syndrome (CFS). Moderate improvements from ‘best practice’ therapy are promising, but to date reported efficacy is based entirely on subjective measures. This is problematic, given the well-documented divergence between subjective perceptions and actual neurocognitive performance, including in this patient group.


Subjective and objective measures of neurocognitive performance were obtained from 25 patients with well-characterised CFS before and after the completion of a 12-week graded-activity program incorporating a cognitive training component. Additionally, self-reported symptoms, cardiac autonomic activity (a relevant biomarker of stress responsivity), and their relation to neurocognitive improvements were examined.


Substantive post-intervention improvements in subjective (p=0.006) and objective (including faster responses speeds and greater accuracy, p’s<0.001) neurocognitive performance were documented. Participants also demonstrated reduced autonomic reactivity to the cognitive challenge at follow-up (p’s≤0.01). These improvements were accompanied by improvements in symptom ratings (p’s≤0.01). However, subjective ratings of neurocognitive difficulties, and CFS-related symptoms were not linked to objective performance improvements. CONCLUSIONS These initial data provide the first evidence of objective neurocognitive performance improvements accompanied by a significant reduction in responsiveness in stress-related neural pathways consequent to cognitive-behavioural/ graded exercise therapy programs. These findings provide support for the effectiveness of such programs in remediating clinical status. These promising findings warrant further investigation, including replication in a larger sample utilising more controlled study designs.

From International Journal of Behavioral Medicine, published online 19 February 2016 (open access).

Differences in Physical and Psychosocial Characteristics Between CFS and Fatigued Non-CFS Patients, a Case-Control Study

Veronique De Gucht , Franshelis Katerinee Garcia, Marielle den Engelsman, Stan Maes
Health, Medical, and Neuropsychology Unit, Leiden University, Wassenaarseweg 52, P.O. BOX 955, 2300 RB, Leiden, The Netherlands



The main research question is: “Do CFS patients differ from fatigued non-CFS patients with respect to physical, cognitive, behavioral, social, and emotional determinants?” In addition, group differences in relevant outcomes were explored.


Patients who met the Centers for Disease Control (CDC) criteria for CFS were categorized as CFS; these patients were mainly recruited via a large Dutch patient organization. Primary care patients who were fatigued for at least 1 month and up to 2 years but did not meet the CDC criteria were classified as fatigued non-CFS patients. Both groups were matched by age and gender (N = 192 for each group).


CFS patients attributed their fatigue more frequently to external causes, reported a worse physical functioning, more medical visits, and a lower employment rate. The results of a multiple logistic regression analysis showed that patients who believe that their fatigue is associated with more severe consequences, that their fatigue will last longer and is responsible for more additional symptoms are more likely to be classified as CFS, while patients who are more physically active and have higher levels of “all or nothing behavior” are less likely to be classified as having CFS.


A longitudinal study should explore the predictive value of the above factors for the transition from medically unexplained fatigue to CFS in order to develop targeted interventions for primary care patients with short-term fatigue complaints.


0344 576 5326

Available every day of the week between these times: 10am - 12noon, 2pm - 4pm and 7pm - 9pm.

Calls cost the same as other standard landline numbers (starting 01 or 02). If you have a call package for your landline or mobile phone then calls will normally come out of your inclusive minutes.