• Welcome to Phoenix Rising!

    Created in 2008, Phoenix Rising is the largest and oldest forum dedicated to furthering the understanding of and finding treatments for complex chronic illnesses such as chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), long COVID, postural orthostatic tachycardia syndrome (POTS), mast cell activation syndrome (MCAS), and allied diseases.

    To register, simply click the Register button at the top right.

Chronic fatigue syndrome - A neuroimmunological model (Arnett et al., 2011)


Senior Member
I just read this. It's a hypothesis paper so no new data although it does draw together some data from CFS and other areas (which might be new to people) e.g. anti-TNF drugs have been tried in Alzheimers' Disease

Chronic fatigue syndrome - A neuroimmunological model.

Med Hypotheses. 2011 Apr 5. [Epub ahead of print]

Arnett SV, Alleva LM, Korossy-Horwood R, Clark IA.

Research School of Biology, Australian National University, Australia.

(I've given every line its own paragraph)

The aetiological and pathophysiological basis of chronic fatigue syndrome (CFS) remains a controversial field of inquiry in the research community.

While CFS and similar disease conditions such as fibromyalgia (FM) and post-infectious encephalopathy have been the focus of intense scrutiny for the past 20 years, results of research were often contradictory and a cohesive pathological model has remained elusive.

However, recent developments in understanding the unique immunophysiology of the brain may provide important clues for the development of a truly comprehensive explanation of the pathology of CFS.

We argue that CFS pathogenesis lies in the influence of peripheral inflammatory events on the brain and the unique immunophysiology of the central nervous system.

There is also evidence that CFS patients have a relative immunodeficiency that predisposes to poor early control of infection that leads to chronic inflammatory responses to infectious insults.

The neurological and endocrine changes have been described in CFS patients support the view that CFS has an inflammatory pathogenesis when considered as a whole.

An inflammatory model of disease also provides an explanation for the marked female sex bias associated with CFS.

This review therefore posits the hypothesis that CFS as a disease of long-term inflammatory processes of the brain.

We will also provide an investigative framework that could be used to justify the use of anti-TNF biological agents as a reliable and effective treatment approach to CFS, a syndrome that to date remains frustratingly difficult for both patients and health care professionals to manage.

Copyright 2011 Elsevier Ltd. All rights reserved.

PMID:21474251[PubMed - as supplied by publisher]


Senior Member
Section on graduated exercise therapy (GET)

It has a section on graduated exercise therapy (GET).

Nothing definitive but I know lots of people are interested in mentions of it:

The use of graduated exercise therapy and cognitive behavioural
therapy in managing CFS

As mentioned previously, two therapeutic interventions have
found widespread use in the management of CFS CBT and GET
[23]. CBT is the training of CFS patients to recognise exposures
and thought processes in their daily life that worsen symptoms,
to develop strategies to avoid or limit the impact of these exposures.
However, only 2040% of patients report any improvement
following cognitive behavioural therapy, and while it produces
some benefit in symptom scores it has not been shown to improve
cure rates [90,91]. In comparison, GET is the use of a graduated increase
in physical exercise over time with the aim of improving tolerance
to physical exertion as well as improving symptoms.
However, there have been recent challenges to the validity of using
GET in CFS in light of evidence that GET produced a marginal benefit
at best and in some cases exacerbated symptoms [92,93]. Most
recently, Nunez et al. demonstrated that GET failed to produce a
consistent quality of life benefit, but worsened pain and physical
function scores for many patients [94]. In contrast, White et al. reported
an improvement in mean fatigue scores between patients
receiving GET compared to those receiving standard medical care
[95]. Both investigators used the short form 36 questionnaire to assess
physical function in patients, and post-intervention evaluations
were conducted at 12 months in both studies.

The effect of exercise on immune and neural physiology is complex.
There is substantial evidence that effects are dose-dependent
sustained exercise regimes with a gradual increase in exertion induce
different responses to a sudden bout of high-intensity exertion.
The former has been shown to produce an antiinflammatory
effect, depressing serum TNF and increasing serum
IL-1 receptor antagonist, soluble TNF receptor and IL-10 concentrations
through the actions of IL-6 [96,97]. This immunomodulatory
effect is driven by mechanical stress incurred by skeletal myocytes,
which are the cellular source of the elevated IL-6 seen in individuals
who exercise regularly. Serum IL-6 production is proportional
to exercise duration, intensity and force exerted [98]. While IL-6
has been classically regarded as a pro-inflammatory cytokine,
there is evidence that it has a substantial anti-inflammatory effect
on the immune system; it stimulates IL-1 receptor antagonist production
and IL-10 production without increasing production of
pro-inflammatory cytokines such as TNF or IL-1b [96]. Furthermore,
both IL-6 knockout mice and mice treated with anti-IL-6
monoclonal antibodies show elevated basal serum TNF concentration
[96]. Therefore, IL-6 production by myocytes in response to
physical stress can exert an anti-inflammatory effect on the immune
system. There is also more direct evidence of a physiologically
relevant anti-inflammatory effect a preceding regular
exercise program reduces the TNF response to Escherichia coli challenge
in mouse models [96]. However, the potential pro-inflammatory
effects of exercise must also be considered. Exercise increases
circulating numbers of lymphocytes, monocytes, neutrophils and
NK cells [99], while abrupt high intensity exercise induces production
of pro-inflammatory cytokines [100,101]. In healthy individuals
the pro- and anti-inflammatory effects of exercise are roughly
balanced and no significant adverse effects develop. However, in
individuals with underlying inflammatory states such as traumatic
injury, infection, atopy or autoimmune disease, the balance is disturbed
and exercise has a pro-inflammatory effect (discussed in
detail in Cooper et al. [102]).

These considerations may provide an explanation for the unreliable
efficacy and potential adverse effects of GET in managing CFS
[92,93]. If CFS pathophysiology ultimately lies in inflammatory responses
to infection, then the variable pro- and anti-inflammatory
effects of exercise could either improve or exacerbate disease
symptoms on an individual basis. Explanation of this variable clin-
ical efficacy may lie in the sub-groupings of CFS patients described
by investigators such as Zhang et al. [9]. It may be that patients
with less severe persistent peripheral inflammation receive an
anti-inflammatory contribution from exercise, but the same exertions
are pro-inflammatory in patients with higher circulating
cytokine concentrations leading to exacerbation of symptoms.
Whatever the explanation, the use of GET in the management of
CFS is in serious doubt, and there stands a need to develop a method
of identifying which patients respond poorly to physical exercise
and should be advised to avoid GET.

[90] Price JR, Mitchell E, Tidy E, Hunot V. Cognitive behaviour therapy for chronic
fatigue syndrome in adults. Cochrane Database Syst Rev 2008;16:CD001027.
[91] Leone SS, Huibers MJ, Kant I, van Amelsvoort LG, van Schayck CP, Bleijenberg
G, et al. Long-term efficacy of cognitive-behavioral therapy by general
practitioners for fatigue: a 4-year follow-up study. J Psychosom Res
[92] Maes M, Twisk FN. Chronic fatigue syndrome: la bete noire of the Belgian
health care system. Neuro Endocrinol Lett 2009;30:30011.
[93] Twisk FN, Maes M. A review on cognitive behavorial therapy (CBT) and
graded exercise therapy (GET) in myalgic encephalomyelitis (ME) / chronic
fatigue syndrome (CFS): CBT/GET is not only ineffective and not evidencebased,
but also potentially harmful for many patients with ME/CFS. Neuro
Endocrinol Lett 2009;30:28499.
[94] Nunez M, Fernandez-Sola J, Nunez E, Fernandez-Huerta JM, Godas-Sieso T,
Gomez-Gil E, et al. Health-related quality of life in patients with chronic
fatigue syndrome: group cognitive behavioural therapy and graded exercise
versus usual treatment. A randomised controlled trial with 1 year of followup.
Clin Rheumatol 2011:p. 15.
[95] White P, Goldsmith K, Johnson A, Potts L, Walwyn R, Decesare J, et al.
Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded
exercise therapy, and specialist medical care for chronic fatigue syndrome
(PACE): a randomised trial. Lancet 2011:p. 17.
[96] Petersen AM, Pedersen BK. The anti-inflammatory effect of exercise. J Appl
Physiol 2005;98:115462.
[97] Garrod R, Ansley P, Canavan J, Jewell A. Exercise and the inflammatory
response in chronic obstructive pulmonary disease (COPD)Does training
confer anti-inflammatory properties in COPD? Med Hypotheses
[98] Mathur N, Pedersen BK. Exercise as a mean to control low-grade systemic
inflammation. Mediators Inflamm 2008;2008:109502.
[99] Adams GR, Zaldivar FP, Nance DM, Cooper DM. Exercise and leukocyte
interchange among central circulation, lung, spleen, and muscle. Brain Behav
Immun 2011;14:14.
[100] Ostrowski K, Rohde T, Asp S, Schjerling P, Pedersen BK. Pro- and antiinflammatory
cytokine balance in strenuous exercise in humans. J Physiol
1999;515(Pt 1):28791.
[101] Pedersen BK, Ostrowski K, Rohde T, Bruunsgaard H. The cytokine response to
strenuous exercise. Can J Physiol Pharmacol 1998;76:50511.
[102] Cooper DM, Radom-Aizik S, Schwindt C, Zaldivar Jr F. Dangerous exercise:
lessons learned from dysregulated inflammatory responses to physical
activity. J Appl Physiol 2007;103:7009.


Senior Member
A quick response before reading in full Dolphin - it is good to see some serious hypothesising now.


Senior Member
Victoria, Australia
I like the sound of this, from what I have read!

Does anyone know if the full text article has yet been published as this abstract in April was 'Epub ahead of print'? (This is a different question than, which author and publication which has already been asked).


Senior Member
I like the sound of this, from what I have read!

Does anyone know if the full text article has yet been published as this abstract in April was 'Epub ahead of print'? (This is a different question than, which author and publication which has already been asked).
It can be consideded as published from when it was made available as a full article i.e. can be quoted already. I have no idea when it might be in a print edition.


Near Cognac, France
Sounds plausible and certainly ties in with my own subjective feelings of brain inflammation and with Maes' gut permeability leading to inflammation paper.

As the paper points out, inhibiting TNF alpha may not be a good thing with a dysfunctional immune system or if there is persistent infection.

There are a range of natural TNF alpha inhibitors :


I tend to use curcumin.

Given the above caveats it might be best to try a compound that inhibits TNF alpha plus has an anti-viral action.