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“The decreased production [of BDNF] in those with CFS was unexpected and a novel finding. This finding could reflect a reduced ability to maintain neuronal structure and function in … CFS.” Authors


ME/CFS gets paired with another neuroimmune disorder and the results are illuminating

Chronic fatigue syndrome and multiple sclerosis don’t get paired in studies very often, and that’s a shame.  Both are neuro-immune disorders and both are associated with enormous fatigue.  The authors of this study suggested MS could provide something of a guide to research possibilities in ME/CFS, and after this study it’s hard to see how it could not.

Two Extremely Fatiguing Disorders

In the face of the neurological devastation visited upon people with MS we sometimes forget that fatigue is the most common and often the most disabling symptom present.  It is fatigue that is the greatest contributor to disability in MS, and fatigue more than any other symptom determines  the quality of life MS patients experience; the more fatigued an MS patient is, the lower their quality of life.

Note that, while fatigue is commonly found in diseases, the very severe and often disabling type of fatigue found in ME/CFS and MS is not common at all and is only shared by relatively few disorders.

As in ME/CFS, the cause of the fatigue in MS remains obscure. Pro-inflammatory cytokines with their ability to invoke ‘sickness behavior’ are a possibility. As in ME/CFS, the pro-inflammatory cytokine situation in MS is a complex one. Pro-inflammatory cytokines could both be part of the disease process and could be elevated by the psychological stressor associated with having MS.


Fatigue may be common in medicine but few diseases have the degree of fatigue found in Chronic Fatigue Syndrome and mulitiple sclerosis

Increased levels of tumor necrosis factor a (TNF-a) have been associated both with the demyelination processes occurring in MS and the stress associated with having the disease. TNF-a‘s contribution to the disease process in MS means that psychological stressors which elevate TNF-a in MS patients could worsen their MS.

Factors other than fatigue may bind ME/CFS and MS together.  One of the first ME/CFS findings to appear was the presence of small white-matter hyperintensities in the brains of some people with ME/CFS. Those unidentified bright objects – most of them found in the frontal lobes – could reflect an immunological disease process in the central nervous system that has some similarity to that found in MS.

We’ve got immune and neurological problems and a large symptom overlap in ME/CFS and MS. What’s not to like about a study comparing the two?

Brain Derived Neurotrophic  Factor (BDNF)

BDNF is a neurotrophic factor.   Calling neurotrophic factors important nervous system agents is like calling eggs important ingredients in omelettes.  Neurotrophic factors are involved in the proliferation, differentiation, maintenance, plasticity, survival and function of neurons in both the central and peripheral nervous systems.  (What else is left?)

BDNF is the most abundant neurotrophic factor in our central nervous system. BDNF regulates the growth of nerve axons, neuron differentiation, proliferation and survival. It’s a key player in neuroplasticity  – the ability of the brain to adapt to new  situations –  across the central  nervous system as well as with neural regeneration across the body.


BDNF is a key player neuroplasticity – the ability of the brain to adapt to new situations

BDNF also protects against damage occurring during ischemia – the low blood flows some studies suggest may be present in ME/CFS.

BDNF issues have been implicated in both neurological and neuropsychiatric disorders and it probably plays a role in the small fiber neuropathies found in the periphery (the body). Down regulation of BDNF has also been tied to neuronal atrophy in the hippocampus and the progression of stress induced depression.  Reduced BDNF levels in different parts of the brain have been tied to Alzheimer’s, Parkinson’s and Huntington’s disorders.

BDNF is getting a lot of study these days and it’s become a major molecular target for drug companies seeking to treat neurological disorders.

Given the neuronal atrophy in MS and the neuro-immune components of ME/CFS, it made sense to take a look at BDNF levels in both disorders.  Blood BDNF levels (measured as peripheral blood mononucleated cells orPBMCs) in stimulated and unstimulated cultures were assessed in 15 people with ME/CFS, 57 MS patients, and 37 healthy controls.

The results were astonishing.


The researchers probably suspected the MS patients would have abnormal BDNF levels given the amount of neuronal destruction present, but no one suspected what they found in the ME/CFS patients.  Both the MS and the ME/CFS patients’ BDNF levels were a paltry 25% of those found in the healthy controls. This highly significant finding (p<.001) suggested, of course, that a key factor in neuron repair was hardly present in either group.

empty brain

Very low BDNF levels in both the ME/CFS and MS patients suggest low rates of neuron repair are present in both

Adding factors to the blood (phorbol myristate acetate or PMA, and pyridoxalated-hemoglobin-polyoxyethylene conjugate or PHP) that are designed to stimulate BDNF revealed profound deficits in BDNF production in the MS  patients, significant deficits in BDNF production in ME/CFS patients, and normal increases in BDNF production in healthy controls.

The small numbers of ME/CFS patients in the study made this essentially a pilot study for ME/CFS.

The authors suggested that low levels of nerve repair agents could be responsible for the small central nervous system lesions found in the frontal lobes of some people with ME/CFS.  The fact that fatigue scores are correlated with frontal lobe lesions in MS suggest these lesions could play a role in the fatigue in ME/CFS.  Low hippocampal BDNF levels were also found in a mouse model of ME/CFS.

(When we talk about weakened nerves the term neurasthenia does come to mind.  It has some negative connotations but the original term referred to ‘weakened nerves’ and ‘nervous system exhaustion’ – two factors that could be explained by low levels of the key neuron repair and proliferation protein – BDNF.)


The study was small but strikingly low levels of a key nerve factor (BDNF) in both ME/CFS (and multiple sclerosis) suggested that both neuron repair and proliferation could be inhibited in Chronic Fatigue Syndrome. The low BDNF levels could explain the abnormal frontal lobe MRI findings in ME/CFS which in turn could be associated with fatigue.  Similarly low BDNF findings in different parts of the brain occur in several neurological and neuropsychiatric disorders.

  • In Part II of our BDNF and ME/CFS series, “Breaking the BDNF Blues“, Dr. Courtney Craig examines and fleshes out the BDNF situation in ME/CFS, suggests it may be linked to findings of neuroinflammation, and provides treatment options.


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