Tuesday, 25 August 2015

ResearchSpeak: could cognitive fatigue be linked to specific neuronal pathways?

Have we found the brain's fatigue pathway? #ResearchSpeak #MSBlog #MSResearch 

"I have been very interested in the neural substrate that underpins fatigue in people in general and in people with MS. Unlike other symptoms there is not a specific area of the brain where the percept of fatigue lies. What I mean is that unlike other sensory percepts (a conscious awareness of sensations) that have a specific area of the cerebral cortex allocated to them there is no area that has been identified for fatigue. Why? I am not sure and this is why we think fatigue is similar to alertness or wakefulness and is controlled by a distributed network that comes from the brainstem."

"The study below suggests that in MSers with fatigue there is a disruption of the projections linking the posterior hypothalamus to the brain stem. This is very interesting; if fatigue can be made worse by focal brainstem or hypothalamic pathology it could explain the disconnect between fatigue and physical disability. Not everyone who is physically disabled necessarily has pathology in this pathway. Similarly, people with 'benign MS' may have a lesion in this pathway and have profound fatigue and no physical or cognitive disabilities. Clearly this study needs to be repeated and some basic science done in this area. Who knows it may lead to a new treatment for MS-related fatigue."

"Did you know fatigue comes out on top of the list of symptoms that MSers would like to get rid of?"

"Please note that the negative affect, or low mood, associated with chronic fatigue is controlled by an area of the brain located the frontal lobe called the anterior cingulate gyrus. This area controls mood and not fatigue. If you lesion this area you potentially remove, or neutralise, the negative emotions that are associated with several unpleasant percepts, for example chronic intractable pain."

"I hope you are beginning to realise that although the central nervous system is modular, it is a highly connected network, which makes decoding its function at a molecular, cellular or network level so interesting. You can't say neuroscience and neurology are boring."

Hanken et al. On the relation between self-reported cognitive fatigue and the posterior hypothalamic-brainstem network. Eur J Neurol. 2015 Aug. doi: 10.1111/ene.12815.

BACKGROUND AND PURPOSE: Various causes have been suggested for multiple sclerosis (MS) related fatigue. Hypothalamus-brainstem fibres play a role in sleep-wake regulation and in hypothalamic deactivation during inflammatory states. Hence, they may play a role for experiencing fatigue by changing bottom-up hypothalamic activation.

METHODS: Multiple sclerosis patients with and without self-reported cognitive fatigue and healthy controls were analysed with respect to the integrity of hypothalamus-brainstem fibres using diffusion-tensor imaging based tractography, focusing on the anterior, medial and posterior hypothalamic areas, controlling for clinical impairment and excluding participants with depressive mood.

RESULTS: Multiple sclerosis patients without self-reported cognitive fatigue showed increased axial and radial diffusivity levels specifically for fibres connecting the right posterior hypothalamus with the right locus coeruleus, but not for the medial hypothalamus and the corpus callosum. Moreover, there were no differences between MS patients with and without fatigue in brain atrophy and lesion load, which could explain our results.

CONCLUSION: Multiple sclerosis patients not experiencing fatigue show increased axial and radial diffusivity for fibres connecting the posterior hypothalamus and the brainstem, which might prevent bottom-up activation of the posterior hypothalamus and therefore downregulation of structures responsible for wakefulness and exploratory states of mind.


  1. Prof G and the physical fatigue, would be more related to the inflammatory process itself? Or it could be this same mechanism of cognitive fatigue? Participate in a group in which many patients report not doing virtually nothing and still feel exhausted, or agree already exhausted, even having had a peaceful sleep ...

  2. Are there potentially 2 mechanisms going on here? I say this because I, and some other MSers, suffer from 2 symptoms relating to fatigue - exhaustion, AND a feeling like you're coming down with the flu. They can present apparently independently of each other. Given research into ME, perhaps the flu-like symptoms are not described by damage to the brain relating to wakefulness, but instead as a result of the inflammatory processes of MS?:
    * Rituximab use in treating ME symptoms: https://www.newscientist.com/article/dn27813-antibody-wipeout-found-to-relieve-chronic-fatigue-syndrome/?source=fromBetaSite

    * http://www.neuroscientistnews.com/research-news/robust-evidence-discovered-chronic-fatigue-syndrome-biological-illness (I assume cytokine levels are already used as a biomarker in some MS studies? or not?)
    "Short duration patients had increased amounts of many different types of immune molecules called cytokines. The association was unusually strong with a cytokine called interferon gamma that has been linked to the fatigue that follows many viral infections, including Epstein-Barr virus (the cause of infectious mononucleosis). Cytokine levels were not explained by symptom severity."

    * http://www.neuroscientistnews.com/research-news/research-sheds-new-light-cause-chronic-fatigue-syndromemyalgic-encephalomyelitis - ME symptoms mimac MS fatigue for some of us.

    I'd be very interested to know what your thoughts are on what causes the flu-like symptoms some of us get with our fatigue (as there does not seem to be much if any info out there as to what this is / what it means). Many Thanks.

    1. I'm answering part of my own question by citing your blog post: http://multiple-sclerosis-research.blogspot.com/2014/01/clinic-speak-fatigue-trial.html

      "Firstly, inflammation in the brain causes fatigue. This is due to inflammatory mediators (IL-1 and TNF-alpha) triggering sickness behaviour. The latter is a behavioral response we have to inflammation, which forces us to rest and sleep, so that the body can recover."

      Thank you St Barts for the blog posts on fatigue, our neuros have never had the time to go into different types of fatigue, the causes, symptoms, or lifestyle improvements for many of us. Yet another example of how crucial and beneficial your blog is to so many of us!


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