Can MRI explain fatigue in MS?


Mult Scler. 2017 Jun 1:1352458517717807. doi: 10.1177/1352458517717807. [Epub ahead of print]

Abnormal functional connectivity of thalamic sub-regions contributes to fatigue in multiple sclerosis.

Hidalgo de la Cruz M, d’Ambrosio A, Valsasina P, Pagani E, Colombo B, Rodegher M, Falini A, Comi G, Filippi M, Rocca MA.



To investigate sub-regional thalamic resting-state (RS) functional connectivity (FC) abnormalities in multiple sclerosis (MS) and their correlation with fatigue and its subcomponents (physical, cognitive, and psychosocial).


From 122 MS patients and 94 healthy controls, 5 thalamic sub-regions (frontal, motor, postcentral, occipital, temporal) were parcellated based on their cortico-thalamic structural connectivity and used for a seed-based RS FC analysis. Abnormalities of thalamic RS FC in MS patients and their correlation with Modified Fatigue Impact Scale (MFIS) were assessed.


Compared to controls and non-fatigued MS ( n = 86), fatigued MS patients ( n = 36) showed thalamic RS FC abnormalities with middle frontal gyrus, sensorimotor network, precuneus, insula, and cerebellum, which correlated with global MFIS. Higher thalamic RS FC with precuneus and lower RS FC with posterior cerebellum correlated with cognitive MFIS. Higher thalamic RS FC with sensorimotor network in frontal-, motor-, and temporal thalamic sub-regions correlated with physical and psychosocial MFIS. Reduced thalamic RS FC with right insula in motor-, postcentral-, and occipital thalamic sub-regions correlated with psychosocial fatigue.


Regional thalamic RS FC abnormalities with different cortical regions, including the frontal lobe, sensorimotor network, precuneus, insular cortices, and cerebellum contribute to fatigue in MS. Abnormal RS FC of selected thalamo-cortical connections explains different components of fatigue.

I’m on the Rhyd Ddu path (or commonly known as the South Ridge, 8.5 miles) of m.Snowdon in Wales. As a vegetarian for my whole life, I’ve struggled with fatigue under the strains of my busy working life. But, over the years the old me has gradually metamorphosed into a person of greater endurance, as a rock climbing, mountain climbing chick. Change was key, and for me at least tiredness seems to be a thing of the past.

I am old, Gandalf. I don’t look it, but I am beginning to feel it in my heart of hearts. Well-preserved indeed! Why, I feel all thin, sort of stretched, if you know what I mean: like butter that has been scraped over too much bread. That can’t be right. I need a change, or something.”
― J.R.R. Tolkien, The Lord of the Rings    

MS like all illness afflicting the body consumes energy, resulting in debilitating tiredness, but is there more to this than that? Can changes in the brain itself be an explanation for this?

Previously. brain volume assessments by MRI have hinted at loss of volume in the forebrain (frontal, sensorimotor, temporal cortices, and precuneus) to be associated with fatigue in MS. Here, the authors have looked at a specific region deep in the brain, called the thalamus, which is the relay centre for integrating communication between the different brain regions. They’ve based their thinking around previous work, which has demonstrated that both functional and structural abnormalities in this area of the brain can contribute to fatigue in neurological disorders. In MS, in particular, cognitive (ability to think and process) fatigue has been linked to microstructural abnormalities in the white matter tracts of the thalamus.

The authors included 187 PwMS with the following characteristics: 1) relapse free and having not received steroids for at least 3 months before the scan, 2) having no significant medical illness or substance abuse that can interfere with fatigue assessment, 3) not on treatments for fatigue, 4) no psychiatric or mood/sleep disorders, 5) right-handed (to give a left-sided dominant brain and to subsequently match to controls). They were then compared to 94 age and sex-matched, right-handed individuals without MS.

On the day of the scan, participants had a battery of assessments, including cognition assessments and fatigue impact scale. They found that compared to controls and non-fatigued PwMS, fatigued PwMS showed lowered connectivity between the thalamus and the different cortical regions: superior frontal gyrus, middle frontal gyrus (deals with preparation and execution of movements, decision making and social behaviour), sensorimotor network, precuneus, insula, and posterior lobes of the cerebellum. Pretty much everywhere! Interestingly, there were associations with different components of fatigue; involvement of the precuneus (a critical node of the default-mode network linking to the dorso-lateral pre-frontal cortex, and therefore modulates the awake state) and posterior region of the cerebellum in cognitive fatigue, whilst sensorimotor regions contributed to physical and psychosocial fatigue, with the addition of abnormalities in the anterior insula (deals with emotion) contributing to psychosocial fatigue. 

What this means is that a multi-modality approach to tackling fatigue is needed in MS, in order to modulate these different network regions: cognitive rehabilitation, physical exercise, behavioural, and problem-solving techniques being some of them. As a next step, it would be good to see if behavioural modifications can in fact lead to changes in the thalamic connections over time.

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Neuro Doc Gnanapavan


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  • This review of the study is very well presented and structured coming from someone with higher level of cognition
    I hate to be a bummer , but isn´t fatigue a main symptom of Autoimmune diseases?
    Like Ra, lupus ,systemic sclerosis,sps,etc.. Does this patients have brain atrophy? Have you talk to some one with Ra ,lupus….They feel fatigue ….Do they have to do an Mri?

    • Yes, the chemicals produced by the cells causing inflammation make you feel tired, same as when you get the flu. I kept hearing from people on Tysabri that the main thing they noticed was their fatigue had gone.

    • Hi Luis, inflammation (good which is seen in flu and bad which is seen in MS) has been associated with fatigue, but it's not assume that the link is causal. Also, a number of other factors can lead to the same end result. In the same way the opposite cannot be said to be causal i.e. Fatigue=inflammation, although fatigue is a feature of inflammation and therefore an association.

    • hanks for replying
      Flu is pathogenic related, Ms is aseptic chronic inflamation also lupus scleroderma ,Ra,Sps… So it can be multifactor

  • Would it be visible on MRI only when the pwMS is experiencing fatigue or visible all the time?
    My fatigue comes and goes, it's not every day.

    • Interesting question, this study is a simple snapshot of abnormalities vs fatigue scores. Dynamic measures would be more complex and may not capture any diurnal variation in fatigue levels

  • So many things influence fatigue – temperature, stage of menstrual cycle, psychological factors influencing "brain chemicals". Inflammation may be part of it, but no way is it the whole story. I notice that too much sleep / time in bed is much worse than too little for me. Fitness levels are important too, and I remember what one sport science student at uni said – the less you do, the more tired you feel. That goes for everybody, MS or no.

    • Haha, only just spotted that! (Remarkably low key super wet logo and no bright orange anywhere!)

    • Lol, this is what happens when I let MD have at it with comments 😉 No sponsors for my antics, all in the name of fun. You can see my mates legging it down Snowdon at the threat of being included in a selfi.



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