Brain footprints tell us which way did it go

Sometimes for us to know the future, we need to look back into the past.
We can predect how an MS brain will be if we looked back to how it was.

Human beings have large heads compared to other animals. This is one of the reasons human babies need to be born well before reaching brain maturity or otherwise they will get stuck and never come out!

In anthropology, when you get a skull of a human and you need to know how much this person’s brain reached, scientists simply fill the cavity of the skull with a certain fluid substance and then get the volume of the fluid. The volume inside the skull is a fingerprint of the brain’s largest size during a lifetime.

High field MRI scanners (ideally 1.5 or 3 Tesla) together with mathematical computer algorithms can do the job of a hard-working anthropologist but in an oviously safer in-vivo way than to fill a person’s skull with fluid.

Brain Tissue Reserve (MLBG)

Using a high resolution T1 MRI sequence, you can simply measure the volume of the entire intra-cranial (Skull) cavity as well as the brain size.

The full-sized brain will occupy the whole intracranial cavity, which is termed “Maximal lifetime brain growth” (MLBG). If the brain loses some of its cells and fibres then its volume will shrink from the full-sized MLBG. After reaching our full-sized brain, we normally lose some volume (~0.4%) annually. This rate accelerates in many neurological conditions and MS is a classical example for that.

MLBG is very informative measure and may well guide individualized MS care. Sumowski et. al, showed that patients with MS (PWMS) who had larger MLBG can withstand cognitive decline compared to lower values. Larger MLBG indicates more brain tissue that can compensate for damage before burn out eventually.

This concept is termed “Brain Tissue Reserve” in analogy to the term “cognitive reserve” which is the rich intellectual attainment for every one of us. Both reserves help us withstand any degenerative or a destructive process that may take place in our brains.

Intellectual enrichment in PWMS showed a moderating effect similar to larger MLBG on cognition in the same study.

In clinical practice, if we can get an estimate of MLBG early after diagnosis, we may be able to direct specialized care to those who are at increased risk of cognitive affection.

Brain Volume at MS onset may tell the story before it starts

But one other point that impresses me even more about MLBG. Using MLBG, I can compare my today’s brain to my largest brain volume that used to occupy the whole skull cavity.

We now know that MS damage starts well before onset of first symptom, and at the moment we confirms MS diagnosis the brain suffers years of volume change.

Comparing MS brain volume on diagnosis to its MLBG may give an idea about how fast/severe is MS damage over the period preceeding diagnosis.

In fact other factors might be affecting the degree of this atrophy such as environmental toxins or smoking (among many others), but it remains that if brain atrophy is significant, then there is a loss of tissue reserve and probably ability to compensate for further MS damage. This should alerts using an effective therapy for this patient population.

Brain atrophy on first presentation of MS has been always associated with wors long-term outcome.

PWMS who had higher rate of brain volume loss at their first year of diagnosis have worse outcome compared to others.

We can simply have a look into the future by looking back into the past.

Why brain volume is not widely available?

There are plenty of technical and resource kind of problems that make it not widely available, but one major conceptual difficulty still outstanding.

We have no universal reference values for what is normal and what it abnormal in brain volumes. In other words, it is difficult to compare one brain to another.

Brain volume is quite variable between individuals, geographical regions, ethnicities, and even within the same person (your brain volume is different before and after drinking a lot of water for example).

If your brain should be compared to another brain, then it is the best to be your very same brain at a different time point.

Most neuroimaging research has been focusing on comparing your today’s brain to your future brain on follow up. Two brain scans, one year apart, and then calculate the rate of change between the two scans. This is termed the percentage brain volume change (PBVC), and by far this is the most reliable way to measure brain volume change.

If we compare the today’s brain size to its MLBG (the past brain), we may be getting an idea on aggressivenss of MS damage on an individual level, and be able to direct better theraputic options earlier.

About the author

Dr Wafa


  • I don’t really understand why one would want to use this information to choose therapies… Isn’t already obvious that even the mildest form of MS is a really bad disease that should be treated as aggressively as possible? Wondering about how severe a particular case is should really only be an academic exercise.

    • Re: “Wondering about how severe a particular case is should really only be an academic exercise”……….not necessarily, IMO.

      It might actually be easier to convince a newly diagnosed pwms to use a more risky yet aggressive DMT first/early, if they are given sufficient evidence about the “aggressiveness” of their disease course.

      Right now there are very few markers that provide this evidence, so I welcome Dr. Wafa’s approach and thesis.

      I do agree that all types of MS should be treated early and aggressive, regardless of the perceived severity of initial symptoms.

  • I and my students have worked on the analysis of brain MRI’s about 5 years ago. So I don’t know about the advances made in the past 5 years, but we had difficulty finding out the intracranial volume. It doesn’t seem like a difficult task, but the skull is dark on MRI and depending on the modality the CSF might be dark too. ( It would be great if we had CT scans of the patients for this purpose 😉

    • Well CT definietly be more accurate.
      There are a number of ways to the total intracranial volume.

      I used a simple one before based on SIENAX scaling factor and the intracranial volume of the MNI atlas.
      I beleive theer are many other ways to do it and it is not problematic at all.

      • That is indeed a most used method.
        *Explanation for interested readers*
        You can ‘extract’ the brain from the MRI image so that there is nothing else left other than the brain. The ‘MNI’-atlas represents the ‘normal’-brain. Structures on this atlas have been segmented. So has the intracranial volume (ICV). The MNI-atlas also has a corresponding MRI-scan. With a computer algorithm, you can find out how the brain of a patient differs from the atlas. With this information, you can ‘transform’ (warp) the atlas onto the patient’s MRI (or the other way around). This gives you the entire atlas warped on top of the patient’s brain. From that, you can also get the intracranial volume. Also ‘Freesurfer’ works kind of the same (they call it eTIV – estimated Total Intracranial Volume).
        This method is somewhat biased:

        I’d love to think more about this. It has been some time ago that I have… (stopped working at the university two years after my MS diagnosis). Let me know if you or anyone in your team wants to brainstorm about this 🙂

  • I don’t have any symptoms but I do worry about BVL. Therefore I don’t have any DMTs . What I need is information which this excellent Blog gives me. If I knew what my BVL is then I would be able to lobby for some kind of intervention. Whether I’d get it is another matter. So I disagree with Anonymous as interventions might (probably would) slow BVL down. As I take no meds I rely on swimming running tai chi the gym but I am 73 so running is not getting any easier. Skeletons tend to start playing up. Not that I have anything much to complain of there but my knees have a point of view about my exercise regime and I don’t always have the flexibility to run nowadays. So exercise is probably the most neuro protective thing I can do with the proviso that normal aging affects most of the body not just the brain.

    • Excercise is neuroprotective..and so good spirit and psychological good being. please keep them up 🙂

  • Informative and accessible post that I’ve enjoyed reading.
    Agree with Anon at 6am that having information of this nature may help PwMS to be clearer as to why they’d benefit from the stronger DMTs and it might also facilitate the adoption of more of a brain healthy lifestyle.

  • NFL levels are surely an more accurate representation of what’s going on in the brain, rather than brain volume loss.

    Will people with MS be able to regularly and easily have a bio marker test maybe an home test of some sort to check NFL levers or an equivalent bio marker? To check how the brain is responding treatments etc.

    • NFL levels reflects another important factor in estimating disease activity.

      However, NFL reflects the current state but not necessarily what has been taking place before.

      In my opinion NFL and volume loss reflects two different yet complementary views on MS damage

      • Will we see any sort of at home bio marker test, similar to blood sugar test for people with diabetes?

        Is there anything in the pipeline?

        • I think bood NFL levels are the closest to the pipeline but suffers a problem with sensetivity.

          I remember that prof. G once was talking that a very handy gadget to think about is a sub-dermal plant that gauges NFL levels and warns when something rise up. Or this is how I understood the idea. It is an out of the box idea to me..maybe we can see it in the future.

          To my knowledge, no home-testing thingy is showing up but I do hope something can see the light in the future

          Thanks for your question

  • Interesting ideas that make sense and may indeed help persuade the newly diagnosed.. However, “we” need to be careful of the implications of “saying” that “a larger brain is better than a smaller brain”. All sorts of “nasty stuff”, socially, has transpired when this assumption has played out in various disciplines, in the past.

    • What’s that got todo with any thing.

      This is about brain volume loss in MS, and the fact that it’s important to normalise the rate of brain atrophy, not about who you might offend by talking about such a rate of loss.

      Always someone who has to be offended by something that’s not even applicable.

    • “However, “we” need to be careful of the implications of “saying” that “a larger brain is better than a smaller brain”.

      Google Einstaein had a huge brain:

      His brain was notable for the density of the neurons and connections…not really for it’s size or weight.

      Did Einstein donate his brain?
      Although Einstein did not want his brain or body to be studied or worshipped, while performing the autopsy, Princeton pathologist Thomas Harvey removed the scientist’s brain without permission and kept it aside in the hope of unlocking the secrets of his genius.

      • “larger brain may be a swollen brain”

        yeah.. of course that’s why brain loss in ms is always going to be underestimated.

By Dr Wafa



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