The brain has been showing up a lot recently (vintage image by Oberholster Venita from Pixabay)
Back to the brain! Years ago, Andrew Lloyd of the Dubbo studies noted that the symptoms in ME/CFS were all symptoms produced by the brain – and we are overflowing with brain studies right now.
We just looked at the Bedard group’s study, which proposed the brain is the major player in fatigue. A new paper on brain norepinephrine was recently published, and Griffith’s group in Australia has published two brain studies – one on the glymphatic system, and one on water movement through the brain – which the current blog focuses on.
The Study
Brain imaging studies are usually small, and this one by Singh, while not bad for a brain imaging study, is of that ilk (37 ME/CFS, 19 Long COVID, 27 healthy controls). The Griffith group has been digging into the brain in ME/CFS for years. Their latest study, “Microstructural alterations in brain tissue of ME/CFS and long COVID using diffusion tensor imaging and diffusion kurtosis imaging“, expands on an earlier one and brings something new to the field.
It adds something called diffusion kurtosis imaging (DKI) to the diffusion tensor imaging (DTI) that’s usually done. Instead of blood, DTI assesses how easily water moves through brain tissue and in which directions. Because healthy axons, which the nerves use to communicate with each other, affect water movement differently than unhealthy axons, DTI is often used to assess the microstructural integrity of white matter that the nerve axons are made of.
Because DTI studies are focused on the axons, they’re concerned with the brain’s “wiring” or how the different regions of the brain communicate with each other.
DTI/DKI assess the movement of water along the long axons that connect one nerve cell to another (Image from Anatomy and Physiology US National Cancer Institute’s SEER Program, DHP 1080_ Wikimedia_Commons)
DTI’s can tell us, for instance, if the prefrontal cortex is not communicating well with, say the limbic part of the brain. It cannot tell us why, however. For instance, it cannot differentiate between demyelinated axons, damaged axons, or processes like neuroinflammation that could impair nerve transmission as well.
Diffusion kurtosis imaging (DKI) uses the same (but longer) MRI and adds a more sophisticated modeling and statistical analysis. It can also assess water flow through the surrounding tissues and detect pathologies that DTI would miss. It’s particularly useful in assessing neurodegeneration, ischemia, and aging.
Various measurements are done using DTI. They include
- FA: We want free water movement in the brain along nerve axons. Increased FA could result from axon issues, edema/neuroinflammation, myelin loss, etc.
- MD: average overall diffusivity. Increased MD levels would indicate increased water content.
- AD/RD: diffusion parallel/perpendicular to the fitted primary direction. They are sometimes interpreted as axon- and myelin-related proxies, but neither is a direct measure of axonal injury or myelin content.
Results
The ME/CFS results
Cognition Gets a Double Hit
The increased FA on conventional DTI and increased KFA on diffusion kurtosis imaging in the left cingulum were a strong reading because abnormalities showed up on both DTI/DKI in almost exactly the same region of the brain. That is strong, suggesting the Australian group is onto something there.
The increased FA suggests that something is off with the axons, which is interfering with water movement. This could be due to problems with nerve fibers, cellular swelling, or alterations in the extracellular spaces surrounding the nerves.
The cellular swelling that interferes with the free flow of water in the brain is intriguing because it could result from an infection and/or microglial or astrocyte activation (neuroinflammation).
The increased DFI suggests that something is altering the direction of the water flows. It could be something to do with the axons, the myelin coating them, the glia cells that hold them in place, or again – the extracellular space surrounding them.
If you experience brain fog, an inability of the cingulum pathway to relay signals normally may be one reason why. A long nerve pathway linking cingulate, frontal, parietal and temporal regions, the cingulum is involved in attention, executive control, memory, emotion and internally directed cognition.
The Supplementary Motor Area (Again)
The motor areas found in the frontal lobe. The SMA is in green at top. (Image from Chouinard PA and Paus T (2010) Front. Hum. Neurosci. 4173. doi10.3389fnhum.2010.00173)
The significantly lower values across all three DTI measures (MD, AD, and RD) strongly indicated that water movement is obstructed in all directions within the supplementary motor area (SMA).
The SMA is a most intriguing part of the brain because it’s involved in “motor planning,” i.e., movement, including initiating and organizing voluntary movement.
The name “supplementary” motor area kind of downplays how important this part of the brain is.. It’s an intriguing area for ME/CFS because it’s in the SMA that the brain transitions from the intention “I want to move” to the actual production of movement.
In my experience, it’s that transition from intention to movement that often seems so tricky. I might want to move, I might think or feel like I can move, but once I start to move, the problems start. Problems here would translate into more effortful movement, reduced motor drive (reduced muscle recruitment), poor coordination, and increased fatigue.
This is also, notably, one of the same brain areas where the Bedard paper found reduced activation. In fact, the supplementary motor area was one of the most underactivated parts of the brain.
These two findings suggest that the movement problem in ME/CFS may be primarily in the deeper brain pathways involved in planning, rather than in the motor cortex. They also align with the idea that the brain is a major source of fatigue in ME/CFS.
The findings might suggest there’s less actual axon damage than there are problems in the microenvironment around the axons. That’s probably a good thing as the less nerve damage the better! That could point us toward neuroinflammation or connective tissue problems that are impairing the free flow of fluids. More on that later.
A Big Wire Gets Hit
A big wire gets hit! Damage to this connector could affect sustained attention, difficulty switching tasks, mental fatigue, movement, and sensory stimuli (Image from Gray’s Anatomy 1918)
The authors proposed that the decreased axial kurtosis in the genu/body of the corpus callosum “probably means there is axonal injury or loss of integrity.” The corpus callosum finding makes so much sense given what we know of these diseases. It is a large nerve fiber that connects the two hemispheres of the brain and affects a triad: cognition, movement, and sensory function.
Problems with sustained attention, difficulty switching tasks, mental fatigue, movement, and sensory stimuli could result.
The decreased axial kurtosis suggests that the microstructure of the axons in the corpus callosum itself has been affected. It does not mean that the axons are damaged per se – they may just be weaker and not working well. They could be thinner than usual, the myelin protective coating may be affected, or extracellular space problems could be kicking in.
Impaired Diffusion
We don’t know what’s causing these issues, but note that this study measured “diffusion,” i.e., the free flow of water along neurons. Problems with the extracellular spaces were particularly prominent in two of them.
The authors didn’t focus on extracellular spaces, but they’re interesting because a changed or remodeled extracellular matrix could easily inhibit the flows of solutes around the neurons.
That brings us back to, who else, Rob Wust and the extracellular matrix remodeling his group found in the microvasculature of muscles. It looked like thickened basement membranes were blocking blood flow to the muscles. They believed these changes were reducing oxygen/nutrient delivery to the muscles and toxic metabolite removal from them.
Check out the massive basement membrane (BM) found in an ME/CFS/long-COVID patient. Could something similar be happening in the brain?
If extracellular-matrix/basement-membrane were also “remodeled” in the brain, they could impair the movement of water/solutes from the tiny interstitial spaces surrounding the neurons to the perivascular spaces surrounding the blood vessel.
Infection-triggered chronic inflammation/neuroinflammation could do the trick. So could, interestingly, problems producing energy. If ATP-dependent ion pumps fail, water could flow into the cells, causing them to swell, which could impair fluid flows outside the cells. Impaired cerebral blood flows could be responsible as well.
Note that while axon damage could be occurring, it’s not required to produce any of this.
In this scenario, the glymphatic system and cerebrospinal fluid flow would likely be affected. A recent Griffiths paper and a recent Stanford paper suggest a clogged-up glymphatic system could play a major role in ME/CFS.
That potentially fits an intriguing theme in these diseases – problems with the free flow of liquids, whether they are in the brain (blood, water, lymph, cerebrospinal fluid), or the muscles (microvascular blood flows).
Connections
It doesn’t seem like damage to a single brain region is going to be it for ME/cFS or long COVID – and that’s probably a good thing. Instead, the problems will probably lie in damaged connections between brain regions.
The deeper researchers dig, the more connections they find – a very good thing. The light bulb or driver at the heart of all this is still unclear, but could be inflammation, metabolic problems, and/or disruptions to fluid/blood flows.
Quite a few brain networks are impacted in ME/CFS. Some of the major ones include the salience network, default mode network, the prefrontal cortex and its network, and autonomic‑brainstem circuit. These networks can produce symptoms such as sensory overload, a wired-but-tired feeling, brain fog, reduced attention spans, and difficulty standing and exercising.
The brain regions that popped up in the last couple of studies – motor planning / motor cortex / SMA / cingulate cortex / corpus callosum / brainstem – fit quite nicely into the picture. While the other regions deal more with inputs, these regions deal more with the output side of the equation; i.e., they come into play when you decide that you want to walk across the room.
Here’s the problem for them. They have to take into account the signals already present in the brain (low energy, high pain/sensory stimuli, autonomic issues) and then try to add movement on top of them. The inevitable outcome is a high degree of effort.
They’re showing a kind of brain that’s designed to knock you down and keep you down. No wonder functionality is so poor.
It’s a pretty devastating picture, but the nice thing is that it all makes sense. We’re not seeing weird brain regions that no one can make head or tail out of popping up in these studies. Even with their small sample size, the brain imaging studies are producing a coherent picture, and that’s crucial for this field.
Every study opens up new possibilities. By adding DKI to the equation, the Griffiths researchers showed that it’s not just the axons but also the regions outside them that are affected in these diseases.
A follow-up study could include brain imaging to assess neuroinflammation and myelin damage, and would evaluate brain vascular basement membrane or extracellular matrix markers, as well as perivascular spaces, to determine whether anything is impeding the free flow of water and solutes in the brain.
That would tell us whether the nerves themselves are damaged, whether inflammation could be a culprit, and whether the passageways through the brain are being squeezed.
The systemic nature of the findings in ME/CFS and long COVID suggests that a fundamental, bodywide factor is responsible. Something that inhibits the free flow of fluids (blood, water, lymph, and/or cerebrospinal fluid) would surely fit the bill. Time will tell!
“In my experience, it’s that transition from intention to movement that often seems so tricky. I might want to move, I might think or feel like I can move, but once I start to move, the problems start.”
That I know well. Especially when I was at my worst, it was very common of wanting to stand up from a chair, doing ‘in the brain, the intend’ everything I usually do and nothing happened. Not a single bit of movement. Not even feeling a slight tension in my leg muscles. I then had to focus manyfold (emergency peak adrenaline strength!) as strong as normal for my legs to move. A similar stronger need to focus was nescessary for near any action ranging from thinking to swallowing food. And as many of you who experienced this too will be able too tell, that amount of focus is very exhausting and rapidely coming with a great payback cost.
It’s exactly the opposite of the ‘PACE study’ conclusion: patients with ME/CFS do not do less effort to get anything done, but massively more! Telling they are afraid trying to do anything and will only get better if they try harder isn’t going to help them if this study and what it means holds true!
When it comes to tissue deformation, it is well known in engineering that a round (2D) or spherical (3D) shape provides more strength per amount of building material then more uneven forms like egg-shaped or ellipse.
Hence: if tissue quality becomes poor, contracting the tissues and reshaping to a more round-ish shape is going to use less material for the same contained surface (2D) or volume (3D). Or for the same amount of material, the ‘walls’ will become more dense and stronger.
Artheries in ME/CFS tend to contract. That yields smaller cross sections with less blood flow, but also stronger arterial walls for the same amount of cells and walls available. And at the same pressure the pull strength on the tissue will further decrease if the enclosed volume becomes smaller. It’s a quadratic (eg very strong) relationship and well known in pipe calculations. High pressure pipes in hydraulic machinery all have a small inner cross section for fluids to flow and plenty of metal / material for the pipe. If you’d see a cross section of it, much to most of the area is the outer material building the pipe leaving only a bit of area for fluid flow.
Anyhow: if tissue is weakened / damaged and can reshape, then reshaping from a long dragged out form to a more circular and spherical form is a very logical thing to do. Oxidative stress or an overactive immune system is quite an assault to cell membranes and tissues.
When plenty of tissues start to ‘shape-shift’, that might give the impression of creating more space. While true, swelling can counteract that (or if you look at it this way swelling may require taking up a more spherical form in order to not splash a cell open) and any form of deformation can create local pressure or tension on other tissues. Nothing exactly fits the way it is supposed too anymore.