Is the answer to ME/CFS in the brain?

Cort Johnson from the Health Rising blog takes a look at some of the ways in which the brain may be involved in ME/CFS, and recent research aiming to explore this further, including one study newly funded by ME Research UK.

Andrew Lloyd, the originator of the influential series of ME Dubbo studies, once said that all the symptoms of ME/CFS – the fatigue, cognitive problems, sleep problems, even exercise issues – could originate in the brain. The potential is certainly there.

Indeed the definition of the type of fatigue produced by the brain (‘central fatigue’) is a close match for ME/CFS: “A sustained feeling of tiredness, which is not directly related to physical activity, although that can worsen it disproportionately, and additionally, does not improve with rest”.

A recent review of the neurological symptoms of ME/CFS’s sister disease, long COVID (which include fatigue; ‘brain fog’; headache; cognitive impairment; sleep, mood, smell or taste disorders; myalgias; sensorimotor deficits; and dysautonomia) could have, with the exception of post-exertional malaise (PEM) – which the authors may not have known about – pretty well  sum up ME/CFS.

A black box no longer?

The brain, with its billions of neurons, can seem, even to neuroscientists, “depressingly complex“. Rapidly advancing technologies, though, are allowing it to yield its secrets.

Newly developed ‘fast MRI’ techniques (DIANA), more accurate ways of measuring neuron activity (neuronal current imaging), and envisioning the brain and its functioning (optical microscopes fPACT) are emerging rapidly. The remarkable discovery in 2012 of the brain’s cleansing system – the glymphatic system – opened new opportunities for understanding neurological diseases, including ME/CFS.

The ME/CFS field is contributing. Jarred Younger’s heat mapping approach to assess neuroinflammation – currently being assessed with a major NIH grant – presents the potential of an inexpensive, non-invasive (no drugs needed), side-effect free way to assess inflammation in the brain. Not only would the technique be available to more people, but it could be used to assess the effectiveness of treatments on the brain. Similarly, Younger – with help from ME Research UK – has pioneered a way to tell if immune cells from the body are getting into the brain.

Key organ

That’s all good news given the many ways the brain could be involved in ME/CFS.

It just goes on and on. Given all the brain findings in ME/CFS, it is no surprise that a fatigue nucleus and fatigue network – a series of interconnected brain regions responsible for producing fatigue – have been proposed for it and fatiguing diseases like multiple sclerosis.

A window to the body?

The most interesting thing about the brain findings in ME/CFS, though, may be how similar they are in some ways to the results of studies focused on the body.

The results of a 2020 ME/CFS brain imaging review – reduced blood flows, sluggish blood oxygen responses to tasks, problems with serotonin transporters, a hypometabolic state – could almost have been referring to the body. Shungu’s well replicated findings of high lactate, reduced antioxidant and increased oxidative stress levels in ME/CFS patients’ brains are a close analogue to similar findings in the body. Similar problems with blood flows, metabolism and energy production appear to be happening across the body and in the brain.

While blood flows have captured the most attention, the fluid issues in ME/CFS do not appear to be confined to the blood. The gut motility issues that many people struggle with reflect an inability to move the gut contents through that big tube. The intracranial hypertension one study found suggests the cerebral spinal fluid may not be draining properly either – and then there’s the newly discovered lymphatic system in the brain.

Lymphatic system to the fore?

The inability to properly drain the brain of its toxins, for instance, through the lymphatic system – another possible vessel under attack – could impact energy production, the immune system, sleep, cognition, etc. and exacerbate neuroinflammation. Because neuroinflammation produces its own accumulations of fluid, a good working lymphatic system is needed to cleanse the brain of its byproducts as well.

Given that it’s interesting that reduced lymphatic storage capacity in women may make them more susceptible to neurological diseases like ME/CFS, it’s also interesting that it’s during the kind of sleep often missing in ME/CFS (deep, slow-wave sleep) that the lymphatic system drains the metabolic wastes that accumulate during waking times from the brain.

No one who has ever experienced brain fog or feelings of toxicity in ME/CFS would likely be surprised to learn that an inability to cleanse the brain of its accumulated toxins could be to blame. A small trial suggested that a lymphatic drainage (Perrin technique) that could help detoxify the brain might be helpful in ME/CFS.

First neuroinflammation – lymphatic system study

ME Research UK recently funded a new ME/CFS study that has been a long time coming. When the brain’s lymphatic system was charted, it quickly became the subject of study in neurological disorders, but until now nobody has checked to see if problems with lymphatic drainage problems are present in ME/CFS.

The new Australian study by Dr Zack Shan and colleagues will attempt to kill two birds with one stone. It will assess the brain’s lymphatic system (a first) as well as neuroinflammation (an understudied subject in ME/CFS if there ever was one). The study will combine the thermography (heatmapping) technique developed by Jarred Younger with a metabolite study to assess neuroinflammation, and, if it’s found, assess whether a balky brain lymphatic system is involved.

Finding a lymphatic connection in ME/CFS could ultimately provide more treatment options. Lymphatic drainage has become a big deal in neurological diseases like Alzheimer’s, Parkinson’s and multiple sclerosis. Given that, it’s no surprise that treatments to improve it (transcranial magnetic stimulationVEGF-CYoda-1exogenous IL-33 photobiomodulationfocused ultrasoundmanual lymphatic drainage) are being explored.

We don’t know that lymphatic drainage is being affected in ME/CFS, but given the sludgy blood, the problematic gut, and the blocked up intracranial spinal fluid, as well as the brain fog found in ME, no one would probably be surprised if an ME/CFS brain was also an inflamed and ‘toxic brain’”’ that is badly in need of a cleanse.

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