What Causes All The Symptoms Of Long COVID And ME/CFS? The Brainstem Could Be The Key

ME/CFS and the closely related long COVID could be caused by damage to the brainstem, according to a new scientific theory. If their new model turns out to be right, the scientists behind it suggest it could explain why these conditions affect so many systems in the body, and could help inform the search for long-awaited treatments. 

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ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome) is a historically misunderstood and stigmatized chronic condition. As the name suggests, one of the key symptoms is severe fatigue, but patients experience symptoms affecting a whole range of organs and systems, from pain, to temperature and light sensitivity, to brain fog.

There are different degrees of severity and no known cure, and there’s been a lot of debate and controversy in recent years around treatment approaches. There has also been landmark research to attempt to identify the causes and develop a reliable test for the condition. 

One trigger that has been recognized is viral infection. Though not all patients can trace the onset of their symptoms back to a viral illness, in many cases it’s thought that infection with a virus such as Epstein-Barr sparks the development or worsening of ME/CFS.

This conviction was only strengthened when COVID-19 came on the scene. Back in 2020, some of the earliest COVID patients were reporting that they had recovered from their initial illness, only to be struck down by a constellation of symptoms that would go on to persist for months or even years. This was what came to be known as long COVID. 

A 2025 study identified a strong link between ME/CFS and long COVID, and there is substantial symptom overlap between the two conditions. As understanding of long COVID has increased and research into its causes and potential treatments has ramped up, many in the ME/CFS community have expressed hope that this could have a knock-on positive impact on research into ME/CFS as well. 

A new paper from scientists mainly based at Renegade Research in Denver, Colorado is forming part of the effort to figure out the underlying basis of some of the overlapping symptoms. According to the team’s modeling, damage to the brainstem could be the key. 

“In vulnerable individuals,” they write, “an infection may damage the connective tissue structures responsible for maintaining the physical integrity of the brainstem. This can lead to neuromechanical pathologies such as craniocervical instability (CCI) and intracranial pressure dysregulation that cause mechanical deformation or displacement of the brainstem.”

This, they say, could impact the immune system, autonomic nervous system, and metabolism, explaining the multi-system nature of these conditions. 

They go on to outline a seven-step pathological process beginning with the initial infection and immune response. In some cases, they believe that the immune system could go too far and cause excess damage to the tissues in the brainstem that maintain its structure, and if this does not heal it could eventually lead to chronic brain inflammation. 

Because the brainstem is a major control center for a lot of vital functions, the longer this goes on, the more chance of downstream effects like re-activation of dormant viruses, immune dysregulation, and gastrointestinal dysfunction. 

It’s an interesting hypothesis, one that the authors say fills in some of the gaps in other theories of how ME/CFS develops. 

“While there can be individual variability in the presentation of ME/CFS, the core diagnostic features involve processes that are regulated by the brainstem. These features are present in all people with the diagnosis,” they write. 

They also point to previous brain imaging studies in patient populations that have identified brainstem abnormalities in both long COVID and ME/CFS. 

One of the authors of the paper is also offered as a case study – he claims that his own severe ME went into remission after surgery to correct a CCI. While the team accepts that anecdotal evidence like this can’t necessarily be applied more broadly to other patients, they propose that it could offer a basis for further research.

“This model can be tested at each step of the causal chain. It has interdisciplinary relevance and can be explored and tested by many different fields of research,” they write.

“Our hope is to inspire new research and treatments for patients suffering from a neglected and debilitating disease that has long been considered a mystery.”

The paper is published in the journal Medical Hypotheses.