Lots of areas of the brain (prefrontal cortex, anterior cingulate cortex, insula, amygdala, motor cortex, and more) have been implicated in chronic fatigue syndrome (ME/CFS), but somehow it fits that the most difficult-to-reach and hard-to-study part of the brain – the brainstem – might just be the cat’s meow.
As Van Elzakker pointed out in his fine-tuned review of the brainstem in ME/CFS, most MRI studies that focus on the upper part of the brain can only really catch a glimpse at what’s happening down in the brainstem.
The little brainstem – about the size of one’s thumb – is one of the most “primitive” parts of the brain (if you can call anything in the brain “primitive”). It controls many of the involuntary aspects of our physiology – you know, little things like breathing, sleeping, eating, and pain sensitivity. When we exercise, it’s our brainstem that senses the amount of carbon dioxide present and has us breathe faster to remove it – and speeds up the flow of oxygen to our muscles. The brainstem also relays messages traveling up and down the spinal cord. Through its reticular activating system (RAS), it controls how alert and aware we are, and is an important source of the major brain neurotransmitters dopamine, norepinephrine, and serotonin. It’s easy to see how it could be ground zero for these diseases.
Researchers have proposed that everything from viral invasion, and inflammation, to blood vessel problems could be causing the brainstem to throw off some pretty core physiological processes in these diseases. Indeed, if any disease affects really core physiological processes – you know the kind that really affect functioning – one would think it would be diseases like ME/CFS and long COVID.
Let’s not leave out fibromyalgia, though. Problems in the parabrachial nucleus (PBN) of the brainstem have been linked to increased pain sensitivity and a recent FM study found alterations in connectivity between the PBN and other parts of the brain.
One review called the PBN “a ‘hub’ for pain and aversion” that responds to any potentially dangerous situation. Not surprisingly, PBN neurons have been associated with the “freeze response”. One researcher likened the PBN to a home alarm:
“The alarm goes off while you’re away, and you don’t know if it’s a broken window, an intruder, or a fire—you just know that something bad has happened.”
Interestingly, given the possibility produced by Bob Naviaux that people with chronic fatigue may exist in a kind of hibernation-like metabolic state, the vast convergence of different sensory inputs (cardiovascular, respiratory, metabolic, and pain) at the PBN appears to give it a key role in determining whether an organism enters into hibernation.
The evidence of brainstem dysfunction in long COVID has slowly been growing. In “The Vagal Autonomic Pathway of COVID-19 at the Crossroad of Alzheimer’s Disease and Aging: A Review of Knowledge“, French researchers report that the SARS-CoV-2 coronavirus has a predilection for nestling itself within the vagus nerve, then moving from there into the dorsal vagal center of the brainstem – an “integrative center” that regulates both respiration and inflammation.
One paper stated that “overwhelming evidence” linked acute respiratory failure in COVID-19 to viral entry into the brainstem. A Malaysian researcher proposed that long COVID is caused by a “persistent, low-grade brainstem dysfunction” driven by a viral invasion of the brainstem. He stated:
“Notably, long-COVID resembles and is closely associated with myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS)… Interestingly, brain imaging research has found that symptom severity of ME/CFS associates and correlates with brainstem dysfunction, particularly at the reticular activating system (RAS).”
The virus apparently produces a “neurogenic switch” that causes, among other things, hypoventilation – which has been found in abundance in ME/CFS. Plus, it’s possible that viral entry into the brainstem is also causing increased sympathetic (“fight or flight”) activation and decreased parasympathetic (“rest and digest”) activation – exactly what is found in ME/CFS and fibromyalgia (FM).
What other viruses can invade the brainstem? There’s no evidence that it has in ME/CFS, but Epstein-Barr virus can as well.
Chronic Fatigue Syndrome (ME/CFS)
People with ME/CFS who have craniocervical instability (CCI) have given us a vivid display of what a tweaked brainstem can produce. Lax ligaments that allow the skull to settle onto the brainstem were able to produce virtually every symptom associated with ME/CFS.
Thus far, ME/CFS studies have been able to associate some symptom severity with brainstem issues. One study found a “communication breakdown” between different parts of the brainstem as well as with other parts of the brain that Barden believed could produce problems with movement, maintaining movement, sleep quality, autonomic functioning, remaining alert, and cognition.
Another found white matter loss that seemed to be associated with reduced autonomic nervous system functioning and could impair motor and cognitive activities: i.e. movement and thinking. A third found widespread issues associated, again, with autonomic nervous system functioning; plus, a fourth study found microstructural issues in the brainstem.
- One of the most “primitive” parts of the brain, the little brainstem at the base of the brain, controls many of the involuntary aspects of our physiology – you know, little things like breathing, sleeping, alertness, eating, and pain sensitivity. When we exercise, it’s our brainstem that senses the amount of carbon dioxide present and has us breathe faster to remove it – and speeds up the flow of oxygen to our muscles.
- The fact that it affects such core processes makes it of real interest in ME/CFS. Recent studies suggest that brainstem dysfunction in the parabrachial nucleus (PBN) may be present in fibromyalgia as well. One review called the PBN “a ‘hub’ for pain and aversion” that responds to any potentially dangerous situation.
- With regard to long COVID, the coronavirus apparently has a predilection for nestling in the brainstem, and one researcher has proposed that long COVID is caused by a “persistent, low-grade brainstem dysfunction” driven by a viral invasion of the brainstem.
- Through a series of studies, an Australian team has found problems with “communication” inside and outside the brainstem, microstructural changes, and white matter changes that appeared to affect symptoms as well as autonomic nervous system functioning in ME/CFS.
- Their latest study employed the most powerful MRI in the world – a Tesla 7 – to assess the volume of the brainstem and its different regions in a small number of ME/CFS and long-COVID patients and healthy controls.
- The study found increased volume of the brainstem as a whole and in several regions of it in both ME/CFS and long-COVID patients but not in the healthy controls. It was only, however, able to link only one symptom – pain – to increased brainstem volume. (Shortness of breath was associated with reduced volumes of the midbrain.)
- Larger is not better with the brainstem. A larger brainstem suggests that inflammation and/or viral invasion has occurred. Interestingly, studies indicate that inflammation outside the brainstem can end up producing inflammation inside it – suggesting that taming inflammation, say, in the gut, might be able to reduce inflammation in the brainstem itself.
- This study does three things. One, it links ME/CFS and long COVID ever more closely together. We can add increased brainstem volume to the long list of similar findings (EBV reactivation, invasive CPET abnormalities, low heart rate variability, small fiber neuropathy, gut flora alteration, blood vessel issues, hypercoagulation, dysautonomia) in these diseases.
- Two, this study and past studies have been too small to definitively tell us if the brainstem is playing a major role in ME/CFS. Now we need larger studies that can tell definitively us if this intriguing part of the body really does play a major role in these diseases.
- Lastly, this study puts a focus on viruses (EBV can infect the brainstem) and on inflammation and ways to tame it.
This study, “Brainstem volume changes in myalgic encephalomyelitis/chronic fatigue syndrome and long COVID patients”, used the most powerful MRI in the world – a Tesla 7 – to investigate brainstem issues in ME/CFS. The 7 is quite the evolutionary leap. Weighing in at 25 tons, it provides more than double the strength and clarity of past MRIs. Researchers at Brigham and Women’s Hospital at Harvard went gaga when they got one. They planned to quickly put their new baby (which required a crane to put it into the building) to use on the brain, stating that “it will allow clinicians to visualize critical structures and pathologies of the brain that until now were not visible.”
Thapaliya and Barnden used the Tesla 7 to assess the volumes of the different subregions of the brainstem, as well as in the brainstem as a whole, in people with ME/CFS (10), long COVID (8) and in healthy controls (10). They also sought to see if they were associated with any symptoms.
When Larger Isn’t Better…
The study found significantly larger volumes of the pons, the superior cerebellar peduncle (SCP), and the whole brainstem in both long-COVID and ME/CFS patients. As these help to make up the reticular activation system (RAS), the authors cited the effects these larger volumes could be having on attention, sensory perception, problem-solving, memory, wake/sleep cycles, pain, breathing and even walking (gait). Ultimately, they stated these changes “could result in severe and varied deficits in brain function”. (Severe and varied – sounds like ME/CFS and long COVID…)
Larger brainstem volumes were associated with more pain – a finding that made sense given a recent finding in fibromyalgia. Plus, smaller midbrain volumes were associated with more severe breathing issues. Note, though, that despite assessing a variety of symptoms, as well as using the SF-36 functional capacity tool, no other symptoms or associations with reduced functional capacity were found.
The larger brainstem volumes could be caused by inflammation or viral invasion. The inflammation can even be sparked by outside the brainstem (like maybe the gut) – which is encouraging, as removing that inflammation should allow the brainstem to calm down. This brings us back to Yong’s long-COVID hypothesis paper. Yong noted that because brainstem issues causing severe damage to the brainstem are usually associated with life-threatening outcomes, researchers don’t really consider what lesser amounts of damage could cause.
Yong reports, though, that brainstem issues have been associated with musculoskeletal pain, migraines, and, of course, ME/CFS. He proposes that “persistent, low-grade brainstem dysfunction” could be behind long COVID and ME/CFS.
Welcome to the club! Brainstem abnormalities now join the list of other issues (EBV reactivation, CPET abnormalities, small fiber neuropathy, dysautonomia, low cortisol, symptoms, etc.) that are linking ME/CFS and long COVID together ever more tightly.
The brainstem is of so much interest because it could conceivably account for so many problems in these. We know this because of what the brainstem is involved in but also because some ME/CFS patients with brainstem problems (aka craniocervical instability) recovered when their brainstem problems were resolved. Despite this, perhaps because it was so small, this study was only able to link two symptoms (pain, and problems breathing) with its findings.
All the ME/CFS brainstem studies are small and they’re all finding issues of different sorts. Because of their size, though, none could be called definitive. They’re more pointing to possible problems than anything else. Now that a bevy of studies have found a host of different problems in this most interesting part of the brain, let’s hope we’ll see some big studies in long COVID and/or ME/CFS that will tell us if the brainstem has been kind of teasing us all along or if it’s the real deal.