“An Outstanding study” Avindra Nath

UK Biobank

The UK Biobank study is the first of many biobank studies we should see in COVID over time.

The UK Biobank study, “SARS-CoV-2 is associated with changes in brain structure in UK Biobank“, published in the Nature journal, no less, is the first of many of its type we are likely to see over the next couple of years, and highlights what an extraordinary opportunity the COVID-19 pandemic presents for researchers.

The study took advantage of a large number of pre-COVID MRI brain scans UK researchers had access to. This meant they could readily compare the changes in the brains from the pre-COVID state to the long-COVID state. While this kind of study won’t get at what’s happening in the brains during the time of the initial infectious event, it should give us a really good grasp of what’s happened over time. As an added benefit, it almost solely focused on people who’d had mild COVID-19.

I don’t know if we’ve had any studies like this in ME/CFS or fibromyalgia, but we should have them in spades in long COVID. The National Institutes of Health (NIH), for instance, will be scouring large databases of patients who have sometimes been followed for decades, to see what happens to them after they come down with long COVID.

The other notable thing about this study, and the studies to come, is their size. This study examined a remarkable 785 brain scans (401 people infected by the coronavirus; 384 controls) of people older than 51. Contrast that with the typical brain imaging study size in ME/CFS and fibromyalgia with 20 to 50 patients. On MEDPAGE TODAY, Avindra Nath called it an “outstanding study.”

Shrinking Brains?

The authors assessed the differences in the MRI brain scans and gave the participants some pretty rudimentary cognitive tests.


The study found that some parts of the brains of those who had been infected with the coronavirus were shrinking 7-9x faster than normal.

The findings were striking. While no one wants to hear that their brains are shrinking, in several ways, we do want to find biological abnormalities that are consistent with the cognitive problems that people with long COVID are experiencing, and the study was notable for its ability to do that. The study found, in the authors’ own words, a “significant, deleterious impact associated with (the) SARS-CoV-2 (coronavirus).”

The New York Times reported that Dr. Steven Deeks, an HIV researcher at the University of California, San Francisco, said:

“This study provides the most definitive clinical data available to date that SARS-CoV-2 directly or indirectly damages nerves and that this, in turn, can have systemic effects, including changes in the brain…It contributes to an emerging theme that nerve damage was common during the first few waves of the pandemic.”


The older the person was, the greater the grey matter reductions. This was the orbitofrontal cortex (coronavirus infections – tan, non-infected-blue).

Most of the abnormalities were found in the limbic and olfactory regions. That the regions of the brain associated with smell (olfaction) were affected was no surprise. It’s not clear whether the researchers were surprised to find atrophy in some of the limbic regions of the brain, but that finding would be of no surprise to ME/CFS or fibromyalgia researchers. Many studies have found altered limbic functioning in both ME/CFS and fibromyalgia. A repetitive transcranial magnetic stimulation UCLA study is currently attempting to alter the functioning of the limbic areas of the brain in ME/CFS.

Limbic system dysfunction could contribute to everything from an activated fight/flight system, increased anxiety and fear, cognition, sleep, and autonomic nervous system, and endocrine problems.

The most prominent reductions in grey matter were found in the left parahippocampal gyrus – a part of the limbic system which encodes memory – and the lateral orbitofrontal cortex (decision-making, emotional lability). The study found reductions in four parts of the limbic system – hippocampus (short-term memory, neuroplasticity), anterior cingulate cortex (attention, motivation, pain processing, autonomic nervous system), amygdala (fear response, autonomic nervous system), and insula (homeostasis, pain processing, motor control, autonomic nervous system) – as well as the orbitofrontal cortex which has strong connections to the limbic system.  A part of the cerebellum was also significantly affected.

The olfactory and limbic regions weren’t the only regions associated with grey matter loss. On a more subtle level, it appeared to be present across the entire cortex (the outermost layer of the brain.)

On the whole, these weren’t massive changes in the brain: the authors pointed out that the “structural and microstructural” changes were “modest in size”. Still, at their worst, parts of the  COVID-19 patients’ brains shrank 7-9x’s more quickly than expected (our brains shrink over time.) The reductions in diffusion, along with an increase in cerebral spinal fluid, suggested that some tissue damage had occurred. It was likely due to a loss of grey matter found in the nerve bodies. (White matter refers to the sheaths covering the nerves.)

The increase in cerebrospinal volume seemed interesting given the increased cerebral spinal fluid pressure studies that have been found in both fibromyalgia and ME/CFS. (Intracranial hypertension has not been assessed yet in long COVID).

Under Pressure: Large Spinal Study Finds Intracranial Hypertension Common in ME/CFS

The Nose – the Key to Limbic System Dysfunction in Post-Infectious Diseases?

nasal connection to the limbic system

Could the nose’s connection to the limbic system lead to limbic system problems in post-infectious diseases?

The connections between the olfactory and limbic regions might be able to explain why the limbic region of the brain gets hit so hard, not just in long COVID, but in post-infectious disorders like ME/CFS.

Much of the discussion regarding the coronavirus and the olfactory regions has focused on the smell problems, but as viruses often enter the body through the nose, nearby regions of the brain might be affected in many post-infectious diseases.

In fact, reductions of grey matter in the orbitofrontal cortex and insula have been found in chronic rhinosinusitis – which the authors called a post-infectious state. (One of my doctors got her treatments and lab tests covered by using rhinosinusitis as a diagnosis). Baraniuk’s studies have shown the nose is affected in strange ways in ME/CFS.

What “Phantom Nasal Congestion” May Tell Us About ME/CFS and Fibromyalgia

Cognition Affected

The cognitive tests were relatively crude but did show that the COVID group had experienced reductions in information processing and attention. Given the alterations found in the parahippocampal gyrus – the seat of short-term memory – the authors questioned whether COVID-19 patients might be at increased risk of dementia further down the road. Thankfully, an international effort to answer this question is underway.

The evidence for an increased risk of dementia in diseases like ME/CFS/FM is mixed, with one fibromyalgia study suggesting not and one suggesting yes.

Is the Fibro-fog in Fibromyalgia a Prelude to Dementia?

Without mentioning the ME/CFS connection, the study also authors noted one of the most intriguing overlaps between long COVID and ME/CFS – white matter hyperintensities. It isn’t just that microhemorrhages have been found in the brains of both long COVID and people with ME/CFS. It’s the unique pattern that they’ve taken – in both ME/CFS, with its different triggering event, and long COVID – the white matter hyperintensities seem to be spread randomly throughout the brain. Interestingly, a similar nonspecific microhemorrhage pattern also appears to crop up in “long Lyme disease” (i.e posttreatment Lyme disease syndrome), and is reportedly found in multiple sclerosis as well

The Slow Way or the Fast Way – Take Your Pick.

Innovative ME/CFS field

The ME/CFS field has much to offer long-COVID researchers and patients.

Asked to comment on the study, a Yale researcher, Dr. Spudich, stated that “this is pretty convincing evidence that something changes in brains of this overall group of people with Covid”, and then qualified her statement: “To make a conclusion that this has some long-term clinical implications for the patients I think is a stretch.”

The Gist

  • A UK Biobank MRI study examined the brains of 785 people over time – about half of whom had been infected with the coronavirus. The average time after infection was about 5 months.
  • The study authors found a “significant, deleterious impact associated with (the) SARS-CoV-2 (coronavirus).”
  • Most of the abnormalities concerned reductions in the grey matter that makes up the nerve bodies in the limbic and olfactory regions. The reductions were “modest” but some parts of the brain shrank at 7-9x their normal rate. Smaller amounts of shrinkage were found over the entire cortex (outer covering of the brain). Older people experienced greater degrees of “shrinkage”.
  • Limbic system dysfunction has been found in ME/CFS and FM as well and could contribute to everything from an activated fight/flight system, increased anxiety and fear, cognition, sleep, and autonomic nervous system, and endocrine problems.
  • The nose’s close connection to the limbic system, and the limbic system findings in ME/CFS and fibromyalgia, suggest that this area may be at risk of being damaged in post-infectious illnesses.
  • Increased cerebral spinal fluid (CSF) levels suggested that damaged grey matter was being flushed into the CSF.
  • Reduced brain volumes have also been found in ME/CFS.
  • Studies with younger participants, which assess symptoms and which contrast long COVID with recovered coronavirus patients are needed. As this study did not differentiate long COVID from recovered patients, its findings may understate the damage found in long COVID.
  • This is surely just the first of many before/after studies that will examine the brain in COVID-19 and long COVID.

In a rather odd statement which suggested that he believed that the participants would recover (?), Dr. Benedict Michael agreed: “we don’t know if it’s just a transient change that gets better with recovery”, and “We don’t know that it actually means anything for the patient’s quality of life or function.”

Similarly, Columbia University neurologist Scott Small told the Washington Post “This paper might be the beginning of something — but they would have to do a lot more to show this is permanent or that the patients showed interesting changes in cognition.”

All are calling for more research to be done to see if the finding holds up. Of course, that research needs to be done but researchers should also feel comfortable moving forward now, trying to understand the why and how of the findings. That work, after all, has already been done in another post-infectious disease – chronic fatigue syndrome (ME/CFS).

They missed the fact that long COVID already has a potential stand-in that could help them from re-inventing the wheel and saving long-COVID patients some precious time. With similar symptoms, and exercise, blood vessel, small nerve fiber, autonomic nervous system, microbiome, brain, and brain blood flow findings, these researchers might consider taking a gander at ME/CFS research to help them better understand long COVID and the effects it has over time.

Similarly, long-COVID advocates wary at getting lumped in with a controversial disease (or any disease), or who shy away from having ME/CFS experts being involved, might worry less if they understood how embracing ME/CFS could hurry things along. With regard to cognition, for instance, more sophisticated cognitive tests show that the cognitive hit in ME/CFS, and therefore probably long COVID, is indeed lasting.

Long-COVID advocates and researchers might also want to check out the novel approaches that have been developed over time in ME/CFS that could shave years off the time needed to understand and treat long COVID.

Few diseases, for instance, use exercise stressors as a tool to understand them, but decades of work have shown them to be invaluable tools in studying ME/CFS. Tests that show little when people with ME/CFS are at rest suddenly sprout abnormalities when a researcher puts ME/CFS patients on a bike or has them stand for a while or get on a tilt table.

Similarly, compare the results of standard one-day exercise tests – which sometimes suggested people with ME/CFS were merely deconditioned – to the 2-day exercise studies that a) definitively demonstrate that exercise impairs ME/CFS patients’ ability to generate energy; and b) provide a gold standard test for disability. Those tests had been largely abandoned by the medical researchers until ME/CFS researchers resurrected them.  Long-COVID researchers could move more quickly if they took these and other innovations developed by the ME/CFS field into account.

The Exercise Intolerance in ME/CFS – Is it Unique?

Modest But Significant Changes

modest amounts of brain damage COVID-19

“Modest” amounts of “brain damage” were found.

Dr. Douad, one of the co-authors of the study, told the New York Times that It is brain damage, but it is possible that it is reversible…it is still relatively scary because it was in mildly infected people.

Brain damage is a scary term – but seriously what did we expect? Problems with cognition, stimuli hypersensitivity, high rates of fear and anxiety, fatigue, even autonomic nervous system problems all suggest some kind of “brain damage” is present.

Let’s not overplay the damage, though. In the paper, the authors stated that the large numbers in the study would allow them to detect “subtle, but consistent spatially distributed sites of damage associated with the infection”, and relatively subtle – small but surprising changes in grey matter volume and some other findings – were what they found.

As the paper noted, more studies are needed; in particular, studies in younger patients, studies that assess symptoms, which contain better cognitive testing, etc., and, in particular, which focus on long-COVID patients. Time will tell, but it’s possible that the study’s outcomes are quite a bit understated as the study simply included everyone who’d been infected by the virus, whether they had long COVID or not.

If as suspected, the brains of people with long COVID are more affected than those who don’t develop it, we may see more alarming results in the future. The study’s short time frame (approximately 5 months after infection) also means we know nothing about the longer-term changes in the brain as well.

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