Even Mild Cases of Covid-19 Pose Serious Risks to Brain Health

By Dr. Ziyad Al-Aly

From the very early days of the pandemic, “brain fog” emerged as a significant health condition that many experience after COVID-19.

Brain fog is a colloquial term that describes a state of mental sluggishness or lack of clarity and haziness that makes it difficult to concentrate, remember things and think clearly.

Fast-forward four years and there is now abundant evidence that being infected with SARS-CoV-2 – the virus that causes COVID-19 – can affect brain health in many ways.

In addition to brain fog, COVID-19 can lead to an array of problems, including headaches, seizure disorders, strokes, sleep problems, and tingling and paralysis of the nerves, as well as several mental health disorders.

A large and growing body of evidence amassed throughout the pandemic details the many ways that COVID-19 leaves an indelible mark on the brain. But the specific pathways by which the virus does so are still being elucidated, and curative treatments are nonexistent.

Now, two new studies published in the New England Journal of Medicine shed further light on the profound toll of COVID-19 on cognitive health.

I am a physician scientist, and I have been devoted to studying long COVID since early patient reports about this condition – even before the term “long COVID” was coined. I have testified before the U.S. Senate as an expert witness on long COVID and have published extensively on this topic.

Here are some of the most important studies to date documenting how COVID-19 affects brain health:

• Large epidemiological analyses showed that people who had COVID-19 were at an increased risk of cognitive deficits, such as memory problems.

• Imaging studies done in people before and after their COVID-19 infections show shrinkage of brain volume and altered brain structure after infection.

• A study of people with mild to moderate COVID-19 showed significant prolonged inflammation of the brain and changes that are commensurate with seven years of brain aging.

• Severe COVID-19 that requires hospitalization or intensive care may result in cognitive deficits and other brain damage that are equivalent to 20 years of aging.

• Laboratory experiments in human and mouse brain organoids designed to emulate changes in the human brain showed that SARS-CoV-2 infection triggers the fusion of brain cells. This effectively short-circuits brain electrical activity and compromises function.

• Autopsy studies of people who had severe COVID-19 but died months later from other causes showed that the virus was still present in brain tissue. This provides evidence that contrary to its name, SARS-CoV-2 is not only a respiratory virus, but it can also enter the brain in some individuals. But whether the persistence of the virus in brain tissue is driving some of the brain problems seen in people who have had COVID-19 is not yet clear.

• Studies show that even when the virus is mild and exclusively confined to the lungs, it can still provoke inflammation in the brain and impair brain cells’ ability to regenerate.

• COVID-19 can also disrupt the blood brain barrier, the shield that protects the nervous system – which is the control and command center of our bodies – making it “leaky.” Studies using imaging to assess the brains of people hospitalized with COVID-19 showed disrupted or leaky blood brain barriers in those who experienced brain fog.

• A large preliminary analysis pooling together data from 11 studies encompassing almost 1 million people with COVID-19 and more than 6 million uninfected individuals showed that COVID-19 increased the risk of development of new-onset dementia in people older than 60 years of age.

Autopsies have revealed devastating damage in the brains of people who died with COVID-19.

Drops in IQ

Most recently, a new study published in the New England Journal of Medicine assessed cognitive abilities such as memory, planning and spatial reasoning in nearly 113,000 people who had previously had COVID-19. The researchers found that those who had been infected had significant deficits in memory and executive task performance.

This decline was evident among those infected in the early phase of the pandemic and those infected when the delta and omicron variants were dominant. These findings show that the risk of cognitive decline did not abate as the pandemic virus evolved from the ancestral strain to omicron.

In the same study, those who had mild and resolved COVID-19 showed cognitive decline equivalent to a three-point loss of IQ. In comparison, those with unresolved persistent symptoms, such as people with persistent shortness of breath or fatigue, had a six-point loss in IQ. Those who had been admitted to the intensive care unit for COVID-19 had a nine-point loss in IQ. Reinfection with the virus contributed an additional two-point loss in IQ, as compared with no reinfection.

Generally the average IQ is about 100. An IQ above 130 indicates a highly gifted individual, while an IQ below 70 generally indicates a level of intellectual disability that may require significant societal support.

To put the finding of the New England Journal of Medicine study into perspective, I estimate that a three-point downward shift in IQ would increase the number of U.S. adults with an IQ less than 70 from 4.7 million to 7.5 million – an increase of 2.8 million adults with a level of cognitive impairment that requires significant societal support.

Another study in the same issue of the New England Journal of Medicine involved more than 100,000 Norwegians between March 2020 and April 2023. It documented worse memory function at several time points up to 36 months following a positive SARS-CoV-2 test.

Memory and Cognitive Decline

Taken together, these studies show that COVID-19 poses a serious risk to brain health, even in mild cases, and the effects are now being revealed at the population level.

A recent analysis of the U.S. Current Population Survey showed that after the start of the COVID-19 pandemic, an additional 1 million working-age Americans reported having “serious difficulty” remembering, concentrating or making decisions than at any time in the preceding 15 years. Most disconcertingly, this was mostly driven by younger adults between the ages of 18 to 44.

Data from the European Union shows a similar trend – in 2022, 15% of people in the EU reported memory and concentration issues.

Looking ahead, it will be critical to identify who is most at risk. A better understanding is also needed of how these trends might affect the educational attainment of children and young adults and the economic productivity of working-age adults. And the extent to which these shifts will influence the epidemiology of dementia and Alzheimer’s disease is also not clear.

The growing body of research now confirms that COVID-19 should be considered a virus with a significant impact on the brain. The implications are far-reaching, from individuals experiencing cognitive struggles to the potential impact on populations and the economy.

Lifting the fog on the true causes behind these cognitive impairments, including brain fog, will require years if not decades of concerted efforts by researchers across the globe. And unfortunately, nearly everyone is a test case in this unprecedented global undertaking.

Ziyad Al-Aly, MD, is Chief of Research and Development at VA St. Louis Health Care System and a Senior Clinical Epidemiologist at Washington University in St. Louis.

Dr. Al-Aly’s laboratory was the first to produce evidence on the effects of vaccines on Long Covid, the health consequences of repeated infections with SARS-CoV-2, and the effect of antivirals on the short- and long-term outcomes of SARS-CoV-2 infection. He also co-chaired the Biden Administration committee that developed the National Research Action Plan for Long Covid.

This article originally appeared in The Conversation and is republished with permission.

Brain Changes Found in Patients with Long-Term Lyme Disease

By Pat Anson, PNN Editor

Researchers at Johns Hopkins University have documented changes in the brains of patients with post-treatment Lyme disease that may explain symptoms such as brain fog, memory loss and other cognitive issues. The finding could also have implications for patients with long covid, fibromyalgia, multiple sclerosis, chronic fatigue and other health conditions who have cognitive problems.    

Lyme disease is a bacterial illness spread by ticks that causes a rash, flu-like aches and fever, joint pain and fatigue. Most patients fully recover when treated early with antibiotics, but up to 20% of those with post-treatment Lyme disease (PTLD) have long-term symptoms, including depression, insomnia and cognitive difficulties. There is usually no clinical or laboratory evidence to explain their ongoing issues.

“Objective biologic measures of post-treatment Lyme symptoms typically can’t be identified using regular MRIs, CT scans, or blood tests,” says John Aucott, MD., director of the Johns Hopkins Lyme Disease Clinical Research Center.

Aucott and his colleagues recruited 12 PTLD patients and 18 people without a history of Lyme to undergo functional MRI (fMRI) scans while performing a short-term memory task. The scans allow investigators to track blood flow and other changes in the brain in real time.

Their findings, published in the journal PLOS ONE, suggest that cognitive difficulties in PTLD patients are linked to functional and structural changes in the “white matter” of the brain, which is crucial for processing and relaying information. The imaging tests revealed unusual activity in the frontal lobe, an area of the brain responsible for memory recall and concentration. Patients with post-treatment Lyme needed longer periods of time to complete the memory task.

“We saw certain areas in the frontal lobe under-activating and others that were over-activating, which was somewhat expected,” said lead author Cherie Marvel, PhD, an associate professor of neurology at Johns Hopkins.

“However, we didn’t see this same white matter activity in the group without post-treatment Lyme.”

To confirm their finding, researchers used another form of imaging called diffusion tensor imaging (DTI) on all 12 patients with Lyme and 12 of the non-Lyme participants. DTI detects the direction of water movement within brain tissue. Water was diffusing, or leaking, in the the same white matter regions identified in the fMRI.

Researchers believe the increased activity they saw in white matter may reflect an immune system response in the PTLD patients, which may also explain cognitive issues in patients with other chronic health conditions.

PLOS ONE

“Results reported here may have implications for other diseases in which white matter pathology has been demonstrated (e.g., multiple sclerosis) or in illnesses in which cognitive complaints follow disease onset,” researchers said. “The use of multimodal neuroimaging methods, like the ones used in the current study, may be a viable approach for obtaining information on brain function and structure to identify biomarkers of disease burden.”

Researchers say larger studies with more patients will be needed to confirm their findings, as well as long-term tracking of brain changes from the initial Lyme infection through development of PTLD.

Nearly 500,000 people are believed to get Lyme disease each year in the United States. Diagnoses of Lyme have soared over the past 15 years, according to a recent analysis of insurance claims that found Lyme cases rose 357% in rural areas and 65% in urban areas. The highest rates of Lyme were in New Jersey, Vermont, Maine, Rhode Island and Connecticut.

Cognitive Problems Persist in Patients with Long Covid

By Pat Anson, PNN Editor

About 70% of people with long covid have concentration and memory problems several months after their initial infection with Covid-19, according to new research at the University of Cambridge. The severity of the symptoms appears to be linked to the level of fatigue and headache people experienced during their initial illness.

Long covid is a poorly understood disorder characterized by body pain, fatigue, cognitive impairment and difficulty sleeping. About a third of people infected with coronavirus develop symptoms that can last for many months.   

In their study of 181 long covid patients, published in the journal Frontiers in Aging Neuroscience, researchers found that 78% reported difficulty concentrating, 69% had brain fog, 68% experienced forgetfulness, and 60% had trouble finding the right word to use in speech. They also performed poorly in cognitive tests, with significantly lower ability to remember words and pictures.

“This is important evidence that when people say they’re having cognitive difficulties post-COVID, these are not necessarily the result of anxiety or depression. The effects are measurable - something concerning is happening,” said co-author Muzaffer Kaser, PhD, a psychiatrist and researcher at the University of Cambridge. “Memory difficulties can significantly affect people’s daily lives, including the ability to do their jobs properly.”

The findings are further evidence that Covid-19 will have a lasting impact around the world, long after the pandemic subsides. Cambridge researchers say their study supports other findings that suggest society will face a “long tail” of workforce illness due to long covid.

“Long covid has received very little attention politically or medically. It urgently needs to be taken more seriously, and cognitive issues are an important part of this. When politicians talk about ‘Living with COVID’ – that is, unmitigated infection, this is something they ignore. The impact on the working population could be huge,” said senior author Lucy Cheke, PhD, a psychologist and lecturer at Cambridge.

To help understand the cause of the cognitive problems, Cheke and her colleagues investigated other symptoms that might be linked. They found that people who experienced fatigue and neurological symptoms, such as dizziness and headache, during their initial illness were more likely to have cognitive issues later on.

Participants were assigned to carry out multiple tasks to assess their decision-making and memory. These included remembering words on a list, and remembering which two images appeared together. The results revealed a consistent pattern of memory problems in people with long covid -- problems that were more pronounced in those whose initial neurological symptoms were more severe.

“People think that long covid is ‘just’ fatigue or a cough, but cognitive issues are the second most common symptom - and our data suggest this is because there is a significant impact on the ability to remember. There is growing evidence that COVID-19 impacts the brain, and our findings reflect that,” said Cheke.

Study participants were recruited between October 2020 and March 2021, when the Alpha variant and the original form of SARS-CoV-2 were still the dominant forms of the virus.

Very few of the patients had symptoms severe enough to be admitted to a hospital. But even among those who were not hospitalized, researchers found that people with severe initial symptoms were more likely to develop long covid than those with mild symptoms. They also found that people over 30 were more likely to have severe ongoing symptoms than younger ones.

“Infection with the virus that causes COVID-19 can lead to inflammation in the body, and this inflammation can affect behaviour and cognitive performance in ways we still don’t fully understand, but we think are related to an early excessive immune response,” said Kaser.

As is often the case with chronic illness, half of the patients with long covid reported difficulty getting medical providers to take their symptoms seriously, perhaps because cognitive symptoms do not get the same attention as respiratory problems.

The Cambridge study currently has no data on long covid associated with the Delta or Omicron variants of coronavirus, although new patients are being recruited to fill that void. The researchers say more studies are needed to understand the complex effects of Covid on the brain, cognition and mental health.

One way to reduce your risk of long covid is to get vaccinated. A UK study last year found that people who received the Moderna, Pfizer or AstraZeneca vaccines had significantly lower risk of an infection that turns into long covid.

Can We Forget About Chronic Pain?

By Ann Marie Gaudon, PNN Columnist

I recently came across a clinical report which describe two patients with a lengthy history of chronic pain severe enough to warrant opiate therapy. Both patients experienced sudden memory loss and forgot about their pain – literally.

Central sensitization is a process known to occur in the spinal cord and brain where if short-term acute pain is allowed to persist, then changes occur within the central nervous system which can lead to chronic or intractable pain.

That’s what happened to me. I have a diagnosis of a visceral pain syndrome, as opposed to a progressive pain condition. I experienced one vicious organ assault and after more than 30 years of it being healed, I remain in pain.

Other patients who have experienced painful trauma may relive painful episodes that evoke recurring memories -- they experience their pain over and over again. That is a classic symptom of post-traumatic stress disorder (PTSD). Think of a war veteran or survivor of sexual violence.

Either way, neurophysiologic changes which relate to learning, memory and pain can result in a maladaptive learning process which leaves one in chronic pain. These intricacies happen outside of conscious awareness. We are not aware of or in control of this dysfunctional process while it is occurring within our brain and spinal cord circuits.

Here is an overview of the two patients discussed in the report:

Patient #1

The first patient is a 47-year old female with complicated health problems. She had undergone multiple surgeries and treatment modalities for gastric ulcers, endometriosis, thyroid cancer, hypothyroidism, seizure disorder, malnutrition and chronic abdominal pain over 10 years.

Her pain was managed with high doses of opiate medications in various forms, including intravenous, transdermal and oral. During a complex 12-month hospital stay, she had at least five seizures and suffered memory loss so severe she could not remember her entire stay in the hospital.

She did eventually become fully alert and oriented to the present, but she no longer complained of her pain symptoms and no longer demonstrated a need for consistent pain medication.

Six months after discharge, the patient was living at home in stable condition and only occasionally using tramadol. She reported her symptoms as minimal and 1-2 on the pain scale. She still has no memory of many aspects of her long hospitalization.

Patient #2

A 57-year old male was described as a “highly functioning architect” with a 10-year history of low back and right extremity pain. He had undergone many unsuccessful treatments for pain, including surgery, and was being admitted to hospital to have an intrathecal pump surgically implanted for pain control. He was taking no less than nine medications for pain including high doses of opiate therapy.

Initially after the pump was placed, he reported having a partial reduction of pain in his leg. However, in the next six months he was requesting higher doses of intrathecal as well as oral opiates.

One month after this, the patient was in a minor motor vehicle accident where he did not lose consciousness, but inexplicably had partial memory loss. His physicians felt the accident was not the cause, as the memory loss symptoms occurred long afterward. The cause of the amnesia was unknown and tests including a brain MRI showed as normal.

The patient could not remember the names of his doctors, where he lived, what type of work he did, or why he had a pain pump implanted. He was weaned off opiates without any complaint of increased pain and subsequently had the pump removed at his request.

Eight months later, this patient was found minimally responsive in his home. It is not known what occurred, but there was a suspicion that he had fallen and incurred a head injury. The patient experienced profound memory loss, with no memory of who he was, his family members or his back pain.

His pain medications were discontinued with no complaint of pain, but he required placement in a long-term care home due to severe amnesia. Over the next two years, this patient regained partial memory, along with some back and leg pain. He has not requested or required opiate therapy.

Emotions, Pain and Memory

We know pain perception can be caused by nociceptive stimuli, yet we also know that emotional and psychological factors can increase our perception of pain. A complex play of nerve fibers which transmit messages to the brain and spinal cord suggest there is a relationship between emotions, pain and memory. The best evidence that memory plays a role in pain is that of phantom limb pain.

The two cases presented here suggest that memory may influence the perception of pain, and that amnesia can be accompanied by a loss of or significant reduction of pain in the absence of any physical factors.

Treatments that reduce “pain memories” in the brain and spinal cord, along with a focus on preventing pain to reduce or eliminate these memories, may someday have a more widespread role in the management of chronic pain. To have a treatment or ability to effectively erase a maladaptive pain memory leaves me with just three words:

Count me in.

Ann Marie Gaudon is a registered social worker and psychotherapist in the Waterloo region of Ontario, Canada with a specialty in chronic pain management. 

Ann Marie has been a chronic pain patient for over 30 years and works part-time as her health allows. For more information about her counseling services, visit her website.

This column is for informational purposes only and represents the author’s opinions alone. It does not inherently express or reflect the views, opinions and/or positions of Pain News Network.

Does Chronic Pain Affect Memory?

By Ann Marie Gaudon, PNN Columnist

Pain is a complex experience. It not only affects us biologically, but we also experience it cognitively and emotionally. Does it affect our memory? You bet it does.

Chronic pain patients often complain of memory problems and there are numerous studies which confirm these challenges are indeed a reality.

Twenty-four studies evaluating working memory (WM) and/or long-term memory (LTM) in chronic pain groups and control groups were reviewed last year by French researchers. WM was defined as the processing and manipulation of information within a short period of time (a few seconds), while LTM involved the “storage” of knowledge and memories over a long period of time.

Concentration and memory deficits on a daily basis were the most frequently reported cognitive difficulties. Memory complaints included forgetfulness and problems performing everyday tasks and conversations.

Emotional distress common to pain patients, such as depression, anxiety and rumination (the inability to divert attention away from pain), was also found to play an important role in memory difficulties.

One study compared two groups of pain patients who had minor or major memory complaints. Between the two, no significant differences were found with regard to age, gender, education level, marital status, medication use, long-term pain or pain intensity.

However, patients in the major memory complaint group suffered from emotional distress to a significantly greater degree. They also reported a lack of family support and discontent with their social and sexual lives. These were noted as additional daily sources of suffering for this group.

Adding to potential negative effects on memory were comorbidities which many pain syndromes share. Conditions such as depression, anxiety, sleep disturbances, and chronic fatigue could alone or combined affect memory. A major concern expressed was the need to disentangle pain-related cognitive effects from those resulting from these comorbidities.

Medications and Memory

The review really became interesting when it came to medication, because researchers found contradictory results. One European study reported that opioids exerted a negative effect on working memory -- finding a clear association between higher levels of analgesics and perceived memory dysfunction in chronic back pain patients. Some studies confirmed that medication can have a negative effect on memory, but others showed improvements in memory following analgesic treatment. That suggests that effective pain relief may also reverse pain-induced memory impairment.

The researchers concluded it was unclear whether analgesic medications are beneficial or detrimental, because both scenarios were reported.

Age was also identified as an important factor in the relationship between chronic pain and memory, but not in the way you may think. Surprisingly, it was shown that an increase in age did not additionally affect memory performance.

One study reported that gender and age significantly affected memory decline in those suffering from chronic migraine headaches. Cognitive decline in migraineurs was greater among younger individuals, and females showed greater decline during headache intervals than males. It was acknowledged that gender as a factor in pain-related experience is poorly investigated.

Like all reviews, this one has its limitations. There was a “large heterogeneity” of tests within the 24 studies. This diversity of tests did not allow for a suggestion of which memory processes were altered by chronic pain itself. The study populations were also heterogeneous regarding pain etiologies and an assessment of the intensity of pain was not performed.

Studies which included a mix of chronic pain disorders did not provide data on whether specific memory impairments were more frequently observed in specific disorders. The authors suggest there is a need for comparative studies across pain-related disorders in order to determine whether impairments are pain-related or a consequence of other pathophysiological features.

These numerous studies confirmed the memory decline that is often reported by chronic pain patients. Even if these effects are mild, the impact on quality of life could be substantial as they may indeed worsen suffering including depression, anxiety, and limitations on activity.

Researchers suggested that examining memory function should be part of the clinical assessment of chronic pain patients. The spectrum of cognitive difficulties must become acknowledged and understood in order to find ways to overcome them.

Ann Marie Gaudon is a registered social worker and psychotherapist in the Waterloo region of Ontario, Canada with a specialty in chronic pain management.  She has been a chronic pain patient for over 30 years and works part-time as her health allows. For more information about Ann Marie's counseling services, visit her website.

The information in this column should not be considered as professional medical advice, diagnosis or treatment. It is for informational purposes only and represents the author’s opinions alone. It does not inherently express or reflect the views, opinions and/or positions of Pain News Network.