Long COVID symptoms linked to measurable damage in the brain’s dopamine system

A recent study published in eBioMedicine provides evidence that individuals suffering from long COVID show a measurable reduction in the brain’s dopamine-releasing neurons. These physical brain changes tend to be associated with common persistent symptoms such as apathy, memory problems, and a slowing of physical movements. The findings suggest that treatments aimed at boosting dopamine function could offer a new therapeutic direction for people experiencing the neuropsychiatric effects of long COVID.

Long COVID is a condition where individuals experience ongoing physical and mental symptoms long after their initial infection with the COVID-19 virus has resolved. Many people report persistent brain-related symptoms, including a profound lack of motivation, difficulty experiencing pleasure, memory lapses, and general cognitive sluggishness. The biological mechanisms responsible for these lingering issues remain poorly understood by the medical community.

Past medical research primarily focused on how immune system overreactions and persistent brain inflammation might drive these symptoms. Jeffrey Meyer, a Canada Research Chair, senior research scientist, and professor in the department of psychiatry at the University of Toronto, authored the new study. His prior work focused extensively on similar inflammatory processes.

“We had top international level expertise in measuring brain inflammation in psychiatric illnesses,” Meyer said. “When COVID came, I decided to use the same imaging tools to study long COVID.”

During that earlier research, Meyer found a distinct pattern linking inflammation and specific brain networks. He noted that the most intense areas of inflammation overlapped with the brain’s dopamine pathways.

“When I discovered evidence for brain inflammation in long COVID, I noticed that the greatest elevations in the inflammation marker were in regions where there are nerve terminals that release dopamine,” Meyer said.

These brain regions also control basic physical movements. Dopamine is a chemical messenger in the brain that regulates motivation, learning, and physical movement, and its neurons are highly concentrated in a deep brain structure called the striatum.

“Also, the inflammation marker correlated with a measure of movement speed that can be affected by injury to dopamine releasing nerves so I speculated that injury to dopamine releasing nerves could account for the symptom of slowed movement speed, and be related to inflammation in the same region,” Meyer said. “Sometimes inflammation can damage dopamine releasing nerves.”

Scientists had additional reasons to look at the dopamine system in relation to COVID-19. The specific cells that produce dopamine contain high levels of the receptor proteins that the COVID-19 virus uses to enter and infect human cells.

“Also, the key binding site for the virus to enter cells is higher density on nerves that release dopamine which is another reason to see if their terminals are lost,” Meyer added.

To measure the health of dopamine neurons, the researchers looked at a protein called vesicular monoamine transporter 2. This protein acts like a microscopic pump, packaging dopamine into tiny cellular sacs so that it can be released to communicate with neighboring cells. Because this protein is almost exclusively found within dopamine-releasing neurons in the striatum, measuring its presence provides a highly accurate estimate of how many intact dopamine nerve terminals exist.

The researchers conducted a case-control study involving 24 adults diagnosed with long COVID and 24 healthy adults matched closely for age. The healthy control group was later expanded to 43 participants for additional exploratory comparisons. Participants in the long COVID group had experienced only mild to moderate illness during their initial infection. However, they all developed significant neuropsychiatric symptoms within three months of their acute illness, and these symptoms had persisted for at least three months.

The scientists established strict exclusion criteria for all participants to ensure the accuracy of their measurements. Anyone with a history of neurological illness prior to their COVID-19 infection was excluded from the study. The team also excluded individuals with a history of moderate or severe substance abuse, as well as anyone who had smoked cigarettes or used recreational drugs within the past two months.

Participants underwent brain imaging using positron emission tomography. This is a medical imaging technique that uses a safe, mildly radioactive tracer to visualize and measure specific cellular processes in the body. For this study, the scientists used a specific tracer designed to bind directly to the vesicular monoamine transporter 2 protein.

In addition to brain scans, participants completed a battery of psychological and physical assessments. Motivation levels were measured using the Marin Apathy Evaluation Scale. Fine motor speed was gauged using the Finger Tapping Test, which requires participants to tap a mechanical counter as quickly as possible. Memory retention and cognitive function were assessed using the Hopkins Verbal Learning Test-Revised and the Cognitive Failures Questionnaire.

The brain imaging revealed that the 24 individuals with long COVID had significantly lower levels of the dopamine transporter protein compared to the healthy controls. Specifically, the long COVID group showed an overall reduction in protein binding across three key regions of the striatum.

“The magnitude of loss is about 18% of the dopamine nerve terminals on average,” Meyer told PsyPost. “In other illnesses this magnitude of loss is associated with symptoms i.e. loss in one region is associated with trouble with motivational energy problems, loss in another region is associated with some slowness of movement and loss in a third region is associated with memory trouble.”

Lower protein levels in specific brain regions correlated directly with the severity of the participants’ symptoms. In the ventral striatum, which helps process motivation, reduced dopamine cell density was associated with higher apathy scores and increased reports of daily cognitive failures. In the dorsal putamen, a region heavily involved in movement, lower cell density correlated with slower performances on the physical finger-tapping test. In the dorsal caudate, which supports learning, reduced cell density was linked to poorer scores on the delayed memory recall test.

“The correlations in loss of the marker of dopamine nerves with symptoms were stronger than expected and correlated with a wider range of symptoms than expected,” Meyer said.

The scientists also tested blood samples from the participants to see if peripheral biomarkers of dopamine metabolism or general nerve damage matched the brain scan results. They found no significant correlations between the blood markers and the imaging data in the long COVID group. This indicates that simple blood tests may not accurately reflect the specific dopamine cell damage occurring deep within the central nervous system.

Observational studies of this nature cannot definitively prove causality. The data shows an association between lower dopamine cell density and long COVID symptoms, but it does not confirm that the virus directly killed the cells. Other biological responses triggered by the virus could potentially contribute to both the brain changes and the neuropsychiatric symptoms.

Another limitation relates to what the positron emission tomography scans physically measure. The imaging tracks the density of the transporter proteins rather than the physical brain cells themselves. It is theoretically possible that the neurons remain structurally intact but have simply stopped producing normal levels of the transporter protein.

The study utilized a relatively small sample size of 24 long COVID patients, and all these individuals suffered from a specific set of severe psychological and cognitive symptoms. As a result, these findings might not apply to people whose long COVID primarily involves respiratory or cardiovascular issues. Future research will need to replicate these brain scans in much larger and more diverse groups of patients to confirm the generalizability of the findings.

A key consideration is that these findings represent a specific point in time, and the long-term trajectory for patients remains unknown. The nervous system has a capacity to heal, and symptom persistence varies from person to person.

“It doesn’t mean people can’t regrow the nerve terminals without treatment or that it is permanent for everyone,” Meyer said. “But it may be that some people will need additional treatment to help.”

The authors suggest that these findings point toward new potential treatments for long COVID. Because the data suggests a localized loss of dopamine function, clinical trials could explore whether existing dopamine-enhancing medications might alleviate symptoms.

“People with long COVID with symptoms of low motivational energy, slowed speed taking longer to complete activities and problems with remembering words probably have lost nerves that release a chemical called dopamine,” Meyer said. “Some people may grow new nerve terminals and recover but for those who do not, there is an opportunity to make treatments to help nerves either release more dopamine or regrow nerve terminals.”

Medications that inhibit dopamine breakdown or provide precursors to dopamine might help restore motivation and cognitive speed in affected patients. The research team is currently working to test this hypothesis in a clinical setting.

“I am close to receiving approval for a clinical study to repurpose a medication for long COVID,” Meyer said. “The medication would help nerves release more dopamine and lower some types of brain inflammation. We hope it will help with memory problems and difficulty with motivational energy.”

The study, “Loss of vesicular monoamine transporter 2 in striatum of long COVID and relationship to neuropsychiatric symptoms,” was authored by Yuhan Karida Liu, Devina Persaud, Erica L. Vieira, Joeffre Braga, Pablo Rusjan, Laura Miler, Jennifer S. Rabin, Tina McCluskey, Isabelle Boileau, Thomas Chao, Michael Bagby, Lucas Narciso, Lauren Rose Gray, Neil Vasdev, Kimberly Desmond, Stefan Kloiber, Jerry Warsh, Muhammad Ishrat Husain, Kelly Smart, Wei Wang, and Jeffrey H. Meyer.