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.

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“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.”

An accompanying commentary published in the same journal provides an independent interpretation of the research. The commentary was co-authored by Eric Guedj, a researcher at Aix Marseille University in France, and Danielle Beckman, a researcher at Helmholtz Munich in Germany.

“The editors of eBioMedicine invited me to comment on the study in the context of our previous work on brain imaging in long COVID,” Guedj told PsyPost. “In earlier research, we identified changes in brain glucose metabolism using FDG-PET and later proposed that these changes could involve dysfunction of astrocytes, the brain cells that support neurons and help regulate their energy supply.”

He noted that the new research builds on this foundation by targeting a more specific chemical network in the brain.

“The study by Liu and colleagues was particularly interesting because it moved from a broad measure of brain metabolism toward a more specific marker of dopamine-related nerve endings,” Guedj said.
A major takeaway from the commentary is that invisible symptoms can have measurable physical roots. Routine magnetic resonance imaging scans, commonly known as MRIs, often fail to capture the microscopic cellular biology driving long COVID.

“A broader lesson is that a normal structural MRI does not necessarily mean that the brain is functioning normally,” Guedj said. “Molecular imaging can reveal changes in brain chemistry and energy use that conventional scans cannot detect.”

“The main message is that symptoms such as apathy, cognitive slowing, memory difficulties and slower movements can have measurable biological correlates in the brain, even when a conventional structural MRI appears normal,” he added.

Guedj highlighted the specific regional associations found in the brain scans.

“The most striking aspect was the consistency between the location of the abnormalities and the symptoms,” Guedj said. “Changes in a region involved in motivation were associated with apathy, changes in a region involved in movement were associated with motor slowing, and changes in another region were associated with memory performance.”

“This anatomical consistency makes the findings biologically plausible, although they still need to be confirmed in larger and more diverse groups of patients,” he added.

The commentary authors also emphasized several limitations regarding the interpretation of the brain scans. They noted that the findings do not establish a universal rule for all patients experiencing lingering symptoms after a COVID-19 infection.

“This does not mean that long COVID is generally a dopamine disorder,” Guedj said. “It suggests that there may be a subgroup of patients whose symptoms are linked to changes in dopamine-related brain circuits.”

Additionally, a lower protein signal in a brain scan does not guarantee that the cells are dead. The cells might simply be struggling to function normally under stress.

“A lower VMAT2 signal does not necessarily mean that dopamine-producing neurons have been permanently lost,” Guedj said. “It could also reflect a potentially reversible change in how dopamine nerve endings store or regulate dopamine.”

He also pointed out that the single time-point design of the study limits the conclusions that can be drawn about cause and effect.

“The study was relatively small and included patients with prominent neuropsychiatric symptoms,” Guedj said. “The findings therefore cannot yet be generalized to everyone with long COVID. Because participants were examined at a single point in time, the study also cannot establish whether the dopamine-related changes caused the symptoms or resulted from another underlying process.”

To build on this research, scientists will need to track patients over extended periods. Guedj suggested that combining different types of advanced brain scans could provide a more complete picture of the condition.

“The next step should be to conduct larger studies that follow patients over time and include appropriate neurological and psychiatric comparison groups,” Guedj said. “Combining different forms of molecular imaging could also help researchers examine dopamine, brain energy metabolism, inflammation and supporting brain cells within the same biological framework.”

“This could show whether the abnormalities are temporary, persistent or progressive, and whether they identify meaningful subgroups of patients,” he added. “In the longer term, brain imaging may help select patients for targeted clinical trials and measure their response to treatment.”

Finally, the commentary positions long COVID as an illness that bridges the gap between the body’s physical systems and the brain’s internal networks.

“The study also supports the idea that long COVID should be understood at the brain-body interface,” Guedj said. “Immune, vascular, metabolic and inflammatory changes elsewhere in the body may ultimately affect vulnerable brain circuits.”

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.

The commentary, “Dopaminergic vulnerability in long COVID: striatal PET imaging at the brain-body interface,” was authored by Eric Guedj and Danielle Beckman.