Fatigue that makes simple tasks exhausting, the feeling that the body has slowed down and memory difficulties that can persist for months or years after Covid-19 may be linked to changes in the brain's dopamine system.
A neuroimaging study found, in people with long Covid and neuropsychiatric symptoms, a reduction of up to 20% in a marker associated with the integrity of nerve endings that release dopamine. The lower this marker in certain brain regions, the more intense symptoms such as apathy, slow movement and memory difficulties tended to be.
The research, published in the scientific journal "eBioMedicine", initially compared brain scans of 24 adults with long Covid and 24 healthy people of similar age. Participants were, on average, just over 30 years old.
The main discovery was a reduction in binding to the vesicular monoamine transporter 2, known as VMAT2, used in the work as an indicator of the integrity of the endings of neurons that release dopamine.
The scientists analyzed three regions of the striatum and found a reduction in the marker in all of them:
ventral striatum, related, among other functions, to motivation: reduction of approximately 20% and symptoms associated with more apathy;
dorsal putamen, associated with movement control: drop of around 16% and symptoms associated with slower movements;
dorsal caudate, involved in processes linked to memory: reduction of approximately 17% and worse performance in verbal memory tests.
The results help to raise a new hypothesis to explain part of the neurological symptoms of long Covid. But there is an important caveat: the study shows an association and does not allow us to state that the change in dopamine is the cause of the symptoms or that neuron death has occurred.
“The study found a sign of possible dopaminergic impairment, the nature of which still needs to be clarified” explained psychiatrist and neuroscientist Rodrigo Bressan, associate professor at Unifesp, PhD and visiting professor at King’s College London, to g1.
What does dopamine have to do with long Covid?
Dopamine participates in different circuits of the brain involved in functions such as motivation, initiative, movement and cognition.
To investigate whether this system could be compromised in long Covid, the researchers used positron emission tomography (PET) with a radiotracer capable of measuring binding to VMAT2.
According to the study, approximately 95% of VMAT2 binding in the striatum occurs in neurons that release dopamine. A reduction in this measurement may, therefore, indicate compromised integrity of these nerve endings.
Jeffrey Meyer, one of the authors of the work, explained to g1 that the main conclusion is precisely the identification of reduced levels of this marker in people with long Covid and the relationship of these reductions with important symptoms.
According to Meyer, lower levels in specific regions correlated with equally specific manifestations: loss of motivation or apathy, which some people may experience as extreme fatigue, slow movement and delayed verbal memory.
Bressan explains that the distribution of associations makes sense given the functions performed by these areas.
In the ventral striatum, dopamine is related to motivation and initiative; in the putamen, to the execution of movements; and, in the caudate, cognitive processes.
In the study, precisely a lower connection to VMAT2 in the ventral striatum accompanied greater apathy. In the putamen, it was related to lower motor speed. And, in the caudate, the worst performance in a verbal memory test.
“This gives biological plausibility to the finding, without proving that the dopaminergic alteration is the cause of the symptoms”, highlights Bressan.
The relationship with memory requires even more caution, according to him, because this function also depends on other brain regions and systems and the analysis carried out in the study was exploratory.
Marker reduction means loss of neurons?
This is one of the main questions raised by the study and also one of the points that require greater caution when interpreting the results.
Meyer states that low levels of VMAT2 typically reflect loss of dopaminergic nerve terminals. The researcher also notes that a significant portion of participants with long Covid had levels of the marker outside the range found in healthy groups.
He considers, however, that there is another possibility. As VMAT2 is located in small vesicles that store chemicals, mainly dopamine, at the ends of these neurons, a reduction in the marker could also reflect a smaller number of these vesicles.
Bressan reinforces this caveat. The exam does not directly observe neurons or determine how many of them there are. It measures binding to a protein present in vesicles that store neurotransmitters.
Therefore, a smaller signal may mean fewer nerve endings, but also a smaller number of vesicles or VMAT2 in each ending.
Furthermore, participants were examined only once. Therefore, it is not possible to know from this study whether the change appeared after the infection, whether it was already present previously or whether it may disappear with recovery.
Meyer notes that there was no relationship between the reduction in VMAT2 and the time elapsed since the last episode of acute Covid-19, which, according to him, suggests that the change could have been present for some time.
The researcher considers it possible that some people recover marker levels as symptoms decrease, while others, with more difficult recovery, remain at reduced levels. To answer this question, however, further studies would be needed with repeat examinations over time.
Apathy, slowness and memory problems
In addition to imaging exams, researchers measured participants' symptoms and performance on specific tests.
All 24 members of the group with long Covid had apathy and at least five neuropsychiatric symptoms associated with a major depressive episode, including anhedonia (reduced ability to feel pleasure), depressed mood, low concentration, memory decline and low energy.
The symptoms had started up to three months after the acute phase of Covid-19 and persisted for at least three months. The initial cases of the disease had been mild or moderate and confirmed by PCR or rapid antigen test.
No association was found with the coronavirus variant predominant during infection or with the interval between the acute phase of the disease and the brain examination.
According to Meyer, memory problems are among the brain symptoms of long Covid that can persist for longer. Recovery, however, varies from person to person.
Could neuroinflammation be behind the change?
One of the hypotheses to explain the possible impairment of the dopaminergic system is inflammation in the brain.
Meyer explains that neurons that release dopamine may be vulnerable to damage from nearby inflammation. In some cases, according to him, cells involved in the inflammatory process can eliminate nerve endings.
Another possibility raised by the researcher would be a direct action of the virus on dopaminergic neurons.
But these possibilities were not demonstrated by the current study.
Bressan highlights that the research did not directly measure neuroinflammation in the participants nor did it show that it caused a reduction in VMAT2.
According to him, other mechanisms also need to be investigated, including vascular changes, mitochondrial dysfunction, persistent immune responses and possible changes in the regulation of VMAT2 itself.
Different processes can also occur simultaneously.
Result cannot be applied to everyone with long Covid
Another important limitation is the profile of the participants.
The study did not evaluate people with all possible manifestations of long Covid. The 24 participants had a specific profile: they all presented apathy and several persistent neuropsychiatric symptoms.
“The study informs mainly about this subgroup, and not about all people with long Covid, a condition that can manifest itself in many ways”, says Bressan.
The small sample also limits conclusions. Furthermore, there was no comparison group made up of people with similar psychiatric symptoms but without long Covid.
Larger studies, with patients with different manifestations and follow-up over time, will be necessary to determine in which people the finding is repeated.
Having had Covid, in itself, did not explain the change
The study also brought another important piece of information. In exploratory analyses, the researchers expanded the group of healthy people and were able to compare participants who had already had Covid-19 with people who had never been infected.
There was no significant difference in VMAT2 between these two groups.
For researchers, this reinforces the possibility that the finding is related to the persistent condition studied or factors associated with it and not simply to the fact that a person was infected by the coronavirus.
Bressan emphasizes, however, that the comparison was exploratory and involved a small group. Therefore, the absence of a significant difference does not allow us to conclude that the two groups are identical.
Discovery could pave the way for testing treatments
The results also raise a practical question: if part of the symptoms are really related to impairment of the dopaminergic system, would it be possible to treat them by acting on dopamine?
For now, there is not enough evidence to recommend dopaminergic medications as a routine treatment for long Covid.
Bressan says the results provide justification for conducting controlled clinical trials, but the imaging does not demonstrate that increasing dopamine signaling would improve symptoms, which medication might work, or which patients would benefit.
Medications of this type can also cause adverse effects, which vary according to the class, including nausea, drop in blood pressure, sleep changes and, in some people, confusion or psychotic symptoms. Some still require attention to drug interactions.
Meyer states that there are still no randomized, double-blind, placebo-controlled clinical trials that demonstrate the effectiveness of medications aimed at enhancing dopaminergic function for these symptoms of long Covid.
The team, however, intends to move in this direction.
The researchers plan a randomized, double-blind, placebo-controlled clinical trial with about 100 participants. In this design, neither the patients nor the team members who have contact with them will know who received the medicine and who received the placebo.
The main symptoms assessed should be late verbal memory problems, apathy (perceived as low motivation or intense fatigue) and motor slowness, which can be felt as a longer delay in carrying out tasks.
