For years, long COVID has been defined almost entirely by what patients report feeling: fatigue, brain fog, memory lapses, a loss of motivation that won’t lift. Doctors have struggled to treat a symptom with no clear physical marker, and the condition has reshaped workplaces as employers scramble to accommodate it. But despite the shared symptoms, there’s been little for doctors to point to and say, “this is what changed in your body.”

Now, a new study from researchers at the Centre for Addiction and Mental Health and the University of Toronto may start to change that. Led by Jeffrey Meyer, a psychiatry professor at the University of Toronto, researchers used PET imaging to measure a protein called VMAT2, found on the nerve terminals that release dopamine, in 24 long COVID patients and 24 healthy people who’d had only mild or moderate initial infections.

The study found patients with long COVID had significantly lower VMAT2 levels across the brain region tied to motivation, movement, and memory (the striatum). The reduction ranged from 16% in the region tied to planning (dorsal putamen) to 20% in the region most closely tied to motivation and apathy (ventral striatum).

“By showing that there’s reductions in the nerves that release dopamine in these areas, and then showing the relationship of them to the symptoms, that’s two pieces of information that makes a strong connection to long COVID,” Meyer told Fortune.

This builds on a 2023 study from his team, which found elevated inflammation in these same brain regions. That study measured a different protein, one found on inflammatory cells. “They’re measuring fundamentally different processes, but it may be that one is leading to the other,” he explained. Inflammatory cells can damage the ends of dopamine-releasing nerves, or injury to the nerves themselves could be generating the inflammation.

What sets the new study apart, Meyer said, is how closely the imaging results tracked with specific symptoms. Reduced dopamine markers in the region associated with apathy (ventral striatum) lined up with memory problems. Markers in the planning region (dorsal putamen) tracked with slowed movement. A third region tracked with loss of motivation.

Finally, a biological marker

Long COVID has long been criticized for lacking any objective marker that doctors could point to, leaving patients with a diagnosis built almost entirely on self-reported symptoms.

“Because we’ve now pinpointed a change that indicates loss of dopamine nerve terminals, and that it relates to symptoms,” Meyer said. “Having that information puts us in a position to do a lot more studies that are targeted in this area, and hopefully develop new cures that aren’t going to be that far away.”

He added: “The definite strength of the study is the strong relationship to important symptoms, and it’s also a clear interpretation that this marker is low in people who have these symptoms.”

The dopamine loss is different from ordinary dips in mood or motivation, Meyer said. It reflects an actual reduction in the density of nerve terminals, not simply lower dopamine output from nerves that remain intact. Whether that’s reversible is still unclear. Meyer said some patients may recover as damaged nerve terminals regrow or sprout new connections, particularly with exercise or activities that engage the affected brain regions. For others, ongoing inflammation may be blocking that recovery entirely, meaning they would need a targeted treatment rather than time alone.

That treatment is already taking shape. Meyer’s team is preparing a clinical trial that would repurpose an existing dopamine-related medication, one his group has already shown crosses into the brain. “A couple of people have had positive responses to it that have been quite striking,” he said. The team wants to move forward with a full trial, but a grant proposal for the trial has narrowly missed two funding rounds in a row, according to Meyer.

Some people will recover through effort and adaptation, while others will need medical intervention to get there. “Some people will get a lot of improvement,” Meyer said, “but it might be that we need these kinds of treatments to get a full cure.”