Long COVID Imaging Finds Damage in Dopamine Circuits

Researchers studying targeted treatments for long COVID have identified measurable structural damage in dopamine-releasing brain circuits, shifting the effort toward drug repurposing and clinical testing. The findings came from specialized brain imaging at Canada’s Centre for Addiction and Mental Health (CAMH) and the University of Toronto.

The study examined 24 long COVID patients with persistent cognitive and physical symptoms, alongside 24 healthy individuals who had recovered from mild or moderate acute SARS-CoV-2 infections without long-term sequelae. Using positron emission tomography (PET), researchers measured vesicular monoamine transporter 2 (VMAT2), a specialized presynaptic membrane protein that packages dopamine into synaptic vesicles for transmission across neurons.

In the ventral striatum, VMAT2 levels were 20 percent lower among long COVID patients. This region is part of the brain’s reward and motivational pathways, and the reduction mapped directly to clinical assessments of apathy, loss of motivation, and memory dysfunction.

The imaging also found a 16 percent reduction in VMAT2 in the dorsal putamen, which is important for motor execution and movement planning. Decreases in this area corresponded precisely with measurable physical slowness and motor lag in affected patients. A third sub-region of the striatum showed corresponding VMAT2 depletion that correlated directly with diminished task-directed drive.

The striatum includes the caudate nucleus and putamen and regulates voluntary movement, action planning, decision-making, and motivation. Unlike transient chemical fluctuations, in which intact neurons temporarily release lower volumes of neurotransmitters, the results indicate a physical reduction in the density of presynaptic dopamine nerve terminals themselves.

Lead investigator Dr. Jeffrey Meyer, a professor of psychiatry at the University of Toronto, is preparing a clinical trial of an existing therapeutic compound capable of crossing the blood-brain barrier to target the affected pathways. Preliminary observations with dopamine-modulating agents produced notable clinical responses in select patients, although the trial initiative faces financial hurdles after narrowly missing approval in two consecutive competitive grant funding rounds.

The work builds on a 2023 investigation by Meyer’s laboratory that identified elevated neuroinflammation across the same striatal regions. That study used PET imaging to track translocator protein (TSPO), a marker expressed on activated microglial cells during neuroinflammatory cascades.

Researchers hypothesize that persistent post-viral neuroinflammation may cause microglial cells to release inflammatory cytokines that degrade delicate presynaptic nerve endings. Another possibility is that primary structural injury to dopamine terminals triggers chronic, localized inflammatory responses that prevent the brain’s innate repair mechanisms from functioning. Together, the two studies outline a biological mechanism underlying post-acute sequelae of SARS-CoV-2 (PASC).

The objective identification of VMAT2 loss addresses a major diagnostic challenge for long COVID, which affects millions of people globally and remains a primary cause of post-viral disability. Historically, post-viral fatigue conditions, including Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), have relied on clinical diagnoses of exclusion based on patient-reported symptom inventories, without standardized blood markers or imaging tests to verify tissue-level brain changes.

Whether damaged dopaminergic pathways can recover may depend on neuroplastic remodeling. In some individuals, nerve terminals may sprout new functional connections over time, a process that can be assisted by physical exercise and targeted cognitive activities engaging the striatal circuitry. In patients whose active neuroinflammation persistently obstructs endogenous repair, however, spontaneous recovery remains unlikely without pharmaceutical intervention to break the inflammatory cycle and support dopaminergic signaling.