In the weeks, months, and even years following a COVID infection, it is not uncommon for those who have recovered from the virus’s acute symptoms to be dogged by persistent depressive symptoms. Often, such depression is accompanied by cognitive symptoms; sometimes the latter can occur in the absence of depression symptoms. Researchers have been trying to get a fix on what causes these post-infection brain-based symptoms, and a new study suggests one possible source.

Scientists believe that a majority of the global population has by now experienced at least one acute episode of COVID illness. Mild to moderate symptoms, predominantly respiratory, but which often include flu-like fever, headache, and/ or muscle pain or weakness and fatigue, are also commonplace, occurring in an estimated 95% of those who are infected with the Omicron variant and about 80% of those infected with the original SARS Co-V-2 strain of the virus.

Depressive symptoms with or without cognitive impairment are quite prevalent, note researchers who conducted the new study, appearing in JAMA Psychiatry. They are estimated to have occurred in about 15% of those infected with the original strain of COVID, who of course had not been vaccinated. But these symptoms also occur in about 5% of triple-vaccinated people who are exposed to the Delta and Omicron variants of the virus. Many of the symptoms, which include anhedonia (inability to feel pleasure), slowing of motor skills, low motivation and low energy, and short-term memory impairment, can persist for years and are thus, say the researchers, “a major public health problem,” especially considering the vast number of people who are infected by COVID every year.

The team, led by Jeffrey H. Meyer, M.D., Ph.D., of the University of Toronto, Canada, a 2015 BBRF Distinguished Investigator and 2000 and 1998 BBRF Young Investigator, tested the hypothesis that COVID-DC (COVID with lingering depression and/or cognitive symptoms) may involve a condition called gliosis, marked by a proliferation of glial cells in the brain. Gliosis has been linked with depression and other neuropsychiatric conditions, as well as neurodegenerative disorders such as Alzheimer’s disease. Glial cells, which include microglia and astroglia, are often described as “helper” cells. Abnormal proliferation of glial cells is known to occur after damage to the central nervous system or brain. The researchers explored the idea that gliosis might also be among the possible consequences of COVID infection, whose effects are known from postmortem and other studies to directly affect brain cells.

The researchers recruited 40 people for their study, conducted in 2021 and 2022. Twenty subjects had mild to moderate cases of acute COVID infection from which they had recovered, but with continuing depression and/or cognitive symptoms (COVID-DC). The other 20 were healthy controls. Participants were about 60% female and on average in their early thirties. Of the 20 who had COVID-DC, 60% developed depressive or cognitive symptoms 0 to 6 months after being diagnosed with COVID; in 40%, the interval was 7 to 24 months.

The 40 participants were given PET scans, an imaging technology that is able to measure the prevalence (“distribution volume”) of a molecule called translocator protein. This measure, called TSPO V_T, is used as an index to detect the presence and severity of gliosis in the brain. Measurements in the healthy controls provided a reliable contrast with COVID-DC patients since they had been recruited and scanned for other research prior to the beginning of the pandemic.

The PET scans measured TSPO V_T in five brain regions, all of which, when injured, can exhibit gliosis, and all of which are implicated in the depressive and cognitive symptoms associated with COVID-DC. The five regions are: the dorsal putamen, ventral striatum, prefrontal cortex, anterior cingulate cortex, and hippocampus.

At the time of their PET scans, in addition to depression, 30% of those with COVID-DC reported headaches and 15% confusion; many also reported continuing physical symptoms such as nasal congestion or runny nose, fatigue, and aches and pains. 45% had suffered a major depressive episode prior to being infected with the COVID virus.

Compared with the controls, participants who had COVID-DC were found to have elevated TSPO V_T levels, particularly in two brain regions: the ventral striatum and dorsal putamen. Higher readings in the latter area also were found to correlate with motor slowing in those participants.

What do these findings mean? Higher TSPO V_T levels are understood to signal “greater density of activated microglia, and to a lesser extent, astroglia.” This is evidence that gliosis is occurring, and the researchers said that one explanation was that such an inflammatory response may be a direct response to injury, with the greatest injury, based on this evidence, occurring in the two cited regions. There is good evidence in other brain illnesses that higher TSPO V_T also occurs, for example, in the hippocampus in Alzheimer’s and in other regions in obsessive-compulsive disorder, as well as following brain injury or stroke.

“Injury to the ventral striatum and dorsal putamen is a plausible explanation for evidence of gliosis and is consistent with many symptoms observed in COVID-DC,” the team said. Aberrant ventral striatal function may lead to anhedonia, and dorsal putamen injury is associated with motor slowing and low motivation or energy, they added.

The possible injuries to these affected regions could be the result, they said, of direct virally induced injury to the striatum and projections from other brain areas that lead to it, combined with “additional brain-wide effects of virally induced injury and elevated bodily inflammatory signaling-initiated brain gliosis.” Interestingly, gliosis may have both damaging and curative dimensions, but chronic gliosis is generally associated with neuropsychiatric disease.

For this reason, the researchers said, “clinical trials of novel interventions for COVID-DC may consider suppressing adverse consequences of gliosis or suppressing gliosis entirely.” They suggested clinical tests of two investigational drugs now in phase 2 and 3 tests: one that targets translocator protein (TSPO) and the other, called a P2X7 inhibitor, thought to reduce proliferation of microglia. It remains possible, the researchers said, that gliosis, while present, may play a subordinate role to other pathology, such as injury to neurons, in causing or promoting the depressive and cognitive symptoms of COVID-DC.

The team also included Romina Mizrahi, M.D., Ph.D., a 2014 BBRF Independent Investigator and 2010 BBRF Young Investigator; Nathan Kolla, M.D., Ph.D., a 2013 BBRF Young Investigator; and M. Ishrat Husain, MBBS, M.D., a 2019 BBRF Young Investigator.