Chances are, the COVID-19 pandemic has affected your health — even if you have never been infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). According to new research from Harvard Medical School, the stress of isolation from lockdown and stay-at-home measures is making people sick. Their medRxiv* study suggests people not infected with SARS-CoV-2 are experiencing increased markers of neuroinflammation, otherwise known as "pandemic brain."
Neuroinflammation is associated with mood disorders such as depression. In addition, neuroimmune changes are characterized by fatigue, brain fog, and other psychological symptoms that have been observed during the pandemic.
How they did it
The researchers examined the brains of healthy and non-infected individuals before (n = 57) or after lockdown (n=15) in Massachusetts. To start, the team gave out a questionnaire that would evaluate a participant's mental and physical health during the pandemic. Then, brain imaging was performed to identify any markers of neuroinflammation.
Pandemic-associated stressors trigger changes in the neuroimmune response
People were more likely to report more issues with their mental and physical health after lockdown. For example, about 54% reported mood changes, 36% felt mentally exhausted, 27% were physically exhausted, and 18% said they had difficulty concentrating.
Post-lockdown [11C]PBR28 PET signal elevations in ROI group analyses. Group comparison of [11C]PBR28 PET data collected before (HCPRE) or after lockdown (HCPOST), in apriori ROIs. Standardized uptake value ratio (SUVR) adjusted for age, TSPO polymorphism, and scanner is displayed. ACC=Anterior Cingulate Cortex. Error bars denote 25th to 75th inter-quartile range, and the horizontal line represents the median. Triangles denote data from Scanner 1 and circles denote data from Scanner 2. *=p < 0.05, corrected; **= p < 0.01, corrected.
The symptoms mentioned above coincided with an increase in [11C]PBR28 signal, a radioactive biochemical substance for the glial marker 18 kDa translocator protein (TSPO). High expression of TSPO is associated with the activation of microglia and astrocytes during a neuroinflammatory response. Additionally, the signal elevation was higher in people's brains after lockdown than before lockdown.
For brains imaged after lockdown, there was an increase in the brain levels of [11C]PBR28 in several cortical and subcortical regions. The brain regions included precentral, postcentral, superior, middle, and inferior frontal gyri, precuneus, superior parietal lobule, anterior and posterior insula, amygdala, putamen, supplementary motor cortex, anterior, middle, posterior cingulate, and subcallosal cortex.
Post-lockdown [11C]PBR28 PET signal elevations in voxelwise group analyses. Areas of elevated PET [11C]PBR28 signal (SUVR) in HCPOST subjects compared to HCPRE subjects. (A) Mean images computed from 57 HCPRE and 15 HCPOST subjects are displayed as maximum intensity projections. (B) Significant cluster from the HCPOST>HCPRE voxel-wise contrast is shown in a red–yellow color scale. There were no significant regions for the HCPRE > HCPOST contrast. (C) Visualization of mean [11C]PBR28 SUVR extracted from sub-portions of the cluster statistically significant in A. IPS=Intraparietal Sulcus, PCUN=Precuneus, IC=Insular Cortex, SCC=Subcallosal Cortex, ACC=Anterior Cingulate Cortex, NAc= Nucleus Accumbens, SMA=Supplementary Motor Area, MFG=Middle Frontal Gyrus, HIPP=Hippocampus. Error bars denote 25th to 75th inter-quartile range. Triangles denote data from Scanner 1 and circles denote data from Scanner 2.
The [11C]PBR28 signal was more elevated in people who reported more symptoms than those who reported little or no symptoms. Increased markers associated with neuroinflammation were present in participants who reported physical fatigue. Mental fatigue or mood changes were associated with [11C]PBR28 signal changes in the hippocampus.
The [11C]PBR28 signal changes after lockdown parallel changes in gene expression in cells involved in neuroinflammation.
Two genes, AQP4 and CSF1R, were highly expressed in glial cells such as astrocytes and microglia. The monocyte marker CCR1 also showed increased expression. The increased gene expression was related to biological pathways for neuroimmune signaling.
"Collectively, these findings provide support to neuroimmune responses as mechanisms underlying stress, depression and other symptoms of psychological distress. Further, the regional variability in increased [11C]PBR28 signal could be predicted by constitutive expression of genes related to glial neuroimmune response in healthy post-mortem human brains," concluded the researchers.
Several points should be considered when interpreting the study's results. First, since clinical research was temporarily halted during the pandemic, only a small number of participants were available to undergo a brain scan after lockdown compared to people who had brain scans before lockdown.
The researchers did not conduct the questionnaire the same day as the brain scan, leaving the possibility that people may have felt different symptoms at the time of their visit. Therefore, the clinical symptoms collected during the questionnaire will need to be validated in future studies.
Post-lockdown [11C]PBR28 PET signal elevations are proportional to symptom burden. Post-lockdown [11C]PBR28 signal shows elevations in the IPS, PCUN and HIPP for those individuals who showed higher symptom burden (physical fatigue, mental fatigue and/or mood alterations). Pre-lockdown data are also displayed as reference, for visualization purposes only. Data are adjusted for TSPO genotype. Error bars denote 25th to 75th inter-quartile range, and the horizontal line represents the median. Triangles denote data from Scanner 1 and circles denote data from Scanner 2. *=p < 0.05, corrected; **= p < 0.01, corrected. Abbreviations: Mood Alter. = Mood Alterations.
Overall, the results indicate that the virus has a broad impact on physical health. In an effort to mitigate infection, pandemic-related lifestyle disruptions may have had indirect consequences on the brain. Future research looking at COVID-19-pandemic–related neuroinflammatory responses is needed to know how this may affect people in the long run.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.