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. 2022 May:102:89-97.
doi: 10.1016/j.bbi.2022.02.018. Epub 2022 Feb 16.

The pandemic brain: Neuroinflammation in non-infected individuals during the COVID-19 pandemic

Ludovica Brusaferri  1 , Zeynab Alshelh  1 , Daniel Martins  2 , Minhae Kim  1 , Akila Weerasekera  1 , Hope Housman  1 , Erin J Morrissey  1 , Paulina C Knight  1 , Kelly A Castro-Blanco  1 , Daniel S Albrecht  1 , Chieh-En Tseng  1 , Nicole R Zürcher  1 , Eva-Maria Ratai  1 , Oluwaseun Akeju  3 , Meena M Makary  4 , Ciprian Catana  1 , Nathaniel D Mercaldo  1 , Nouchine Hadjikhani  5 , Mattia Veronese  6 , Federico Turkheimer  2 , Bruce R Rosen  1 , Jacob M Hooker  1 , Marco L Loggia  7
Affiliations

The pandemic brain: Neuroinflammation in non-infected individuals during the COVID-19 pandemic

Ludovica Brusaferri et al. Brain Behav Immun. 2022 May.

Abstract

While COVID-19 research has seen an explosion in the literature, the impact of pandemic-related societal and lifestyle disruptions on brain health among the uninfected remains underexplored. However, a global increase in the prevalence of fatigue, brain fog, depression and other "sickness behavior"-like symptoms implicates a possible dysregulation in neuroimmune mechanisms even among those never infected by the virus. We compared fifty-seven 'Pre-Pandemic' and fifteen 'Pandemic' datasets from individuals originally enrolled as control subjects for various completed, or ongoing, research studies available in our records, with a confirmed negative test for SARS-CoV-2 antibodies. We used a combination of multimodal molecular brain imaging (simultaneous positron emission tomography / magnetic resonance spectroscopy), behavioral measurements, imaging transcriptomics and serum testing to uncover links between pandemic-related stressors and neuroinflammation. Healthy individuals examined after the enforcement of 2020 lockdown/stay-at-home measures demonstrated elevated brain levels of two independent neuroinflammatory markers (the 18 kDa translocator protein, TSPO, and myoinositol) compared to pre-lockdown subjects. The serum levels of two inflammatory markers (interleukin-16 and monocyte chemoattractant protein-1) were also elevated, although these effects did not reach statistical significance after correcting for multiple comparisons. Subjects endorsing higher symptom burden showed higher TSPO signal in the hippocampus (mood alteration, mental fatigue), intraparietal sulcus and precuneus (physical fatigue), compared to those reporting little/no symptoms. Post-lockdown TSPO signal changes were spatially aligned with the constitutive expression of several genes involved in immune/neuroimmune functions. This work implicates neuroimmune activation as a possible mechanism underlying the non-virally-mediated symptoms experienced by many during the COVID-19 pandemic. Future studies will be needed to corroborate and further interpret these preliminary findings.

Keywords: MRS; Mental health; Neuroimaging; PET; Pandemic; Stress.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
[11C]PBR28 PET signal elevations in the Pandemic group. (A) Mean images computed from 57 Pre-pandemic and 15 Pandemic subjects are displayed as maximum intensity projections. (B) Significant cluster from the Pandemic > Pre-Pandemic voxel-wise contrast is shown in a red–yellow color scale. There were no significant regions for the Pre-Pandemic > Pandemic 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. (D) Case study of one subject scanned before- (September 2016) and during the pandemic (October 2020) in Scanner 1. Bar graph of mean [11C]PBR28 SUVR are extracted from the cluster sub-portions in (C) and difference image (post-pre) are reported in red-yellow and cyan-blue color bars. E) Mean [11C]PBR28 SUVR extracted from sub-clusters in (C) and sorted by scan date. The range of the color scale was set for each region independently to best illustrate the pandemic PET signal increase, for visualization purposes.
Fig. 2
Fig. 2
[11C]PBR28 PET signal elevations in the Pandemic group are proportional to symptom burden. [11C]PBR28 signal in the subset of Pandemic subjects who completed the questionnaire on the impact of the pandemic con physical and mental health (n = 11) 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-pandemic data (n = 57) 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; **= p < 0.01. Abbreviations: Mood Alter. = Mood Alterations. See Fig. 2 caption for abbreviations.
Fig. 3
Fig. 3
Plasma inflammatory marker elevations in the Pandemic group. Plasma inflammatory marker (IL-16 and MCP-1) elevation in the Pandemic group (n = 13) compared to Pre-Pandemic group (n = 11) (A), and their correlation with [11C]PBR28 signal (B). Error bars denote 25th to 75th inter-quartile range, and the horizontal line represents the median. GLM group difference accounts for age as regressor of no interest. Partial correlations are computed adjusting for TSPO genotype. Triangles denote data from Scanner 1 and circles denote data from Scanner 2. *=p < 0.05.
Fig. 4
Fig. 4
Imaging transcriptomics analyses. (A) First component of the PLS analyses (PLS1; weight scores), AQP4 (astrocyte marker) and CSF1R (microglia marker) gene expression (normalized units) plotted against [11C]PBR28 contrast t-stat (Pandemic > Pre-pandemic; see Fig. 1) in the 41 regions of left hemisphere regions (34 cortical plus 7 subcortical regions) of the Desikan-Killiany atlas. Genes with positive weights in PLS1 have higher-than-average expression where [11C]PBR28 showed the largest increases and lower-than-average expression in regions with minimal changes. Of note, pSPATIAL is obtained via spatial permutation testing (spin test) to account for the inherent spatial autocorrelation of the imaging data (see Supplementary materials). (B) Histogram (150 bins) of gene weights in PLS1 with the highly-ranked positions of AQP4 and CSF1R highlighted (scores 4.31 and 4.40 respectively). (C) Brain cell-type gene set enrichment analysis. Positive normalized enrichment ratios (in orange-red shades) indicate enrichment for genes of a certain cell-type among those genes with high expression in regions with the largest increases in [11C]PBR28 signal (positive weights in PLS1). Negative normalized enrichment ratios (in blue shades) indicate enrichment for genes of a certain cell-type among genes with high expression in regions with minimal or negligible increases in [11C]PBR28 signal (negative weights in PLS1). *=p < 0.05, after FDR correction for the total number of cell-types tested. Abbreviations: OPCs = Oligodendrocyte Precursor Cells; Oligodendroc. = Oligodendrocytes; Neuron Exc. = Excitatory Neurons; Neuron Inb. = Inhibitory Neurons.
Fig. 5
Fig. 5
Elevations in the Pandemic group in 1H-MRS-measured myoinositol concentration. (A) Probabilistic map of thalamic voxel placement in standard space, calculated via non-linear transformation between each subjects’ MPRAGE volume and MNI151 template, then applied to the MRS voxel. (B) Group comparison in mIns concentration (left thalamus) between Pre-pandemic (n = 13) and Pandemic (n = 11) cohorts. Error bars denote 25th to 75th inter-quartile range. Triangles denote data from Scanner 1 and circles denote data from Scanner 2.
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