Morphometric similarity network alterations in COVID-19 survivors correlate with behavioral features and transcriptional signatures

Abstract

Objectives: To explore the differences in the cortical morphometric similarity network (MSN) between COVID-19 survivors and healthy controls, and the correlation between these differences and behavioralfeatures and transcriptional signatures.

Materials & methods: 39 COVID-19 survivors and 39 age-, sex- and education years-matched healthy controls (HCs) were included. All participants underwent MRI and behavioral assessments (PCL-17, GAD-7, PHQ-9). MSN analysis was used to compute COVID-19 survivors vs. HCs differences across brain regions. Correlation analysis was used to determine the associations between regional MSN differences and behavioral assessments, and determine the spatial similarities between regional MSN differences and risk genes transcriptional activity.

Results: COVID-19 survivors exhibited decreased regional MSN in insula, precuneus, transverse temporal, entorhinal, para-hippocampal, rostral middle frontal and supramarginal cortices, and increased regional MSN in pars triangularis, lateral orbitofrontal, superior frontal, superior parietal, postcentral, and inferior temporal cortices. Regional MSN value of lateral orbitofrontal cortex was positively associated with GAD-7 and PHQ-9 scores, and rostral middle frontal was negatively related to PHQ-9 scores. The analysis of spatial similarities showed that seven risk genes (MFGE8, MOB2, NUP62, PMPCA, SDSL, TMEM178B, and ZBTB11) were related to regional MSN values.

Conclusion: The MSN differences were associated with behavioral and transcriptional signatures, early psychological counseling or intervention may be required to COVID-19 survivors. Our study provided a new insight into understanding the altered coordination of structure in COVID-19 and may offer a new endophenotype to further investigate the brain substrate.

Keywords: Allen Human Brain Atlas; Behavioral assessment; COVID-19; Gene transcription; Morphometric similarity network.

Fig. 1

Overview of the experimental design. a MRI and behavioral assessment. Forty-two COVID-19 survivors were recruited from 562 consecutive patients who had been diagnosed with COVID-19 and discharged for about 1 month. Behavioral assessments (PCL-17, GAD-7 and PHQ-9) and 3D-T1WI were performed for all participants. Three COVID-19 survivors (2 subcortical ischemic foci and 1 arachnoid cyst) and 2 Health controls (1 subcortical ischemic foci and 1 arachnoid cyst) were excluded. b Morphometric similarity network (MSN) analysis. Individual MSN was constructed across five morphometric features (GM, SA, CT, GC and MC) to produce a 308 × 308 matrix (depicted by a subdivision of the Desikan-Killiany atlas, D-K 308). Then, COVID-19 survivors vs. HCs (case vs. control) differences across regions were computed. c Gene expression profiles. Gene expression profiles from the Allen Human Brain Atlas (HABA) in 152 regions (left hemisphere only) were averaged across 6 postmortem brains, yielding a regional gene expression matrix. Finally, Pearson’s correlation analysis was used to determine the spatial similarities between regional MSN differences and risk genes transcriptional activity, and determine the associations between regional MSN differences and behavioral assessments. PCL-17: 17-item Post-Traumatic Stress Disorder Checklist; GAD-7: 7-item Generalized Anxiety Disorder module; PHQ-9: 9-item Patient Health Questionnaire; GM: gray matter volume; SA: surface area; CT; cortical thickness; GC: Gaussian (intrinsic) curvature; MC: mean curvature.

Fig. 2

COVID-19 survivors (case) vs. HCs (control) differences of regional morphometric similarities. a,b Mean regional morphometric similarity network (MSN) pattern of COVID-19 survivors and HCs.). Higher/lower values are presented as warm/cold colors. c Case vs. control comparison (t-map) of regional MSN (p < 0.05, unthresholded). The right bilateral transverse temporal cortex and right postcentral cortex showed statistically significant differences (p < 0.05, corrected).

Fig. 3

Scatter plots of the significant correlations between regional MSN differences and behavioral scores (GAD-7 and PHQ-9) in COVID-19 survivors. The regional MSN of the rostral middle frontal was negatively correlated with PHQ-9 (r_s = -0.44, p_FDR = 0.04), and the regional MSN of the lateral orbitofrontal cortex was positively associated with GAD-7 (r_s = 0.45, p_FDR = 0.04) and PHQ-9 (r_s = 0.48, p_FDR = 0.03).

Fig. 4

Scatter plots of the significant correlations between risk gene expressions of COVID-19 and regional MSN differences. Seven risk genes related to regional MSN differences in terms of spatial similarity, including MFGE8 (r = 0.19, p_FDR = 0.02), MOB2 (r = 0.26, p_FDR = 0.004), NUP62 (r = 0.21, p_FDR = 0.01), PMPCA (r = 0.23, p_FDR = 0.009), SDSL (r = 0.19, p_FDR = 0.02), TMEM178B (r = 0.22, p_FDR = 0.01), and ZBTB11 (r = 0.27, p_FDR = 0.004).