Brain correlates of depression, post-traumatic distress, and inflammatory biomarkers in COVID-19 survivors: A multimodal magnetic resonance imaging study

Abstract

Psychiatric sequelae substantially contribute to the post-acute burden of disease associated with COVID-19, persisting months after clearance of the virus. Brain imaging shows white matter (WM) hypodensities/hyperintensities, and the involvement of grey matter (GM) in prefrontal, anterior cingulate (ACC) and insular cortex after COVID, but little is known about brain correlates of persistent psychopathology. With a multimodal approach, we studied whole brain voxel-based morphometry, diffusion-tensor imaging, and resting-state connectivity, to correlate MRI measures with depression and post-traumatic distress (PTSD) in 42 COVID-19 survivors without brain lesions, at 90.59 ​± ​54.66 days after COVID. Systemic immune-inflammation index (SII) measured in the emergency department, which reflects the immune response and systemic inflammation based on peripheral lymphocyte, neutrophil, and platelet counts, predicted worse self-rated depression and PTSD, widespread lower diffusivity along the main axis of WM tracts, and abnormal functional connectivity (FC) among resting state networks. Self-rated depression and PTSD inversely correlated with GM volumes in ACC and insula, axial diffusivity, and associated with FC. We observed overlapping associations between severity of inflammation during acute COVID-19, brain structure and function, and severity of depression and post-traumatic distress in survivors, thus warranting interest for further study of brain correlates of the post-acute COVID-19 syndrome. Beyond COVID-19, these findings support the hypothesis that regional GM, WM microstructure, and FC could mediate the relationship between a medical illness and its psychopathological sequelae, and are in agreement with current perspectives on the brain structural and functional underpinnings of depressive psychopathology.

Keywords: Anxiety; COVID-19; Depression; Diffusion-tensor imaging; Functional connectivity; Grey matter; Magnetic resonance imaging; PTSD; Resting state; SARS-COV-2; White matter.

Fig. 1

Brain areas where severity of psychopathology associated with regional grey matter volumes. Top: Zung Self-rating Depression Scale (ZSDS); Middle: Beck Depression Inventory (BDI); Bottom: Impact of Event Scale (IES-R).

Fig. 2

Widespread effects of biomarkers of inflammation at the admission in the emergency department (Left: SII; Right: CRP) on axial diffusivity in the white matter skeleton (TBSS analysis). Voxels surviving the statistical threshold of corrected p ​< ​0.05 ​at TFCE are overlaid in radiologic projection on the 152 MNI T1 template and in glass brains.

Fig. 3

Negative association between severity of psychopathology (A, top: IES-R; B, bottom: BDI) with axial diffusivity in the white matter skeleton (TBSS analysis). Voxels surviving the statistical threshold of corrected p ​< ​0.05 ​at TFCE are shown in a 3D rendering and in glass brains.

Fig. 4

Effects of inflammatory biomarkers (SII, CRP) and severity of post-traumatic distress (IES-R score) in reducing (blue) or enhancing (red) resting-state functional connectivity from MVPA seeds to target clusters. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)