BACKGROUND: Most COVID-19 neuroimaging research focuses on clinically evident lesions occurring during the acute period after infection. Chronic effects on brain structure, especially at a microstructural level, are less well defined. Existing advanced neuroimaging studies report inconsistent differences in white matter integrity after COVID-19 infection. Our aim was to systematically evaluate the advanced neuroimaging literature with a specific focus on examining diffusion MRI (dMRI) abnormalities observable after the resolution of the acute phase of COVID-19 illness. METHODS: A search of the literature was conducted on PubMed, Embase, and Scopus on May 27th, 2023, and an updated search was performed September 20th, 2024. Inclusion criteria were a quantitative comparison of dMRI metrics between COVID-19 patients and non-COVID-19 volunteers with MRI acquired >
6 weeks after COVID-19. Studies that included only subgroups of COVID-19 patients with specific symptoms, case reports, and post-mortem studies were excluded. Forwards and backwards citation chasing were performed. RESULTS: The initial search identified 1709 unique records, and 11 met inclusion criteria. Most studies included hospitalized COVID-19 patients, with brain MRI acquired between 2 and 6 months after COVID-19 infection. The majority of studies reported lower fractional anisotropy and higher mean diffusivity in the post-COVID-19 cohort, compared to non-COVID-19 controls. However, there were inconsistent findings, with one study reporting higher fractional anisotropy after COVID-19 infection. Cohorts with a more severe acute COVID-19 illness tended to have lower fractional anisotropy and higher mean diffusivity than cohorts with a milder illness course. Compared to shorter follow-up periods, a longer time between COVID-19 and MRI was associated with fewer differences between COVID-19 patients and non-COVID-19 volunteers. CONCLUSION: A review of the literature indicates that the heterogeneity of findings regarding dMRI metrics after the resolution of the acute phase of COVID-19 illness may be due in part to the severity of COVID-19 illness and the time between COVID-19 and MRI. Future studies should also consider how different SARS-CoV-2 variants differentially affect the structural brain differences after COVID-19.