Brainstem subfield volume alterations in COVID-19 patients: Implications for respiratory and arousal circuits

Respiratory failure is a leading cause of mortality in coronavirus disease 2019 (COVID-19). While the brainstem centrally governs respiratory control, its ascending arousal nuclei regulate consciousness and wakefulness. Many COVID-19 patients exhibit prolonged unresponsiveness or delayed arousal from sedation. These clinical observations suggest the potential involvement of the brainstem and its associated arousal systems. However, region-specific structural and microstructural differences in the brainstem and ascending arousal network following COVID-19 remains unclear. We analyzed previously collected structural and diffusion-weighted magnetic resonance imaging data from 73 COVID-19 patients (mean age: 42.1 years) and 27 age-matched non-COVID-19 controls (mean age: 42.8 years). Diffusion data were available for 71 and 18 participants, respectively. Regional volumes were normalized to estimated total intracranial volume, and diffusion tensor measures included fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity. In false-discovery-rate-adjusted analyses, the COVID-19 group had a larger normalized superior cerebellar peduncle (SCP) volume and smaller ventral tegmental area and periaqueductal gray volume estimates. In the diffusion subset, the SCP showed lower fractional anisotropy and axial diffusivity and higher radial and mean diffusivity, indicating subtle but nonspecific differences in tissue microstructural organization. Within the COVID-19 group, higher anxiety scores were associated with lower midbrain volume. These findings identify region-specific structural and diffusion differences involving the SCP and selected arousal-related nuclei in individuals assessed during the post-acute phase of COVID-19. The inverse association between anxiety and midbrain volume suggests potential clinical relevance. However, higher-resolution, prospectively acquired multimodal studies are needed to determine whether these observations are related to post-COVID respiratory, arousal, or neuropsychiatric symptoms.