Dynamic multivariate patterns of brain structure–neuropsychiatric symptom associations in long COVID

Abstract Long COVID presents with heterogeneous and persistent neuropsychiatric symptoms, suggesting possible shared neural underpinnings. However, the dynamic brain structure-symptom relationships and their potential for predicting long-term outcomes remain unclear. We conducted a longitudinal study of 144 individuals with long COVID (mean age: 37.8 ± 10.1 years, 48.6% male). All participants experienced mild COVID-19 and were not hospitalized. Structural MRI and comprehensive psychiatric and cognitive assessments were performed at one, three, and twelve months post-infection. A cohort of 68 healthy controls (mean age: 36.0 ± 10.3 years; 41.2% male) completed the same assessment protocol at baseline. Regularized canonical correlation analysis was employed to identify multivariate associations between 13 psychiatric and cognitive measures and both gray matter volume and cortical thickness, and to assessed whether early structural features predicted symptom outcomes at one year. Neuropsychiatric symptoms were linked to coordinated structural covariance patterns across distributed brain regions in long COVID; these associations strengthened from one to three months post-infection and were absent in controls. A stable cognitive-affective symptom dimension showed the strongest brain-behavior coupling. Notably, the neural substrates of this coupling diverged over time: gray matter volume associations remained localized to prefrontal-limbic circuits, whereas cortical thickness associations expanded to frontoparietal regions. Critically, reduced gray matter volume in the right cuneus and superior frontal gyri, along with decreased cortical thickness in the left supramarginal gyrus at three months post-infection, were significantly linked to poorer executive function and greater fatigue one year later. Our findings delineate evolving neuroanatomical signature of long COVID, where distinct patterns of gray matter volume and cortical thickness underpin a core symptom profile and predict long-term neuropsychiatric symptoms. These results provide insight into the neural mechanisms of long COVID and identify specific targets for monitoring and early intervention.