Neuroimaging predictors of functional outcomes in schizophrenia at baseline and 6-month follow-up

Abstract

Purpose: Studies show that deficit syndrome schizophrenia patients, characterized by primary negative symptoms and poor functional outcome, have impairment in specific neural circuits. We assessed whether these same neural circuits are directly linked to functional outcomes across schizophrenia patients.

Methods: T1- and diffusion-weighted MR images were obtained for schizophrenia (n=30) and matched healthy control participants (n=30). Negative symptoms and functional outcome were assessed at baseline and 6-month follow-up. Cortical thickness and tract-wise fractional anisotropy (FA) were compared between groups. To assess relationships of neuroimaging measures with functional outcome, principal component analysis (PCA) was performed on tract-wise FA values and components were entered into a multiple regression model for schizophrenia participants.

Results: Consistent with the literature, schizophrenia participants showed frontotemporal reductions in cortical thickness and tract-wise FA compared to controls. The top two components from PCA explained 71% of the variance in tract-wise FA values. The second component (associated with inferior longitudinal and arcuate fasciculus FA) was significantly correlated with functional outcome (baseline: β=0.54, p=0.03; follow-up: β=0.74, p=0.047); further analysis revealed this effect was mediated by negative symptoms. Post-hoc network analysis revealed increased cortical coupling between right inferior frontal and supramarginal gyri (connected by the arcuate fasciculus) in schizophrenia participants with poorer functional outcome.

Conclusions: Our findings indicate that impairment in the same neural circuitry susceptible in deficit syndrome schizophrenia predicts functional outcome in a continuous manner in schizophrenia participants. This relationship was mediated by negative symptom burden. Our findings provide novel evidence for brain-based biomarkers of longitudinal functional outcome in people with schizophrenia.

Keywords: Arcuate fasciculus; Cortical thickness; Diffusion tensor imaging; Fractional anisotropy; Inferior longitudinal fasciculus; Network analysis.

Figure 1. Right inferior longitudinal fasciculus and arcuate fasciculus

Sagittal view of the right inferior longitudinal fasciculus and right arcuate fasciculus as modeled by the tractography pipeline used in this study.

Figure 2. Mediation Model

Model showing the relationship between the second principal component and functional outcome in schizophrenia participants, which was partially mediated by negative symptoms. The direct effect (c’=0.25, p=0.26) was less than the total effect (c=0.59, p=0.02). Mediation was validated by the Sobel test, demonstrating a significant effect (ab=0.3, p=0.05) of negative symptoms on the relationship between neural circuitry and functional outcome. Similarly, partial mediation of the relationship between baseline tract FA and functional outcome in the follow-up sample was also observed (c=0.75, p=0.04; c’=0.11, p=0.71).