Aberrant salience is selectively associated with ventral midbrain connectivity to the dorsal but not ventral striatum.

The dorsal midbrain-striatal dopaminergic stream encodes salience in animals, while it's unknown in humans. The midbrain-striatal dopaminergic hyperactivity is postulated to attribute aberrantly-heightened salience to ordinary stimuli, forming delusion and hallucination. While animal studies implicate the ventral midbrain-striatal stream, patient studies suggest the dorsal stream, leaving the precise localization of aberrant salience unclear. We investigated these issues by examining midbrain-striatal functional connectivity. Resting-state functional MRI was acquired from 116 patients with schizophrenia (SCZ) and 224 age- and sex-matched healthy controls (HC). Subjective aberrant salience was assessed using the Aberrant Salience Inventory (ASI). Functional connectivity was computed between six striatal seeds (bilateral ventral limbic, dorsal executive, and dorsal sensorimotor striata) and the dopaminergic midbrain voxels (ventral tegmental area and substantia nigra). We tested (1) the presence of a ventral-to-dorsal connectivity gradient along anterior-to-posterior and inferior-to-superior axes; (2) the main effects of diagnosis and ASI and their interaction on connectivity; and (3) their associations with psychotic symptoms. Both anterior-to-posterior and inferior-to-superior connectivity gradients were confirmed. A significant main effect of diagnosis was observed in connectivity between the left anterior midbrain and ventral limbic striatum, which was reduced in SCZ than in HC. A significant diagnosis-by-ASI sensory subscale interaction was found for connectivity between the left anteroinferior midbrain and the dorsal sensorimotor striatum. This ASI subscale was significantly correlated with positive symptoms (all P < 0.05 family-wise error fully corrected). These findings demonstrate the ventral-to-dorsal midbrain-striatal gradients in humans and indicate a more complex localization of aberrant salience than previously assumed.