Effective Connectivity and Dopaminergic Function of Fronto-Striato-Thalamic Circuitry in First-Episode Psychosis, Established Schizophrenia, and Healthy Controls

Dysfunction of fronto-striato-thalamic (FST) circuits is thought to contribute to dopaminergic dysfunction and symptom onset in psychosis, but it remains unclear whether this dysfunction is driven by aberrant bottom-up subcortical signaling or impaired top-down cortical regulation. Here, we used spectral dynamic causal modelling (DCM) of resting-state functional magnetic resonance imaging (fMRI) to characterize the effective connectivity of dorsal and ventral FST circuits in a sample of 46 antipsychotic-naive first-episode psychosis (FEP) patients and 23 controls and an independent sample of 36 patients with established schizophrenia (SCZ) patients and 100 controls. We found that midbrain and thalamic connectivity were implicated across both patient groups. Dysconnectivity in FEP patients was mainly restricted to the subcortex, with positive symptom severity being associated with midbrain connectivity. Dysconnectivity between the cortex and subcortical systems was only apparent in SCZ patients. In another independent sample of 33 healthy individuals who underwent concurrent fMRI and [18F]DOPA positron emission tomography, we found that striatal dopamine synthesis capacity was associated with the effective connectivity of nigrostriatal and striatothalamic pathways, implicating similar circuits as those associated with psychotic symptom severity in patients. Our findings thus indicate that subcortical dysconnectivity is salient in the early stages of psychosis, that cortical dysfunction may emerge later in the illness, and that nigrostriatal and striatothalamic signaling are closely related to striatal dopamine synthesis capacity, which is a robust risk marker for psychosis.