Circuit-Based Approaches to Understanding Corticostriatothalamic Dysfunction Across the Psychosis Continuum

Abstract

Dopamine is known to play a role in the pathogenesis of psychotic symptoms, but the mechanisms driving dopaminergic dysfunction in psychosis remain unclear. Considerable attention has focused on the role of corticostriatothalamic (CST) circuits, given that they regulate and are modulated by the activity of dopaminergic cells in the midbrain. Preclinical studies have proposed multiple models of CST dysfunction in psychosis, each prioritizing different brain regions and pathophysiological mechanisms. A particular challenge is that CST circuits have undergone considerable evolutionary modification across mammals, complicating comparisons across species. Here, we consider preclinical models of CST dysfunction in psychosis and evaluate the degree to which they are supported by evidence from human resting-state functional magnetic resonance imaging studies conducted across the psychosis continuum, ranging from subclinical schizotypy to established schizophrenia. In partial support of some preclinical models, human studies indicate that dorsal CST and hippocampal-striatal functional dysconnectivity are apparent across the psychosis spectrum and may represent a vulnerability marker for psychosis. In contrast, midbrain dysfunction may emerge when symptoms warrant clinical assistance and may thus be a trigger for illness onset. The major difference between clinical and preclinical findings is the strong involvement of the dorsal CST in the former, consistent with an increasing prominence of this circuitry in the primate brain. We close by underscoring the need for high-resolution characterization of phenotypic heterogeneity in psychosis to develop a refined understanding of how the dysfunction of specific circuit elements gives rise to distinct symptom profiles.