The thalamus in psychosis spectrum disorder.

Psychosis spectrum disorder affects 1% of the world population and leads to chronic disability. Developing treatments for its cognitive deficits is hindered by a weak link between neurobiological understanding and clinical symptoms. This perspective highlights an opportunity combining non-invasive human neuroimaging with insights into thalamic regulation of cortical connectivity. The thalamus forms forebrain-wide functional loops critical for processing external inputs and updating internal models. Evidence shows PSD symptomatology may stem from faulty network organization with the thalamus as a central coordinator. Animal work clarifies thalamic circuits regulating cortical dynamics and cognition.

Study at a glance

Abstract

Psychosis spectrum disorder (PSD) affects 1% of the world population and results in a lifetime of chronic disability, causing devastating personal and economic consequences. Developing new treatments for PSD remains a challenge, particularly those that target its core cognitive deficits. A key barrier to progress is the tenuous link between the basic neurobiological understanding of PSD and its clinical phenomenology. In this perspective, we focus on a key opportunity that combines innovations in non-invasive human neuroimaging with basic insights into thalamic regulation of functional cortical connectivity. The thalamus is an evolutionary conserved region that forms forebrain-wide functional loops critical for the transmission of external inputs as well as the construction and update of internal models. We discuss our perspective across four lines of evidence: First, we articulate how PSD symptomatology may arise from a faulty network organization at the macroscopic circuit level with the thalamus playing a central coordinating role. Second, we discuss how recent animal work has mechanistically clarified the properties of thalamic circuits relevant to regulating cortical dynamics and cognitive function more generally. Third, we present human neuroimaging evidence in support of thalamic alterations in PSD, and propose that a similar "thalamocortical dysconnectivity" seen in pharmacological imaging (under ketamine, LSD and THC) in healthy individuals may link this circuit phenotype to the common set of symptoms in idiopathic and drug-induced psychosis. Lastly, we synthesize animal and human work, and lay out a translational path for biomarker and therapeutic development.