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

Area of Science:

• Neuroscience
• Psychiatry
• Functional Neuroimaging

Background:

• Dopamine's role in psychosis pathogenesis is established, but mechanisms of dopaminergic dysfunction are unclear.
• Corticostriatothalamic (CST) circuits are central to dopaminergic modulation and implicated in psychosis.
• Preclinical models of CST dysfunction in psychosis exist but face challenges due to evolutionary circuit modifications.

Purpose of the Study:

• To evaluate preclinical models of CST dysfunction in psychosis using human resting-state functional magnetic resonance imaging (fMRI) data.
• To examine functional connectivity across the psychosis continuum, from subclinical schizotypy to schizophrenia.
• To compare findings from human fMRI studies with preclinical models of psychosis.

Main Methods:

• Analysis of resting-state fMRI data from human participants across the psychosis spectrum.
• Comparison of functional connectivity patterns with established preclinical models of CST dysfunction.
• Investigation of dorsal CST and hippocampal-striatal circuit involvement.

Main Results:

• Human studies partially support preclinical models, revealing dorsal CST and hippocampal-striatal functional dysconnectivity across the psychosis spectrum.
• This dysconnectivity may serve as a vulnerability marker for psychosis.
• Midbrain dysfunction appears associated with clinically significant symptoms, potentially triggering illness onset.

Conclusions:

• Dorsal CST functional dysconnectivity is a key feature in human psychosis, more so than suggested by some preclinical models.
• Midbrain dysfunction may be linked to clinical symptom manifestation.
• Further high-resolution phenotyping is crucial to link specific circuit dysfunctions to distinct psychosis symptom profiles.