title: Task-evoked substantia nigra hyperactivity associated with prefrontal hypofunction, prefrontonigral disconnectivity and nigrostriatal connectivity predicting psychosis severity in medication naïve first episode schizophrenia.
abstract: The widely cited prefrontal dysfunction - excess subcortical dopamine model of schizophrenia posits that prefrontal deficits give rise to cognitive impairments and the disinhibition of subcortical dopamine release underlying psychosis. While this has been one of the most influential schizophrenia models, only a handful of studies have provided evidence supporting it directly in patients with schizophrenia. We previously demonstrated task-evoked substantia nigra hyperactivity in the context of prefrontal hypofunction and prefrontonigral functional disconnectivity. In addition, nigrostriatal functional connectivity was identified as a potential marker of psychosis. Because patients in this prior study had chronic schizophrenia and were treated with antipsychotics, in the present study we tested whether these findings were confounded by illness chronicity and medication effects by seeking to reproduce these findings in an independent sample of antipsychotic naïve, first episode (FE) patients. We compared event-related fMRI activations from 12 FE patients with 15 demographically matched healthy control subjects during cognitive testing. We found substantia nigra hyperactivity associated with prefrontal hypofunction and prefrontonigral functional disconnectivity, as well as the magnitude of nigrostriatal functional connectivity positively correlating with severity of psychosis. This study adds to the body of evidence supporting the prefrontal-dopamine model of schizophrenia and further validates nigrostriatal functional connectivity as a marker of psychosis.
authors.affiliation: Stanford University, Department of Psychiatry and the Behavioral Sciences, United States; Veterans Affairs Palo Alto Health Care System, United States.
authors.forename: Jong H
authors.initials: JH
authors.lastname: Yoon
authors.affiliation: University of California Davis, Department of Psychiatry, United States.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Westphal
authors.affiliation: University of California San Francisco, Department of Psychiatry, United States; San Francisco Veterans Affairs Medical Center, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Minzenberg
authors.affiliation: University of California Davis, Department of Psychiatry, United States.
authors.forename: Tara
authors.initials: T
authors.lastname: Niendam
authors.affiliation: University of California Davis, Department of Psychiatry, United States.
authors.forename: J Daniel
authors.initials: JD
authors.lastname: Ragland
authors.affiliation: University of California Davis, Department of Psychiatry, United States.
authors.forename: Tyler
authors.initials: T
authors.lastname: Lesh
authors.affiliation: University of California Davis, Department of Psychiatry, United States; University of California Davis, MIND Institute, United States.
authors.forename: Marjorie
authors.initials: M
authors.lastname: Solomon
authors.affiliation: University of California Davis, Department of Psychiatry, United States; University of California Davis, Center for Neuroscience, United States.
authors.forename: Cameron S
authors.initials: CS
authors.lastname: Carter
mesh_terms: D000328:Adult; D063132:Connectome; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D017072:Neostriatum / Q000503:physiopathology*; D017397:Prefrontal Cortex / Q000503:physiopathology*; D011618:Psychotic Disorders / Q000503:physiopathology; D012559:Schizophrenia / Q000503:physiopathology*; D012720:Severity of Illness Index; D013378:Substantia Nigra / Q000503:physiopathology*; D055815:Young Adult
keywords: Basal ganglia; Dopamine; Prefrontal cortex; Psychosis; Striatum; Substantia nigra; fMRI