Abnormal Frontostriatal Interactions in People With Prodromal Signs of Psychosis

CONTEXT: Alterations in dopaminergic neurotransmission and function of the prefrontal cortex are thought to be central to the pathophysiology of schizophrenia, but the relationship between these factors in the development of psychosis is unclear. OBJECTIVE: To investigate the relationship between striatal dopamine activity and prefrontal function in people at ultra high risk of psychosis. DESIGN: Subjects were studied using functional magnetic resonance imaging while performing a working memory (N-back) task. Positron emission tomography with fluorine 18-labeled fluorodopa was used to investigate presynaptic striatal dopamine activity. SETTING: Outpatient service for people with prodromal signs of psychosis. PATIENTS AND OTHER PARTICIPANTS: Thirty-four subjects participated in the study: 14 healthy volunteers and 20 subjects with an at-risk mental state (ARMS). MAIN OUTCOME MEASURES: Regional brain activation (blood oxygen level-dependent response), Ki for (18)Ffluorodopa uptake, and objective ratings of psychopathology at the time of scanning. RESULTS: In the associative part of the striatum, the Ki for (18)Ffluorodopa was higher in the ARMS group than in the controls. During the N-back task, ARMS subjects displayed less activation in the right middle frontal gyrus, the medial frontal gyri, and the left superior parietal lobule than controls. The Ki for (18)Ffluorodopa was positively correlated with activation in the right middle frontal gyrus in controls but negatively correlated with activation in this region in the ARMS group. CONCLUSIONS: In people with prodromal signs of psychosis, there are direct correlations between altered prefrontal cortical function and subcortical dopamine synthesis capacity, consistent with the notion that frontostriatal interactions play a critical role in the pathoetiology of schizophrenia.