Abstract
Preclinical rodent models suggest that psychosis involves alterations in the activity and glutamatergic function in the hippocampus, driving dopamine activity through projections to the striatum. The extent to which this model applies to the onset of psychosis in clinical subjects is unclear. We assessed whether interactions between hippocampal glutamatergic function and activity/striatal connectivity are associated with adverse clinical outcomes in people at clinical high-risk (CHR) for psychosis. We measured functional Magnetic Resonance Imaging of hippocampal activation/connectivity, and 1H-Magnetic Resonance Spectroscopy of hippocampal glutamatergic metabolites in 75 CHR participants and 31 healthy volunteers. At follow-up, 12 CHR participants had transitioned to psychosis and 63 had not. Within the clinical high-risk cohort, at follow-up, 35 and 17 participants had a poor or a good functional outcome, respectively. The onset of psychosis (ppeakFWE = 0.003, t = 4.4, z = 4.19) and a poor functional outcome (ppeakFWE < 0.001, t = 5.52, z = 4.81 and ppeakFWE < 0.001, t = 5.25, z = 4.62) were associated with a negative correlation between the hippocampal activation and hippocampal Glx concentration at baseline. In addition, there was a negative association between hippocampal Glx concentration and hippocampo-striatal connectivity (ppeakFWE = 0.016, t = 3.73, z = 3.39, ppeakFWE = 0.014, t = 3.78, z = 3.42, ppeakFWE = 0.011, t = 4.45, z = 3.91, ppeakFWE = 0.003, t = 4.92, z = 4.23) in the total CHR sample, not seen in healthy volunteers. As predicted by preclinical models, adverse clinical outcomes in people at risk for psychosis are associated with altered interactions between hippocampal activity and glutamatergic function.
Highlights
The onset of psychosis is commonly preceded by a clinical highrisk (CHR) phase, characterised by ‘attenuated’ psychotic symptoms and a marked decline in social and occupational functioning [1]
We assessed whether interactions between hippocampal glutamatergic function and activity/striatal connectivity are associated with adverse clinical outcomes in people at clinical high-risk (CHR) for psychosis
Preclinical models propose that psychosis is associated with increased resting hippocampal activity [4,5,6], and altered hippocampal glutamate activity [5, 7] which is thought to drive an increase in subcortical dopamine activity through glutamatergic projections from the hippocampus to striatum [6]
Summary
The onset of psychosis is commonly preceded by a clinical highrisk (CHR) phase, characterised by ‘attenuated’ psychotic symptoms and a marked decline in social and occupational functioning [1]. This syndrome is associated with a 20–30% risk of developing psychosis in the following 2–3 years [1,2,3]. Data from preclinical studies in rats suggest that the onset of psychosis involves an increase in resting hippocampal activity [4,5,6], which may be secondary to a dysregulation of hippocampal glutamatergic neurotransmission [5, 7]. Consistent with preclinical studies [4,5,6,7], neuroimaging studies in CHR individuals have identified alterations in the functional connectivity of the hippocampus [18, 19]
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