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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 t = 5.52, z = 4.81 and ppeakFWE 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.

Preclinical models suggest that psychosis involves alterations in activity and glutamate 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 =.003, t=4.4, z=4.19) and a poor functional outcome (ppeakFWE ppeakFWE ppeakFWE=.016, t=3.73, z=3.39, ppeakFWE=.014, t=3.78, z=3.42, ppeakFWE=.011, t=4.45, z=3.91, ppeakFWE=.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.

Background We recently used Magnetic Resonance Spectroscopy (MRS) to show that transition to psychosis is associated with higher baseline hippocampal glutamate levels (1). We also used functional Magnetic Resonance Imaging (fMRI) in the same CHR subjects and showed that compared to healthy controls (HC), subjects at a clinical high-risk of psychosis (CHR) show decreased hippocampal activation to novel stimuli and increased novelty-modulated hippocampal-striatal connectivity (2). The aim of the present analysis was to explore the relationship between hippocampal glutamatergic metabolites, hippocampal activity, and hippocampal-striatal connectivity in these CHR subjects. Methods 75 CHR and 31 HC subjects participated in a novelty salience task whilst undergoing fMRI to measure hippocampal and striatal activation, and MRS to measure hippocampal glutamatergic metabolite levels. First, we tested for a three-way interaction between the hippocampal response to novel versus neutral stimuli, hippocampal glutamatergic metabolite levels, and group, using a Region of Interest approach in the bilateral hippocampus. Second, we carried out a Psychophysiological Interaction (PPI) analysis on the extracted hippocampal coordinates from the first analysis and tested for an interaction with hippocampal glutamatergic metabolite levels and group. Results The CHR group had higher clinical scores and lower GAF scores at baseline than HC. CHR subjects were younger, more were taking antipsychotic medication and they smoked more cigarettes than HC. At follow-up, 12 CHR subjects (16%) developed a first episode of psychosis (CHR-TR) and 63 (86%) did not (CHR-NTR). The CHR-TR subjects smoked fewer cigarettes than the CHR-NTR subjects. The first analysis revealed a significant interaction between group, fMRI activity and MRS Glx (a combined measure of glutamate and glutamine) in the right hippocampus (pFWE= 0.03; x y z = 28 -32 -4; t=3.61, z=3.49). This was driven by the CHR-TR group: contrast estimates indicated a positive relationship between fMRI activity and MRS Glx in the HC and CHR-NTR subjects, but a negative relationship between fMRI activity and glutamate in the CHR-TR subjects. The second analysis revealed that CHR-TR individuals exhibited greater connectivity between the hippocampus and the striatum (pFWE= 0.03; x y z = -6 6 -8; t=3.35, z=3.17), but that this was not associated with Glx. Discussion Whilst hippocampal glutamate metabolite levels are associated with altered hippocampal activity in CHR individuals - especially in those who later transition to psychosis - hippocampal glutamate metabolite levels do not modulate connectivity between the hippocampus and striatum. These findings are broadly consistent with previous work indicating a role for glutamate in hippocampal dysfunction and risk for psychosis, and indicate a potential biomarker for psychosis risk. References