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Interactions between hippocampal activity and striatal dopamine in people at clinical high risk for psychosis: relationship to adverse outcomes.

ABSTRACT: Preclinical models propose that increased hippocampal activity drives subcortical dopaminergic dysfunction and leads to psychosis-like symptoms and behaviors. Here, we used multimodal neuroimaging to examine the relationship between hippocampal regional cerebral blood flow (rCBF) and striatal dopamine synthesis capacity in people at clinical high risk (CHR) for psychosis and investigated its association with subsequent clinical and functional outcomes. Ninety-five participants (67 CHR and 28 healthy controls) underwent arterial spin labeling MRI and ¹⁸F-DOPA PET imaging at baseline. CHR participants were followed up for a median of 15 months to determine functional outcomes with the global assessment of function (GAF) scale and clinical outcomes using the comprehensive assessment of at-risk mental states (CAARMS). CHR participants with poor functional outcomes (follow-up GAF < 65, n = 25) showed higher rCBF in the right hippocampus compared to CHRs with good functional outcomes (GAF ≥ 65, n = 25) (p_fwe = 0.026). The relationship between rCBF in this right hippocampal region and striatal dopamine synthesis capacity was also significantly different between groups (p_fwe = 0.035); the association was negative in CHR with poor outcomes (p_fwe = 0.012), but non-significant in CHR with good outcomes. Furthermore, the correlation between right hippocampal rCBF and striatal dopamine function predicted a longitudinal increase in the severity of positive psychotic symptoms within the total CHR group (p = 0.041). There were no differences in rCBF, dopamine, or their associations in the total CHR group relative to controls. These findings indicate that altered interactions between the hippocampus and the subcortical dopamine system are implicated in the pathophysiology of adverse outcomes in the CHR state.

SUBMITTER: Modinos G

PROVIDER: S-EPMC8209204 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportancePreclinical and human data suggest that hippocampal dysfunction plays a critical role in the onset of psychosis. Neural hyperactivity in the hippocampus is thought to drive an increase in subcortical dopamine function through glutamatergic projections to the striatum.ObjectiveTo examine the association between hippocampal glutamate levels in individuals at clinical high risk for psychosis and their subsequent clinical outcomes.Design, setting, and participantsThis cross-sectional study of 86 individuals at clinical high risk for psychosis and 30 healthy control individuals, with a mean follow-up of 18.5 months, was conducted between November 1, 2011, and November 1, 2017, at early detection services in London and Cambridge, United Kingdom.Main outcomes and measuresConcentrations of glutamate and other metabolites were measured in the left hippocampus using 3-T proton magnetic resonance spectroscopy at the first clinical presentation. At follow-up, clinical outcomes were assessed in terms of transition or nontransition to psychosis using the Comprehensive Assessment of the At-Risk Mental State criteria and the level of overall functioning using the Global Assessment of Function scale.ResultsOf 116 total participants, 86 were at clinical high risk for psychosis (50 [58%] male; mean [SD] age, 22.4 [3.5] years) and 30 were healthy controls (14 [47%] male; mean [SD] age, 24.7 [3.8] years). At follow-up, 12 clinical high-risk individuals developed a first episode of psychosis whereas 74 clinical high-risk individuals did not; 19 clinical high-risk individuals showed good overall functioning (Global Assessment of Function ≥65), whereas 38 clinical high-risk individuals had a poor functional outcome (Global Assessment of Function <65). Compared with clinical high-risk individuals who did not become psychotic, clinical high-risk individuals who developed psychosis showed higher hippocampal glutamate levels (mean [SD], 8.33 [1.48] vs 9.16 [1.28] glutamate levels; P = .048). The clinical high-risk individuals who developed psychosis also had higher myo-inositol levels (mean [SD], 7.60 [1.23] vs 6.24 [1.36] myo-inositol levels; P = .002) and higher creatine levels (mean [SD], 8.18 [0.74] vs 7.32 [1.09] creatine levels; P = .01) compared with clinical high-risk individuals who did not become psychotic, and higher myo-inositol levels compared with healthy controls (mean [SD], 7.60 [1.23] vs 6.19 [1.51] myo-inositol levels; P = .005). Higher hippocampal glutamate levels in clinical high-risk individuals were also associated with a poor functional outcome (mean [SD], 8.83 [1.43] vs 7.76 [1.40] glutamate levels; P = .02). In the logistic regression analyses, hippocampal glutamate levels were significantly associated with clinical outcome in terms of transition and nontransition to psychosis (β = 0.48; odds ratio = 1.61; 95% CI, 1.00-2.59; P = .05) and overall functioning (β = 0.53; odds ratio = 1.71; 95% CI, 1.10-2.66; P = .02).Conclusions and relevanceThe findings indicate that adverse clinical outcomes in individuals at clinical high risk for psychosis may be associated with an increase in baseline hippocampal glutamate levels, as well as an increase in myo-inositol and creatine levels. This conclusion suggests that these measures could contribute to the stratification of clinical high-risk individuals according to future clinical outcomes.

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Interactions between hippocampal activity and striatal dopamine in people at clinical high risk for psychosis: relationship to adverse outcomes.

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