Altered activation and connectivity in a hippocampal\u2013basal ganglia\u2013midbrain circuit during salience processing in subjects at ultra high risk for psychosis

T Winton-Brown,A A Grace,E Duzel,P Mcguire,N Bunzeck,S Kapur,P Fusar-Poli,J P Roiser,A Egerton,A Schmidt,O D Howes

doi:10.1038/tp.2017.174

Abstract

Animal models of psychosis propose that abnormal hippocampal activity drives increased subcortical dopamine function, which is thought to contribute to aberrant salience processing and psychotic symptoms. These effects appear to be mediated through connections between the hippocampus, ventral striatum/pallidum and the midbrain. The aim of the present study was to examine the activity and connectivity in this pathway in people at ultra high risk (UHR) for psychosis. Functional magnetic resonance imaging was used to compare neural responses in a hippocampal–basal ganglia–midbrain network during reward, novelty and aversion processing between 29 UHR subjects and 32 healthy controls. We then investigated whether effective connectivity within this network is perturbed in UHR subjects, using dynamic causal modelling (DCM). Finally, we examined the relationship between alterations in activation and connectivity in the UHR subjects and the severity of their psychotic symptoms. During reward anticipation, UHR subjects showed greater activation than controls in the ventral pallidum bilaterally. There were no differences in activation during novelty or aversion processing. DCM revealed that reward-induced modulation of connectivity from the ventral striatum/pallidum to the midbrain was greater in UHR subjects than controls, and that in UHR subjects, the strength of connectivity in this pathway was correlated with the severity of their abnormal beliefs. In conclusion, ventral striatal/pallidal function is altered in people at UHR for psychosis and this is related to the level of their psychotic symptoms.

Highlights

Two neural hallmarks of psychosis are increased presynaptic striatal dopamine function[1] and structural and functional abnormalities in the hippocampus.[2]
In dynamic causal modelling (DCM) for functional magnetic resonance imaging (fMRI), the dynamics of the neural states underlying regional BOLD responses are modelled by a bilinear differential equation that describes how the neural states change as a function of endogenous interregional connections, modulatory effects on these connections and driving inputs.[23]
In the current study, based on the group-level fMRI findings, we explicitly explored how the coupling strengths between hippocampus, ventral striatum/pallidum and midbrain were changed by reward-predicting cues

Summary

Introduction

Two neural hallmarks of psychosis are increased presynaptic striatal dopamine function[1] and structural and functional abnormalities in the hippocampus.[2]. Animal models of psychosis propose that these two abnormalities may be linked via a polysynaptic pathway involving the hippocampus, basal ganglia and midbrain.[7,8] Cognitive models of psychosis propose that psychotic symptoms develop as a result of altered salience processing.[9] Taken together, these models propose that the presence of a salient stimulus in healthy subjects is associated with increased hippocampal activity and descending glutamatergic drive to GABAergic neurons in the ventral striatum. Data from multimodal neuroimaging studies in UHR individuals are consistent with this model, indicating that the relationship between hippocampal activity and glutamate levels with striatal dopamine function is significantly altered compared to that in controls.[14]

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