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

AbstractPreclinical 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) (pfwe = 0.026). The relationship between rCBF in this right hippocampal region and striatal dopamine synthesis capacity was also significantly different between groups (pfwe = 0.035); the association was negative in CHR with poor outcomes (pfwe = 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.

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

10.1101/2020.12.08.20245902 ◽

2020 ◽

Author(s):

Gemma Modinos ◽

Anja Richter ◽

Alice Egerton ◽

Ilaria Bonoldi ◽

Matilda Azis ◽

...

Keyword(s):

High Risk ◽

Functional Outcome ◽

Clinical Outcomes ◽

Striatal Dopamine ◽

Psychotic Symptoms ◽

Dopamine Synthesis ◽

Clinical High Risk ◽

Hippocampal Activity ◽

The Relationship

AbstractBackgroundPreclinical models propose that the onset of psychosis involves increased hippocampal activity which drives subcortical dopaminergic dysfunction. We used multi-modal 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 outcomes.MethodsNinety-five participants (67 CHR and 28 healthy controls) underwent pseudo-continuous arterial spin labelling and 18F-DOPA PET imaging at baseline. Clinical outcomes in CHR participants were determined after a median of 15 months follow-up, using the Comprehensive Assessment of At Risk Mental States (CAARMS) and the Global Assessment of Function (GAF) scale.ResultsCHR participants with a poor functional outcome (follow-up GAF<65, n=25) showed higher rCBF in the right hippocampus compared to CHRs with a good functional outcome (GAF≥65, n=25) (familywise error [FWE] p=0·026). The relationship between right hippocampal rCBF and striatal dopamine synthesis capacity was also significantly different between groups (pFWE=0·035); the association was negative in CHR with poor outcomes (pFWE=0·012), but non-significant in CHR with good outcomes. The correlation between rCBF in this right hippocampal region and striatal dopamine function also predicted a longitudinal increase in the severity of positive psychotic symptoms (p=0·041). The relationship between hippocampal rCBF and striatal dopamine did not differ in the total CHR group relative to controls.InterpretationThese findings indicate that altered interactions between the hippocampus and the subcortical dopamine system are implicated in the pathophysiology of psychosis-related outcomes.

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Glutamatergic and dopaminergic function and the relationship to outcome in people at clinical high risk of psychosis: a multi-modal PET-magnetic resonance brain imaging study

Neuropsychopharmacology ◽

10.1038/s41386-019-0541-2 ◽

2019 ◽

Vol 45 (4) ◽

pp. 641-648 ◽

Cited By ~ 6

Author(s):

Oliver D. Howes ◽

Ilaria Bonoldi ◽

Robert A. McCutcheon ◽

Matilda Azis ◽

Mathilde Antoniades ◽

...

Keyword(s):

High Risk ◽

Imaging Study ◽

Striatal Dopamine ◽

Psychotic Symptoms ◽

Dopamine Synthesis ◽

Clinical High Risk ◽

Magnetic Resonance Brain Imaging ◽

The Relationship ◽

Brain Imaging Study

Abstract Preclinical models of psychosis propose that hippocampal glutamatergic neuron hyperactivity drives increased striatal dopaminergic activity, which underlies the development of psychotic symptoms. The aim of this study was to examine the relationship between hippocampal glutamate and subcortical dopaminergic function in people at clinical high risk for psychosis, and to assess the association with the development of psychotic symptoms. 1H-MRS was used to measure hippocampal glutamate concentrations, and 18F-DOPA PET was used to measure dopamine synthesis capacity in 70 subjects (51 people at clinical high risk for psychosis and 19 healthy controls). Clinical assessments were undertaken at baseline and follow-up (median 15 months). Striatal dopamine synthesis capacity predicted the worsening of psychotic symptoms at follow-up (r = 0.35; p < 0.05), but not transition to a psychotic disorder (p = 0.22), and was not significantly related to hippocampal glutamate concentration (p = 0.13). There were no differences in either glutamate (p = 0.5) or dopamine (p = 0.5) measures in the total patient group relative to controls. Striatal dopamine synthesis capacity at presentation predicts the subsequent worsening of sub-clinical total and psychotic symptoms, consistent with a role for dopamine in the development of psychotic symptoms, but is not strongly linked to hippocampal glutamate concentrations.

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Altered activation and connectivity in a hippocampal–basal ganglia–midbrain circuit during salience processing in subjects at ultra high risk for psychosis

Translational Psychiatry ◽

10.1038/tp.2017.174 ◽

2017 ◽

Vol 7 (10) ◽

pp. e1245-e1245 ◽

Cited By ~ 22

Author(s):

T Winton-Brown ◽

A Schmidt ◽

J P Roiser ◽

O D Howes ◽

A Egerton ◽

...

Keyword(s):

Basal Ganglia ◽

High Risk ◽

Ventral Striatum ◽

Effective Connectivity ◽

Psychotic Symptoms ◽

Neural Responses ◽

Hippocampal Activity ◽

Ultra High Risk ◽

Aberrant Salience ◽

The Relationship

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.

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Characterising cognitive heterogeneity in individuals at clinical high-risk for psychosis: a cluster analysis with clinical and functional outcome prediction

European Archives of Psychiatry and Clinical Neuroscience ◽

10.1007/s00406-021-01315-2 ◽

2021 ◽

Author(s):

Kate Haining ◽

Ruchika Gajwani ◽

Joachim Gross ◽

Andrew I. Gumley ◽

Robin A. A. Ince ◽

...

Keyword(s):

Cluster Analysis ◽

High Risk ◽

Functional Outcomes ◽

Early Stage ◽

Psychotic Symptoms ◽

First Episode ◽

Cognitively Impaired ◽

Clinical High Risk ◽

Global Functioning

AbstractSchizophrenia is characterised by cognitive impairments that are already present during early stages, including in the clinical high-risk for psychosis (CHR-P) state and first-episode psychosis (FEP). Moreover, data suggest the presence of distinct cognitive subtypes during early-stage psychosis, with evidence for spared vs. impaired cognitive profiles that may be differentially associated with symptomatic and functional outcomes. Using cluster analysis, we sought to determine whether cognitive subgroups were associated with clinical and functional outcomes in CHR-P individuals. Data were available for 146 CHR-P participants of whom 122 completed a 6- and/or 12-month follow-up; 15 FEP participants; 47 participants not fulfilling CHR-P criteria (CHR-Ns); and 53 healthy controls (HCs). We performed hierarchical cluster analysis on principal components derived from neurocognitive and social cognitive measures. Within the CHR-P group, clusters were compared on clinical and functional variables and examined for associations with global functioning, persistent attenuated psychotic symptoms and transition to psychosis. Two discrete cognitive subgroups emerged across all participants: 45.9% of CHR-P individuals were cognitively impaired compared to 93.3% of FEP, 29.8% of CHR-N and 30.2% of HC participants. Cognitively impaired CHR-P participants also had significantly poorer functioning at baseline and follow-up than their cognitively spared counterparts. Specifically, cluster membership predicted functional but not clinical outcome. Our findings support the existence of distinct cognitive subgroups in CHR-P individuals that are associated with functional outcomes, with implications for early intervention and the understanding of underlying developmental processes.

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Duration of basic and attenuated-psychotic symptoms in individuals at clinical high risk for psychosis: pattern of symptom onset and effects of duration on functioning and cognition

BMC Psychiatry ◽

10.1186/s12888-021-03267-2 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Lorna Staines ◽

Ruchika Gajwani ◽

Joachim Gross ◽

Andrew I. Gumley ◽

Stephen M. Lawrie ◽

...

Keyword(s):

High Risk ◽

Cognitive Deficits ◽

Psychotic Symptoms ◽

Healthy Controls ◽

Clinical High Risk ◽

Basic Symptoms ◽

Secondary Objective ◽

Secondary Phenomenon ◽

The Relationship ◽

At Risk Mental State

Abstract Introduction Duration of risk symptoms (DUR) in people at clinical high risk for psychosis (CHR-P) has been related to poorer clinical outcomes, such as reduced functioning, but it is currently unclear how different symptoms emerge as well as their link with cognitive deficits. To address these questions, we examined the duration of basic symptoms (BS) and attenuated psychotic symptoms (APS) in a sample of CHR-P participants to test the hypothesis that BS precede the manifestation of APS. As a secondary objective, we investigated the relationship between DUR, functioning and neuropsychological deficits. Methods Data from 134 CHR-P participants were assessed with the Comprehensive Assessment of At-Risk Mental State and the Schizophrenia Proneness Interview, Adult Version. Global, role and social functioning and neurocognition were assessed and compared to a sample of healthy controls (n = 57). Results In CHR-P participants who reported both APS and BS, onset of BS and APS was not significantly related. When divided into short and long BS duration (</> 8 years), CHR-P participants with a longer duration of BS showed evidence for an onset of BS preceding APS (n = 8, p = 0.003). However, in the short BS duration group, APS showed evidence of preceding BS (n = 56, p = 0.020). Finally, there were no significant effects of DUR on cognition or functioning measures. Conclusion The present findings do not support the view that APS constitute a secondary phenomenon to BS. Moreover, our data could also not confirm that DUR has a significant effect on functioning and cognitive deficits. These findings are discussed in the context of current theories regarding emerging psychosis and the importance of DUR.

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Clinical and functional characteristics of youth at clinical high-risk for psychosis who do not transition to psychosis

Psychological Medicine ◽

10.1017/s0033291718002258 ◽

2018 ◽

Vol 49 (10) ◽

pp. 1670-1677 ◽

Cited By ~ 25

Author(s):

Jean Addington ◽

Jacqueline Stowkowy ◽

Lu Liu ◽

Kristin S. Cadenhead ◽

Tyrone D. Cannon ◽

...

Keyword(s):

Longitudinal Study ◽

High Risk ◽

Functional Outcomes ◽

Recent Literature ◽

Clinical Symptoms ◽

Detailed Examination ◽

Psychotic Symptoms ◽

Healthy Controls ◽

Clinical High Risk ◽

Psychotic Illness

AbstractBackgroundMuch of the interest in youth at clinical high risk (CHR) of psychosis has been in understanding conversion. Recent literature has suggested that less than 25% of those who meet established criteria for being at CHR of psychosis go on to develop a psychotic illness. However, little is known about the outcome of those who do not make the transition to psychosis. The aim of this paper was to examine clinical symptoms and functioning in the second North American Prodrome Longitudinal Study (NAPLS 2) of those individuals whose by the end of 2 years in the study had not developed psychosis.MethodsIn NAPLS-2 278 CHR participants completed 2-year follow-ups and had not made the transition to psychosis. At 2-years the sample was divided into three groups – those whose symptoms were in remission, those who were still symptomatic and those whose symptoms had become more severe.ResultsThere was no difference between those who remitted early in the study compared with those who remitted at one or 2 years. At 2-years, those in remission had fewer symptoms and improved functioning compared with the two symptomatic groups. However, all three groups had poorer social functioning and cognition than healthy controls.ConclusionsA detailed examination of the clinical and functional outcomes of those who did not make the transition to psychosis did not contribute to predicting who may make the transition or who may have an earlier remission of attenuated psychotic symptoms.

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Neural Correlates of Mentalizing in Individuals With Clinical High Risk for Schizophrenia: ALE Meta-Analysis

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.634015 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ksenija Vucurovic ◽

Stéphanie Caillies ◽

Arthur Kaladjian

Keyword(s):

High Risk ◽

Meta Analysis ◽

Mental States ◽

Neural Correlates ◽

Psychotic Symptoms ◽

Middle Temporal Gyrus ◽

Healthy Controls ◽

Clinical High Risk ◽

Temporoparietal Junction ◽

The Right

Psychotic disorder refers to a spectrum of disorders that have multiple etiologies, due to the complex interaction of biological and genetic vulnerability with familial and cultural factors. A clinical high risk (CHR) for schizophrenia is defined as the presence of brief, attenuated, or intermittent psychotic symptoms in non-schizophrenic individuals. The transition to schizophrenia appears significantly more frequent in this at-risk population than in the general population. Moreover, the ability to attribute mental states to others, known as mentalizing or theory of mind, and its neural correlates found in individuals with CHR are similar to those described in patients with schizophrenia. We have therefore explored neurofunctional correlates of mentalizing in individuals with CHR vs. healthy controls, in order to identify the differences in brain activation. A neural coordinate-based activation likelihood estimation meta-analysis of existing neuroimaging data revealed that three regions displayed decreased activation in individuals with CHR, compared with healthy controls: the right temporoparietal junction, the right middle temporal gyrus, and the left precuneus. These results, combined with those in the literature, further support the hypothesis that abnormal activation of posterior brain regions involved in mentalizing correlates with psychotic symptoms in help-seeking individuals.

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Faculty Opinions recommendation of Efficacy and Acceptability of Interventions for Attenuated Positive Psychotic Symptoms in Individuals at Clinical High Risk of Psychosis: A Network Meta-Analysis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.733520235.793567538 ◽

2019 ◽

Author(s):

Vijay Mittal

Keyword(s):

High Risk ◽

Meta Analysis ◽

Psychotic Symptoms ◽

Clinical High Risk

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What makes the psychosis ‘clinical high risk’ state risky: psychosis itself or the co-presence of a non-psychotic disorder?

Epidemiology and Psychiatric Sciences ◽

10.1017/s204579602100041x ◽

2021 ◽

Vol 30 ◽

Author(s):

Laila Hasmi ◽

Lotta-Katrin Pries ◽

Margreet ten Have ◽

Ron de Graaf ◽

Saskia van Dorsselaer ◽

...

Keyword(s):

High Risk ◽

Drug Use ◽

Psychotic Disorder ◽

Positive Family History ◽

Mental Health Service Use ◽

Psychotic Symptoms ◽

Polygenic Risk Score ◽

Clinical High Risk ◽

Drug Use Disorders ◽

Per Se

Abstract Aims Although attenuated psychotic symptoms in the psychosis clinical high-risk state (CHR-P) almost always occur in the context of a non-psychotic disorder (NPD), NPD is considered an undesired ‘comorbidity’ epiphenomenon rather than an integral part of CHR-P itself. Prospective work, however, indicates that much more of the clinical psychosis incidence is attributable to prior mood and drug use disorders than to psychosis clinical high-risk states per se. In order to examine this conundrum, we analysed to what degree the ‘risk’ in CHR-P is indexed by co-present NPD rather than attenuated psychosis per se. Methods We examined the incidence of early psychotic experiences (PE) with and without NPD (mood disorders, anxiety disorders, alcohol/drug use disorders), in a prospective general population cohort (n = 6123 at risk of incident PE at baseline). Four interview waves were conducted between 2007 and 2018 (NEMESIS-2). The incidence of PE, alone (PE-only) or with NPD (PE + NPD) was calculated, as were differential associations with schizophrenia polygenic risk score (PRS-Sz), environmental, demographical, clinical and cognitive factors. Results The incidence of PE + NPD (0.37%) was lower than the incidence of PE-only (1.04%), representing around a third of the total yearly incidence of PE. Incident PE + NPD was, in comparison with PE-only, differentially characterised by poor functioning, environmental risks, PRS-Sz, positive family history, prescription of antipsychotic medication and (mental) health service use. Conclusions The risk in ‘clinical high risk’ states is mediated not by attenuated psychosis per se but specifically the combination of attenuated psychosis and NPD. CHR-P/APS research should be reconceptualised from a focus on attenuated psychotic symptoms with exclusion of non-psychotic DSM-disorders, as the ‘pure' representation of a supposedly homotypic psychosis risk state, towards a focus on poor-outcome NPDs, characterised by a degree of psychosis admixture, on the pathway to psychotic disorder outcomes.

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