scholarly journals Correction: Adverse clinical outcomes in people at clinical high-risk for psychosis related to altered interactions between hippocampal activity and glutamatergic function

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Paul Allen ◽  
Emily J. Hird ◽  
Natasza Orlov ◽  
Gemma Modinos ◽  
Matthijs Bossong ◽  
...  
Keyword(s):  
High Risk ◽  
Clinical Outcomes ◽  
Clinical High Risk ◽  
Hippocampal Activity

scholarly journals Adverse clinical outcomes in people at clinical high-risk for psychosis related to altered interactions between hippocampal activity and glutamatergic function

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Paul Allen ◽  
Emily J. Hird ◽  
Natasza Orlov ◽  
Gemma Modinos ◽  
Matthijs Bossong ◽  
...  
Keyword(s):  
High Risk ◽  
Magnetic Resonance ◽  
Healthy Volunteers ◽  
Functional Outcome ◽  
Clinical Outcomes ◽  
Resonance Spectroscopy ◽  
Clinical High Risk ◽  
Hippocampal Activity ◽  
High Risk Cohort

AbstractPreclinical 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.

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

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.

scholarly journals Adverse clinical outcomes in people at clinical high-risk for psychosis related to activity and glutamate function in the hippocampus

2021 ◽  
Author(s):  
Paul Allen ◽  
Emily J. Hird ◽  
Natasza Orlov ◽  
Gemma Modinos ◽  
Matthijs Bossong ◽  
...  
Keyword(s):  
High Risk ◽  
Magnetic Resonance ◽  
Healthy Volunteers ◽  
Functional Outcome ◽  
Clinical Outcomes ◽  
Resonance Spectroscopy ◽  
Clinical High Risk ◽  
Preclinical Models ◽  
Hippocampal Activity

AbstractPreclinical 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 <.001, t=5.52, z=4.81 and ppeakFWE <.001, t=5.25, z=4.62) were associated with a negative correlation between hippocampal activation and hippocampal Glx concentration at baseline. In addition, there was a negative association between hippocampal Glx concentration and hippocampo-striatal connectivity (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.

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

2021 ◽  
Author(s):  
Gemma Modinos ◽  
Anja Richter ◽  
Alice Egerton ◽  
Ilaria Bonoldi ◽  
Matilda Azis ◽  
...  
Keyword(s):  
High Risk ◽  
Functional Outcomes ◽  
Mental States ◽  
Adverse Outcomes ◽  
Striatal Dopamine ◽  
Psychotic Symptoms ◽  
Dopamine Synthesis ◽  
Clinical High Risk ◽  
Hippocampal Activity ◽  
The Relationship

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.

scholarly journals Relationship between jumping to conclusions and clinical outcomes in people at clinical high-risk for psychosis

2020 ◽  
pp. 1-9
Author(s):  
Ana Catalan ◽  
Stefania Tognin ◽  
Matthew J. Kempton ◽  
Daniel Stahl ◽  
Gonzalo Salazar de Pablo ◽  
...  
Keyword(s):  
High Risk ◽  
Clinical Outcomes ◽  
Cox Regression ◽  
Mental States ◽  
Clinical High Risk ◽  
Level Of Functioning ◽  
Jumping To Conclusions ◽  
Reasoning Bias ◽  
Beads Task

Abstract Background Psychosis is associated with a reasoning bias, which manifests as a tendency to ‘jump to conclusions’. We examined this bias in people at clinical high-risk for psychosis (CHR) and investigated its relationship with their clinical outcomes. Methods In total, 303 CHR subjects and 57 healthy controls (HC) were included. Both groups were assessed at baseline, and after 1 and 2 years. A ‘beads’ task was used to assess reasoning bias. Symptoms and level of functioning were assessed using the Comprehensive Assessment of At-Risk Mental States scale (CAARMS) and the Global Assessment of Functioning (GAF), respectively. During follow up, 58 (16.1%) of the CHR group developed psychosis (CHR-T), and 245 did not (CHR-NT). Logistic regressions, multilevel mixed models, and Cox regression were used to analyse the relationship between reasoning bias and transition to psychosis and level of functioning, at each time point. Results There was no association between reasoning bias at baseline and the subsequent onset of psychosis. However, when assessed after the transition to psychosis, CHR-T participants showed a greater tendency to jump to conclusions than CHR-NT and HC participants (55, 17, 17%; χ2 = 8.13, p = 0.012). There was a significant association between jumping to conclusions (JTC) at baseline and a reduced level of functioning at 2-year follow-up in the CHR group after adjusting for transition, gender, ethnicity, age, and IQ. Conclusions In CHR participants, JTC at baseline was associated with adverse functioning at the follow-up. Interventions designed to improve JTC could be beneficial in the CHR population.

scholarly journals Real-World Clinical Outcomes Two Years After Transition to Psychosis in Individuals at Clinical High Risk: Electronic Health Record Cohort Study

2020 ◽  
Vol 46 (5) ◽  
pp. 1114-1125 ◽  
Author(s):  
Paolo Fusar-Poli ◽  
Andrea De Micheli ◽  
Rashmi Patel ◽  
Lorenzo Signorini ◽  
Syed Miah ◽  
...  
Keyword(s):  
Cohort Study ◽  
High Risk ◽  
Electronic Health Record ◽  
Clinical Outcomes ◽  
Real World ◽  
First Episode ◽  
Cumulative Probability ◽  
Health Record ◽  
Clinical High Risk ◽  
Electronic Health

Abstract The objective of this study is to describe the 2-year real-world clinical outcomes after transition to psychosis in patients at clinical high-risk. The study used the clinical electronic health record cohort study including all patients receiving a first index primary diagnosis of nonorganic International Classification of Diseases (ICD)-10 psychotic disorder within the early psychosis pathway in the South London and Maudsley (SLaM) National Health Service (NHS) Trust from 2001 to 2017. Outcomes encompassed: cumulative probability (at 3, 6, 12, and 24 months) of receiving a first (1) treatment with antipsychotic, (2) informal admission, (3) compulsory admission, and (4) treatment with clozapine and (5) numbers of days spent in hospital (at 12 and 24 months) in patients transitioning to psychosis from clinical high-risk services (Outreach and Support in south London; OASIS) compared to other first-episode groups. Analyses included logistic and 0-inflated negative binomial regressions. In the study, 1561 patients were included; those who had initially been managed by OASIS and had subsequently transitioned to a first episode of psychosis (n = 130) were more likely to receive antipsychotic medication (at 3, 6, and 24 months; all P &lt; .023), to be admitted informally (at all timepoints, all P &lt; .004) and on a compulsory basis (at all timepoints, all P &lt; .013), and to have spent more time in hospital (all timepoints, all P &lt; .007) than first-episode patients who were already psychotic when seen by the OASIS service (n = 310), or presented to early intervention services (n = 1121). The likelihood of receiving clozapine was similar across all groups (at 12/24 months, all P &lt; .101). Transition to psychosis from a clinical high-risk state is associated with severe real-world clinical outcomes. Prevention of transition to psychosis should remain a core target of future research. The study protocol was registered on www.researchregistry.com; researchregistry5039).

scholarly journals 40 Hz Auditory Steady-State Responses Predict Clinical Outcomes in Clinical-High-Risk Participants: A MEG Study

2020 ◽  
Author(s):  
Tineke Grent-‘t-Jong ◽  
Ruchika Gajwani ◽  
Joachim Gross ◽  
Andrew I. Gumley ◽  
Rajeev Krishnadas ◽  
...  
Keyword(s):  
Steady State ◽  
High Risk ◽  
Clinical Outcomes ◽  
Classification Accuracy ◽  
Clinical High Risk ◽  
Potential Biomarker ◽  
Steady State Responses ◽  
Auditory Steady State Responses ◽  
State Responses ◽  
40 Hz

AbstractObjectiveTo examine whether 40-Hz Auditory Steady-State Responses (ASSRs) are impaired in participants at clinical high-risk for psychosis (CHR-P) and predict clinical outcomes.MethodMagnetoencephalography data were collected during a 40-Hz ASSR paradigm for a group of 116 CHR-P participants, 33 first-episode-psychosis patients (FEP, 15 antipsychotic-naïve), a psychosis-risk-negative group (CHR-N: n=38) and 49 healthy controls. Analysis of group differences of 40-Hz Inter-trial-phase-coherence (ITPC) and 40-Hz amplitude focused on right Heschl’s gyrus [RHES], superior temporal gyrus, hippocampus [RHIP], and thalamus [RTHA], after establishing significant activations during 40-Hz stimulation. Linear regression and linear discriminant analyses (LDA) were used to predict clinical outcomes, including transition to psychosis and persistence of attenuated psychotic symptoms (APS) in CHR-Ps.ResultsCHR-P and FEP-patients were impaired in 40-Hz amplitude in RTHA and RHIP. In addition, FEP-patients were impaired in 40-Hz amplitude in RHES and CHR-Ps in 40-Hz ITPC in RHES. 40-Hz ASSR deficits were pronounced in CHR-Ps who later transitioned to psychosis (n=13) or showed persistent APS (n=40). Importantly, both APS-persistence and transition to psychosis were predicted by 40-Hz ASSR impairments. Classification accuracy was 73.7% for non-persistent-APS and 72.5% for persistent-APS group (Area under the curve (AUC)=0.842). For transition risk to psychosis, classification accuracy was 76.7% and 53.8% for non-transitioned and transitioned CHR-P participants, respectively (AUC=0.810).ConclusionsOur data indicate that deficits in gamma entrainment in primary auditory cortex and subcortical areas constitute a potential biomarker for predicting clinical outcomes in CHR-P participants.

scholarly journals M163. GLUTAMATE METABOLITES ARE ASSOCIATED WITH ALTERED HIPPOCAMPAL ACTIVATION BUT NOT HIPPOCAMPAL-STRIATAL CONNECTIVITY IN SUBJECTS WITH A CLINICAL HIGH RISK FOR PSYCHOSIS

2020 ◽  
Vol 46 (Supplement_1) ◽  
pp. S198-S198
Author(s):  
Emily Hird ◽  
Paul Allen ◽  
Natasza Orlov ◽  
Gemma Modinos ◽  
Matthijs Bossong ◽  
...  
Keyword(s):  
High Risk ◽  
Magnetic Resonance ◽  
Negative Relationship ◽  
Region Of Interest ◽  
First Episode ◽  
Resonance Spectroscopy ◽  
Clinical High Risk ◽  
Hippocampal Activity ◽  
Potential Biomarker ◽  
Psychophysiological Interaction

Abstract 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

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