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 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 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 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

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 S64. COGNITIVE IMPAIRMENTS AND PREDICTION OF FUNCTIONAL OUTCOME IN INDIVIDUALS AT CLINICAL HIGH-RISK FOR PSYCHOSIS

2020 ◽  
Vol 46 (Supplement_1) ◽  
pp. S57-S58
Author(s):  
Kate Haining ◽  
Gina Brunner ◽  
Ruchika Gajwani ◽  
Joachim Gross ◽  
Andrew Gumley ◽  
...  
Keyword(s):  
Machine Learning ◽  
High Risk ◽  
Functional Outcome ◽  
Processing Speed ◽  
Cross Validation ◽  
Clinical High Risk ◽  
Role Functioning ◽  
Gaf Scores ◽  
Fold Cross Validation

Abstract Background Research in individuals at clinical-high risk for psychosis (CHR-P) has focused on developing algorithms to predict transition to psychosis. However, it is becoming increasingly important to address other outcomes, such as the level of functioning of CHR-P participants. To address this important question, this study investigated the relationship between baseline cognitive performance and functional outcome between 6–12 months in a sample of CHR-P individuals using a machine-learning approach to identify features that are predictive of long-term functional impairments. Methods Data was available for 111 CHR-P individuals at 6–12 months follow-up. In addition, 47 CHR-negative (CHR-N) participants who did not meet CHR criteria and 55 healthy controls (HCs) were recruited. CHR-P status was assessed using the Comprehensive Assessment of At-Risk Mental States (CAARMS) and the Schizophrenia Proneness Instrument, Adult version (SPI-A). Cognitive assessments included the Brief Assessment of Cognition in Schizophrenia (BACS) and the Penn Computerized Neurocognitive Battery (CNB). Global, social and role functioning scales were used to measure functional status. CHR-P individuals were divided into good functional outcome (GFO, GAF ≥ 65) and poor functional outcome groups (PFO, GAF &lt; 65). Feature selection was performed using LASSO regression with the LARS algorithm and 10-fold cross validation with GAF scores at baseline as the outcome variable. The following features were identified as predictors of GAF scores at baseline: verbal memory, verbal fluency, attention, emotion recognition, social and role functioning and SPI-A distress. This model explained 47% of the variance in baseline GAF scores. In the next step, Support Vector Machines (SVM), Linear Discriminant Analysis (LDA), Logistic Regression (LR), Gaussian Naïve Bayes (GNB), and Random Forest (RF) classifiers with 10-fold cross validation were then trained on those features with GAF category at follow-up used as the binary label column. Models were compared using a calculated score incorporating area under the curve (AUC), accuracy, and AUC consistency across runs, whereby AUC was given a higher weighting than accuracy due to class imbalance. Results CHR-P individuals had slower motor speed, reduced attention and processing speed and increased emotion recognition reaction times (RTs) compared to HCs and reduced attention and processing speed compared to CHR-Ns. At follow-up, 66% of CHR-P individuals had PFO. LDA emerged as the strongest classifier, showing a mean AUC of 0.75 (SD = 0.15), indicating acceptable classification performance for GAF category at follow-up. PFO was detected with a sensitivity of 75% and specificity of 58%, with a total mean weighted accuracy of 68%. Discussion The CHR-P state was associated with significant impairments in cognition, highlighting the importance of interventions such as cognitive remediation in this population. Our data suggest that the development of features using machine learning approaches is effective in predicting functional outcomes in CHR-P individuals. Greater levels of accuracy, sensitivity and specificity might be achieved by increasing training sets and validating the classifier with external data sets. Indeed, machine learning methods have potential given that trained classifiers can easily be shared online, thus enabling clinical professionals to make individualised predictions.

scholarly journals Glutathione as a molecular marker of functional impairment in patients with at-risk mental state: 7-Tesla 1H-MRS study

2020 ◽  
Author(s):  
Peter Jeon ◽  
Roberto Limongi ◽  
Sabrina D. Ford ◽  
Cassandra Branco ◽  
Michael Mackinley ◽  
...  
Keyword(s):  
High Risk ◽  
Magnetic Resonance ◽  
Magnetic Resonance Spectroscopy ◽  
Functional Outcomes ◽  
Risk Group ◽  
High Risk Group ◽  
7 Tesla ◽  
Resonance Spectroscopy ◽  
Clinical High Risk ◽  
Healthy Control

AbstractA substantial number of individuals with clinical high-risk (CHR) mental state do not transition to psychosis. However, regardless of future diagnostic trajectories, many of these individuals develop poor social and occupational functional outcomes. The levels of glutathione, a crucial cortical antioxidant, may track variations in functional outcomes in early psychosis and prodromal states.Thirteen clinical high-risk and 30 healthy control volunteers were recruited for a 7-Tesla magnetic resonance spectroscopy scan with voxel positioned within the dorsal anterior cingulate cortex (ACC). Clinical assessment scores were collected to determine if any association was observable with glutathione levels.Bayesian Spearman test revealed a positive association between the Social and Occupational Functioning Assessment Scale (SOFAS) and the glutathione concentration in the clinical high-risk group but not in the healthy control group. After accounting for variations in SOFAS, CHR group had higher GSH levels than the healthy subjects.This study is the first to use 7-Tesla magnetic resonance spectroscopy to test whether ACC glutathione levels related to social and occupational functioning in a clinically high-risk group and offers preliminary support for glutathione levels as a clinically actionable marker of prognosis in emerging adults presenting with risk features for various severe mental illnesses.

scholarly journals Unmet needs in patients with brief psychotic disorders: Too ill for clinical high risk services and not ill enough for first episode services

2019 ◽  
Vol 57 ◽  
pp. 26-32 ◽  
Author(s):  
Amedeo Minichino ◽  
Grazia Rutigliano ◽  
Sergio Merlino ◽  
Cathy Davies ◽  
Dominic Oliver ◽  
...  
Keyword(s):  
Mental Health ◽  
High Risk ◽  
Clinical Outcomes ◽  
Psychotic Disorders ◽  
Pathways To Care ◽  
First Episode ◽  
Clinical High Risk ◽  
Early Intervention Services

AbstractBackground:Patients with acute and transient psychotic disorders (ATPDs) are by definition remitting, but have a high risk of developing persistent psychoses, resembling a subgroup of individuals at Clinical High Risk for Psychosis (CHR-P). Their pathways to care, treatment offered and long-term clinical outcomes beyond risk to psychosis are unexplored. We conducted an electronic health record-based retrospective cohort study including patients with ATPDs within the SLaM NHS Trust and followed-up to 8 years.Methods:A total of 2561 ATPDs were included in the study. A minority were detected (8%) and treated (18%) by Early Intervention services (EIS) and none by CHR-P services. Patients were offered a clinical follow-up of 350.40 ± 589.90 days. The cumulative incidence of discharges was 40% at 3 months, 60% at 1 year, 69% at 2 years, 77% at 4 years, and 82% at 8 years. Treatment was heterogeneous: the majority of patients received antipsychotics (up to 52%), only a tiny minority psychotherapy (up to 8%).Results:Over follow-up, 32.88% and 28.54% of ATPDS received at least one mental health hospitalization or one compulsory hospital admission under the Mental Health Act, respectively. The mean number of days spent in psychiatric hospital was 66.39 ± 239.44 days.Conclusions:The majority of ATPDs are not detected/treated by EIS or CHR-P services, receive heterogeneous treatments and short-term clinical follow-up. ATPDs have a high risk of developing severe clinical outcomes beyond persistent psychotic disorders and unmet clinical needs that are not targeted by current mental health services.

scholarly journals Neural Autoantibodies in Cerebrospinal Fluid and Serum in Clinical High Risk for Psychosis, First-Episode Psychosis, and Healthy Volunteers

2021 ◽  
Vol 12 ◽  
Author(s):  
Christian G. Bien ◽  
Cathrin Rohleder ◽  
Juliane K. Mueller ◽  
Corinna I. Bien ◽  
Dagmar Koethe ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
High Risk ◽  
Magnetic Resonance ◽  
Healthy Volunteers ◽  
Serum Antibody ◽  
Mental Illnesses ◽  
First Episode ◽  
Clinical High Risk ◽  
Igg Antibodies ◽  
Resonance Imaging

The pathophysiological role of neural autoantibodies in acute psychotic disorders is receiving increased attention. However, there is still an ongoing debate, whether predominantly psychotic manifestations of autoimmune encephalitides exist that may remain undetected and, thus, untreated. Furthermore, it is discussed if such conditions can be diagnosed based on serum antibody results or if a reliable diagnosis requires additional cerebrospinal fluids (CSF) results. In this study, we screened pairs of serum and CSF samples from antipsychotic-naïve individuals with first-episode schizophrenic psychosis (FEP, n = 103), clinical high risk for psychosis (CHR, n = 47), and healthy volunteers (HV, n = 40) for eight different antibodies against various antigens that have been shown to be associated with autoimmune encephalitides: N-methyl-D-aspartate receptor (NMDAR, NR1 subunits only), glutamic acid decarboxylase (GAD65), leucine-rich glioma inactivated protein 1 (LGI1), contactin-associated protein-like 2 protein (CASPR2), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunit 1, AMPAR subunit 2, γ-aminobutyric acid-B receptors (GABABR), and glycine receptors. All patients were within the norm with regards to a careful neurological examination, a magnetic resonance imaging (MRI) of the brain, an electroencephalogram (EEG), and routine blood pathology. All CSF samples were autoantibody-negative. In three serum samples of individuals with FEP, we detected low-titer CASPR2 immunoglobulin (Ig) G antibodies (≤1:160, n = 2) and non-IgG antibodies against NMDAR (n = 1) (overall serum-autoantibody prevalence in FEP: 2.91%). However, the IgG titers were below the laboratory cut-off defined for positivity, and non-IgG antibodies are of no clinical relevance. This suggests that there were no cases of autoimmune encephalitis in our cohort. Our results highlight the importance and the high specificity of CSF analysis to reliably detect autoantibodies. They confirm the hypothesis that pure psychotic manifestations of antibody-associated autoimmune encephalitides without any additional neuropsychiatric findings are very rare. However, special attention must be paid to those presenting with atypical mental illnesses with additional neurological symptoms, evidence of clinically-significant cognitive involvement, profound sleep-wake perturbations, seizures, electroencephalographic, or magnetic resonance imaging pathologies to be able to identify cases with autoimmune-mediated psychiatric syndromes.

scholarly journals Glutathione as a Molecular Marker of Functional Impairment in Patients with At-Risk Mental State: 7-Tesla 1H-MRS Study

2021 ◽  
Vol 11 (7) ◽  
pp. 941
Author(s):  
Peter Jeon ◽  
Roberto Limongi ◽  
Sabrina D. Ford ◽  
Cassandra Branco ◽  
Michael Mackinley ◽  
...  
Keyword(s):  
High Risk ◽  
Magnetic Resonance ◽  
Magnetic Resonance Spectroscopy ◽  
Functional Outcomes ◽  
Risk Group ◽  
High Risk Group ◽  
7 Tesla ◽  
Resonance Spectroscopy ◽  
Clinical High Risk ◽  
Healthy Control

A substantial number of individuals with clinical high-risk (CHR) mental state do not transition to psychosis. However, regardless of future diagnostic trajectories, many of these individuals develop poor social and occupational functional outcomes. The levels of glutathione, a crucial cortical antioxidant, may track variations in functional outcomes in early psychosis and prodromal states. Thirteen clinical high-risk and 30 healthy control volunteers were recruited for a 7-Tesla magnetic resonance spectroscopy scan with a voxel positioned within the dorsal anterior cingulate cortex (ACC). Clinical assessment scores were collected to determine if any association was observable with glutathione levels. The Bayesian Spearman’s test revealed a positive association between the Social and Occupational Functioning Assessment Scale (SOFAS) and the glutathione concentration in the clinical high-risk group but not in the healthy control group. After accounting for variations in the SOFAS scores, the CHR group had higher GSH levels than the healthy subjects. This study is the first to use 7-Tesla magnetic resonance spectroscopy to test whether ACC glutathione levels relate to social and occupational functioning in a clinically high-risk group and offers preliminary support for glutathione levels as a clinically actionable marker of prognosis in emerging adults presenting with risk features for various severe mental illnesses.

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