Integrated metastate functional connectivity networks predict change in symptom severity in clinical high risk for psychosis.

The ability to identify biomarkers of psychosis risk is essential in defining effective preventive measures to potentially circumvent the transition to psychosis. Using samples of people at clinical high risk for psychosis (CHR) and Healthy controls (HC) who were administered a task fMRI paradigm, we used a framework for labelling time windows of fMRI scans as 'integrated' FC networks to provide a granular representation of functional connectivity (FC). Periods of integration were defined using the 'cartographic profile' of time windows and k-means clustering, and sub-network discovery was carried out using Network Based Statistics (NBS). There were no network differences between CHR and HC groups. Within the CHR group, using integrated FC networks, we identified a sub-network negatively associated with longitudinal changes in the severity of psychotic symptoms. This sub-network comprised brain areas implicated in bottom-up sensory processing and in integration with motor control, suggesting it may be related to the demands of the fMRI task. These data suggest that extracting integrated FC networks may be useful in the investigation of biomarkers of psychosis risk.

An initial investigation of abnormal bodily phenomena in subjects at ultra high risk for psychosis: Their prevalence and clinical implications.

BACKGROUND: Contemporary phenomenological research has considered abnormal bodily phenomena (ABP) to be a phenotypic trait of subjects with schizophrenia in their first psychotic episode. Yet the prevalence of ABP and their clinical significance in subjects at Ultra High Risk (UHR) of psychosis remain unidentified. This study is an exploratory investigation of ABP in UHR subjects and matched healthy controls (HCs) examining their relation to clinical features and basic self-disturbances. METHODS: A sample of 26 UHR and 14 HC subjects from three prodromal and early intervention clinics in South London, West London and Cambridge was assessed with the Abnormal Bodily Phenomena questionnaire (ABPq), Comprehensive Assessment of At-Risk Mental States (CAARMS), the Positive and Negative Syndrome Scale (PANSS), the Social and Occupational Functioning Assessment Scale (SOFAS) and the Examination of Anomalous Self Experiences (EASE) checklist. RESULTS: In our sample ABP occurred in 73.1% of UHR subjects and prominent ABP (proABP) were referred in 53.8% of them. No HC subject reported ABP. The UHR group with proABP had lower CAARMS total score (t=-9.265, p=0.006). There were no differences in PANSS total score (t=-1.235, p=0.277), SOFAS score (H(2) 22.27, p=0.666) and EASE total scores (z=8.565, adjusted p=0.185) in the UHR subjects with prominent ABP versus those that did not. DISCUSSION: This initial investigation suggests that ABP could be a prevalent phenotypic feature of UHR subjects.

Neural Circuitry of Novelty Salience Processing in Psychosis Risk: Association With Clinical Outcome.

Psychosis has been proposed to develop from dysfunction in a hippocampal-striatal-midbrain circuit, leading to aberrant salience processing. Here, we used functional magnetic resonance imaging (fMRI) during novelty salience processing to investigate this model in people at clinical high risk (CHR) for psychosis according to their subsequent clinical outcomes. Seventy-six CHR participants as defined using the Comprehensive Assessment of At-Risk Mental States (CAARMS) and 31 healthy controls (HC) were studied while performing a novelty salience fMRI task that engaged an a priori hippocampal-striatal-midbrain circuit of interest. The CHR sample was then followed clinically for a mean of 59.7 months (~5 y), when clinical outcomes were assessed in terms of transition (CHR-T) or non-transition (CHR-NT) to psychosis (CAARMS criteria): during this period, 13 individuals (17%) developed a psychotic disorder (CHR-T) and 63 did not. Functional activation and effective connectivity within a hippocampal-striatal-midbrain circuit were compared between groups. In CHR individuals compared to HC, hippocampal response to novel stimuli was significantly attenuated (P = .041 family-wise error corrected). Dynamic Causal Modelling revealed that stimulus novelty modulated effective connectivity from the hippocampus to the striatum, and from the midbrain to the hippocampus, significantly more in CHR participants than in HC. Conversely, stimulus novelty modulated connectivity from the midbrain to the striatum significantly less in CHR participants than in HC, and less in CHR participants who subsequently developed psychosis than in CHR individuals who did not become psychotic. Our findings are consistent with preclinical evidence implicating hippocampal-striatal-midbrain circuit dysfunction in altered salience processing and the onset of psychosis.

Association of Hippocampal Glutamate Levels With Adverse Outcomes in Individuals at Clinical High Risk for Psychosis.

Importance: Preclinical 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. Objective: To examine the association between hippocampal glutamate levels in individuals at clinical high risk for psychosis and their subsequent clinical outcomes. Design, Setting, and Participants: This 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 Measures: Concentrations 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. Results: Of 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 (ß = 0.48; odds ratio = 1.61; 95% CI, 1.00-2.59; P = .05) and overall functioning (ß = 0.53; odds ratio = 1.71; 95% CI, 1.10-2.66; P = .02). Conclusions and Relevance: The 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.

Basic Self-Disturbances Related to Reduced Anterior Cingulate Volume in Subjects at Ultra-High Risk for Psychosis.

Introduction: Alterations of the "pre-reflective" sense of first-person perspective (e.g., of the "basic self") are characteristic features of schizophrenic spectrum disorders and are significantly present in the prodromal phase of psychosis and in subjects at ultra-high risk for psychosis (UHR). Studies in healthy controls suggest that neurobiological substrate of the basic self involves cortical midline structures, such as the anterior and posterior cingulate cortices. Neuroimaging studies have identified neuroanatomical cortical midline structure abnormalities in schizophrenic spectrum disorders. Objectives: i) To compare basic self-disturbances levels in UHR subjects and controls and ii) to assess the relationship between basic self-disturbances and alterations in cortical midline structures volume in UHR subjects. Methods: Thirty-one UHR subjects (27 antipsychotic-naïve) and 16 healthy controls were assessed using the 57-item semistructured Examination of Anomalous Self-Experiences (EASE) interview. All subjects were scanned using magnetic resonance imaging (MRI) at 3 T, and gray matter volume was measured in a priori defined regions of interest (ROIs) in the cortical midline structures. Results: EASE scores were much higher in UHR subjects than controls (p < 0.001). The UHR group had smaller anterior cingulate volume than controls (p = 0.037). There were no structural brain imaging alterations between UHR individuals with or without self-disturbances. Within the UHR sample, the subgroup with higher EASE scores had smaller anterior cingulate volumes than UHR subjects with lower EASE scores and controls (p = 0.018). In the total sample, anterior cingulate volume was inversely correlated with the EASE score (R = 0.52, p < 0.016). Conclusions: Basic self-disturbances in UHR subjects appear to be related to reductions in anterior cingulate volume.

Correction: Prefrontal GABA levels, hippocampal resting perfusion and the risk of psychosis.

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Prefrontal GABA levels, hippocampal resting perfusion and the risk of psychosis.

Preclinical models propose that the onset of psychosis is associated with hippocampal hyperactivity, thought to be driven by cortical GABAergic interneuron dysfunction and disinhibition of pyramidal neurons. Recent neuroimaging studies suggest that resting hippocampal perfusion is increased in subjects at ultra-high risk (UHR) for psychosis, but how this may be related to GABA concentrations is unknown. The present study used a multimodal neuroimaging approach to address this issue in UHR subjects. Proton magnetic resonance spectroscopy and pulsed-continuous arterial spin labeling imaging were acquired to investigate the relationship between medial prefrontal (MPFC) GABA+ levels (including some contribution from macromolecules) and hippocampal regional cerebral blood flow (rCBF) in 36 individuals at UHR of psychosis, based on preclinical evidence that MPFC dysfunction is involved in hippocampal hyperactivity. The subjects were then clinically monitored for 2 years: during this period, 7 developed a psychotic disorder and 29 did not. At baseline, MPFC GABA+ levels were positively correlated with rCBF in the left hippocampus (region of interest analysis, p = 0.044 family-wise error corrected, FWE). This correlation in the left hippocampus was significantly different in UHR subjects who went on to develop psychosis relative to those who did not (p = 0.022 FWE), suggesting the absence of a correlation in the latter subgroup. These findings provide the first human evidence that MPFC GABA+ concentrations are related to resting hippocampal perfusion in the UHR state, and offer some support for a link between GABA levels and hippocampal function in the development of psychosis.

Increased Resting Hippocampal and Basal Ganglia Perfusion in People at Ultra High Risk for Psychosis: Replication in a Second Cohort.

We recently reported that resting hippocampal, basal ganglia and midbrain perfusion is elevated in people at ultra high risk (UHR) for psychosis. The present study sought to replicate our previous finding in an independent UHR cohort, and examined the relationship between resting perfusion in these regions, psychosis and depression symptoms, and traumatic experiences in childhood. Pseudo-Continuous Arterial Spin Labelling (p-CASL) imaging was used to measure resting cerebral blood flow (rCBF) in 77 UHR for psychosis individuals and 25 healthy volunteers in a case-control design. UHR participants were recruited from clinical early detection services at 3 sites in the South of England. Symptoms levels were assessed using the Comprehensive Assessment of At Risk Mental States (CAARMS), the Hamilton Depression Scale (HAM-D), and childhood trauma was assessed retrospectively using the Childhood Trauma Questionnaire (CTQ). Right hippocampal and basal ganglia rCBF were significantly increased in UHR subjects compared to controls, partially replicating our previous finding in an independent cohort. In UHR participants, positive symptoms were positively correlated with rCBF in the right pallidum. CTQ scores were positively correlated with rCBF values in the bilateral hippocampus and negatively associated with rCBF in the left prefrontal cortex. Elevated resting hippocampal and basal ganglia activity appears to be a consistent finding in individuals at high risk for psychosis, consistent with data from preclinical models of the disorder. The association with childhood trauma suggests that its influence on the risk of psychosis may be mediated through an effect on hippocampal function.

Corticolimbic dysfunction during facial and prosodic emotional recognition in first-episode psychosis patients and individuals at ultra-high risk.

Emotional processing dysfunction is widely reported in patients with chronic schizophrenia and first-episode psychosis (FEP), and has been linked to functional abnormalities of corticolimbic regions. However, corticolimbic dysfunction is less studied in people at ultra-high risk for psychosis (UHR), particularly during processing prosodic voices. We examined corticolimbic response during an emotion recognition task in 18 UHR participants and compared them with 18 FEP patients and 21 healthy controls (HC). Emotional recognition accuracy and corticolimbic response were measured during functional magnetic resonance imaging (fMRI) using emotional dynamic facial and prosodic voice stimuli. Relative to HC, both UHR and FEP groups showed impaired overall emotion recognition accuracy. Whilst during face trials, both UHR and FEP groups did not show significant differences in brain activation relative to HC, during voice trials, FEP patients showed reduced activation across corticolimbic networks including the amygdala. UHR participants showed a trend for increased response in the caudate nucleus during the processing of emotionally valenced prosodic voices relative to HC. The results indicate that corticolimbic dysfunction seen in FEP patients is also present, albeit to a lesser extent, in an UHR cohort, and may represent a neural substrate for emotional processing difficulties prior to the onset of florid psychosis.

Prevalence and implications of Truman symptoms in subjects at ultra high risk for psychosis.

Preliminary qualitative research has suggested that patients with early stages of psychosis and those at Ultra High Risk (UHR) may experience "Truman symptoms" (TS). This study is an exploratory investigation of TS in a sample of 26 UHR subjects and 14 matched controls (HC) recruited from three prodromal and early intervention clinics and its relation with clinical features, depersonalization and basic self-disturbances. The UHR were assessed with the Comprehensive Assessment of At-Risk Mental States (CAARMS), Social and Occupational Functioning Assessment Scale (SOFAS), the Positive and Negative Syndrome Scale (PANSS), the Cambridge Depersonalization Scale (CDS) and the Examination of Anomalous Self Experiences (EASE) checklist. In our sample, TS were specific (TS absent in HC) and highly prevalent (50%) in UHR subjects. We found a significant difference in EASE total scores across HC, UHR with TS and without TS but post-hoc analyses showed similar scores in the two latter groups. The presence of TS in our UHR sample was associated with significant higher PANSS general psychopathology but with non-significant difference in the CAARMS, CDS and SOFAS scores. This study of TS in UHR subjects suggested that they might be prevalent and specific of this population.

Neural correlates of aberrant emotional salience predict psychotic symptoms and global functioning in high-risk and first-episode psychosis.

Neurobiological and behavioral findings suggest that psychosis is associated with corticolimbic hyperactivity during the processing of emotional salience. This has not been widely studied in the early stages of psychosis, and the impact of these abnormalities on psychotic symptoms and global functioning is unknown. We sought to address this issue in 18 patients with first-episode psychosis (FEP), 18 individuals at ultra high risk of psychosis (UHR) and 22 healthy controls (HCs). Corticolimbic response and subjective ratings to emotional and neutral scenes were measured using functional magnetic resonance imaging. The clinical and functional impact of corticolimbic abnormalities was assessed with regression analyses. The FEP and UHR groups reported increased subjective emotional arousal to neutral scenes compared with HCs. Across groups, emotional vs neutral scenes elicited activation in the dorsomedial prefrontal cortex, inferior frontal gyrus/anterior insula and amygdala. Although FEP and UHR participants showed reduced activation in these regions when viewing emotional scenes compared with controls, this was driven by increased activation to neutral scenes. Corticolimbic hyperactivity to neutral scenes predicted higher levels of positive symptoms and poorer levels of functioning. These results indicate that disruption of emotional brain systems may represent an important biological substrate for the pathophysiology of early psychosis and UHR states.