Clinical High Risk Participants Research Articles

Cognitive functions following initiation of antipsychotic medication in adolescents and adults at clinical high risk for psychosis: a naturalistic sub group analysis using the MATRICS consensus cognitive battery

BackgroundThe effects of antipsychotic (AP) medications on cognitive functions in individuals at clinical high-risk (CHR) of psychosis are poorly understood. This study compared the effects of AP treatment on cognitive improvement in CHR adolescents and adults.MethodsA total of 327 CHR participants, with an age range of 13 to 45 years, who underwent baseline neuropsychological assessments and a 1-year clinical follow-up were included. Participants with CHR were categorized into four groups based on their age: adolescents (aged < 18) and adults (aged ≥ 18), as well as their antipsychotic medication status (AP+ or AP−). Therefore, the four groups were defined as Adolescent-AP−, Adolescent-AP+, Adult-AP−, and Adult-AP+.ResultsDuring the follow-up, 231 CHR patients received AP treatment, 94 converted to psychosis, and 161 completed the 1-year follow-up. The Adolescent-AP+ group had more positive symptoms, lower general functions, and cognitive impairments than the Adolescent-AP− group at baseline, but no significant differences were observed among adults. The Adolescent-AP+ group showed a significant increase in the risk of conversion to psychosis (p < 0.001) compared to the Adolescent-AP− group. The Adult-AP+ group showed a decreasing trend in the risk of conversion (p = 0.088) compared to the Adult-AP− group. The Adolescent-AP− group had greater improvement in general functions (p < 0.001), neuropsychological assessment battery mazes (p = 0.025), and brief visuospatial memory test-revised (p = 0.020), as well as a greater decrease in positive symptoms (p < 0.001) at follow-up compared to the Adolescent-AP+ group. No significant differences were observed among adults.ConclusionsEarly use of AP was not associated with a positive effect on cognitive function in CHR adolescents. Instead, the absence of AP treatment was associated with better cognitive recovery, suggesting that AP exposure might not be the preferred choice for cognitive recovery in CHR adolescents, but may be more reasonable for use in adults.

Negative self‐reference as a component of subthreshold psychotic symptoms in clinical high‐risk youth

AbstractAimSchizophrenia is a leading cause of disability worldwide; early detection and intervention are critical. Early in their illness, individuals at clinical high‐risk (CHR) for psychosis have subthreshold psychotic symptoms that are often derogatory and self‐directed. We hypothesized that CHR participants with negative self‐reference (NSR) as a component of subthreshold psychosis would also have higher levels of social anxiety and depression, lower self‐esteem and lower social/role/global functioning as compared with CHR participants without NSR.MethodsOne hundred and sixty‐eight participants from the National Institute of Mental Health (NIMH) funded Regroup Cognitive Behavioural Social Skills Training (CBSST) study were included. Clinical vignettes that included the Scale of Psychosis‐Risk Symptoms were coded categorically to indicate whether NSR was present. t‐tests were used to determine the association between NSR, symptom, and functional measures.ResultsParticipants with NSR demonstrated significantly more social interaction anxiety (p &lt; .001), negative beliefs about the self (p ≤ .001), defeatist beliefs (p &lt; .05), depressive symptoms (p &lt; .05) and positive symptoms (p &lt; .005). There were no significant differences in social self‐efficacy, positive or negative beliefs about others, positive beliefs about the self or psychosocial functioning between the two groups.ConclusionsClinically significant differences were found between CHR participants with and without NSR, suggesting that this may be a useful factor to identify and address. Follow‐up studies are needed to determine whether NSR responds to CBSST and whether or not its resolution would be associated with improvement in other symptom domains.

Eye Movement Characteristics for Predicting a Transition to Psychosis: Longitudinal Changes and Implications.

Substantive inquiry into the predictive power of eye movement (EM) features for clinical high-risk (CHR) conversion and their longitudinal trajectories is currently sparse. This study aimed to investigate the efficiency of machine learning predictive models relying on EM indices and examine the longitudinal alterations of these indices across the temporal continuum. EM assessments (fixation stability, free-viewing, and smooth pursuit tasks) were performed on 140 CHR and 98 healthy control participants at baseline, followed by a 1-year longitudinal observational study. We adopted Cox regression analysis and constructed random forest prediction models. We also employed linear mixed-effects models (LMMs) to analyze longitudinal changes of indices while stratifying by group and time. Of the 123 CHR participants who underwent a 1-year clinical follow-up, 25 progressed to full-blown psychosis, while 98 remained non-converters. Compared with the non-converters, the converters exhibited prolonged fixation durations, decreased saccade amplitudes during the free-viewing task; larger saccades, and reduced velocity gain during the smooth pursuit task. Furthermore, based on 4 baseline EM measures, a random forest model classified converters and non-converters with an accuracy of 0.776 (95% CI: 0.633, 0.882). Finally, LMMs demonstrated no significant longitudinal alterations in the aforementioned indices among converters after 1 year. Aberrant EMs may precede psychosis onset and remain stable after 1 year, and applying eye-tracking technology combined with a modeling approach could potentially aid in predicting CHRs evolution into overt psychosis.

Proteomic Biomarkers for the Prediction of Transition to Psychosis in Individuals at Clinical High Risk: A Multi-cohort Model Development Study.

Psychosis risk prediction is one of the leading challenges in psychiatry. Previous investigations have suggested that plasma proteomic data may be useful in accurately predicting transition to psychosis in individuals at clinical high risk (CHR). We hypothesized that an a priori-specified proteomic prediction model would have strong predictive accuracy for psychosis risk and aimed to replicate longitudinal associations between plasma proteins and transition to psychosis. This study used plasma samples from participants in 3 CHR cohorts: the North American Prodrome Longitudinal Studies 2 and 3, and the NEURAPRO randomized control trial (total n = 754). Plasma proteomic data were quantified using mass spectrometry. The primary outcome was transition to psychosis over the study follow-up period. Logistic regression models were internally validated, and optimism-corrected performance metrics derived with a bootstrap procedure. In the overall sample of CHR participants (age: 18.5, SD: 3.9; 51.9% male), 20.4% (n = 154) developed psychosis within 4.4 years. The a priori-specified model showed poor risk-prediction accuracy for the development of psychosis (C-statistic: 0.51 [95% CI: 0.50, 0.59], calibration slope: 0.45). At a group level, Complement C8B, C4B, C5, and leucine-rich α-2 glycoprotein 1 (LRG1) were associated with transition to psychosis but did not surpass correction for multiple comparisons. This study did not confirm the findings from a previous proteomic prediction model of transition from CHR to psychosis. Certain complement proteins may be weakly associated with transition at a group level. Previous findings, derived from small samples, should be interpreted with caution.

The temporal association between social isolation, distress, and psychotic experiences in individuals at clinical high-risk for psychosis.

Psychotic experiences (PEs) and social isolation (SI) seem related during early stages of psychosis, but the temporal dynamics between the two are not clear. Literature so far suggests a self-perpetuating cycle wherein momentary increases in PEs lead to social withdrawal, which, subsequently, triggers PEs at a next point in time, especially when SI is associated with increased distress. The current study investigated the daily-life temporal associations between SI and PEs, as well as the role of SI-related and general affective distress in individuals at clinical high risk (CHR) for psychosis. We used experience sampling methodology in a sample of 137 CHR participants. We analyzed the association between SI, PEs, and distress using time-lagged linear mixed-effects models. SI did not predict next-moment fluctuations in PEs, or vice versa. Furthermore, although SI-related distress was not predictive of subsequent PEs, general affective distress during SI was a robust predictor of next-moment PEs. Our results suggest that SI and PEs are not directly related on a moment-to-moment level, but a negative emotional state when alone does contribute to the risk of PEs. These findings highlight the role of affective wellbeing during early-stage psychosis development.

A mixed-methods study to evaluate the feasibility and preliminary efficacy of delivering the optimal health program (OHP) for youth at clinical high risk (CHR) for psychosis: A study protocol.

Individuals with clinical high risk (CHR) for psychosis experience significant distress, impaired general functioning and a high lifetime risk of self-harm and attempted suicide. The CHR period is an important phase in an individual's mental health where appropriate interventions may reduce the risk of progression to several negative outcomes, including the development of schizophrenia. Given that up to 80% of individuals with CHR have another diagnosable mental illness and almost half experience poor psychosocial functioning, developing interventions that address psychosocial functioning in young people with CHR is of great importance. This mixed-methods study aims to employ qualitative and quantitative methods to adapt an evidence-based comprehensive psychosocial and mental health self-efficacy program, the Optimal Health Program (OHP), and evaluate the feasibility, acceptability and preliminary clinical efficacy in young people with CHR. We aim to recruit 30 CHR participants (age 16-29 years) in a single-arm 12-week exploratory clinical trial. Feasibility metrics will include recruitment, retention, and data completion rates. Acceptability will be informed by the Client Satisfaction Questionnaire. Clinical assessments (psychosis spectrum symptoms, depression, and anxiety), functional measures, and cognitive outcomes will be completed at study entry and repeated post-intervention at 12-weeks. We will run pre-post test data analysis to examine changes following engagement in the OHP intervention. Qualitative interviews will be conducted post-intervention to further evaluate the acceptability of the intervention and the trial design, and will be analyzed using thematic analysis. OHP may enhance the long-term mental health, well-being and functioning of CHR youth. However, the intervention must first be adapted to a CHR population; then, the feasibility and preliminary efficacy of delivering an intervention tailored around the varied needs of the CHR group must be established before a larger-scale appropriately powered study is pursued. Trial registration: The trial is registered with ClinicalTrials.gov NCT05757128.

Clinical high risk for psychosis syndrome is associated with reduced neural responding to unpleasant images.

Deficits in emotion processing are core features of psychotic disorders. Electrophysiology research in schizophrenia suggests deficits in sustained engagement with emotional content (indexed by the late positive potential [LPP]) may contribute to emotion processing impairments. Despite similar behavioral emotion processing dysfunction in those at clinical high risk (CHR) for psychosis, limited research has examined neural mechanisms of impaired emotion processing in the high-risk period, where research can inform risk models. To examine mechanisms of emotion processing deficits in those at CHR for psychosis, the present study used a passive viewing task to elicit the LPP in response to emotionally engaging and neutral stimuli in 28 CHR and 32 control participants (60% female). Relative to controls, CHR participants showed reduced LPP amplitude when viewing unpleasant images (d = 0.75, p = .005) but similar LPP amplitude in response to both neutral (d = 0.35, p = .19) and pleasant images (d = 0.31, p = .24). This pattern suggests that individuals at CHR for psychosis exhibit a deficit in sustained engagement with unpleasant stimuli. Clinical and trait questionnaires were administered to examine potential exploratory explanations for group differences in LPP amplitude. Consistent with evidence suggesting LPP amplitude reflects engagement of approach/avoidance motivational systems, greater LPP amplitude was associated with greater trait-level behavioral avoidance in control participants (r = .42, p = .032) but not CHR participants (r = -.21, p = .40). Together, the present research is consistent with LPP studies in psychosis and implicates reduced sustained engagement with emotional content in the high-risk period. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Speech characteristics yield important clues about motor function: Speech variability in individuals at clinical high-risk for psychosis

Background and hypothesis: Motor abnormalities are predictive of psychosis onset in individuals at clinical high risk (CHR) for psychosis and are tied to its progression. We hypothesize that these motor abnormalities also disrupt their speech production (a highly complex motor behavior) and predict CHR individuals will produce more variable speech than healthy controls, and that this variability will relate to symptom severity, motor measures, and psychosis-risk calculator risk scores. Study design: We measure variability in speech production (variability in consonants, vowels, speech rate, and pausing/timing) in N = 58 CHR participants and N = 67 healthy controls. Three different tasks are used to elicit speech: diadochokinetic speech (rapidly-repeated syllables e.g., papapa…, pataka…), read speech, and spontaneously-generated speech. Study results: Individuals in the CHR group produced more variable consonants and exhibited greater speech rate variability than healthy controls in two of the three speech tasks (diadochokinetic and read speech). While there were no significant correlations between speech measures and remotely-obtained motor measures, symptom severity, or conversion risk scores, these comparisons may be under-powered (in part due to challenges of remote data collection during the COVID-19 pandemic). Conclusion: This study provides a thorough and theory-driven first look at how speech production is affected in this at-risk population and speaks to the promise and challenges facing this approach moving forward.

Functional connectivity in people at clinical and familial high risk for schizophrenia

Patients diagnosed with schizophrenia (SZ) exhibit compromised functional connectivity within extensive brain networks. However, the precise development of this impairment during disease progression in the clinical high-risk (CHR) population and their relatives remains unclear. Our study leveraged data from 128 resting electroencephalography (EEG) channels acquired from 30 SZ patients, 21 CHR individuals, 17 unaffected healthy relatives (RSs; those at heightened SZ risk due to family history), and 31 healthy controls (HCs). These data were harnessed to establish functional connectivity patterns. By calculating the geometric distance between EEG sequences, we unveiled local and global nonlinear relationships within the entire brain. The process of dimensionality reduction led to low-dimensional representations, providing insights into high-dimensional EEG data. Our findings indicated that CHR participants exhibited aberrant functional connectivity across hemispheres, whereas RS individuals showcased anomalies primarily concentrated within hemispheres. In the realm of low-dimensional analysis, RS participants' third-dimensional occipital lobe values lay between those of the CHR individuals and HCs, significantly correlating with scale scores. This low-dimensional approach facilitated the visualization of brain states, potentially offering enhanced comprehension of brain structure, function, and early-stage functional impairment, such as occipital visual deficits, in RS individuals before cognitive decline onset.

Differential Expression of Anomalous Self-Experiences in Spontaneous Speech in Clinical High-Risk and Early-Course Psychosis Quantified by Natural Language Processing

BackgroundBasic self-disturbance, or anomalous self-experiences (ASEs), is a core feature of the schizophrenia spectrum. We propose a novel method of natural language processing to quantify ASEs in spoken language by direct comparison to an inventory of self-disturbance, the Inventory of Psychotic-Like Anomalous Self-Experiences (IPASE). We hypothesized that there would be increased similarity in open-ended speech to the IPASE items in individuals with early-course psychosis (PSY) compared with healthy individuals, with clinical high-risk (CHR) individuals intermediate in similarity. MethodsOpen-ended interviews were obtained from 170 healthy control participants, 167 CHR participants, and 89 PSY participants. We calculated the semantic similarity between IPASE items and “I” sentences from transcribed speech samples using S-BERT (Sentence Bidirectional Encoder Representation from Text). Kolmogorov-Smirnov tests were used to compare distributions across groups. A nonnegative matrix factorization of cosine similarity was performed to rank IPASE items. ResultsSpoken language of CHR individuals had the greatest semantic similarity to IPASE items when compared to both healthy control (s = 0.44, p < 10−14) and PSY (s = 0.36, p < 10−6) individuals, while IPASE scores were higher among PSY than CHR group participants. In addition, the nonnegative matrix factorization approach produced a data-driven domain that differentiated the CHR group from the others. ConclusionsWe found that open-ended interviews elicited language with increased semantic similarity to the IPASE by participants in the CHR group compared with patients with psychosis. This demonstrates the utility of these methods for differentiating patients from healthy control participants. This complementary approach has the capacity to scale to large studies investigating phenomenological features of schizophrenia and potentially other clinical populations.

Serum Levels of Tumor Necrosis Factor-α and Vascular Endothelial Growth Factor in the Subtypes of Clinical High Risk Individuals: A Prospective Cohort Study.

Numerous studies have established the roles of inflammation and angioneurins in the pathogenesis of schizophrenia (SCZ). This study aimed to compare the serum levels of tumour necrosis factor (TNF)-α and vascular endothelial growth factor (VEGF) in patients at clinical high risk (CHR) for psychosis or SCZ at baseline and one year after treatment. A total of 289 CHR participants from the Shanghai At Risk for Psychosis Extended Program (SHARP) were tracked for a year. They were divided into two and four subtypes based on symptom severity according to the Structured Interview for Prodromal Syndromes (SIPS) and received standard medical care. At baseline and one-year follow-up, TNF-α and VEGF were detected using enzyme-linked immunosorbent assay, and pathological features were assessed using the Global Assessment of Function (GAF) score. Baseline TNF-α levels did not differ significantly, while VEGF levels were lower in patients with more severe symptoms. VEGF showed a negative correlation with negative features, both overall (r = -0.212, p = 0.010) and in the subgroup with higher positive scores (r = -0.370, p = 0.005). TNF-α was positively correlated with negative symptoms in the subgroup with higher negative scores (r = 0.352, p = 0.002). A three-way multivariate analysis of variance demonstrated that participants in Subtype 1 of positive or negative symptoms performed better than those in Subtype 2, with significant main effects and interactions of group and both cytokines. TNF-α and VEGF levels are higher and lower, respectively, in CHR patients with more severe clinical symptoms, particularly negative symptoms, which point to a worsening inflammatory and vascular status in the brain.

Hippocampal Subfields, Daily Stressors, and Resting Cortisol in Individuals at Clinical High-Risk for Psychosis

The hippocampus, comprised of functionally distinct subfields, both regulates stress and is affected by it during psychosis pathogenesis. Hippocampal abnormalities are evident across psychosis spectrum and are associated with aberrant cortisol levels and greater environmental stressors exposure. These associations, particularly at the subfield-level, are poorly understood in individuals at clinical high-risk (CHR) for psychosis- a population characterized by an interplay between environmental stressors and biological susceptibility. A total of 121 participants including 51 CHR (mean age=18.61) and 70 healthy controls (HC; mean age=18.3) were enrolled. Participants completed a structural scan, salivary cortisol assays, and a self-report measure assessing distress from daily stressors exposure (DSI). Hippocampal subfield segmentation was conducted using Freesurfer. Smaller hippocampal subfields were associated with greater stress levels. Greater DSI was associated with lower volumes in CA1 (r=-.38) and CA2/3 (r=-.29), but not in CA4/DG (r=-.28), presubiculum (r=-.09), or subiculum (r=-.17). Higher resting cortisol was associated with lower volumes in presubiculum (r=-.4) but not subiculum (r=-.22), CA1 (r=.08), CA2/3 (r=.1), or CA4/DG (r=-.005). Regressions indicated effects for CA1 and DSI (b=.57, p=.03) and presubiculum and cortisol (b=.61, p=.02) are specific to CHR participants relative to HCs. The findings provided insights into links between stress and brain vulnerability during psychosis-risk period. Regional differences highlighted potentially different mechanisms by which stress impacts specific subfields. Presubiculum may be more susceptible to the impact of early stress on HPA-axis and cornu amonis to acute stressors.

The impact of early factors on persistent negative symptoms in youth at clinical high risk for psychosis.

Persistent negative symptoms (PNS) are described as continuing moderate negative symptoms. More severe negative symptoms have been associated with poor premorbid functioning in both chronic schizophrenia and first episode psychosis patients. Furthermore, youth at clinical high risk (CHR) for developing psychosis may also present with negative symptoms and poor premorbid functioning. The aim of this current study was to: (1) define the relationship between PNS and premorbid functioning, life events, trauma and bullying, previous cannabis use, and resource utilization, and (2) to examine what explanatory variables best predicted PNS. CHR participants (N = 709) were recruited from the North American Prodrome Longitudinal Study (NAPLS 2). Participants were divided into two groups: those with PNS (n = 67) versus those without PNS (n = 673). A K-means cluster analysis was conducted to distinguish patterns of premorbid functioning across the different developmental stages. The relationships between premorbid adjustment and other variables were examined using independent samples t-tests or chi square for categorical variables. There was significantly more males in the PNS group. Participants with PNS had significantly lower levels of premorbid adjustment in childhood, early adolescence, and late adolescence, compared to CHR participants without PNS. There were no differences between the groups in terms of trauma, bullying, and resource utilization. The non-PNS group had more cannabis use and more desirable and non-desirable life events. In terms of better understanding relationships between early factors and PNS, a prominent factor associated with PNS was premorbid functioning, in particular poor premorbid functioning in later adolescence.

Increased parietal and occipital lobe gyrification predicts conversion to syndromal psychosis in a clinical high-risk cohort.

Local gyrification index (lGI), indicative of the degree of cortical folding is a proxy marker for early cortical neurodevelopmental abnormalities. We studied the difference in lGI between those who do and do not convert to psychosis (non-converters) in a clinical high-risk (CHR) cohort, and whether lGI predicts conversion to psychosis. Seventy-two CHR participants with attenuated positive symptom syndrome were followed up for two years. The difference in baseline whole-brain lGI was examined on the T1-weighted MRIs between, i)CHR (N=72) and healthy controls (N=19), ii)Converters to psychosis (N=24) and non-converters (N=48), adjusting for age and sex, on Freesurfer-6.0. The significant cluster obtained in the converters versus non-converters comparison was registered as a region of interest to individual images of all 72 participants and lGI values were extracted from this region. A cox proportional hazards model was applied with these values to study whether lGI predicts conversion to psychosis. lGI was not different between CHR and healthy controls. lGI was increased in converters in the right-sided inferior parietal and lateral occipital areas (corrected cluster-wise-p-value=0.009, cohen's f=0.42) compared to non-converters, which significantly increased the risk of onset of psychosis (p=0.029, hazard ratio=1.471). Increased gyrification in the right-sided inferior parietal and lateral occipital area differentiates converters to psychosis in CHR, significantly increasing the risk of conversion to psychosis. This measure may reflect underlying traits in parts of the brain that develop earliest in-utero (parietal and occipital), conferring a heightened vulnerability to convert to syndromal psychosis subsequently.

14. Frequency of Cannabis-Use, Neurocognitive Performance and Functioning in Clinical High-Risk Participants From the NAPLS-3 Cohort: Moderate Use is Associated With Better Performance and Functioning

14. Frequency of Cannabis-Use, Neurocognitive Performance and Functioning in Clinical High-Risk Participants From the NAPLS-3 Cohort: Moderate Use is Associated With Better Performance and Functioning

Serum immune markers and transition to psychosis in individuals at clinical high risk

Individuals at clinical high risk (CHR) for psychosis have been found to have altered cytokine levels, but whether these changes are related to clinical outcomes remains unclear. We addressed this issue by measuring serum levels of 20 immune markers in 325 participants (n = 269 CHR, n = 56 healthy controls) using multiplex immunoassays, and then followed up the CHR sample to determine their clinical outcomes. Among 269 CHR individuals, 50 (18.6 %) developed psychosis by two years. Univariate and machine learning techniques were used to compare levels of inflammatory markers in CHR subjects and healthy controls, and in CHR subjects who had (CHR-t), or had not (CHR-nt) transitioned to psychosis.An ANCOVA identified significant group differences (CHR-t, CHR-nt and controls) and post-hoc tests indicated that VEGF levels and the IL-10/IL-6 ratio were significantly higher in CHR-t than CHR-nt, after adjusting for multiple comparisons. Using a penalised logistic regression classifier, CHR participants were distinguished from controls with an area-under the curve (AUC) of 0.82, with IL-6 and IL-4 levels the most important discriminating features. Transition to psychosis was predicted with an AUC of 0.57, with higher VEGF level and IL-10/IL-6 ratio the most important discriminating features. These data suggest that alterations in the levels of peripheral immune markers are associated with the subsequent onset of psychosis. The association with increased VEGF levels could reflect altered blood–brain-barrier (BBB) permeability, while the link with an elevated IL-10/IL-6 ratio points to an imbalance between anti- and pro-inflammatory cytokines.

The relevance of social anxiety for understanding social functioning and facial emotion recognition in individuals at clinical high-risk for psychosis.

Individuals at clinical high risk (CHR) for psychosis often experience poor social functioning and impaired facial emotion recognition (FER); however, the impact of frequently comorbid symptoms upon these processes is underexplored. In particular, social anxiety is characteristic of this population and also related to poor social functioning and FER biases, such as misinterpreting neutral faces as negative or threatening; however, little is known about how social anxiety relates to these processes in CHR individuals. The present study examined the overlap of social anxiety, social functioning, and FER accuracy and bias. Participants (CHR N=62, healthy controls N=52) completed the self-report Social Interaction Anxiety Scale (SIAS), Penn Emotion Recognition-40 (ER-40) behavioural task, and interviewer-rated Global Functioning Scale-Social (GFS-S). The ER-40 was used to assess both FER accuracy (e.g., overall number of correct responses) and bias (e.g., mislabelling neutral faces as angry). Consistent with previous research, relative to controls, CHR participants had more social anxiety (d=-1.07), poorer social functioning (d=-1.62), and performed more poorly on the FER task (e.g., d=-.37). Within CHR participants, social anxiety was related to an anger detection bias (r=.28), above and beyond positive symptom severity, which in turn was related to FER accuracy (r=.26) and social functioning (r=-.28). These findings suggest that ongoing work examining social processes within CHR individuals needs to account for social anxiety and that social anxiety may be a useful preventive intervention target.

Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ): developing tools to enable early intervention in the psychosis highrisk state.

Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ): developing tools to enable early intervention in the psychosis highrisk state.

Speech Illusions in People at Clinical High Risk for Psychosis Linked to Clinical Outcome.

Around 20% of people at clinical high risk (CHR) for psychosis later develop a psychotic disorder, but it is difficult to predict who this will be. We assessed the incidence of hearing speech (termed speech illusions [SIs]) in noise in CHR participants and examined whether this was associated with adverse clinical outcomes. At baseline, 344 CHR participants and 67 healthy controls were presented with a computerized white noise task and asked whether they heard speech, and whether speech was neutral, affective, or whether they were uncertain about its valence. After 2 years, we assessed whether participants transitioned to psychosis, or remitted from the CHR state, and their functioning. CHR participants had a lower sensitivity to the task. Logistic regression revealed that a bias towards hearing targets in stimuli was associated with remission status (OR = 0.21, P = 042). Conversely, hearing SIs with uncertain valence at baseline was associated with reduced likelihood of remission (OR = 7.72. P = .007). When we assessed only participants who did not take antipsychotic medication at baseline, the association between hearing SIs with uncertain valence at baseline and remission likelihood remained (OR = 7.61, P = .043) and this variable was additionally associated with a greater likelihood of transition to psychosis (OR = 5.34, P = .029). In CHR individuals, a tendency to hear speech in noise, and uncertainty about the affective valence of this speech, is associated with adverse outcomes. This task could be used in a battery of cognitive markers to stratify CHR participants according to subsequent outcomes.

Large-Scale Thalamocortical Triple Network Dysconnectivities in Patients With First-Episode Psychosis and Individuals at Risk for Psychosis.

Aberrant thalamocortical connectivity and large-scale network interactions among the default mode network (DMN), salience network (SN), and executive control network (ECN) (ie, triple networks) have been regarded as critical in schizophrenia pathophysiology. Despite the importance of network properties and the role of the thalamus as an integrative hub, large-scale thalamocortical triple network functional connectivities (FCs) in different stages of the psychotic disorder have not yet been reported. Thirty-nine first-episode psychosis (FEP) patients, 75 individuals at clinical high risk (CHR) for psychosis, 46 unaffected relatives (URs) of schizophrenia patients with high genetic loading, and 110 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging (rs-fMRI). Modular community detection was used to identify cortical and thalamic resting-state networks, and thalamocortical network interactions were compared across the groups. Thalamic triple networks included higher-order thalamic nuclei. Thalamic SN-cortical ECN FC was greater in the FEP group than in the CHR, UR, and HC groups. Thalamic DMN-cortical DMN and thalamic SN-cortical DMN FCs were greater in FEP and CHR participants. Thalamic ECN-cortical DMN and thalamic ECN-cortical SN FCs were greater in FEP patients and URs. These results highlight critical modulatory functions of thalamic triple networks and the shared and distinct patterns of thalamocortical triple network dysconnectivities across different stages of psychotic disorders. The current study findings suggest that large-scale thalamocortical triple network dysconnectivities may be used as an integrative biomarker for extending our understanding of the psychosis pathophysiology and for targeting network-based neuromodulation therapeutics.