Accelerated cortical thinning precedes and predicts conversion to psychosis: The NAPLS3 longitudinal study of youth at clinical high-risk.

Progressive grey matter loss has been demonstrated among clinical high-risk (CHR) individuals who convert to psychosis, but it is unknown whether these changes occur prior to psychosis onset. Identifying illness-related neurobiological mechanisms that occur prior to conversion is essential for targeted early intervention. Among participants in the third wave of the North American Prodrome Longitudinal Study (NAPLS3), this report investigated if steeper cortical thinning was observable prior to psychosis onset among CHR individuals who ultimately converted (CHR-C) and assessed the shortest possible time interval in which rates of cortical thinning differ between CHR-C, CHR non-converters (CHR-NC), and health controls (HC). 338 CHR-NC, 42 CHR-C, and 62 HC participants (age 19.3±4.2, 44.8% female, 52.5% racial/ethnic minority) completed up to 5 MRI scans across 8 months. Accelerated thinning among CHR-C compared to CHR-NC and HC was observed in multiple prefrontal, temporal, and parietal cortical regions. CHR-NC also exhibited accelerated cortical thinning compared to HC in several of these areas. Greater percent decrease in cortical thickness was observed among CHR-C compared to other groups across 2.9±1.8 months, on average, in several cortical areas. ROC analyses discriminating CHR-C from CHR-NC by percent thickness change in a left hemisphere region of interest, scanner, age, age2, and sex had an AUC of 0.74, with model predictive power driven primarily by percent thickness change. Findings indicate that accelerated cortical thinning precedes psychosis onset and differentiates CHR-C from CHR-NC and HC across short time intervals. Mechanisms underlying cortical thinning may provide novel treatment targets prior to psychosis onset.

Toward Leveraging Human Connectomic Data in Large Consortia: Generalizability of fMRI-Based Brain Graphs Across Sites, Sessions, and Paradigms.

While graph theoretical modeling has dramatically advanced our understanding of complex brain systems, the feasibility of aggregating connectomic data in large imaging consortia remains unclear. Here, using a battery of cognitive, emotional and resting fMRI paradigms, we investigated the generalizability of functional connectomic measures across sites and sessions. Our results revealed overall fair to excellent reliability for a majority of measures during both rest and tasks, in particular for those quantifying connectivity strength, network segregation and network integration. Processing schemes such as node definition and global signal regression (GSR) significantly affected resulting reliability, with higher reliability detected for the Power atlas (vs. AAL atlas) and data without GSR. While network diagnostics for default-mode and sensori-motor systems were consistently reliable independently of paradigm, those for higher-order cognitive systems were reliable predominantly when challenged by task. In addition, based on our present sample and after accounting for observed reliability, satisfactory statistical power can be achieved in multisite research with sample size of approximately 250 when the effect size is moderate or larger. Our findings provide empirical evidence for the generalizability of brain functional graphs in large consortia, and encourage the aggregation of connectomic measures using multisite and multisession data.

Multisite reliability of MR-based functional connectivity.

Recent years have witnessed an increasing number of multisite MRI functional connectivity (fcMRI) studies. While multisite studies provide an efficient way to accelerate data collection and increase sample sizes, especially for rare clinical populations, any effects of site or MRI scanner could ultimately limit power and weaken results. Little data exists on the stability of functional connectivity measurements across sites and sessions. In this study, we assess the influence of site and session on resting state functional connectivity measurements in a healthy cohort of traveling subjects (8 subjects scanned twice at each of 8 sites) scanned as part of the North American Prodrome Longitudinal Study (NAPLS). Reliability was investigated in three types of connectivity analyses: (1) seed-based connectivity with posterior cingulate cortex (PCC), right motor cortex (RMC), and left thalamus (LT) as seeds; (2) the intrinsic connectivity distribution (ICD), a voxel-wise connectivity measure; and (3) matrix connectivity, a whole-brain, atlas-based approach to assessing connectivity between nodes. Contributions to variability in connectivity due to subject, site, and day-of-scan were quantified and used to assess between-session (test-retest) reliability in accordance with Generalizability Theory. Overall, no major site, scanner manufacturer, or day-of-scan effects were found for the univariate connectivity analyses; instead, subject effects dominated relative to the other measured factors. However, summaries of voxel-wise connectivity were found to be sensitive to site and scanner manufacturer effects. For all connectivity measures, although subject variance was three times the site variance, the residual represented 60-80% of the variance, indicating that connectivity differed greatly from scan to scan independent of any of the measured factors (i.e., subject, site, and day-of-scan). Thus, for a single 5min scan, reliability across connectivity measures was poor (ICC=0.07-0.17), but increased with increasing scan duration (ICC=0.21-0.36 at 25min). The limited effects of site and scanner manufacturer support the use of multisite studies, such as NAPLS, as a viable means of collecting data on rare populations and increasing power in univariate functional connectivity studies. However, the results indicate that aggregation of fcMRI data across longer scan durations is necessary to increase the reliability of connectivity estimates at the single-subject level.

Reliability of an fMRI paradigm for emotional processing in a multisite longitudinal study.

Multisite neuroimaging studies can facilitate the investigation of brain-related changes in many contexts, including patient groups that are relatively rare in the general population. Though multisite studies have characterized the reliability of brain activation during working memory and motor functional magnetic resonance imaging tasks, emotion processing tasks, pertinent to many clinical populations, remain less explored. A traveling participants study was conducted with eight healthy volunteers scanned twice on consecutive days at each of the eight North American Longitudinal Prodrome Study sites. Tests derived from generalizability theory showed excellent reliability in the amygdala ( Eρ2 = 0.82), inferior frontal gyrus (IFG; Eρ2 = 0.83), anterior cingulate cortex (ACC; Eρ2 = 0.76), insula ( Eρ2 = 0.85), and fusiform gyrus ( Eρ2 = 0.91) for maximum activation and fair to excellent reliability in the amygdala ( Eρ2 = 0.44), IFG ( Eρ2 = 0.48), ACC ( Eρ2 = 0.55), insula ( Eρ2 = 0.42), and fusiform gyrus ( Eρ2 = 0.83) for mean activation across sites and test days. For the amygdala, habituation ( Eρ2 = 0.71) was more stable than mean activation. In a second investigation, data from 111 healthy individuals across sites were aggregated in a voxelwise, quantitative meta-analysis. When compared with a mixed effects model controlling for site, both approaches identified robust activation in regions consistent with expected results based on prior single-site research. Overall, regions central to emotion processing showed strong reliability in the traveling participants study and robust activation in the aggregation study. These results support the reliability of blood oxygen level-dependent signal in emotion processing areas across different sites and scanners and may inform future efforts to increase efficiency and enhance knowledge of rare conditions in the population through multisite neuroimaging paradigms.

Reliability of functional magnetic resonance imaging activation during working memory in a multi-site study: analysis from the North American Prodrome Longitudinal Study.

Multi-site neuroimaging studies offer an efficient means to study brain functioning in large samples of individuals with rare conditions; however, they present new challenges given that aggregating data across sites introduces additional variability into measures of interest. Assessing the reliability of brain activation across study sites and comparing statistical methods for pooling functional data are critical to ensuring the validity of aggregating data across sites. The current study used two samples of healthy individuals to assess the feasibility and reliability of aggregating multi-site functional magnetic resonance imaging (fMRI) data from a Sternberg-style verbal working memory task. Participants were recruited as part of the North American Prodrome Longitudinal Study (NAPLS), which comprises eight fMRI scanning sites across the United States and Canada. In the first study sample (n=8), one participant from each home site traveled to each of the sites and was scanned while completing the task on two consecutive days. Reliability was examined using generalizability theory. Results indicated that blood oxygen level-dependent (BOLD) signal was reproducible across sites and was highly reliable, or generalizable, across scanning sites and testing days for core working memory ROIs (generalizability ICCs=0.81 for left dorsolateral prefrontal cortex, 0.95 for left superior parietal cortex). In the second study sample (n=154), two statistical methods for aggregating fMRI data across sites for all healthy individuals recruited as control participants in the NAPLS study were compared. Control participants were scanned on one occasion at the site from which they were recruited. Results from the image-based meta-analysis (IBMA) method and mixed effects model with site covariance method both showed robust activation in expected regions (i.e. dorsolateral prefrontal cortex, anterior cingulate cortex, supplementary motor cortex, superior parietal cortex, inferior temporal cortex, cerebellum, thalamus, basal ganglia). Quantification of the similarity of group maps from these methods confirmed a very high (96%) degree of spatial overlap in results. Thus, brain activation during working memory function was reliable across the NAPLS sites and both the IBMA and mixed effects model with site covariance methods appear to be valid approaches for aggregating data across sites. These findings indicate that multi-site functional neuroimaging can offer a reliable means to increase power and generalizability of results when investigating brain function in rare populations and support the multi-site investigation of working memory function in the NAPLS study, in particular.

Reliability of neuroanatomical measurements in a multisite longitudinal study of youth at risk for psychosis.

Multisite longitudinal neuroimaging designs are used to identify differential brain structural change associated with onset or progression of disease. The reliability of neuroanatomical measurements over time and across sites is a crucial aspect of power in such studies. Prior work has found that while within-site reliabilities of neuroanatomical measurements are excellent, between-site reliability is generally more modest. Factors that may increase between-site reliability include standardization of scanner platform and sequence parameters and correction for between-scanner variations in gradient nonlinearities. Factors that may improve both between- and within-site reliability include use of registration algorithms that account for individual differences in cortical patterning and shape. In this study 8 healthy volunteers were scanned twice on successive days at 8 sites participating in the North American Prodrome Longitudinal Study (NAPLS). All sites employed 3 Tesla scanners and standardized acquisition parameters. Site accounted for 2 to 30% of the total variance in neuroanatomical measurements. However, site-related variations were trivial (<1%) among sites using the same scanner model and 12-channel coil or when correcting for between-scanner differences in gradient nonlinearity and scaling. Adjusting for individual differences in sulcal-gyral geometries yielded measurements with greater reliabilities than those obtained using an automated approach. Neuroimaging can be performed across multiple sites at the same level of reliability as at a single site, achieving within- and between-site reliabilities of 0.95 or greater for gray matter density in the majority of voxels in the prefrontal and temporal cortical surfaces as well as for the volumes of most subcortical structures.

Brains of optimistic older adults respond less to fearful faces.

The authors examined the neural correlates of emotion processing and how they relate to individual differences in optimism among older adults. Brain response during processing of fearful faces was measured by functional magnetic resonance imaging in 16 older adults and was correlated with level of optimism. Greater optimism was associated with reduced activation in the fusiform gyrus and frontal regions, which may reflect decreased salience of negative emotional information or better emotion regulation among optimistic individuals. Relationships persisted after taking into account cortical thickness, amygdala volume, and resting perfusion. Findings have potential implications for the promotion of successful aging.

Development of an anti-inflammatory diet for first-episode psychosis (FEP): a feasibility study protocol.

Background: Evidence suggests inflammation plays a role in the pathophysiology of psychosis even in early illness, indicating a potential avenue for anti-inflammatory interventions that simultaneously address high rates of metabolic disease in this population. The aim of this study is to design a novel anti-inflammatory diet intervention (DI) that is feasible to implement in a first-episode psychosis (FEP) population. Methods: Eligible FEP Participants are aged 15-30. The DI is currently being refined through a multi-phase process that includes the recruitment of focus groups that provide insight into feasibility of measures and nutritional education, as well as the implementation of the DI. The phases in the study are the Development Phase, Formative Phase, and the Feasibility Phase. Results: The Development phase has resulted in the creation of a flexible DI for FEP based on existing research on nutritional health and informed by providers. This study has just completed the Formative phase, recruiting eligible participants to join focus groups that gleaned information about dietary habits, preferences, and food environments to further refine the DI. Conclusion: Findings from earlier phases have advised the current Feasibility Phase in which this novel DI is being administered to a small cohort of FEP participants (N = 12) to determine acceptability of the DI from a lived experience perspective. Naturalistic changes in inflammatory biomarkers, metabolic health, and symptoms will also be measured.

Peripheral and central biomarkers associated with inflammation in antipsychotic naïve first episode psychosis: Pilot studies.

BACKGROUND: Elevated serum pro-inflammatory molecules have been reported in early psychosis. What is not known is whether peripheral inflammatory biomarkers are associated with CNS biomarkers. In the brain, release of pro-inflammatory molecules by microglial hyperactivity may lead to neuronal apoptosis seen in neurodegenerative disorders and account for loss of brain tissue observed in psychotic disorders. Neurochemical changes, including elevated glutamate levels, are also associated with neuroinflammation, present in early psychosis and change with antipsychotic treatment. METHODS: Antipsychotic naïve patients with first episode psychosis (FEP) were studied as part of a collaborative project of neuroinflammation. In Study 1 we explored associations between plasma inflammatory molecules and neurometabolites in the dorsal caudate using magnetic resonance spectroscopy (1H-MRS) in N = 13 FEP participants. Study 2 examined the relationship between inflammatory molecules in the Plasma and CSF in N = 20 FEP participants. RESULTS: In Study 1, the proinflammatory chemokine MDC/CCL22 and IL10 were significantly positively correlated with Glutamate and Glx (glutamate + glutamine) levels in the dorsal caudate. In Study 2, plasma inflammatory molecules (MIP1ß/CCL4, MCP1/CCL2, Eotaxin-1/CCL11 and TNFα) were significantly correlated with CSF MIP1ß/CCL4, IL10, MCP1/CCL2 and Fractalkine/CX3CL1 and symptoms ratings. DISCUSSION: Plasma inflammatory biomarkers are elevated in early psychosis, associated with neurochemical markers as well as CSF inflammatory molecules found in neurodegenerative disorders. Future studies are needed that combine both peripheral and central biomarkers in both FEP and HC to better understand a potential neuroinflammatory subtype of psychosis likely to respond to targeted interventions.

A developmental look at the attentional system in the at risk and first episode of psychosis: age related changes in attention along the psychosis spectrum.

INTRODUCTION: Neurodevelopmental processes of adolescence, when superimposed on a vulnerable brain, may produce additive effects reflecting the subthreshold psychotic symptoms, cognitive, and functional deterioration that are the hallmark of the early stages of schizophrenia. METHODS: As part of a longitudinal study, we investigated Continuous Performance Task, Identical Pairs Version (CPT-IP) performance in a sample of 301 participants (at risk for psychosis: 109; first episode-FE: 90; and controls: 102). Performance across groups was compared using d' of fast and slow, spatial and verbal conditions over two time points. Age effects were investigated using a regression model. RESULTS: Across all four CPT-IP conditions FE patients performed significantly worse than controls while AR individuals significantly differed from healthy subjects in the verbal condition. Age-related performance associations across groups significantly differed in the slow verbal condition because the FE sample did not show a significant association with increasing age like the AR and NC samples. CPT performance was stable over time. CONCLUSIONS: Sustained attention in the putative prodrome of psychosis is not only impaired but associated with age. Research focusing on cognitive and neurobiological age-related changes can help to address fundamental questions about the nature of the disorder, including whether the underlying pathophysiology of early psychosis is static or deteriorating.

Risk of violent behaviour in young people at clinical high risk for psychosis from the North American Prodrome Longitudinal Studies consortium.

AIM: Although violent behaviour has been studied in schizophrenia, violence risk has received little attention in individuals at clinical high risk for psychosis (CHR). This manuscript aims to report and discuss the overall results of the Structured Assessment for Violence Risk in Youth (SAVRY) from the NAPLS-3 project to explore the risk of violence in CHR youth and to determine the relationship between SAVRY violence risk scores, psychosis risk symptoms, and global functioning. We hypothesized that CHR young people are at higher risk of violence as compared to healthy comparison participants due to a similarity between risk factors for psychosis and risk factors for violence, and that this risk is associated with greater severity of symptoms, poor functioning, and risk for conversion to psychosis. METHODS: Participants from the North American Prodrome Longitudinal Study consortium phase 3 (NAPLS-3) included 684 CHR and 96 HC. Assessments included the Structural Assessment of Violence Risk in Youth (SAVRY), clinical and functional measures. RESULTS: The majority of participants across groups were deemed to be at low risk for violence. There were significantly more CHR participants (29.8%) who had moderate or high scores on the SAVRY Summary Risk Rating compared to HC participants (3.1%). Low versus moderate-high SAVRY scores were associated with better social (p < .005) and role (p < .002) functioning and fewer positive (p < .002), negative (p < .002), disorganized (p < .01) and general symptoms (p < .002). CHR participants with higher SAVRY scores were more likely to be diagnosed with borderline personality disorder, ADHD and substance misuse. Among CHR, overall violence risk was not associated with conversion to psychosis. However, those who converted to psychosis scored lower on the protective factors index, primarily driven by less prosocial involvement and fewer resilient personality traits. CONCLUSIONS: This is the first study to assess violence risk in CHR adolescents. Violence risk factors overlap with risk factors for psychosis in general, perhaps accounting for the association. These findings have implications for intervention efforts to reduce violence risk and bolster resiliency in CHR youth.

Compensatory brain activity during encoding among older adults with better recognition memory for face-name pairs: an integrative functional, structural, and perfusion imaging study.

Many neuroimaging studies interpret the commonly reported findings of age-related increases in frontal response and/or increased bilateral activation as suggestive of compensatory neural recruitment. However, it is often unclear whether differences are due to compensation or reflective of other cognitive or physiological processes. This study aimed to determine whether there are compensatory age-related changes in brain systems supporting successful associative encoding while taking into account potentially confounding factors including age-related differences in task performance, atrophy, and resting perfusion. Brain response during encoding of face-name pairs was measured using functional magnetic resonance imaging in 10 older and nine young adults and was correlated with memory performance. During successful encoding, older adults demonstrated increased frontal and decreased occipital activity as well as greater bilateral involvement relative to the young. Findings remained significant after controlling for age-related cortical atrophy and hypoperfusion. Among the older adults, greater response was associated with better memory performance. Cognitive aging may involve recruitment of compensatory mechanisms to improve performance or prevent impairment. Results extend previous findings by suggesting that age-related alterations in activation cannot be attributed to the commonly observed findings of poorer task performance, reduced resting perfusion, or cortical atrophy among older adults.

A review of the brain structure correlates of successful cognitive aging.

Unimpaired cognition is an important feature of successful aging. Differences in cognitive performance among healthy older adults may be related to differences in brain structure. The authors reviewed the literature to examine the relationship between brain-structure size and cognitive performance in older adults. Eighty-three percent of studies found at least one positive relationship between these factors; however, findings were variable. Positive relationships emerged most consistently between the hippocampal formation and global cognition and memory and between frontal measures and executive function. Additional longitudinal study is needed to further evaluate structure-cognition relationships in older adulthood and across the adult lifespan.

Cross-paradigm connectivity: reliability, stability, and utility.

While functional neuroimaging studies typically focus on a particular paradigm to investigate network connectivity, the human brain appears to possess an intrinsic "trait" architecture that is independent of any given paradigm. We have previously proposed the use of "cross-paradigm connectivity (CPC)" to quantify shared connectivity patterns across multiple paradigms and have demonstrated the utility of such measures in clinical studies. Here, using generalizability theory and connectome fingerprinting, we examined the reliability, stability, and individual identifiability of CPC in a group of highly-sampled healthy traveling subjects who received fMRI scans with a battery of five paradigms across multiple sites and days. Compared with single-paradigm connectivity matrices, the CPC matrices showed higher reliability in connectivity diversity, lower reliability in connectivity strength, higher stability, and higher individual identification accuracy. All of these assessments increased as a function of number of paradigms included in the CPC analysis. In comparisons involving different paradigm combinations and different brain atlases, we observed significantly higher reliability, stability, and identifiability for CPC matrices constructed from task-only data (versus those from both task and rest data), and higher identifiability but lower stability for CPC matrices constructed from the Power atlas (versus those from the AAL atlas). Moreover, we showed that multi-paradigm CPC matrices likely reflect the brain's "trait" structure that cannot be fully achieved from single-paradigm data, even with multiple runs. The present results provide evidence for the feasibility and utility of CPC in the study of functional "trait" networks and offer some methodological implications for future CPC studies.

Immuno-inflammatory changes across phases of early psychosis: The impact of antipsychotic medication and stage of illness.

INTRODUCTION: Research examining the role of inflammation in psychosis has produced inconsistent results. Variables that influence inflammation, including antipsychotic medication, are inconsistently controlled across studies and variation of inflammatory analytes across stages of psychosis may also influence findings. The purpose of this study was to assess for evidence of immuno-inflammatory dysregulation across the stages of early psychosis. We examined a immuno-inflammatory analytes in subjects at clinical high risk (CHR) for developing a psychotic disorder, antipsychotic-naïve (-n) and antipsychotic treated (-a) subjects in their first episode of psychosis (FEP), and healthy control (HC) subjects. METHODS: A total of 11 subjects at CHR, 50 subjects within their FEP (40 FEP-n, 10 FEP-a), and 10 HC subjects were recruited from early psychosis programs in San Diego and Mexico City. Plasma was collected for biomarker assay. RESULTS: Immuno-inflammatory analytes significantly differed between groups: Interferon-gamma (IFN-γ), Interleukin-10 (IL-10), Eotaxin-1, Interferon Gamma-Induced Protein-10 (IP-10), Monocyte Chemotactic Protein-1 (MCP-1), Macrophage-Derived Chemokine (MDC), Macrophage Inflammatory Protein-1 beta (MIP-1ß), Thymus and Activation Regulated Chemokine (TARC), and Brain Derived Neurotropic Factor (BDNF). Post-hoc analyses revealed an overall pattern of higher levels of IL-10, MCP-1, MIP-1ß, TARC, and BDNF in CHR as compared to FEP-a, FEP-n, and HC subjects. CONCLUSIONS: Results reveal a profile of immuno-inflammatory dysregulation in early stages of psychosis prior to psychotic conversion and treatment with antipsychotic medication. The CHR phase of early psychosis may represent a period of increased immuno-inflammatory activation, but due to limited sample size, these results deserve replication in a well characterized early psychosis population.

Progressive reconfiguration of resting-state brain networks as psychosis develops: Preliminary results from the North American Prodrome Longitudinal Study (NAPLS) consortium.

Mounting evidence has shown disrupted brain network architecture across the psychosis spectrum. However, whether these changes relate to the development of psychosis is unclear. Here, we used graph theoretical analysis to investigate longitudinal changes in resting-state brain networks in samples of 72 subjects at clinical high risk (including 8 cases who converted to full psychosis) and 48 healthy controls drawn from the North American Prodrome Longitudinal Study (NAPLS) consortium. We observed progressive reduction in global efficiency (P = 0.006) and increase in network diversity (P = 0.001) in converters compared with non-converters and controls. More refined analysis separating nodes into nine key brain networks demonstrated that these alterations were primarily driven by progressively diminished local efficiency in the default-mode network (P = 0.004) and progressively enhanced node diversity across all networks (P < 0.05). The change rates of network efficiency and network diversity were significantly correlated (P = 0.003), suggesting these changes may reflect shared neural mechanisms. In addition, change rates of global efficiency and node diversity were significantly correlated with change rate of cortical thinning in the prefrontal cortex in converters (P < 0.03) and could be predicted by visuospatial memory scores at baseline (P < 0.04). These results provide preliminary evidence for longitudinal reconfiguration of resting-state brain networks during psychosis development and suggest that decreased network efficiency, reflecting an increase in path length between nodes, and increased network diversity, reflecting a decrease in the consistency of functional network organization, may be implicated in the progression to full psychosis.

Schizophrenia patients lack normal positive correlation between age and brain response during verbal learning.

OBJECTIVE: To investigate the differences in the relationship of age to brain function among individuals with schizophrenia and a healthy comparison group. The authors hypothesized that the correlation with age would be more strongly negative among schizophrenia patients, particularly in the frontal cortex. DESIGN: Cross-sectional measures of functional MRI (fMRI) brain response were correlated with age in both groups. SETTING: Participants came to university research facilities for testing. PARTICIPANTS: The authors analyzed data from 30 patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition schizophrenia or schizoaffective disorder ranging in age from 25 to 68 years and 14 healthy comparison participants ranging in age from 21 to 70 years. MEASUREMENTS: Brain response during word pair learning was measured with fMRI in each voxel of the brain. This measure was correlated with age within each group and the correlations were compared across groups in regions of interest determined a priori and based on a whole-brain analysis. In exploratory analyses, the authors examined the interaction of task performance with age and study group. RESULTS: The correlations between age and brain response were more positive in the healthy group than in the schizophrenia group in several regions, including right lateral prefrontal cortex and clusters in midline precuneus and right superior temporal gyrus. Interactions with task performance suggest that age effects on brain function relate differently to cognitive output in patients and comparison participants. CONCLUSIONS: There is no strong evidence that functional brain response during learning changes significantly with age among schizophrenia patients, in contrast to findings of positive associations with age among healthy individuals.

Altered Brain Activation During Memory Retrieval Precedes and Predicts Conversion to Psychosis in Individuals at Clinical High Risk.

Memory deficits are a hallmark of psychotic disorders such as schizophrenia. However, whether the neural dysfunction underlying these deficits is present before the onset of illness and potentially predicts conversion to psychosis is unclear. In this study, we investigated brain functional alterations during memory processing in a sample of 155 individuals at clinical high risk (including 18 subjects who later converted to full psychosis) and 108 healthy controls drawn from the second phase of the North American Prodrome Longitudinal Study (NAPLS-2). All participants underwent functional magnetic resonance imaging with a paired-associate memory paradigm at the point of recruitment and were clinically followed up for approximately 2 years. We found that at baseline, subjects at high risk showed significantly higher activation during memory retrieval in the prefrontal, parietal, and bilateral temporal cortices (PFWE < .035). This effect was more pronounced in converters than nonconverters and was particularly manifested in unmedicated subjects (P < .001). The hyperactivation was significantly correlated with retrieval reaction time during scan in converters (P = .009) but not in nonconverters and controls, suggesting an exaggerated retrieval effort. These findings suggest that hyperactivation during memory retrieval may mark processes associated with conversion to psychosis, and such measures have potential as biomarkers for psychosis prediction.

Cerebello-thalamo-cortical hyperconnectivity as a state-independent functional neural signature for psychosis prediction and characterization.

Understanding the fundamental alterations in brain functioning that lead to psychotic disorders remains a major challenge in clinical neuroscience. In particular, it is unknown whether any state-independent biomarkers can potentially predict the onset of psychosis and distinguish patients from healthy controls, regardless of paradigm. Here, using multi-paradigm fMRI data from the North American Prodrome Longitudinal Study consortium, we show that individuals at clinical high risk for psychosis display an intrinsic "trait-like" abnormality in brain architecture characterized as increased connectivity in the cerebello-thalamo-cortical circuitry, a pattern that is significantly more pronounced among converters compared with non-converters. This alteration is significantly correlated with disorganization symptoms and predictive of time to conversion to psychosis. Moreover, using an independent clinical sample, we demonstrate that this hyperconnectivity pattern is reliably detected and specifically present in patients with schizophrenia. These findings implicate cerebello-thalamo-cortical hyperconnectivity as a robust state-independent neural signature for psychosis prediction and characterization.

A preliminary study of interactive questioning methods to assess and improve understanding of informed consent among patients with schizophrenia.

Growing recognition of the inadequacy of traditional methods of providing informed consent, especially for individuals vulnerable to impaired decisional capacity, has spurred recent interest in how to assess and improve components of consent-related decision making. In this preliminary study, we aimed to compare different methods of interactive questioning during presentation of research consent information among patients with schizophrenia. Patients were randomized to receive either standard administration (SA) of a consent form or one of two interactive questioning methods: Corrective Feedback (CF), in which the correct answer was provided following the participant's response, or Errorless Learning (EL), in which correct answers were provided just prior to the question. The MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR) was used to measure understanding, appreciation, reasoning, and expression of a choice following presentation of the consent form. There was no significant effect of condition (SA vs. EL vs. CF) on any of the components of decisional capacity. Understanding scores measured during the consent process were higher than those measured afterward, but the two scores were highly correlated. Thus, the results of this randomized study suggest that interactive questioning neither helped nor harmed understanding, appreciation, or reasoning among patients with schizophrenia. Other considerations, however, may favor use of such methods in the consenting process.