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1.  Contributions of Feature Binding During Encoding and Functional Connectivity of the Medial Temporal Lobe Structures to Episodic Memory Deficits Across the Prodromal and First-Episode Phases of Schizophrenia 
Patients with and at risk for psychosis may have difficulty using associative strategies to facilitate episodic memory encoding and recall. In parallel studies, patients with first-episode schizophrenia (n = 27) and high psychosis risk (n = 28) compared with control participants (n = 22 and n = 20, respectively) underwent functional MRI during a remember-know memory task. Psychophysiological interaction analyses, using medial temporal lobe (MTL) structures as regions of interest, were conducted to measure functional connectivity patterns supporting successful episodic memory. During encoding, patients with first-episode schizophrenia demonstrated reduced functional coupling between MTL regions and regions involved in stimulus representations, stimulus selection, and cognitive control. Relative to control participants and patients with high psychosis risk who did not convert to psychosis, patients with high psychosis risk who later converted to psychosis also demonstrated reduced connectivity between MTL regions and auditory-verbal and visual-association regions. These results suggest that episodic memory deficits in schizophrenia are related to inefficient recruitment of cortical connections involved in associative memory formation; such deficits precede the onset of psychosis among those individuals at high clinical risk.
PMCID: PMC4349206  PMID: 25750836
psychotic disorders; memory; schizophrenia; neuroimaging; functional imaging
2.  Progressive Reduction in Cortical Thickness as Psychosis Develops: A Multisite Longitudinal Neuroimaging Study of Youth at Elevated Clinical Risk 
Biological psychiatry  2014;77(2):147-157.
Individuals at clinical high-risk (CHR) who progress to fully psychotic symptoms have been observed to show a steeper rate of cortical gray matter reduction compared with those without symptomatic progression and with healthy controls. Whether such changes reflect processes associated with the pathophysiology of schizophrenia or exposure to antipsychotic drugs is unknown.
In this multisite study, 274 CHR cases, including 35 who converted to psychosis, and 135 healthy comparison subjects were scanned with MRI at baseline, 12-month follow-up, and/or the point of conversion for those who developed fully psychotic symptoms.
In a traveling subjects sub-study, we observed excellent reliability for measures of cortical thickness and subcortical volumes. Controlling for multiple comparisons throughout the brain, CHR converters showed a steeper rate of gray matter loss in right superior frontal, middle frontal, and medial orbitofrontal cortical regions, as well as a greater rate of expansion of the third ventricle, compared with CHR non-converters and healthy controls. Differential tissue loss was present among cases who had not received antipsychotic medications during the inter-scan interval and was predicted by baseline levels of an aggregate measure of pro-inflammatory cytokines in plasma.
These findings demonstrate that the brain changes are not explained by exposure to antipsychotic drugs, but likely play a role in psychosis pathophysiology. Given that the cortical changes were more pronounced among cases with briefer durations of prodromal symptoms, contributing factors may predominantly play a role in acute-onset forms of psychosis.
PMCID: PMC4264996  PMID: 25034946
schizophrenia; psychosis; prodromal; MRI; prefrontal cortex; inflammation
3.  Cognitive Endophenotypes Inform Genome-Wide Expression Profiling in Schizophrenia 
Neuropsychology  2016;30(1):40-52.
We performed a whole-genome expression study to clarify the nature of the biological processes mediating between inherited genetic variations and cognitive dysfunction in schizophrenia.
Gene expression was assayed from peripheral blood mononuclear cells using Illumina Human WG6 v3.0 chips in twins discordant for schizophrenia or bipolar disorder and control twins. After quality control, expression levels of 18,559 genes were screened for association with California Verbal Learning Test (CVLT) performance, and any memory-related probes were then evaluated for variation by diagnostic status in the discovery sample (N = 190), and in an independent replication sample (N = 73). Heritability of gene expression using the twin design was also assessed.
After Bonferroni correction (p < 2.69 × 10−6), CVLT performance was significantly related to expression levels for 76 genes, 43 of which were differentially expressed in schizophrenia patients, with comparable effect sizes in the same direction in the replication sample. For 41 of these 43 transcripts, expression levels were heritable. Nearly all identified genes contain common or de novo mutations associated with schizophrenia in prior studies.
Genes increasing risk for schizophrenia appear to do so in part via effects on signaling cascades influencing memory. The genes implicated in these processes are enriched for those related to RNA processing and DNA replication and include genes influencing G-protein coupled signal transduction, cytokine signaling, and oligodendrocyte function.
PMCID: PMC4693618  PMID: 26710095
schizophrenia; gene expression; cognition; endophenotype; genome-wide association study
4.  Reliability of functional magnetic resonance imaging activation during working memory in a multi-site study: Analysis from the North American Prodrome Longitudinal Study 
NeuroImage  2014;0:41-52.
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 is 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.
PMCID: PMC4065837  PMID: 24736173
fMRI; multi-site; working memory; reliability; G-theory
5.  Reliability of an fMRI Paradigm for Emotional Processing in a Multisite Longitudinal Study 
Human brain mapping  2015;36(7):2558-2579.
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.
PMCID: PMC4478164  PMID: 25821147
fMRI; reliability; multisite; emotion; meta-analysis; amygdale
6.  Prediction of conversion to psychosis: review and future directions 
This article reviews recent findings on predictors of conversion to psychosis among youth deemed at ultra high risk (UHR) based on the presence of subpsychotic-intensity symptoms or genetic risk for psychosis and a recent decline in functioning. Although transition rates differ between studies, the most well powered studies have observed rates of conversion to full psychosis in the 30–40% range over 2–3 years of follow-up. Across studies, severity of subthreshold positive symptoms, poorer social functioning, and genetic risk for schizophrenia appear to be consistent predictors of conversion to psychosis, with algorithms combining these indicators achieving positive predictive power ≥ 80%. Nevertheless, a substantial fraction of UHR cases do not convert to psychosis. Recent work indicates that UHR cases who present with lower levels of negative symptoms and higher levels of social functioning are more likely to recover symptomatically and no longer meet criteria for an at-risk mental state. In general, it appears that about 1/3 of UHR cases convert to psychosis, about 1/3 do not convert but remain symptomatic and functionally impaired, and about 1/3 recover symptomatically and functionally. Continued efforts to detect early risk for psychosis are critical for informing early intervention and provide increasing promise of delaying or even preventing the onset of psychosis.
PMCID: PMC4098037  PMID: 22286564
psychosis; prodrome; prediction; conversion; functional outcome
7.  Altered Age-Related Trajectories of Amygdala-Prefrontal Circuitry in Adolescents at Clinical High Risk for Psychosis: A Preliminary Study 
Schizophrenia research  2011;134(1):1-9.
Emotion processing deficits are prominent in schizophrenia and exist prior to the onset of overt psychosis. However, developmental trajectories of neural circuitry subserving emotion regulation and the role that they may play in illness onset have not yet been examined in patients at risk for psychosis. The present study employed a cross-sectional analysis to examine age-related functional activation in amygdala and prefrontal cortex, as well as functional connectivity between these regions, in adolescents at clinical high risk (CHR) for psychosis relative to typically developing adolescents. Participants (n=34) performed an emotion processing fMRI task, including emotion labeling, emotion matching, and non-emotional control conditions. Regression analyses were used to predict activation in the amygdala and ventrolateral prefrontal cortex (vlPFC) based on age, group, sex, and the interaction of age by group. CHR adolescents exhibited altered age-related variation in amygdala and vlPFC activation, relative to controls. Controls displayed decreased amygdala and increased vlPFC activation with age, while patients exhibited the opposite pattern (increased amygdala and decreased vlPFC activation), suggesting a failure of prefrontal cortex to regulate amygdala reactivity. Moreover, a psychophysiological interaction analysis revealed decreased amygdala-prefrontal functional connectivity among CHR adolescents, consistent with disrupted brain connectivity as a vulnerability factor in schizophrenia. These results suggest that the at-risk syndrome is marked by abnormal development and functional connectivity of neural systems subserving emotion regulation. Longitudinal data are needed to confirm aberrant developmental trajectories intra-individually and to examine whether these abnormalities are predictive of conversion to psychosis, and of later deficits in socioemotional functioning.
PMCID: PMC3245800  PMID: 22056201
psychosis; brain development; emotion; amygdala; prefrontal cortex; fMRI
8.  Elucidating a Magnetic Resonance Imaging-Based Neuroanatomic Biomarker for Psychosis: Classification Analysis Using Probabilistic Brain Atlas and Machine Learning Algorithms 
Biological psychiatry  2009;66(11):1055-1060.
No objective diagnostic biomarkers or laboratory tests have yet been developed for psychotic illness. Magnetic resonance imaging (MRI) studies consistently find significant abnormalities in multiple brain structures in psychotic patients relative to healthy control subjects, but these abnormalities show substantial overlap with anatomic variation that is in the normal range and therefore nondiagnostic. Recently, efforts have been made to discriminate psychotic patients from healthy individuals using machine-learning-based pattern classification methods on MRI data.
Three-dimensional cortical gray matter density (GMD) maps were generated for 36 patients with recent-onset psychosis and 36 sex- and age-matched control subjects using a cortical pattern matching method. Between-group differences in GMD were evaluated. Second, the sparse multinomial logistic regression classifier included in the Multivariate Pattern Analysis in Python machine-learning package was applied to the cortical GMD maps to discriminate psychotic patients from control subjects.
Patients showed significantly lower GMD, particularly in prefrontal, cingulate, and lateral temporal brain regions. Pattern classification analysis achieved 86.1% accuracy in discriminating patients from controls using leave-one-out cross-validation.
These results suggest that even at the early stage of illness, psychotic patients present distinct patterns of regional cortical gray matter changes that can be discriminated from the normal pattern. These findings indicate that we can detect complex patterns of brain abnormality in early stages of psychotic illness, which has critical implications for early identification and intervention in individuals at ultra-high risk for developing psychosis/schizophrenia.
PMCID: PMC3192809  PMID: 19729150
Classification; cortical pattern matching; MRI; psychosis; PyMVPA; schizophrenia
9.  Prediction of Psychosis in Youth at High Clinical Risk 
Archives of general psychiatry  2008;65(1):28-37.
Early detection and prospective evaluation of individuals who will develop schizophrenia or other psychotic disorders are critical to efforts to isolate mechanisms underlying psychosis onset and to the testing of preventive interventions, but existing risk prediction approaches have achieved only modest predictive accuracy.
To determine the risk of conversion to psychosis and to evaluate a set of prediction algorithms maximizing positive predictive power in a clinical high-risk sample.
Design, Setting, and Participants
Longitudinal study with a 2½-year follow-up of 291 prospectively identified treatment-seeking patients meeting Structured Interview for Prodromal Syndromes criteria. The patients were recruited and underwent evaluation across 8 clinical research centers as part of the North American Prodrome Longitudinal Study.
Main Outcome Measure
Time to conversion to a fully psychotic form of mental illness.
The risk of conversion to psychosis was 35%, with a decelerating rate of transition during the 2½-year follow-up. Five features assessed at baseline contributed uniquely to the prediction of psychosis: a genetic risk for schizophrenia with recent deterioration in functioning, higher levels of unusual thought content, higher levels of suspicion/paranoia, greater social impairment, and a history of substance abuse. Prediction algorithms combining 2 or 3 of these variables resulted in dramatic increases in positive predictive power (ie, 68%–80%) compared with the prodromal criteria alone.
These findings demonstrate that prospective ascertainment of individuals at risk for psychosis is feasible, with a level of predictive accuracy comparable to that in other areas of preventive medicine. They provide a benchmark for the rate and shape of the psychosis risk function against which standardized preventive intervention programs can be compared.
PMCID: PMC3065347  PMID: 18180426
10.  Progressive Brain Structural Changes Mapped as Psychosis Develops in ‘At Risk’ Individuals 
Schizophrenia research  2009;108(1-3):85-92.
Schizophrenia and related psychoses are associated with brain structural abnormalities. Recent findings in ‘at risk’ populations have identified progressive changes in various brain regions preceding illness onset, while changes especially in prefrontal and superior temporal regions have been demonstrated in first-episode schizophrenia patients. However, the timing of the cortical changes and their regional extent, relative to the emergence of psychosis, has not been clarified. We followed individuals at high-risk for psychosis to determine whether structural changes in the cerebral cortex occur with the onset of psychosis. We hypothesized that progressive volume loss occurs in prefrontal regions during the transition to psychosis.
35 individuals at ultra-high risk (UHR) for developing psychosis, of whom 12 experienced psychotic onset by 1-year follow-up (‘converters’), participated in a longitudinal structural MRI study. Baseline and follow-up T1-weighted MR images were acquired and longitudinal brain surface contractions were assessed using Cortical Pattern Matching.
Significantly greater brain contraction was found in the right prefrontal region in the ‘converters’ compared with UHR cases who did not develop psychosis (‘non-converters’).
These findings show cortical volume loss is associated with the onset of psychosis, indicating ongoing pathological processes during the transition stage to illness. The prefrontal volume loss is in line with structural and functional abnormalities in schizophrenia, suggesting a critical role for this change in the development of psychosis.
PMCID: PMC2670732  PMID: 19138834
schizophrenia; MRI; brain mapping; longitudinal; prodrome; ultra-high risk
11.  Decreased neurotrophic response to birth hypoxia in the etiology of schizophrenia 
Biological psychiatry  2008;64(9):797-802.
Obstetric complications, particularly fetal hypoxia, are associated with increased risk for schizophrenia later in life. Such factors are also related to increased severity of certain neuropathological features of schizophrenia, including hippocampal and cortical gray matter reduction, among individuals with a genetic susceptibility to the disorder. However, the molecular mechanisms underlying these associations are unknown. Here we sought to determine whether neurotrophic factors, which are stimulated as part of a neuroprotective response to fetal distress, are differentially expressed in cord blood samples at the time of birth following fetal hypoxia, maternal hypertension/small for gestational age status, and/or prematurity among individuals who developed schizophrenia as adults, as compared with controls.
One hundred and eleven cases with psychotic disorders (70 with schizophrenia) and 333 controls matched for gender, race, and date of birth, were drawn from the Philadelphia cohort of the National Collaborative Perinatal Project, in a nested case-control study. Brain derived neurotrophic factor (BDNF) was assayed from cord and maternal blood samples taken at delivery and stored at −20 C for 45–50 years.
Among controls, birth hypoxia was associated with a significant (10%) increase in BDNF in cord samples, while among cases, hypoxia was associated with a significant (20%) decrease in BDNF. This differential response to fetal hypoxia was specific to schizophrenia and was not explained by other obstetric complications or by the BDNF Val66Met polymorphism.
These findings provide serologically based prospective evidence of disrupted neurotrophic signaling in response to birth hypoxia in the molecular pathogenesis of schizophrenia.
PMCID: PMC2655104  PMID: 18486103
Schizophrenia; Hypoxia; Brain Derived Neurotrophic Factor; Neuroprotection
12.  North American Prodrome Longitudinal Study: A Collaborative Multisite Approach to Prodromal Schizophrenia Research 
Schizophrenia Bulletin  2007;33(3):665-672.
This article presents the rationale, design, and preliminary findings of the North American Prodrome Longitudinal Study (NAPLS), a collaborative, multisite investigation into the earliest phase of psychotic illness. We describe how 8 independently conceived research projects were integrated methodologically, how diagnostic reliability was achieved across sites on the Structured Interview for Prodromal Syndromes, and how baseline and follow-up data were aggregated for 888 at risk and comparison subjects. Data are presented describing the demographic, academic/work, and diagnostic characteristics of 3 relevant subgroups: persons at heightened clinical risk for psychosis, help-seeking comparison subjects, and nonpsychiatric controls. The NAPLS data set will be used to explore a series of questions related to prodromal psychosis, including the descriptive phenomenology of currently accepted diagnostic criteria, conversion rates over a 30-month period, predictors of psychosis onset and functional disability, and the impact of early treatment on the course of prodromal symptoms.
PMCID: PMC2526151  PMID: 17255119
psychosis; prodrome; schizophrenia; consortium; early detection; prevention; NAPLS
13.  Preliminary Findings for Two New Measures of Social and Role Functioning in the Prodromal Phase of Schizophrenia 
Schizophrenia Bulletin  2007;33(3):688-702.
Introduction: Research on prediction and prevention of schizophrenia has increasingly focused on prodromal (prepsychosis) social and role dysfunction as developmentally early, stable, and treatment-resistant illness components. In this report, 2 new measures, Global Functioning: Social and Global Functioning: Role, are presented, along with preliminary findings about psychometric properties and course of social and role (academic/work) functioning in the prodromal phase of psychosis. Methods: Subjects included 69 participants from the Recognition and Prevention program and 52 from the Center for the Assessment and Prevention of Prodromal States. Ages ranged from 12 to 29 years, and all met criteria for Attenuated Positive Symptom syndrome. Retrospective (past year) and baseline data are reported for all 121 prodromal subjects and for 44 normal controls (NCs). Prospective follow-up data are reported for a subsample of patients reevaluated at both 6 and 12 months (N = 44). Results: For both scales, interrater reliability was high, and preliminary data supported construct validity. Relative to NCs, prodromal individuals displayed impaired social and role functioning at baseline. Analyses of change over time indicated that role functioning declined over the year before ascertainment and improved over 12-month follow-up, presumably with treatment. Social impairment, by contrast, was constant across time and predicted later psychosis (P = .002). Discussion: Using 2 new global measures, social functioning was found to be a stable trait, unchanged by treatment, with considerable potential to be a marker of schizophrenia. Role functioning, by contrast, may be a more direct barometer of clinical change and may be responsive to treatment and environmental change.
PMCID: PMC2526147  PMID: 17440198
RAP; CAPPS; functional predictors; prodromal schizophrenia; outcome; psychosis; scale validation; Global Functioning: Social; Global Functioning: Role
14.  Editor's Introduction: The Empirical Status of the Ultra High-Risk (Prodromal) Research Paradigm 
Schizophrenia Bulletin  2007;33(3):661-664.
Given the growth of prodromal research in the past 15 years, the time seems right for assessing whether the ultra high-risk (UHR) research paradigm has delivered on its promise as an approach to identification of individuals at risk for imminent onset of psychosis and as a platform for studies assessing protective benefits of early interventions and for elucidating predictive markers. As demonstrated by the 8 articles on this theme in the present issue, the empirical basis of the prodromal research area has advanced significantly. While there is a lower risk for transition to psychosis in recent studies compared with initial studies, most recent studies still show a 30%–35% risk for psychosis within 1–2 years of follow-up, a rate that is substantially higher than the incidence rate of psychosis among transition age youth in the general population. Moreover, the means with which to improve this predictive equation is rapidly developing, enabled by the collaborative integration of data across multiple sites, the employment of multivariate risk algorithms, and a longitudinal perspective on symptoms, cognition, and functioning. All the initial intervention studies have produced encouraging findings, albeit with small sample sizes and relatively large attrition rates. Nevertheless, the findings in this issue, together with others like them appearing at an increasing rate in the world literature, indicate that the prodromal research area is increasing in maturity and sophistication, providing a useful heuristic for early detection and intervention in those at risk for psychosis.
PMCID: PMC2526144  PMID: 17470445
psychosis; prodrome; prevention
15.  Genetics and Neuropsychology: A Merger Whose Time Has Come 
Neuropsychology  2016;30(1):1-5.
Genetics and neuropsychology have historically been two rather distant and unrelated fields. With the very rapid advances that have been taking place in genetics, research and treatment of disorders of cognition in the 21st century are likely to be increasingly informed by individual differences in genetics and epigenetics. Although neuropsychologists are not expected to become geneticists, it is our view that increased training in genetics should become more central to training in neuropsychology. This relationship should not be unidirectional. Here we note ways in which an understanding of genetics and epigenetics can inform neuropsychology. On the other hand, given the complexity of cognitive phenotypes, neuropsychology can also play a valuable role in informing and refining genetic studies. Greater integration of the two should advance both fields.
PMCID: PMC4758834  PMID: 26710091
genetics; epigenetics; genetic architecture; polygenicity; gene-environment interplay
16.  Functional connectivity in BOLD and CBF data: Similarity and reliability of resting brain networks 
NeuroImage  2014;106:111-122.
Resting-state functional connectivity (FC) fMRI (rs-fcMRI) offers an appealing approach to mapping the brain’s intrinsic functional organization. Blood oxygen level dependent (BOLD) and arterial spin labeling (ASL) are the two main rs-fcMRI approaches to assess alterations in brain networks associated with individual differences, behavior and psychopathology. While the BOLD signal is stronger with a higher temporal resolution, ASL provides quantitative, direct measures of the physiology and metabolism of specific networks. This study systematically investigated the similarity and reliability of resting brain networks (RBNs) in BOLD and ASL. A 2 × 2 × 2 factorial design was employed where each subject underwent repeated BOLD and ASL rs-fcMRI scans on two occasions on two MRI scanners respectively. Both independent and joint FC analyses revealed common RBNs in ASL and BOLD rs-fcMRI with a moderate to high level of spatial overlap, verified by Dice Similarity Coefficients. Test–retest analyses indicated more reliable spatial network patterns in BOLD (average modal Intraclass Correlation Coefficients: 0.905 ± 0.033 between-sessions; 0.885 ± 0.052 between-scanners) than ASL (0.545 ± 0.048; 0.575 ± 0.059). Nevertheless, ASL provided highly reproducible (0.955 ± 0.021; 0.970 ± 0.011) network-specific CBF measurements. Moreover, we observed positive correlations between regional CBF and FC in core areas of all RBNs indicating a relationship between network connectivity and its baseline metabolism. Taken together, the combination of ASL and BOLD rs-fcMRI provides a powerful tool for characterizing the spatiotemporal and quantitative properties of RBNs. These findings pave the way for future BOLD and ASL rs-fcMRI studies in clinical populations that are carried out across time and scanners.
PMCID: PMC4285775  PMID: 25463468
Arterial spin labeling; Default mode network; Functional connectivity; Resting-state; Test–retest repeatability
17.  Decreases in Perceived Maternal Criticism Predict Improvement in Subthreshold Psychotic Symptoms in a Randomized Trial of Family-Focused Therapy for Individuals at Clinical High Risk for Psychosis 
Perceived criticism (PC) is a measure of how much criticism from 1 family member “gets through” to another. PC ratings have been found to predict the course of psychotic disorders, but questions remain regarding whether psychosocial treatment can effectively decrease PC, and whether reductions in PC predict symptom improvement. In a sample of individuals at high risk for psychosis, we examined a) whether Family Focused Therapy for Clinical High-Risk (FFT-CHR), an 18-session intervention that consists of psychoeducation and training in communication and problem solving, brought about greater reductions in perceived maternal criticism, compared to a 3-session family psychoeducational intervention; and b) whether reductions in PC from baseline to 6-month reassessment predicted decreases in subthreshold positive symptoms of psychosis at 12-month follow-up. This study was conducted within a randomized controlled trial across 8 sites. The perceived criticism scale was completed by 90 families prior to treatment and by 41 families at 6-month reassessment. Evaluators, blind to treatment condition, rated subthreshold symptoms of psychosis at baseline, 6- and 12-month assessments. Perceived maternal criticism decreased from pre- to posttreatment for both treatment groups, and this change in criticism predicted decreases in subthreshold positive symptoms at 12-month follow-up. This study offers evidence that participation in structured family treatment is associated with improvement in perceptions of the family environment. Further, a brief measure of perceived criticism may be useful in predicting the future course of attenuated symptoms of psychosis for CHR youth.
PMCID: PMC4673032  PMID: 26168262
schizophrenia; expressed emotion; psychosocial treatment; family interaction
18.  Perceptions of family criticism and warmth and their link to symptom expression in racially/ethnically diverse adolescents and young adults at clinical high risk for psychosis 
Early intervention in psychiatry  2014;9(6):476-486.
Little is known about the role of expressed emotion (EE) in early symptom expression in individuals at clinical high risk (CHR) for psychosis. In patients with established schizophrenia, the effects of EE on clinical outcomes have purportedly varied across racial/ethnic groups, but this has not yet been investigated among CHR patients. Furthermore, studies have traditionally focused upon caregiver levels of EE via interview-based ratings, whereas the literature on patient perceptions of caregiver EE on psychosis symptoms is relatively limited.
Linear regression models were conducted to examine the impact of criticism and perceived warmth in the family environment, from the CHR patient’s perspective, on positive and negative symptom expression in non-Latino white (NLW; n = 38) and Latino (n = 11) adolescents and young adults at CHR for developing psychosis.
Analyses examining the sample as a whole demonstrated that perceived levels of maternal criticism were negatively associated with negative CHR symptomatology. Additional analyses indicated that race/ethnicity moderated the relationship between criticism/warmth and clinical symptomatology. We found evidence of a contrasting role of patient perceived criticism and warmth depending upon the patient’s race/ethnicity.
Family processes shown to impact the course of schizophrenia among NLWs may function differently among Latino than NLW patients. These findings have important implications for the development of culturally appropriate interventions and may aid efforts to improve the effectiveness of mental health services for diverse adolescents and young adults at CHR for psychosis. Given the small sample size of this study, analyses should be replicated in a larger study before more definitive conclusions can be made.
PMCID: PMC4146748  PMID: 24576106
cultural diversity; early psychosis; family caregiver; prodrome
19.  Negative symptoms and impaired social functioning predict later psychosis in Latino youth at clinical high risk in the North American prodromal longitudinal studies consortium 
Early intervention in psychiatry  2014;9(6):467-475.
Examining ethnically related variables in evaluating those at risk for psychosis is critical. This study investigated sociodemographic and clinical characteristics of Latino versus non-Latino clinical high-risk (CHR) subjects and healthy control (HC) subjects in the first North American Prodrome Longitudinal Study.
Fifty-six Latino CHR subjects were compared to 25 Latino HC and 423 non-Latino CHR subjects across clinical and demographic variables. Thirty-nine of the 56 CHR subjects completed at least one subsequent clinical evaluation over the 2.5-year period with 39% developing a psychotic illness. Characteristics of Latino CHR subjects who later converted to psychosis (‘converters’) were compared to those who did not (‘non-converters’).
Latino CHR subjects were younger than non-Latino CHR subjects and had less education than Latino HC subjects and non-Latino CHR counterparts. Latino CHR converters had higher scores than Latino non-converters on the Structured Interview for Prodromal Syndromes total negative symptoms that were accounted for by decreased expression of emotion and personal hygiene/social attentiveness subsections. Latino CHR converters scored lower on the global functioning:social scale, indicating worse social functioning than Latino non-converters.
Based on this sample, Latino CHR subjects may seek treatment earlier and have less education than non-Latino CHR subjects. Deficits in social functioning and impaired personal hygiene/social attentiveness among Latino CHR subjects predicted later psychosis and may represent important areas for future study. Larger sample sizes are needed to more thoroughly investigate the observed ethnic differences and risk factors for psychosis in Latino youth.
PMCID: PMC4362746  PMID: 24576057
clinical high risk; Latino; prodrome; psychosis
20.  Stress Exposure and Sensitivity in the Clinical High-Risk Syndrome: Initial Findings from the North American Prodrome Longitudinal Study (NAPLS) 
Schizophrenia research  2014;160(0):104-109.
There is inconsistent evidence for increased stress exposure among individuals at clinical high risk (CHR) for psychosis. Yet, similar to patients with a diagnosed psychotic illness, the preponderance of evidence suggests that CHR individuals tend to experience stressful life events (LE) and daily hassles (DH) as more subjectively stressful than healthy individuals. The present study utilizes data from the North American Prodrome Longitudinal Study Phase 2 (NAPLS-2) to test the hypotheses that 1) CHR individuals manifest higher self-reported stress in response to both LE and DH, when compared to healthy controls (HC), 2) group differences in self-reported stress increase with age, 3) baseline self-reported stress is associated with follow-up clinical status, and 4) there is a sensitization effect of LE on the response to DH. In contrast to some previous research, the present findings indicate that the CHR group (N= 314) reported exposure to more LE when compared to the HC group (N=162). As predicted, CHR participants rated events as more stressful, and those who progressed to psychosis reported a greater frequency of LE and greater stress from events compared to those whose prodromal symptoms remitted. There was also some evidence of stress-sensitization; those who experienced more stress from LE rated current DH as more stressful. The results indicate that the “prodromal” phase is a period of heightened stress and stress sensitivity, and elevated cumulative lifetime exposure to stressful events may increase reactions to current stressors.
PMCID: PMC4593703  PMID: 25443665
Clinical High Risk; Prodrome; Stress; PERI Life Events Scale; Daily Stress Inventory; Daily Hassles
21.  Evaluating the impact of cannabis use on thalamic connectivity in youth at clinical high risk of psychosis 
BMC Psychiatry  2015;15:276.
Disruptions in thalamic functional connectivity have been observed in people with schizophrenia and in youth at clinical high risk (CHR) of psychosis. However, the impact of environmental risk factors for psychosis on thalamic dysconnectivity is poorly understood. We tested whether thalamic dysconnectivity is related to patterns of cannabis use in a CHR sample.
162 CHR and 105 control participants were assessed on cannabis use severity, frequency, and age at onset of first use as part of the North American Prodrome Longitudinal Study and completed resting-state fMRI scans. Whole-brain thalamic functional connectivity maps were generated using individual subjects’ anatomically defined thalamic seeds.
Thalamic connectivity did not significantly correlate with current cannabis use severity or frequency in either CHR or controls. In CHR cannabis users, a significant correlation emerged between attenuated thalamic connectivity with left sensory/motor cortex and a younger age at onset of cannabis use. CHR who used cannabis before age 15 did not differ on thalamic connectivity as compared to CHR who used after age 15 or CHR who were cannabis naïve. No group differences in thalamic connectivity emerged when comparing CHR separated by moderate/high use frequency, low-frequency or cannabis naïve.
Although a younger age at onset of cannabis use may be associated with disrupted thalamo-cortical coupling, cannabis use does not appear to be an identifying characteristic for thalamic connectivity in CHR with moderate/high use frequency compared to low-frequency users or CHR who are cannabis naïve.
Electronic supplementary material
The online version of this article (doi:10.1186/s12888-015-0656-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4640353  PMID: 26553191
Cannabis; Clinical high risk; Functional connectivity; Resting state functional magnetic resonance imaging; Psychosis; Schizophrenia; Thalamus
22.  The Relationship of Neurocognition and Negative Symptoms to Social and Role Functioning Over Time in Individuals at Clinical High Risk in the First Phase of the North American Prodrome Longitudinal Study 
Schizophrenia Bulletin  2014;40(6):1452-1461.
Objectives: Impaired social, role, and neurocognitive functioning are preillness characteristics of people who later develop psychosis. In people with schizophrenia, neurocognition and negative symptoms are associated with functional impairment. We examined the relative contributions of neurocognition and symptoms to social and role functioning over time in clinically high-risk (CHR) individuals and determined if negative symptoms mediated the influence of cognition on functioning. Methods: Social, role, and neurocognitive functioning and positive, negative, and disorganized symptoms were assessed in 167 individuals at CHR for psychosis in the North American Prodrome Longitudinal Study Phase 1 (NAPLS-1), of whom 96 were reassessed at 12 months. Results: Regression analyses indicated that negative symptoms accounted for unique variance in social and role functioning at baseline and follow-up. Composite neurocognition accounted for unique, but modest, variance in social and role functioning at baseline and in role functioning at follow-up. Negative symptoms mediated the relationship between composite neurocognition and social and role functioning across time points. In exploratory analyses, individual tests (IQ estimate, Digit Symbol/Coding, verbal memory) selectively accounted for social and role functioning at baseline and follow-up after accounting for symptoms. When negative symptom items with content overlapping with social and role functioning measures were removed, the relationship between neurocognition and social and role functioning was strengthened. Conclusion: The modest overlap among neurocognition, negative symptoms, and social and role functioning indicates that these domains make substantially separate contributions to CHR individuals.
PMCID: PMC4193704  PMID: 24550526
social and role functioning; neurocognition; negative symptoms; prodrome
23.  Maternal complement C1q and increased odds for psychosis in adult offspring 
Schizophrenia research  2014;159(1):14-19.
The presence of maternal antibodies to food and infectious antigens may confer an increased risk of developing schizophrenia and psychosis in adult offspring. Complement factor C1q is an immune molecule with multiple functions including clearance of antigen-antibody complexes from circulation and mediation of synaptic pruning during fetal brain development. To determine if maternal C1q was associated with offspring schizophrenia and psychosis, we evaluated 55 matched case-control maternal serum pairs from the National Collaborative Perinatal Project. Sample pairs were composed of mothers whose offspring developed psychoses as adults and those whose offspring were free from psychiatric disease. Matching criteria for offspring included birth date, delivery hospital, race and gender, with further matching based on mother’s age. IgG markers of C1q, bovine milk casein, egg ovalbumin and wheat gluten were measured with enzyme-linked immunosorbent assays. C1q levels were compared to food antigen IgG and to previously generated data for C-reactive protein, adenovirus, herpes simplex viruses, influenza viruses, measles virus and Toxoplasma gondii. C1q was significantly elevated in case mothers with odds ratios of 2.66–6.31 (conditional logistic regressions, p≤0.008–0.05). In case mothers only, C1q was significantly correlated with antibodies to both food and infectious antigens: gluten (R2=0.26, p≤0.004), herpes simplex virus type 2 (R2=0.21, p≤0.02), adenovirus (R2=0.25, p≤0.006). In conclusion, exposure to maternal C1q activity during pregnancy may be a risk factor for the development of schizophrenia and psychosis in offspring. Prenatal measurement of maternal C1q may be an important and convergent screening tool to identify potentially deleterious immune activation from multiple sources.
PMCID: PMC4177507  PMID: 25195065
Innate immune activation; inflammation; maternal exposure; maternal-fetal interface; synapses
24.  Current Status Specifiers for Patients at Clinical High Risk for Psychosis 
Schizophrenia research  2014;158(0):69-75.
Longitudinal studies of the clinical high risk (CHR) syndrome for psychosis have emphasized the conversion vs non-conversion distinction and thus far have not focused intensively on classification among non-converters. The present study proposes a system for classifying CHR outcomes over time when using the Structured Interview for Psychosis-risk Syndromes and evaluates its validity.
The system for classifying CHR outcomes is referred to as “current status specifiers,” with “current” meaning over the month prior to the present evaluation and “specifiers” indicating a set of labels and descriptions of the statuses. Specifiers for four current statuses are described: progression, persistence, partial remission, and full remission. Data from the North American Prodromal Longitudinal Study were employed to test convergent, discriminant, and predictive validity of the current status distinctions.
Validity analyses partly supported current status distinctions. Social and role functioning were more impaired in progressive and persistent than in remitted patients, suggesting a degree of convergent validity. Agreement between CHR current statuses and current statuses for a different diagnostic construct (DSM-IV Major Depression) was poor, suggesting discriminant validity. The proportion converting to psychosis within a year was significantly higher in cases meeting progression criteria than in those meeting persistence criteria and tended to be higher than in those meeting full remission criteria, consistent with a degree of predictive validity.
CHR syndrome current status specifiers could offer a potentially valid and useful description of current clinical status among non-converters. Study in additional samples is needed.
PMCID: PMC4152558  PMID: 25012147
psychosis; clinical high risk; risk syndrome; current status; course of illness
25.  Family-Focused Treatment for Adolescents and Young Adults at High Risk for Psychosis: Results of a Randomized Trial 
Longitudinal studies have begun to clarify the phenotypic characteristics of adolescents and young adults at clinical high risk for psychosis. This 8-site randomized trial examined whether a 6-month program of family psychoeducation was effective in reducing the severity of attenuated positive and negative psychotic symptoms and enhancing functioning among individuals at high risk.
Adolescents and young adults (mean 17.4±4.1 years) with attenuated positive psychotic symptoms, brief and intermittent psychosis, or genetic risk with functional deterioration were randomly assigned to 18 sessions of family-focused therapy for individuals at clinical high risk (FFT-CHR) in 6 months or 3 sessions of family psychoeducation (enhanced care, or EC). FFT-CHR included psychoeducation about early signs of psychosis, stress management, communication training, and problem-solving skills training, whereas EC focused on symptom prevention. Independent evaluators assessed participants at baseline and 6 months on positive and negative symptoms and social-role functioning.
Of 129 participants, 102 (79.1%) were followed at 6 months. Participants in FFT-CHR showed greater improvements in attenuated positive symptoms over 6 months than participants in EC (F[1,97]=5.49, P=.02). Negative symptoms improved independently of psychosocial treatments. Changes in psychosocial functioning depended on age: participants over 19 years showed more role improvement in FFT-CHR, whereas participants between 16 and 19 years showed more role improvement in EC. The results were independent of concurrent pharmacotherapy.
Interventions that focus on improving family relationships may have prophylactic efficacy in individuals at high risk for psychosis. Future studies should examine the specificity of effects of family intervention compared to individual therapy of the same duration and frequency.
PMCID: PMC4112074  PMID: 25062592
attenuated psychotic symptoms; schizophrenia; early warning signs; psychoeducation; family therapy

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