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Background Autism is a heterogeneous condition and there is growing evidence that different features are dissociable and may be underpinned by different risk factors. Several autism risk copy number variants (CNVs) have been identified. It remains unclear whether these CNVs differentially impact autism presentation. This study aimed to contrast autism symptomatology and the clinical profile of different autism risk CNVs. Methods Patients were recruited at several international sites based on genotype, not autism phenotype. This work represents the efforts of several consortia; the ECHO study, IMAGINE-ID consortium, International 22q11.2DS Brain Behaviour Consortium, 16p11.2 European Consortium and Simons VIP. Patients were all assessed using the Autism Diagnostic Interview-Revised (ADI-R) and underwent IQ testing. We focused on 16p11.2 deletion (n=96), 16p11.2 duplication (n=47), 22q11.2 deletion (n=383) and 22q11.2 duplication (n=22) carriers. Patients were aged 4–27 years. We examined autism prevalence based on ADI-R criteria, ADI-R domain scores, whether carriers with autism had additional IQ deficits and autism male-to-female ratio. Results Autism prevalence differed by syndrome (p Discussion Autism risk genetic variants have specific genotype-phenotype correlations. This indicates that autism is dissociable at the genetic level, and supports the view that different biological pathways underpin distinct symptom domains.

Several studies have demonstrated that youth at clinical high risk (CHR) of developing psychosis have a high prevalence of comorbid psychiatric disorders. Less is known about the impact of comorbid diagnoses on later conversion to psychosis and the change over time. The aim of this study was to determine the frequency and distribution of psychiatric diagnoses at baseline and over time in the North American Prodrome Longitudinal Study (NAPLS 2) and the role of comorbid diagnoses in conversion to psychosis. The NAPLS 2 sample consisted of 744 CHR youth and 276 healthy controls. Only 21% of the CHR group did not have a comorbid diagnosis with many have 2-3 DSM-IV comorbid diagnoses. The most common diagnoses were anxiety and depressive disorders, which did improve over time. The only diagnosis at baseline that differentiated the converters from the non-converters was cannabis misuse. Comorbidity, except for cannabis use, was essentially independent of clinical outcome. It is possible that those with comorbid diagnoses are preferentially the help-seeking individuals that present for help in our clinics and research projects and that those who are at risk but do not have a comorbid diagnosis may not be seeking help in the prodromal phase.

Recent research suggests that perceptual abnormalities are a group of diverse experiences, which have been associated with trauma, cannabis use, and anxiety. Of the attenuated psychotic symptoms that are present in youth at clinical high risk (CHR) of psychosis, perceptual abnormalities tend to be one of the most frequently endorsed symptoms. However, very few studies have explored perceptual abnormalities and their relationships with the above environmental and affective factors in a CHR sample. Four hundred and forty-one CHR individuals who met criteria for attenuated psychotic symptom syndrome (APSS) determined by the Structured Interview for Psychosis-risk Syndromes (SIPS) were assessed on the content of their perceptual abnormalities, early traumatic experience, cannabis use and self-reported anxiety. Logistic regression analyses suggested that both simple auditory and simple visual perceptual abnormalities were more likely to be reported by CHR who had early traumatic experiences, who are current cannabis users, and who have higher levels of anxiety. Multiple regression analysis revealed that only trauma and anxiety were independent predictors of both simple auditory and simple visual perceptual abnormalities. It is possible that examining subtypes of perceptual abnormalities in CHR leads to an improved understanding of the prevalence of such symptoms.

22q11.2 deletion syndrome (22q11DS) is a recurrent copy number variant (CNV) with high penetrance for developmental neuropsychiatric disorders. Study of individuals with 22q11DS therefore may offer key insights into neural mechanisms underlying such complex illnesses. Resting-state functional MRI (rs-fMRI) studies in idiopathic schizophrenia have consistently revealed disruption of thalamic and hippocampal circuitry. Here, we sought to test whether this circuitry is similarly disrupted in the context of this genetic high-risk condition. To this end, resting-state functional connectivity patterns were assessed in a sample of young men and women with 22q11DS (n=42) and demographically matched healthy controls (n=39). Neuroimaging data were acquired via single-band protocols, and analyzed in line with methods provided by the Human Connectome Project (HCP). We computed functional relationships between individual-specific anatomically-defined thalamic and hippocampal seeds and all gray matter voxels in the brain. Whole-brain type I error protection was achieved through nonparametric permutation-based methods. 22q11DS patients displayed reciprocal disruptions in thalamic and hippocampal functional connectivity relative to control subjects. Thalamo-cortical coupling was increased in sensorimotor cortex, and reduced across associative networks. The opposite effect was observed for the hippocampus in regards to sensory and associative network connectivity. The thalamic and hippocampal dysconnectivity observed in 22q11DS suggest that high genetic risk for psychiatric illness is linked with disruptions in large-scale cortico-subcortical networks underlying higher-order cognitive functions. These effects highlight the translational importance of large-effect CNVs for informing mechanisms underlying neural disruptions observed in idiopathic developmental neuropsychiatric disorders.SIGNIFICANCE STATEMENTInvestigation of neuroimaging biomarkers in highly penetrant genetic syndromes represents a more biologically tractable approach to identify neural circuit disruptions underlying developmental neuropsychiatric conditions. 22q11.2 deletion syndrome confers particularly high risk for psychotic disorders, and is thus an important translational model in which to investigate systems-level mechanisms implicated in idiopathic illness. Here, we show resting-state fMRI evidence of large-scale sensory and executive network disruptions in youth with 22q11DS. In particular, this study provides the first evidence that these networks are disrupted in a reciprocal fashion with regard to the functional connectivity of the thalamus and hippocampus, suggesting circuit-level dysfunction.

Author(s): Sabb, Fred W; Hellemann, Gerhard; Allen, Nicholas B; Bearden, Carrie E | Abstract: IntroductionWorking Memory and Task-Switching are essential components of cognitive control, which underlies many symptoms evident across multiple neuropsychiatric disorders, including psychotic and mood disorders. Vulnerability to these disorders has a substantial genetic component, suggesting that clinically unaffected first-degree relatives may carry some vulnerability-related traits. Converging evidence from animal and human studies demonstrates that dopamine transmission, striatal and frontal brain regions, and attention and switching behaviors are essential components of a multilevel circuit involved in salience, and disruptions in that circuit may lead to features of psychosis. Yet, it is possible that unaffected relatives may also possess characteristics that protect against development of illness. We hypothesized that reduced switch cost in a cued task-switching task, may be a behavioral expression of this "resilience" phenotype that will be observable in unaffected relatives.MethodsWe tested a large community sample (nn=n536) via the web, to assess different subcomponents of cognitive control, including task-switching and working memory, as well as risk-taking, among individuals who report having an affected relative with a psychotic or mood disorder.ResultsHealthy individuals with suspected genetic risk due to a self-reported familial history of a psychotic disorder demonstrated better task-switching performance compared to healthy people without a psychiatrically ill relative and those with a relative with a mood disorder. This result was specific to illness status and task domain, in that individuals with a personal history of depression or anxiety did not show improved task-switching performance, and this improvement was selective to task-switching and not seen in other putative cognitive control domains (working memory or risk taking).ConclusionsAlthough this study has limitations and independent replication is needed, these preliminary findings suggest a potential avenue for understanding susceptibility to these disorders by highlighting possible protective as well as vulnerability-related aspects of risk phenotypes.

In a recent report of the North American Prodrome Longitudinal Study (NAPLS), clinical high-risk individuals who converted to psychosis showed a steeper rate of cortical gray matter reduction compared with non-converters and healthy controls, and the rate of cortical thinning was correlated with levels of proinflammatory cytokines at baseline. These findings suggest a critical role for microglia, the resident macrophages in the brain, in perturbations of cortical maturation processes associated with onset of psychosis. Elucidating gene expression pathways promoting microglial action prior to disease onset would inform potential preventative intervention targets. Here we used a forward stepwise regression algorithm to build a classifier of baseline microRNA expression in peripheral leukocytes associated with annualized rate of cortical thinning in a subsample of the NAPLS cohort (N=74). Our cortical thinning classifier included nine microRNAs, p=3.63 × 10-08, R2=0.358, permutation-based p=0.039, the gene targets of which were enriched for intracellular signaling pathways that are important to coordinating inflammatory responses within immune cells (p

Social cognition, the mental operations that underlie social interactions, is a major construct to investigate in schizophrenia. Impairments in social cognition are present before the onset of psychosis, and even in unaffected first-degree relatives, suggesting that social cognition may be a trait marker of the illness.In a large cohort of individuals at clinical high risk for psychosis (CHR) and healthy controls, three domains of social cognition (theory of mind, facial emotion recognition and social perception) were assessed to clarify which domains are impaired in this population.Six-hundred and seventy-five CHR individuals and 264 controls, who were part of the multi-site North American Prodromal Longitudinal Study, completed The Awareness of Social Inference Test, the Penn Emotion Recognition task, the Penn Emotion Differentiation task, and the Relationship Across Domains, measures of theory of mind, facial emotion recognition, and social perception, respectively.Social cognition was not related to positive and negative symptom severity, but was associated with age and IQ. CHR individuals demonstrated poorer performance on all measures of social cognition. However, after controlling for age and IQ, the group differences remained significant for measures of theory of mind and social perception, but not for facial emotion recognition.Theory of mind and social perception are impaired in individuals at CHR for psychosis. Age and IQ seem to play an important role in the arising of deficits in facial affect recognition. Future studies should examine the stability of social cognition deficits over time and their role, if any, in the development of psychosis.

Neurofibromatosis type I (NF1) is a genetic disorder caused by mutations in the neurofibromin 1 gene at locus 17q11.2. Individuals with NF1 have an increased incidence of learning disabilities, attention deficits, and autism spectrum disorders. As a single-gene disorder, NF1 represents a valuable model for understanding gene-brain-behavior relationships. While mouse models have elucidated molecular and cellular mechanisms underlying learning deficits associated with this mutation, little is known about functional brain architecture in human subjects with NF1. To address this question, we used resting state functional connectivity magnetic resonance imaging (rs-fcMRI) to elucidate the intrinsic network structure of 30 NF1 participants compared with 30 healthy demographically matched controls during an eyes-open rs-fcMRI scan. Novel statistical methods were employed to quantify differences in local connectivity (edge strength) and modularity structure, in combination with traditional global graph theory applications. Our findings suggest that individuals with NF1 have reduced anterior-posterior connectivity, weaker bilateral edges, and altered modularity clustering relative to healthy controls. Further, edge strength and modular clustering indices were correlated with IQ and internalizing symptoms. These findings suggest that Ras signaling disruption may lead to abnormal functional brain connectivity; further investigation into the functional consequences of these alterations in both humans and in animal models is warranted.

In studies describing the long-term follow-up up of youth at clinical high risk (CHR) of psychosis, little attention has been given to details of specific prodromal symptoms. In this paper we describe the prodromal symptoms of 764 CHR participants recruited in the multi-site North American Prodrome Longitudinal Study (NAPLS). Symptoms were rated on the Scale of Prodromal Symptoms (SOPS) at baseline and 6, 12, 18 and 24 month follow-ups. Clinical outcome at the 2-year assessment was categorized as psychotic, prodromal progression, symptomatic or in remission. The majority of the CHR sample (93%) met criteria for the attenuated positive symptoms syndrome (APSS). Significant improvements in SOPS symptoms were observed overtime. Unusual thought content, disorganized communication and overall ratings on disorganized symptoms differentiated those who transitioned to psychosis from the other clinical outcome groups. Suspiciousness and total positive symptoms differentiated those in remission from the other clinical outcome groups.

Background: Schema Theory proposes that the development of maladaptive schemas are based on a combination of memories, emotions and cognitions regarding oneself and one's relationship to others. A cognitive model of psychosis suggests that schemas are crucial to the development and persistence of psychosis. Little is known about the impact that schemas may have on those considered to be at clinical high risk (CHR) of developing psychosis. Aims: To investigate schemas over time in a large sample of CHR individuals and healthy controls. Method: Sample included 765 CHR participants and 280 healthy controls. Schemas were assessed at baseline, 6 and 12 months using the Brief Core Schema Scale (BCSS). Baseline schemas were compared to 2-year clinical outcome. Results: CHR participants evidenced stable and more maladaptive schemas over time compared to controls. Schemas at initial contact did not vary amongst the different clinical outcome groups at 2 years although all CHR outcome groups evidenced significantly worse schemas than healthy controls. Although there were no differences on baseline schemas between those who later transitioned to psychosis compared to those who did not, those who transitioned to psychosis had more maladaptive negative self-schemas at the time of transition. Associations between negative schemas were positively correlated with earlier abuse and bullying. Conclusions: These findings demonstrate a need for interventions that aim to improve maladaptive schemas among the CHR population. Therapies targeting self-esteem, as well as schema therapy may be important work for future studies.

A recent prospective longitudinal neuroimaging study of 274 prodromal risk syndrome subjects revealed that those who later developed full-blown psychotic symptoms exhibited accelerated gray matter loss and third ventricle expansion around the time of onset of psychosis. Previous studies also indicate that higher levels of unusual thought content during prodromal states are a significant predictor of psychosis in clinically high-risk youth (CHR). However, the relationship between clinical symptoms and changes in neuroanatomical structure has not been previously examined in the North American Prodrome Longitudinal Study (NAPLS) sample at the atlas level. In this report, we investigated whether symptom severity as measured by the Scale of Prodromal Symptoms (SOPS) predicted the accelerated gray matter decline in 274 CHR cases, including 35 who converted to psychosis. Higher levels of unusual thought content (pre-delusional) symptoms at baseline were associated with a steeper rate of gray matter loss in the prefrontal cortex bilaterally among converters. In contrast, there was no association found among non-converters. Steeper gray matter loss seems to be unique to those (CHR) individuals with higher levels of sub-psychotic pre-delusional symptoms that acutely worsen in the ramp-up to full-blown psychosis, and as such may reflect pathophysiological processes driving emergence of psychosis.

22q11.2 deletion syndrome (22q11DS) is a neurogenetic disorder associated with elevated rates of developmental neuropsychiatric disorders and impaired executive function (EF). Disrupted brain structure-function relationships may underlie EF deficits in 22q11DS. We administered the Behavior Rating Inventory of Executive Function (BRIEF) to assess real-world EF in patients with 22q11DS and matched controls (n = 86; age 6-17 years), along with cognitive measures that tap behavioral regulation and metacognition aspects of EF. Using FreeSurfer's whole-brain vertex cortical thickness pipeline, we investigated brain structure-EF relationships in patients with 22q11DS and controls. Behaviorally, patients with 22q11DS were impaired on multiple EF measures. Right orbitofrontal cortical thickness showed a differential relationship between real-world EF in patients with 22q11DS and controls. We also observed a group difference in the relationship between behavioral regulation and metacognition measures with thickness of ventral and dorsolateral prefrontal regions, respectively. Our findings suggest that executive dysfunction characteristic of 22q11DS is underscored by altered prefrontal cortical structure.

Highlights • 22q11DS offers a compelling model to understand the neural substrates of attentional dysfunction. • First study directly comparing neural function in 22q11DS vs. ADHD patients • 22q11DS and ADHD patients show a shared deficit in RI-related activation. • ADHD patients showed greater activity in the middle frontal gyrus than 22q11DS during RI. • Neural activity is inversely correlated with self-reported Cognitive Impulsivity in 22q11DS.

Individuals with schizophrenia (SZ) consistently show deficits in spatial working memory (WM) and associated atypical patterns of neural activity within key WM regions, including the dorsolateral prefrontal cortex (dlPFC) and parietal cortices. However, little research has focused on adolescent psychosis (AP) and potential age-associated disruptions of WM circuitry that may occur in youth with this severe form of illness. Here we utilized each subject's individual spatial WM capacity to investigate task-based neural dysfunction in 17 patients with AP (16.58 ± 2.60 years old) as compared to 17 typically developing, demographically comparable adolescents (18.07 ± 3.26 years old). AP patients showed lower behavioral performance at higher WM loads and lower overall WM capacity compared to healthy controls. Whole-brain activation analyses revealed greater bilateral precentral and right postcentral activity in controls relative to AP patients, when controlling for individual WM capacity. Seed-based psychophysiological interaction (PPI) analyses revealed significantly greater co-activation between the left dlPFC and left frontal pole in controls relative to AP patients. Significant group-by-age interactions were observed in both whole-brain and PPI analyses, with AP patients showing atypically greater neural activity and stronger coupling between WM task activated brain regions as a function of increasing age. Additionally, AP patients demonstrated positive relationships between right dlPFC neural activity and task performance, but unlike healthy controls, failed to show associations between neural activity and out-of-scanner neurocognitive performance. Collectively, these findings are consistent with atypical WM-related functioning and disrupted developmental processes in youth with AP.

While graph theoretical modeling has dramatically advanced our understanding of complex brain systems, the feasibility of aggregating brain graphic data in large imaging consortia remains unclear. Here, using a battery of cognitive, emotional and resting fMRI paradigms, we investigated the reproducibility of functional connectomic measures across multiple 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. Higher reliabilities were detected for cognitive tasks (vs rest) and for weighted networks (vs binary networks). While network diagnostics for several primary functional systems were consistently reliable independently of paradigm, those for cognitive-emotional systems were reliable predominantly when challenged by task. Different data aggregation approaches yielded significantly different reliability. In addition, we showed that after accounting for observed reliability, satisfactory statistical power can be achieved in the multisite context with a total sample size of approximately 250 when the effect size is at least moderate. Our findings provide direct evidence for the generalizability of brain graphs for both resting and task paradigms in large consortia and encourage the use of multisite, multisession scans to enhance power for human functional connectomic studies.

22q11.2 Deletion syndrome (22q11DS) is a genetic disorder associated with numerous phenotypic consequences and is one of the greatest known risk factors for psychosis. We investigated intrinsic-connectivity-networks (ICNs) as potential biomarkers for patient and psychosis-risk status in 2 independent cohorts, UCLA (33 22q11DS-participants, 33 demographically matched controls), and Syracuse (28 22q11DS, 28 controls). After assessing group connectivity differences, ICNs from the UCLA cohort were used to train classifiers to distinguish cases from controls, and to predict psychosis risk status within 22q11DS; classifiers were subsequently tested on the Syracuse cohort. In both cohorts we observed significant hypoconnectivity in 22q11DS relative to controls within anterior cingulate (ACC)/precuneus, executive, default mode (DMN), posterior DMN, and salience networks. Of 12 ICN-derived classifiers tested in the Syracuse replication-cohort, the ACC/precuneus, DMN, and posterior DMN classifiers accurately distinguished between 22q11DS and controls. Within 22q11DS subjects, connectivity alterations within 4 networks predicted psychosis risk status for a given individual in both cohorts: the ACC/precuneus, DMN, left executive, and salience networks. Widespread within-network-hypoconnectivity in large-scale networks implicated in higher-order cognition may be a defining characteristic of 22q11DS during adolescence and early adulthood; furthermore, loss of coherence within these networks may be a valuable biomarker for individual prediction of psychosis-risk in 22q11DS.

The developmental course of daily functioning prior to first psychosis-onset remains poorly understood. This study explored age-related periods of change in social and role functioning. The longitudinal study included youth (aged 12–23, mean follow-up years = 1.19) at clinical high risk (CHR) for psychosis (converters [CHR-C], n = 83; nonconverters [CHR-NC], n = 275) and a healthy control group (n = 164). Mixed-model analyses were performed to determine age-related differences in social and role functioning. We limited our analyses to functioning before psychosis conversion; thus, data of CHR-C participants gathered after psychosis onset were excluded. In controls, social and role functioning improved over time. From at least age 12, functioning in CHR was poorer than in controls, and this lag persisted over time. Between ages 15 and 18, social functioning in CHR-C stagnated and diverged from that of CHR-NC, who continued to improve (p = .001). Subsequently, CHR-C lagged behind in improvement between ages 21 and 23, further distinguishing them from CHR-NC (p < .001). A similar period of stagnation was apparent for role functioning, but to a lesser extent (p = .007). The results remained consistent when we accounted for the time to conversion. Our findings suggest that CHR-C start lagging behind CHR-NC in social and role functioning in adolescence, followed by a period of further stagnation in adulthood.

The Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) Consortium is a global team science effort, now including over 800 scientists spread across 340 institutions in 35 countries, with the shared goal of understanding disease and genetic influences on the brain. This "crowdsourcing" approach to team neuroscience has unprecedented power for advancing our understanding of both typical and atypical human brain development.

Background: The presence and severity of attenuated-psychosis symptoms define a clinical high risk (CHR) population at elevated risk for psychotic disorders. The NAPLS project is a prospective study of mechanisms contributing to psychosis vulnerability in persons at CHR. Here we investigated a hypothesized role for the highly-integrated immune and redox systems in the development of psychosis. Methods: We examined expression of 143 plasma analytes from a subgroup of the NAPLS2 cohort, including 32 CHR with subsequent psychosis conversion, 40 CHR followed for 2years without psychosis, and 35 unaffected subjects. We used a Luminex platform with analytes chosen to reflect immune, redox, hormonal, and metabolic system status, including many analytes previously associated with schizophrenia and psychosis risk. We applied correlation network analysis to discover potentially co-regulated networks associated with later development of psychosis. Results: Several robust (r > .75) and highly significant (P < .0001 after correction for multiple testing) correlation networks were found in all groups, including a network involving IL3, IL5, IL7, and IL13, and a network involving CCL5, BDNF, TSH, and PDGF. There were significantly fewer nodes in CHR-converters compared with CHR-nonconverters and unaffected subjects. In unaffected subjects, plasminogen activator inhibitor-1 (PAI-1) was highly correlated with matrix metallopeptidases (MMP) 7, 9 and 10 and CD40LG, this network was absent in CHR subjects, and in CHR-converters PAI-1 was robustly and significantly correlated with TIMP1, CCL13, and TIMP1. Conclusion: Apattern of robust and highly significant correlation networks in plasma analytes suggests shared regulatory mechanisms for the inter-correlated analytes. The lower number of correlated analytes in CHR subjects who converted to psychosis suggest a shift in regulation, as does the change in the correlation network involving PAI-1. PAI-1 is of interest given studies linking schizophrenia with reduced tissue plasminogen activator (tPA) and increases in negative regulators of tPA, including activation of both PAI-1and TIMP1 with oxidative stress. In addition, a recent study links toxoplasmosis infection and schizophrenia risk to a pathway involving PAI-1 and TIMP1. Patricio O’Donnell, Pfizer Inc.

Background: Recent studies have recognized that signs of functional disability in schizophrenia are evident in early phases of the disorder, and, as a result, can potentially serve as vulnerability markers of future illness. However, functional measures in the psychosis prodrome have focused exclusively on real-world accomplishment (ie, achievement), rather than on the skills required to carry-out a particular real-world function (ie, capacity). From this perspective capacity provides the foundation for what can actually be achieved. This is comparable to the comparison between IQ (capacity) vs grades at school (achievement). In one of the first reports of its kind, we introduced the Map task, a laboratory-based measure specifically designed to assess a young person’s basic capacity to carry-out age-appropriate skills that lead to independent community living (McLaughlin et al., 2016). Poor performance on the Map task was found to be predictive of conversion to psychosis, suggesting that functional capacity in the prodrome may represent a basic biologically-based vulnerability factor. Given that diminished functional capacity is often a key barrier to good functional outcomes in patients with schizophrenia, the current study sought to next evaluate whether deficits in capacity can also predict social and role (ie, academic) functioning in the prodrome.

Background: In a recent report of the North American Prodrome Longitudinal Study (NAPLS), clinical high-risk individuals who converted to psychosis showed a steeper rate of cortical gray matter reduction compared with nonconverters and healthy controls, and the rate of cortical thinning was correlated with levels of proinflammatory cytokines at baseline. These findings suggest a critical role for microglia, the resident macrophages in the brain, in perturbations of cortical maturation processes associated with onset of psychosis. Elucidating gene expression pathways promoting microglial action prior to disease onset would inform potential preventative intervention targets. Methods: We used a forward stepwise regression algorithm to build a classifier of baseline microRNA expression in peripheral leukocytes associated with annualized rate of cortical thinning in a subsample of the NAPLS cohort (N=74). Results: Our cortical thinning classifier included 9 microRNAs, P=3.63 × 108, R2=0.358, permutation-based P=.039, the gene targets of which were enriched for intracellular signaling pathways that are important to coordinating inflammatory responses within immune cells (P < .05, Benjamini-Hochberg corrected). The classifier was also related to proinflammatory cytokine levels in serum (P=.038). Furthermore, miRNAs that predicted conversion status were found to do so in a manner partially mediated by rate of cortical thinning (point estimate=0.078 [95% CIs: 0.003, 0.168], P=.03). Conclusion: Many of the miRNAs identified here have been previously implicated in brain development, synaptic plasticity, immune function, and/or schizophrenia, showing some convergence across studies and methodologies. Altered intracellular signaling within the immune system may interact with cortical maturation in individuals at high risk for schizophrenia promoting disease onset.

Background: Previous work has established a relationship between metabolic abnormalities and poorer health outcomes in individuals with schizophrenia spectrum disorders. It is likely that metabolic abnormalities, inflammation, and oxidative stress observed in individuals with schizophrenia actually begin to occur prior to the onset of psychosis and may potentially serve as a risk factor in populations at clinical high risk for developing psychosis. Further, in the general population, it has been established that Latino individuals have a higher incidence of metabolic abnormalities than non-Latinos, making CHR Latinos especially vulnerable to the compounded effects of pre-existing metabolic disturbances with added risk of further metabolic disturbance associated with the development of psychosis. In a Clinical Trial of Omega 3 Fatty Acid versus Placebo, baseline cardiometabolic and oxidative stress indices were investigated in a group at Clinical High Risk (CHR) for psychosis from the North American Prodromal Longitudinal Studies (NAPLS). The goal of the present report was to compare cardiometabolic indices in Latino versus non-Latino CHR subjects.

Background: In a recent prospective longitudinal neuroimaging study, clinical high-risk (CHR) individuals who later developed full-blown psychosis showed an accelerated rate of gray matter thinning in superior and medial prefrontal cortex (PFC) and expansion of the ventricular system after applying a stringent correction for multiple comparisons. Although cortical and subcortical volume loss and enlarged ventricles are well characterized structural brain abnormalities among patients with schizophrenia, no prior study has evaluated whether these progressive changes of neuroanatomical indicators are linked in time prior to onset of psychosis. Therefore, we investigated the relationship between the changes in cortical gray matter thickness and ventricular volume using the longitudinal neuroimaging data from the North American Prodrome Longitudinal Study (NAPLS) at the whole-brain level. Methods: MRI structural data were acquired at baseline and 12-month follow-up, and follow-up scans for those who developed fully psychotic symptoms were assessed at the point of conversion. In total, 37 CHR cases who converted to psychosis, 230 CHR cases who did not convert (nonconverters), and 132 healthy comparison subjects had usable baseline and second time point scans. Imaging measures were first transformed to annualized rates of percent change (ARCH) in each cortical vertex. Interval is the time between BL and FU scans in years. Relationships between ARCH of total ventricle volume and ARCH of cortical gray matter values were tested vertex-wise using the general linear model. Among the subjects with BL and 12-FU data available, 125 CHR cases and 66 controls were followed to an additional third time point for a 24-month MRI assessment. For the purpose of testing the replicability of our main hypotheses, neuroanatomical ARCH measures between the 12 and 24month follow-ups were also computed with a parallel set of statistical tests as described earlier. Results: The results showed that ventricular expansion is linked in time to progressive reduction of gray matter, rather than to structural changes in proximal subcortical regions, in a broadly distributed set of cortical regions among CHR youth, including superior, medial, lateral, and inferior PFC, superior temporal gyrus, and parietal cortices. In contrast, the healthy controls did not show the same pattern of associations. The main findings were further replicated using a third assessment wave of MRI scans in a subset of study participants who were followed for an additional year. Conclusion: In summary, expansion of the ventricular spaces is linked in time with an accelerated rate of widespread cortical thinning prior to psychosis onset. The cortical regions experiencing altered maturation during the psychosis prodrome may be more widespread than the regionally specific clusters that have been identified in previous case–control studies

Background: The purpose of this study was to evaluate the role of tobacco use in the development of psychosis in individuals at clinical high risk. Methods: The North American Prodrome Longitudinal Study is a 2-year multisite prospective case–control study of persons at clinical high risk that aims to better understand predictors and mechanisms for the development of psychosis. The cohort consisted of 764 clinical high risk and 279 healthy comparison subjects. Clinical assessments included tobacco and substance use and several risk factors associated with smoking. Results: Clinical high risk subjects were more likely to smoke cigarettes than unaffected subjects (Light Smoking OR=3.0, 95%CI=1.9–5; Heavy Smoking OR=4.8, 95%CI=1.7–13.7). In both groups, smoking was associated with substance use, stressful life events, and perceived discrimination and in clinical high risk subjects with childhood emotional neglect and adaption to school. Clinical high risk subjects reported higher rates of several factors previously associated with smoking. After controlling for these factors, the relationship between clinical high risk state and smoking became non-significant (Light Smoking OR=1.9, 95%CI=0.7–5.2; Heavy Smoking OR=0.9, 95%CI=0.1–7.2). Moreover, baseline smoking status (HR=1.16, 95%CI=0.82–1.65) and categorization as ever smoked (HR=1.3, 95%CI=0.8–2.1) did not predict time to conversion. Conclusion: Persons at high risk for psychosis are more likely to smoke compared to unaffected persons. Factors associated with smoking in both groups were more common in the clinical high risk cohort, and smoking status in clinical high risk subjects did not predict conversion risk. These findings did not support a causal relationship between smoking and psychosis. Funding: This study was supported by the National Institute of Mental Health (NIMH) [grant U01 MH081984 to J.A.; grants U01 MH081928; P50 MH080272; Commonwealth of Massachusetts SCDMH82101008006 to L.J.S.; grants R01 MH60720, U01 MH082022 and K24 MH76191 to K.S.C.; grant U01 MH081902 to T.D.C.; P50 MH066286 (Prodromal Core) to C.E.B.; grant U01 MH082004 to D.O.P.; grant U01 MH081988 to E.F.W.; grant U01 MH082022 to S.W.W.; and U01 MH081857-05 grant to B.A.C.] and the National Institute of Environmental Health Sciences (NIEHS) grant T32ES007018 to M.T.W. The NIMH and NIEHS had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Background: The vast majority of studies of neuropsychological (NP) functioning in Clinical High Risk (CHR) cohorts have examined group averages, possibly concealing a range of subgroups ranging from very impaired to high functioning. Our objective was to assess NP profiles and to explore associations with conversion to psychosis, functional and diagnostic outcome. Methods: Data were acquired from individuals (mean age 18.4, SD=4.6) participating in the longitudinal North American Prodrome Longitudinal Study-I (NAPLS-I), a multi-site consortium following individuals at CHR for developing psychosis for up to 2½ years. By applying the Hierarchical Clustering Ward’s method including 8 different neuropsychological tests, we clustered data of 166 CHR individuals, 49 persons with a family history of psychosis without prodromal symptoms, and 109 healthy controls. We then tested whether cluster profiles with more severe NP impairments were associated with higher conversion rates, lower social and role functioning scores, and/or more chronic diagnostic outcomes compared to the lesser-impaired profiles. To examine clinical utility, analyses were repeated after data were clustered based on clinical decision rules that were established by clinical experts in the field. Results: Four distinctive profile clusters best described the level of NP performance in our CHR cohort: Severely Impaired (n=33); Clearly Abnormal (n=82); Borderline (n=145) and Normal (n=64). The Severely Impaired cluster largely distinguished itself from the rest of the clusters by larger deviations on processing speed and memory tasks. We found compelling differences in outcome between cluster profiles. Importantly, those assigned to the most impaired profile had a conversion rate of 42.4%, had a 40% chance of developing a diagnosis in the schizophrenia spectrum (as compared to 24.4% in the Clearly impaired, 7.4 % in the Borderline impaired and 2.9% in the Normal functioning group), and had significantly worse social (P < .001) and role (P < .001) functioning scores at baseline and 12-month follow-up. Similar results were obtained when data were clustered following clinical decision rules. Conclusion: Despite extensive neuropsychological investigations within CHR cohorts, this is one of the first studies to investigate NP clustering profiles as a contributor to heterogeneity in outcome. Our results indicate that the four NP profiles vary substantially in their outcome, underscoring the relevance of cognitive functioning in the prediction of illness progression. Our findings may tentatively suggest that individualized cognitive profiling should be explored in clinical settings, and my point to important directions for personalized treatment.

Background: The presence of altered white matter microstructure in disorders involving psychosis is well established, but the nature and developmental course of these changes are not well understood (Peters & Karlsgodt, 2015). It is not clear whether the presence of attenuated frontal white matter anisotropy at any phase of illness indexes a pathophysiological change that occurs only within the prodromal and/or first episode phases, or whether early white matter changes are part of a lifespan trajectory of accelerated white matter degeneration in patients (Schwehm et al., 2016; Wright et al., 2014). It also remains to be determined whether schizophrenia-linked anisotropy changes are the result of axon damage or if they also reflect organizational changes.

Background: Reductions in the auditory P300 event-related potential (ERP) component are well established in schizophrenia and reflect early attention-mediated auditory processing deficits. Two subcomponents of P300 are evident depending on oddball task conditions; P3b is elicited by infrequent target stimuli and reflects top-down attention allocation, whereas P3a is elicited by infrequent non-target novel distractor stimuli and reflects bottom-up orienting of attention. The present study examined whether auditory P300 abnormalities precede illness onset and are associated with future clinical status by assessing both target P3b and novel P3a in individuals at clinical high risk for psychosis (CHR) and healthy controls (HC) collected as part of the North American Prodrome Longitudinal Study. Methods: CHR (n=552) and HC (n=235) participants completed baseline EEG recording during an auditory oddball task. CHR participants were further categorized by clinical status after 24months of study participation (n=298) and included a subgroup who transitioned to psychosis (CHR-Transition; n=73), a subgroup who did not transition but remained symptomatic (CHR-Symptomatic; n=135), and a subgroup who did not transition and was in symptom remission (CHR-Remission; n=90). Results: CHR participants had reduced target P3b and novel P3a amplitudes relative to HC (Ps < .001). There was also an effect of 24-month clinical status group on both P3b and P3a amplitudes (P < .001 and P=.006, respectively). Planned contrasts revealed that compared to HC, CHR participants had smaller target P3b amplitudes at baseline (P < .001). In addition, CHR-Transition participants had attenuated P3b amplitudes at baseline relative to all CHR participants who did not transition to psychosis (P=.037). Furthermore, both CHR-Transition and CHR-Symptomatic had smaller P3b amplitudes than both HC (Ps < .001) and CHR-Remission (P=.003 and P=.005, respectively), while P3b of CHR-Remission did not differ from HC at baseline (P > .05). In contrast, although CHR participants also had smaller novel P3a amplitudes than HC at baseline (P < .001), P3a did not differentiate CHR-Transition participants from CHR participants who did not transition within 24months (P > .05). Despite CHR-Transition and CHR-Symptomatic having smaller P3a amplitudes than HC (P=.028 and P=.002, respectively), they did not differ from CHR-Remission (Ps > .05) at baseline. Moreover, target P3b predicted the time to psychosis onset in CHR participants over and above novel P3a amplitude (P=.024). Conclusion: Both target P3b and novel P3a are reduced in individuals identified to be at risk for developing a psychotic disorder, and P3b in particular appears sensitive to future transition to psychosis. Given this association with clinical outcomes, results implicate target P3b as a neurophysiological vulnerability marker for psychosis.

Background: Treatment guidelines for the clinical high risk (CHR) syndrome for psychosis currently recommend psychotherapies such as cognitive behavior therapy and focused family therapy as first line treatment. Antipsychotic medications are generally discouraged for routine use, partly because of concern for adverse effects and partly due to a paucity of efficacy data, although some guidelines recommend them for more severe cases. The current study evaluated the safety and efficacy of ziprasidone in delaying or preventing conversion to psychosis among individuals meeting CHR syndrome criteria. Methods: Eligible subjects were treatment-seeking individuals 16 to 40 years old who met diagnostic criteria for CHR according to the Structured Interview for Psychosis-risk Syndromes. Exclusions were (1) use of antipsychotic medication in the previous 3 months, (2) initiation or increase in dosage of an antidepressant within 6 weeks, or (3) medical contraindications to taking ziprasidone (QTcF≥450 msec at screening or baseline, history of arrhythmia or QTc prolongation or syncope, family history of QTc prolongation, current receipt of medication known to prolong QTc, or K+, Mg++, or Ca++ below the normal range). Randomized subjects received ziprasidone 20–160 mg/d vs matching placebo for 24 weeks in two divided doses with meals. In addition, each subject was offered a Supportive Interpersonal Therapy session at each visit. Target enrollment was 80. Analyses were conducted in SPSS 21. Results: Six sites randomized 51 subjects, 27 to placebo, and 24 to ziprasidone. One ziprasidone case was never dispensed medication and was removed from analysis. Two conversions were identified in the placebo group and one in the active group; Cox regression showed no significant effect. Mixed regression on the SOPS positive symptom subscale with slope and intercept each modeled as random effects revealed a significant difference favoring ziprasidone (F = 6.64, df = 1.21, P = .017, slope difference −0.19 points per week, 95% CI −0.35 to −0.04). Two patients met QTcF criteria for safety withdrawal; both were assigned to placebo. Maximum QTcF across follow-up (placebo mean 407 msec, ziprasidone mean 403 msec) did not differ significantly. Mixed regression on weight measurements revealed no significant treatment effect (F = 0.22, df = 1.37, P = 0.645, slope difference −0.05 pounds per week, 95% CI −0.29 to 0.18). Conclusion: The primary outcome was not met, in part because the study did not meet its enrollment target and was consequently underpowered. The significant drug effect on attenuated positive symptoms provides some evidence for efficacy of ziprasidone in CHR syndrome. Together with the lack of QTc prolongation or significant weight gain in this study, the current evidence of efficacy supports consideration of ziprasidone when an antipsychotic is selected for clinical use in CHR syndrome.

Background: Contrary to popular belief the majority of patients with schizophrenia will never commit an act of severe violence. Highest risk for violent offending appears to be during the first episode of psychosis (FEP), a meta-analysis by Large and Nielssen (2010) reporting that about a third of patients in the FEP exhibited some violent behavior before initial treatment. However, most acts involve minor violence and fewer than 1 in 100 patients committed assaults resulting in serious injury. Risk of violence in clinical high risk populations, those with attenuated psychosis symptoms (APS) remains unexplored although recent findings by Marshall and colleagues (2016) suggest that a significant amount of APS involve violent content although most is self-directed violence. The aim of the current study was to explore risk of violence in individuals with attenuated psychosis symptom syndrome (APSS). We were also interested to investigate whether risk of violence as assessed was associated with symptomology. Methods: The Structured Assessment of Violence Risk in Youth (SAVRY) was completed for 285 individuals who met criteria for APSS as well as 44 Healthy Controls. The SAVRY is a clinician rated assessment tool and provides a clinical risk rating for each individual by assessing multiple domains including Historical Risk Factors, Social/Contextual Risk Factors, and Individual/Clinical Factors. Results: Violence risk was significantly different between the two groups with healthy controls assessed to be at a lower risk than individuals in the attenuated psychosis symptoms group, χ2(2)=13.03, P < .001. Only 2 of the APSS group and none of the healthy controls were rated to be at high level of risk for violence. Violence risk was not different between men and women, χ2(2)=4.58, P=1.01. Abetween-group ANOVA conducted to compare severity of attenuated psychotic symptoms and risk of violence within the APSS group showed that symptom severity was significantly different across levels of violence risk, F(2, 235)=6.32; P < .002. This was largely driven by negative symptoms severity. Individuals with low risk for violence as compared to moderate level of violence risk had lower negative symptoms, F(2, 235)=13.42; P < .000. Severity of positive, disorganized, or general symptoms independently did not differ across levels of violence risk. This relationship remained unchanged when income level was adjusted. Level of income, age, ethnicity, or parental education was not associated with level of risk. Conclusion: To our knowledge this is the first study to assess violence risk in individuals with APSS. While, the APSS group was assessed to be at a higher risk for violence as compared to healthy controls, the majority were judged to be at a moderate risk and high risk ratings were rare. In the APSS group higher risk was associated with symptoms. Specifically, results suggest that negative symptoms uniquely contribute to risk of violence.

Rare copy number variants contribute significantly to the risk for schizophrenia, with the 22q11.2 locus consistently implicated. Individuals with the 22q11.2 deletion syndrome (22q11DS) have an estimated 25-fold increased risk for schizophrenia spectrum disorders, compared to individuals in the general population. The International 22q11DS Brain Behavior Consortium is examining this highly informative neurogenetic syndrome phenotypically and genomically. Here we detail the procedures of the effort to characterize the neuropsychiatric and neurobehavioral phenotypes associated with 22q11DS, focusing on schizophrenia and subthreshold expression of psychosis. The genomic approach includes a combination of whole genome sequencing and genome-wide microarray technologies, allowing the investigation of all possible DNA variation and gene pathways influencing the schizophrenia-relevant phenotypic expression. A phenotypically rich data set provides a psychiatrically well-characterized sample of unprecedented size (n=1,616) that informs the neurobehavioral developmental course of 22q11DS. This combined set of phenotypic and genomic data will enable hypothesis testing to elucidate the mechanisms underlying the pathogenesis of schizophrenia spectrum disorders.

© The Author 2017. Nearly one-third of individuals with 22q11.2 deletion syndrome (22q11.2DS) develop a psychotic disorder during life, most of them by early adulthood. Importantly, a fullblown psychotic episode is usually preceded by subthreshold symptoms. In the current study, 760 participants (aged 6-55 years) with a confirmed hemizygous 22q11.2 microdeletion have been recruited through 10 medical sites worldwide, as part of an international research consortium. Of them, 692 were nonpsychotic and with complete measurement data. Subthreshold psychotic symptoms were assessed using the Structured Interview for Prodromal Syndromes (SIPS). Nearly one-third of participants met criteria for positive subthreshold psychotic symptoms (32.8%), less than 1% qualified for acute positive subthreshold symptoms, and almost a quarter met criteria for negative/disorganized subthreshold symptoms (21.7%). Adolescents and young adults (13-25 years) showed the highest rates of subthreshold psychotic symptoms. Additionally, higher rates of anxiety disorders and attention deficit/hyperactivity disorder (ADHD) were found among the study participants with subthreshold psychotic symptoms compared to those without. Full-scale IQ, verbal IQ, and global functioning (GAF) scores were negatively associated with participants' subthreshold psychotic symptoms. This study represents the most comprehensive analysis reported to date on subthreshold psychosis in 22q11.2DS. Novel findings include age-related changes in subthreshold psychotic symptoms and evidence that cognitive deficits are associated with subthreshold psychosis in this population. Future studies should longitudinally follow these symptoms to detect whether and how early identification and treatment of these manifestations can improve long-term outcomes in those that eventually develop a psychotic disorder.

Background Individuals with 22q11.2 microdeletion syndrome (22q11DS) have elevated rates of autism spectrum disorder (ASD), although the diagnosis is controversial. To determine whether there is a biological substrate of ASD in patients with 22q11DS, we examined neurocognitive and structural neuroanatomic differences between those with 22q11DS and an ASD diagnosis (22q11DS-ASD + ) and those with 22q11DS without ASD (22q11DS-ASD − ). We then determined whether these differences were better characterized within a categorical or dimensional framework. Methods We collected multiple neurocognitive measures and high-resolution T1-weighted magnetic resonance imaging scans from 116 individuals (29 patients who were 22q11DS-ASD + , 32 patients who were 22q11DS-ASD − , and 55 typically developing controls) who were between 6 and 26 years of age. Measures of subcortical volume, cortical thickness (CT), and surface area were extracted using the FreeSurfer image analysis software. Group differences in neurocognitive and neuroanatomic measures were assessed; regression analyses were then performed to determine whether a categorical or dimensional measure of ASD was a better predictor of neurocognitive impairment or neuroanatomic abnormalities observed in patients with 22q11DS-ASD + . Results In comparison to 22q11DS-ASD – individuals, 22q11DS-ASD + participants had decreased bilateral parahippocampal CT and decreased right amygdala volumes. Those with 22q11DS-ASD + also showed slowed processing speed and impairments in visuospatial and facial memory. Neurocognitive impairments fit a dimensional model of ASD, whereas reductions in parahippocampal CT were best explained by a categorical measure of ASD. Conclusions A combination of categorical and dimensional measures of ASD may provide the most comprehensive understanding of ASDs in individuals with 22q11DS.

Background Neurofibromatosis Type 1 (NF1) is a genetic disorder that disrupts central nervous system development and neuronal function. Cognitively, NF1 is characterized by difficulties with executive control and visuospatial abilities. Little is known about the neural substrates underlying these deficits. The current study utilized Blood-Oxygen-Level-Dependent (BOLD) functional MRI (fMRI) to explore the neural correlates of spatial working memory (WM) deficits in patients with NF1. Methods BOLD images were acquired from 23 adults with NF1 (age M = 32.69; 61% male) and 25 matched healthy controls (age M = 33.08; 64% male) during an in-scanner visuo-spatial WM task. Whole brain functional and psycho-physiological interaction analyses were utilized to investigate neural activity and functional connectivity, respectively, during visuo-spatial WM performance. Participants also completed behavioral measures of spatial reasoning and verbal WM. Results Relative to healthy controls, participants with NF1 showed reduced recruitment of key components of WM circuitry, the left dorsolateral prefrontal cortex and right parietal cortex. In addition, healthy controls exhibited greater simultaneous deactivation between the posterior cingulate cortex (PCC) and temporal regions than NF1 patients. In contrast, NF1 patients showed greater PCC and bilateral parietal connectivity with visual cortices as well as between the PCC and the cerebellum. In NF1 participants, increased functional coupling of the PCC with frontal and parietal regions was associated with better spatial reasoning and WM performance, respectively; these relationships were not observed in controls. Conclusions Dysfunctional engagement of WM circuitry, and aberrant functional connectivity of ‘task-negative’ regions in NF1 patients may underlie spatial WM difficulties characteristic of the disorder., Highlights • NF1 is a monogenic disorder associated with executive function deficits. • Hypoactivity of working memory circuitry in NF1 patients relative to controls • Increased PCC connectivity with visual cortex/cerebellum in NF1 patients during task • Greater simultaneous deactivation between default mode regions in controls • Greater PCC-frontal coupling associated with better behavioral performance in NF1

Bipolar disorder in children remains a controversial topic in the field of child and adolescent psychiatry. Comorbidity with other mental illnesses, diagnostic criteria, and consequent treatment are among the issues debated within the international community. While DSM-V has allowed for increased diagnostic latitude, many practitioners find diagnosing children with bipolar disorder to be challenging. This has been attributed to multiple reasons, including the greater frequency of mixed episodes in children, the unreliability of child self-report, the fact that children frequently do not meet clear symptom duration criterion, and the difficulty in making clear distinctions between clinically significant symptoms and developmentally normative behaviors. Over the past decade, there has been an explosion of research on childhood bipolar disorder as researchers search for diagnostic clarity. A large number of review papers have been published that seek to consolidate information for the scientific community, laying the foundation for recent research papers investigating brain structure, brain function, and pharmacology. Multiple longitudinal, DSM-based studies have been conducted, with the most influential covered within this chapter. It is our hope that through detailed discussion of the historical context, etiology, symptom presentation, current best practices regarding treatment, and prognosis of childhood bipolar disorder, we will help researchers and clinicians better serve this unique population.

Although gene-gene interaction, or epistasis, plays a large role in complex traits in model organisms, genome-wide by genome-wide searches for two-way interaction have limited power in human studies. We thus used knowledge of a biological pathway in order to identify a contribution of epistasis to autism spectrum disorders (ASDs) in humans, a reverse-pathway genetic approach. Based on previous observation of increased ASD symptoms in Mendelian disorders of the Ras/MAPK pathway (RASopathies), we showed that common SNPs in RASopathy genes show enrichment for association signal in GWAS (P = 0.02). We then screened genome-wide for interactors with RASopathy gene SNPs and showed strong enrichment in ASD-affected individuals (P < 2.2 x 10−16), with a number of pairwise interactions meeting genome-wide criteria for significance. Finally, we utilized quantitative measures of ASD symptoms in RASopathy-affected individuals to perform modifier mapping via GWAS. One top region overlapped between these independent approaches, and we showed dysregulation of a gene in this region, GPR141, in a RASopathy neural cell line. We thus used orthogonal approaches to provide strong evidence for a contribution of epistasis to ASDs, confirm a role for the Ras/MAPK pathway in idiopathic ASDs, and to identify a convergent candidate gene that may interact with the Ras/MAPK pathway., Author Summary The contribution of epistasis to human biology and complex trait architecture has been subject to intense debate. Despite statistical methods to detect interaction, allele frequencies and study designs have limited our power to address this question. Rather than a statistically-motivated approach, we developed a reverse pathway genetic approach to detect epistasis in in autism spectrum disorders (ASDs). Instead of traditional pathway analysis—exploiting unbiased genetic results to identify biological pathways important for pathophysiology—we hypothesized that the reverse approach of leveraging a specific biological pathway to uncover novel aspects of genetic architecture could be fruitful. We drew on knowledge from Mendelian disorders of the Ras/MAPK pathway (RASopathies) associated with ASD to inform our analyses. First, we implemented an epistasis screen in idiopathic ASD for SNPs that interact with the Ras/MAPK pathway, allowing us to detect genome-wide enrichment in epistasis signal as well as specific interacting loci. Second, we performed modifier mapping within RASopathies and identified overlapping signals with our first approach. Finally, we took the top overlapping region and experimentally demonstrated dysregulated expression in iPSC-derived neural cells from RASopathy subjects. Together, our results establish a human genetics motivated reverse-pathway strategy, which can be applied broadly to study epistasis.

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. © 2014 Elsevier Inc.

Impaired temporal processing has historically been viewed as a hallmark feature of attention deficit hyperactivity disorder. Recent evidence suggests temporal processing deficits may also be characteristic of autism spectrum disorder (ASD). However, little is known about the factors that impact temporal processing in children with ASD. The purpose of this study was to assess the effects of co-morbid attention problems, working memory (WM), age, and their interactions, on time reproduction in youth with and without ASD. Twenty-seven high-functioning individuals with ASD and 25 demographically comparable typically developing individuals (ages 9-17; 85% male) were assessed on measures of time reproduction, auditory WM, and inattention/hyperactivity. The time reproduction task required depression of a computer key to mimic interval durations of 4, 8, 12, 16, or 20 sec. Mixed effects regression analyses were used to model accuracy and variability of time reproduction as functions of diagnostic group, interval duration, age, WM, and inattention/hyperactivity. A significant group by age interaction was detected for accuracy, with the deficit in the ASD group being greater in younger children. There was a significant group by WM interaction for consistency, with the effects of poor WM on performance consistency being more pronounced in youth with ASD. All participants tended to underestimate longer interval durations and to be less consistent for shorter interval durations; these effects appeared more pronounced in those who were younger or who had poorer WM performance. Inattention/hyperactivity symptoms in the ASD group were not related to either accuracy or consistency. This study highlights the potential value of temporal processing as an intermediate trait of relevance to multiple neurodevelopmental disorders.

Background: There is increasing evidence that bipolar disorder (BD) and conduct disorder (CD) are co-occurring disorders. Magnetic resonance imaging has revealed differences in the structure and function of the frontal cortex in these disorders when studied separately; however, the impact of BD comorbidity on brain structure in adolescents with CD has not yet been examined. Method: We conducted an optimized voxel based morphometry (VBM) study of juvenile offenders with the following diagnoses: conduct disorder with comorbid bipolar disorder (CD-BD; n = 24), conduct disorder without bipolar disorder (CD; n = 24) and healthy controls (HC, n = 24). Participants were 13–17 years of age, in a residential treatment facility for repeat offenders. The three groups in this study were similar in age, gender, socioeconomic status and ethnicity. Results: We found CD-BD subjects had decreased volume relative to controls at the voxel level in the right medial prefrontal cortex (PFC). Using a Threshold-Free Cluster Enhancement (TFCE) technique, the CD-BD subjects had significantly decreased volumes of the right medial prefrontal cortex and portions of the superior and inferior frontal gyrus, anterior cingulate and temporal gyrus. The CD subjects did not have differences in brain volume compared to control subjects or CD-BD subjects. Conclusions: Our findings suggest the comorbidity between CD and BD is associated with neurobiological impact namely volumetric differences from healthy controls. Furthermore subjects with this comorbidity had poorer lifetime functioning, more mood and attentional dysfunction, and more medication exposure than subjects with CD who were not BD.

Aim 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. Methods 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. Results 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. Conclusion 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.

Author(s): Alderman, T; Addington, J; Bearden, C; Cannon, TD; Cornblatt, BA; McGlashan, TH; Perkins, DO; Seidman, LJ; Tsuang, MT; Walker, EF; Woods, SW; Cadenhead, KS | Abstract: Aim: 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. Methods: 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'). Results: 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. Conclusion: 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.

Objective: Chromosome 22q11.2 deletion syndrome is a neurogenetic disorder associated with high rates of schizophrenia and other psychiatric conditions. The authors report what is to their knowledge the first large-scale collaborative study of rates and sex distributions of psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome. The associations among psychopathology, intellect, and functioning were examined in a subgroup of participants. Method: The 1,402 participants With 22q11.2 deletion syndrome, ages 6-68 years, were assessed for psychiatric disorders with validated diagnostic instruments. Data on intelligence and adaptive functioning were available for 183 participants ages 6 to 24 years. Results: Attention deficit hyperactivity disorder (ADHD) was the most frequent disorder in children (37.10%) and was overrepresented in males. Anxiety disorders were more prevalent than mood disorders at all ages, but especially in children and adolescents. Anxiety and unipolar mood disorders were overrepresented in females. Psychotic disorders were present in 41% of adults over age 25. Males did not predominate in psychotic or autism spectrum disorders. Hierarchical regressions in the subgroup revealed that daily living skills were predicted by the presence of anxiety disorders. Psychopathology was not associated with communication or socialization skills. Conclusions: To the authors' knowledge, this is the largest study of psychiatric morbidity in 22q11.2 deletion syndrome. It validates previous findings that this condition is one of the strongest risk factors for psychosis. Anxiety and developmental disorders were also prevalent. These results highlight the need to monitor and reduce the long-term burden of psychopathology in 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11DS) is a recurrent genetic mutation that is highly penetrant for psychosis. Behavioral research suggests that 22q11DS patients exhibit a characteristic neurocognitive phenotype that includes differential impairment in spatial working memory (WM). Notably, spatial WM has also been proposed as an endophenotype for idiopathic psychotic disorder, yet little is known about the neurobiological substrates of WM in 22q11DS. In order to investigate the neural systems engaged during spatial WM in 22q11DS patients, we collected functional magnetic resonance imaging (fMRI) data while 41 participants (16 22q11DS patients, 25 demographically matched controls) performed a spatial capacity WM task that included manipulations of delay length and load level. Relative to controls, 22q11DS patients showed reduced neural activation during task performance in the intraparietal sulcus (IPS) and superior frontal sulcus (SFS). In addition, the typical increases in neural activity within spatial WM-relevant regions with greater memory load were not observed in 22q11DS. We further investigated whether neural dysfunction during WM was associated with behavioral WM performance, assessed via the University of Maryland letter–number sequencing (LNS) task, and positive psychotic symptoms, assessed via the Structured Interview for Prodromal Syndromes (SIPS), in 22q11DS patients. WM load activity within IPS and SFS was positively correlated with LNS task performance; moreover, WM load activity within IPS was inversely correlated with the severity of unusual thought content and delusional ideas, indicating that decreased recruitment of working memory-associated neural circuitry is associated with more severe positive symptoms. These results suggest that 22q11DS patients show reduced neural recruitment of brain regions critical for spatial WM function, which may be related to characteristic behavioral manifestations of the disorder., Highlights • 22q11DS patients show reduced activation during spatial working memory. • Typical increases in neural activity with greater memory load not seen in 22q11DS. • Neural activity is positively correlated with letter–number sequencing in 22q11DS. • Neural activity is inversely correlated with psychotic symptoms in 22q11DS.

Considerable uncertainty exists about the defining brain changes associated with bipolar disorder (BD). Understanding and quantifying the sources of uncertainty can help generate novel clinical hypotheses about etiology and assist in the development of biomarkers for indexing disease progression and prognosis. Here we were interested in quantifying case-control differences in intracranial volume (ICV) and each of eight subcortical brain measures: nucleus accumbens, amygdala, caudate, hippocampus, globus pallidus, putamen, thalamus, lateral ventricles. In a large study of 1710 BD patients and 2594 healthy controls, we found consistent volumetric reductions in BD patients for mean hippocampus (Cohen's d=-0.232; P=3.50 × 10(-7)) and thalamus (d=-0.148; P=4.27 × 10(-3)) and enlarged lateral ventricles (d=-0.260; P=3.93 × 10(-5)) in patients. No significant effect of age at illness onset was detected. Stratifying patients based on clinical subtype (BD type I or type II) revealed that BDI patients had significantly larger lateral ventricles and smaller hippocampus and amygdala than controls. However, when comparing BDI and BDII patients directly, we did not detect any significant differences in brain volume. This likely represents similar etiology between BD subtype classifications. Exploratory analyses revealed significantly larger thalamic volumes in patients taking lithium compared with patients not taking lithium. We detected no significant differences between BDII patients and controls in the largest such comparison to date. Findings in this study should be interpreted with caution and with careful consideration of the limitations inherent to meta-analyzed neuroimaging comparisons.Molecular Psychiatry advance online publication, 9 February 2016; doi:10.1038/mp.2015.227. ispartof: Molecular Psychiatry vol:21 issue:12 pages:1710-1716 ispartof: location:England status: published

Reciprocal chromosomal rearrangements at the 22q11.2 locus are associated with elevated risk of neurodevelopmental disorders. The 22q11.2 deletion confers the highest known genetic risk for schizophrenia, but a duplication in the same region is strongly associated with autism and is less common in schizophrenia cases than in the general population. Here we conducted the first study of 22q11.2 gene dosage effects on brain structure in a sample of 143 human subjects: 66 with 22q11.2 deletions (22q-del; 32 males), 21 with 22q11.2 duplications (22q-dup; 14 males), and 56 age- and sex-matched controls (31 males). 22q11.2 gene dosage varied positively with intracranial volume, gray and white matter volume, and cortical surface area (deletion < control < duplication). In contrast, gene dosage varied negatively with mean cortical thickness (deletion > control > duplication). Widespread differences were observed for cortical surface area with more localized effects on cortical thickness. These diametric patterns extended into subcortical regions: 22q-dup carriers had a significantly larger right hippocampus, on average, but lower right caudate and corpus callosum volume, relative to 22q-del carriers. Novel subcortical shape analysis revealed greater radial distance (thickness) of the right amygdala and left thalamus, and localized increases and decreases in subregions of the caudate, putamen, and hippocampus in 22q-dup relative to 22q-del carriers. This study provides the first evidence that 22q11.2 is a genomic region associated with gene-dose-dependent brain phenotypes. Pervasive effects on cortical surface area imply that this copy number variant affects brain structure early in the course of development. SIGNIFICANCE STATEMENT Probing naturally occurring reciprocal copy number variation in the genome may help us understand mechanisms underlying deviations from typical brain and cognitive development. The 22q11.2 genomic region is particularly susceptible to chromosomal rearrangements and contains many genes crucial for neuronal development and migration. Not surprisingly, reciprocal genomic imbalances at this locus confer some of the highest known genetic risks for developmental neuropsychiatric disorders. Here we provide the first evidence that brain morphology differs meaningfully as a function of reciprocal genomic variation at the 22q11.2 locus. Cortical thickness and surface area were affected in opposite directions with more widespread effects of gene dosage on cortical surface area.

ImportanceNeurocognition is a central characteristic of schizophrenia and other psychotic disorders. Identifying the pattern and severity of neurocognitive functioning during the "near-psychotic," clinical high-risk (CHR) state of psychosis is necessary to develop accurate risk factors for psychosis and more effective and potentially preventive treatments.ObjectivesTo identify core neurocognitive dysfunctions associated with the CHR phase, measure the ability of neurocognitive tests to predict transition to psychosis, and determine if neurocognitive deficits are robust or explained by potential confounders.Design, setting, and participantsIn this case-control study across 8 sites, baseline neurocognitive data were collected from January 2009 to April 2013 in the second phase of the North American Prodrome Longitudinal Study (NAPLS 2). The dates of analysis were August 2015 to August 2016. The setting was a consortium of 8 university-based, outpatient programs studying the psychosis prodrome in North America. Participants were 264 healthy controls (HCs) and 689 CHR individuals, aged 12 to 35 years.Main outcomes and measuresNeurocognitive associations with transition to psychosis and effects of medication on neurocognition. Nineteen neuropsychological tests and 4 factors derived from factor analysis were used: executive and visuospatial abilities, verbal abilities, attention and working memory abilities, and declarative memory abilities.ResultsThis study included 264 HCs (137 male and 127 female) and 689 CHR participants (398 male and 291 female). In the HCs, 145 (54.9%) were white and 119 (45.1%) were not, whereas 397 CHR participants (57.6%) were white and 291 (42.3%) were not. In the HCs, 45 (17%) were of Hispanic origin, whereas 127 CHR participants (18.4%) were of Hispanic origin. The CHR individuals were significantly impaired compared with HCs on attention and working memory abilities and declarative memory abilities. The CHR converters had large deficits in attention and working memory abilities and declarative memory abilities (Cohen d, approximately 0.80) compared with controls and performed significantly worse on these dimensions than nonconverters (Cohen d, 0.28 and 0.48, respectively). These results were not accounted for by general cognitive ability or medications. In Cox proportional hazards regression, time to conversion in those who transitioned to psychosis was significantly predicted by high verbal (premorbid) abilities (β = 0.40; hazard ratio [HR], 1.48; 95% CI, 1.08-2.04; P = .02), impaired declarative memory abilities (β = -0.87; HR, 0.42; 95% CI, 0.31-0.56; P

Background Language offers a privileged view into the mind; it is the basis by which we infer others’ thoughts. Subtle language disturbance is evident in schizophrenia prior to psychosis onset, including decreases in coherence and complexity, as measured using clinical ratings in familial and clinical high-risk (CHR) cohorts. Bearden et al previously used manual linguistic analysis of baseline speech transcripts in CHR to show that illogical and referential thinking, and poverty of content, predict later psychosis onset. Then, Bedi et al used automated natural language processing (NLP) of CHR transcripts to show that decreased semantic coherence and reduction in syntactic complexity predicted psychosis onset. To determine validity and reproducibility, we have applied automated NLP methods, with machine learning, to Bearden’s original CHR transcripts to identify a language profile predictive of psychosis. Methods Participants in the Bearden UCLA cohort include 59 CHR, of whom 19 developed psychosis (CHR+) within 2 years, whereas 40 did not (CHR-), as well as 16 recent-onset psychosis and 21 healthy individuals, similar in demographics; speech was elicited using Caplan’s “Story Game. Participants in the Bedi NYC cohort include 34 CHR (29 CHR+), with speech elicited using open-ended interview. Speech was audiotaped, transcribed, de-identified and then subjected to latent semantic analysis to determine coherence and part-of-speech tagging to characterize syntactic structure and complexity. A machine-learning speech classifier of psychosis onset was derived from the UCLA CHR cohort, and then applied both to the NYC CHR cohort and to the UCLA psychosis/control comparison, with convex hull (three-dimension depiction of model) and receiver operating characteristics analyses. Correlational analyses with demographics, symptoms and manual linguistic features were also done. Results A four-factor model language classifier derived from the UCLA CHR cohort that comprised three semantic coherence variables and one syntax (usage of possessive pronouns) predicted psychosis t with accuracy of 83% (intra-protocol) for UCLA CHR, 79% (cross-protocol) for NYC CHR, and 72% for discriminating psychosis from normal speech (UCLA psychosis/control). Convex hulls were defined as the smallest space containing all datapoints within a set for CHR- or healthy controls: these convex hulls showed substantial overlap, with CHR+ and psychosis speech datapoints largely outside these convex hulls. Coherence was associated with age, but speech variables did not vary by gender, race, or socioeconomic status in this study. While automated text features were unrelated to prodromal symptom severity, they were highly correlated with manual text features (r = 0.7, p < .000001). Discussion In this small preliminary study, we identified and cross-validated a robust language classifier of psychosis risk that comprised measures of semantic coherence (flow of meaning in language) and syntactic usage (usage of possessive pronouns). This classifier had utility in discriminating speech in individuals with recent-onset psychosis from the norm. It demonstrated concurrent validity in that it was highly correlated with manual linguistic features previously identified by Bearden et al, important as automated methods are fast and inexpensive. Automated language features were unrelated to sex, ethnicity or social class in these small samples, and semantic coherence increased with age, consistent with prior studies of normal language development. Of interest, overlapping convex hulls could be defined for groups of individuals without psychosis (UCLA CHR-, NYC CHR- and UCLA healthy), suggesting a constrained hull of normal language in respect to syntax and semantics, from which pre-psychosis and psychosis speech deviates. The RDoC linguistic corpus-based variables of semantic coherence and syntactic structure hold promise as biomarkers of psychosis risk and expression, with initial validation and reproducibility. Next steps in biomarker development include larger multisite studies with standardization of protocols for speech elicitation, test-retest, and attention to traction/feasibility, acceptability, cost, and utility. Mechanistic studies can also yield neural and physiological correlates of abnormal semantic coherence and syntax.