Carrie E. Bearden - US grants

DESCRIPTION (Adapted from Applicant's Abstract): There is an accumulating body of evidence that schizophrenia is a neurodevelopmental disorder (e.g., Weinberger, 1987). While the clinical expression of the illness is typically delayed for about 2 decades after birth, a small number of cases develop psychotic symptoms much earlier. Currently, the relationship between the child- and adult-onset forms of the disorder is poorly understood. This atypical early onset may represent a more severe variant of the illness. The proposed research will address the question of whether early-onset schizophrenia is qualitatively and quantitatively similar to the adult onset form at the level of symptomatic presentation and cognitive function, by administering a comprehensive neuropsychological battery and clinical evaluation to a sample of 24 neuroleptic-naive, first-episode schizophrenics aged 8-16 and a demographically matched normal control group. A neuropsychological deficit profile that is qualitatively similar to adult-onset patients (i.e., selective deficits in attention, verbal learning and memory) would provide evidence of continuity between the child- and adult-onset forms. At the level of clinical symptoms, which reflect cognitive function in the broadest sense, this study will assess the prevalence and severity of specific positive and negative symptoms to determine whether the distribution of symptoms is similar to that of first-episode adult patients. As the first study of drug-naive patients in this age range, these findings will advance understanding of neurodevelopmental origins of the illness.

[unreadable] DESCRIPTION (provided by applicant): This grant application is for 5 years of funding through the Mentored Patient Oriented Research Career Development Award (K23) program. The objective is to develop the candidate's skills in behavioral genetics research and augment her training in neurobiological endophenotypes of bipolar disorder. The research plan builds on the candidate's experience in behavioral endophenotypes and neurocognition in major mental illness (schizophrenia and bipolar disorder); its basic aim is to assess familial aggregation of measures of neurocognitive function, temperament, and neuroanatomy in unaffected relatives of individuals with severe bipolar disorder, and apply these measures to quantitative trait loci (QTL) analysis. The proposed study will provide an important first step toward the ultimate goal of linking bipolar endophenotypes to specific genes. Both the research and training plan are opportunistic, utilizing previously ascertained study samples from ongoing research, and renowned investigators in the UCLA research community. The Career Development Plan will develop the Pi's skills in: 1) the design of studies that collect and analyze human genetic material, 2) data analytic methods used to examine genetic effects on cognition and neuroanatony, and 3) analysis of quantitative trait loci. Methods of career development include: 1) the proposed study, 2) the mentorship of Drs. Nelson Freimer and Tyrone Cannon , 3) consultation with experts in behavioral and statistical genetics, 4) formal coursework in statistical genetics methodology and brain mapping, 5) attendance at scientific meetings, and 6) data preparation for submission of manuscripts to peer-reviewed journals. Given the candidate's prior training, proposed mentorship, outstanding resources and research environment, a K23 award will allow her to become a successful and independent investigator in the genetics and neurobiological bases of bipolar disorder. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Developmental learning disabilities are a highly prevalent form of cognitive impairment, which present a major public health burden and are associated with poor social outcome and substantial psychiatric morbidity. However, to date no effective pharmacologic treatments have been developed for these severely disabling conditions. Neurofibromatosis type 1 (NF1) is a valuable model for understanding mechanisms of cognitive disability, as it is a common genetic disorder (incidence 1:3000) that results from mutations in a single gene (Nf1) that encodes the neurofibromin protein. Specific learning disabilities are the most common neurological complication in children with this disease. The development of a mouse model of the disorder led to the key discovery that increased Ras activity is responsible for the learning deficits in NF1 (Costa et al. Nature Genet 2001). We have recently demonstrated that treatment with the HMG-CoA reductase inhibitor lovastatin, which acts as a potent inhibitor of Ras activity and is commonly used for the treatment of hypercholesterolemia, can reverse the biochemical, electrophysiological and cognitive deficits observed in a mouse model of NF1 (Li et al. Curr Biol. 2005). For the first time, this allows us to assess a pharmacologic treatment for cognitive deficits of patients with a genetic disorder, using a medication that has been validated in pre- clinical studies and for which substantial clinical safety data is available. We now seek to extend these findings to studies in human subjects with NF1, to determine whether analogous changes in brain structure and function are observed following lovastatin treatment in humans. In the proposed randomized, double-blind, placebo-controlled trial, we will study the effect of a 14-week lovastatin treatment on cognitive function of children and adolescents with NF1 using neurocognitive, behavioral, and neurophysiological outcome measures. Findings from this exploratory treatment study will allow us to establish the feasibility of a larger-scale study pursuing these aims. PUBLIC HEALTH RELEVANCE: Neurofibromatosis type 1 (NF1) is a valuable single-gene model for understanding mechanisms of cognitive disability. Our pre-clinical studies have shown that treatment with lovastatin, commonly used for treatment of hypercholesterolemia, can reverse cognitive deficits observed in a mouse model of NF1. In this exploratory treatment grant, we propose to extend these findings to studies in human subjects with NF1, to determine whether analogous changes in brain structure and function are observed following lovastatin treatment in humans.

PROJECT SUMMARY (See instructions): CORE 4-. PRODROMAL RESEARCH PROGRAM. The primary goal ofthis Core is to provide prodromal participants with a high quality clinical care setting within which the proposed Center research can take place. The objectives are:l) recruit patients with prodromal symptoms and demographically matched controls; 2) conduct diagnostic evaluations to determine study eligibility, and to coordinate subjects' participation in the four TRCBS research projects; 3) sustain subjects' participation in TRCBS research projects by providing extensive case management, psychological, and (when appropriate) psychiatric services; 4) conduct repeated assessments of clinical and functional status, and to assess conversion to schizophrenia or other psychotic disorders. To achieve the first objective, we will engage in community outreach and partner with community mental health sites to generate referrals of patients with prodromal symptoms. Staff will provide talks to educate local mental health programs, schools, and support groups about the psychosis prodrome and our services. To achieve the second objective, we will conduct structured interviews of established reliability and predictive validity, and continue to develop efficient screening instruments to detect prodromal symptoms. For the third objective, we will provide case management, skills training, family education, ongoing monitoring of symptoms and functioning, and, when clinically indicated, psychiatric treatment By offering ongoing evaluation and case management, we hope to detect conversion to psychosis earlier than would otherwise be typical. Earlier intervention is associated with better treatment response and long-term prognosis. To achieve the fourth objective, we will assess clinical and functional status at 6- and 12-month follow-ups, and will re-assess diagnostic status at 24 months. Each TRCBS project will evaluate a set of cognitive and/or emotional processes to determine whether baseline functioning in these systems, and deterioration over time, is associated with psychosis onset. These findings will elucidate mechanisms underlying psychosis onsetandimprove.sensitivity and specificity of prediction ofschizophrenia, so that future primary prevention efforts can be targeted to those who need it most.

Abstract Schizophrenia and other psychotic disorders are highly disabling conditions with poorly understood pathophysiology. One of the central challenges in elucidating mechanisms of psychosis is its remarkable genetic and phenotypic heterogeneity. Taking a `genetics first' approach (i.e., ascertaining patients based on a known, homogeneous genetic etiology) may allow us to overcome the barriers posed by this complexity. 22q11.2 deletion syndrome (Velocardiofacial/DiGeorge syndrome; 22q11DS) is a particularly compelling model, as it represents the greatest known genetic risk factor for psychosis identified to date. As the deletion can be detected very early in development, it offers an extraordinary opportunity for prospective investigation of early biomarkers of psychosis, long before disease-related processes begin to unfold. In the current funding cycle we have elucidated key points of convergence between disturbances in cognition, neural circuitry and gene expression relevant to psychosis in this genetic risk model and in idiopathic psychosis. In this competitive renewal application we plan to continue to prospectively follow a large cohort of youth with 22q11DS (n=90) through the highest risk period for illness onset, and demographically comparable typically developing controls (n=45), in order to establish whether common mechanisms contribute to psychotic symptomatology in 22q11DS and in idiopathic psychosis. Our primary goals (building on our findings from the original funding period) are to elucidate biological pathways and brain biomarkers which may represent convergent mechanisms for disease evolution. Given new discoveries in clinical high risk populations implicating inflammatory and neurohormonal processes in brain changes associated with the development of psychosis, we have added novel measures to assess these domains. In particular, our aims are to: 1) Investigate baseline and progressive abnormalities in structural and functional brain biomarkers, with the prediction that changes in temporal gray matter and thalamo-cortical functional connectivity will predict worsening cognition, social function and increased psychotic symptoms over time; 2) Determine the role of inflammatory mechanisms and stress sensitivity in the evolution of psychotic symptoms, using assays of both peripheral and neural inflammation [i.e., a novel free water diffusion imaging paradigm which is strongly correlated with positron emission tomography (PET) indices of activated microglia] and cortisol at each timepoint; 3) Determine biological pathways associated with psychosis-relevant phenotypes, by investigating upstream regulatory processes of circulating inflammatory markers; and 4) Given the recent discovery that 22q11.2 duplications may be protective against schizophrenia, we will prospectively follow 30 patients with gain of function mutations in the identical locus in order to investigate gene dosage effects on neurobehavioral phenotypes. This work will advance understanding of the genetic and developmental mechanisms by which 22q11.2 haploinsufficiency disrupts brain structure and function and ultimately contributes to disease pathogenesis.

? DESCRIPTION (provided by applicant): There is growing evidence that neurodevelopmental factors play a key role in the susceptibility to severe neuropsychiatric disorders such as schizophrenia (SCZ) and bipolar disorder (BP) that typically have full symptomatic onset in late adolescence or early adulthood. Identifying the earliest biomarkers of these illnesses is particularly critical, given that overt symptom onset may be a late manifestation of the actual disease processes. The Philadelphia Neurodevelopmental Cohort (PNC), an ethnically diverse, population-based sample of over 9,000 youth ages 8-21 from the greater Philadelphia area, offers a unique resource in which to investigate the genetics of neurodevelopmental intermediate phenotypes of psychiatric disorders in children and adolescents. Here, our first aim is to leverage data from the largest studies of the Psychiatric Genomics Consortium - a platform for major discoveries of genetic risk factors for these neuropsychiatric disorders - in order to investigate the shared genetic burden of SCZ and BP in adults with psychotic and mood spectrum disorders that present in youth, and with neurobehavioral (endo)phenotype data in the PNC. We will then define risk groups based on polygenic risk scores for SCZ and BP, in order to investigate the developmental time-course of the expression of traits associated with genetic liability to these disorders. Given the ethnic heterogeneity of the PNC cohort, we will also apply novel population genetics methods to examine the effect of genetic admixture on polygenic risk, and its association with intermediate phenotypes. In our second aim we will apply new methods for estimating genetic distance between unrelated individuals to determine the genetic and environmental covariance between neurocognitive traits and clinical symptoms in PNC cohort members. We will then investigate the stability of genetic and environmental contributions to overall trait variance in pre- and post-adolescent age groups, to provide insight regarding developmental epochs in which environmental factors may play a greater role. Finally, we will utilize the resources of the Encyclopedia of DNA Elements (ENCODE), NIH Epigenomics Roadmap, and expression QTL data of many different cell types from the Genotype-Tissue Expression (GTEx) Consortium, in order to obtain functional genomic insights about the most genetically informative candidate traits in the PNC. Using these resources we will identify specific functional pathways and cell types that play a critical role in the etiology of these trais.

? DESCRIPTION (provided by applicant): The NIMH Research Domains Criteria (RDoC) initiative represents a novel approach to defining mental disorders, based on quantifiable dimensions of behavior and neurobiological measures that may span multiple diagnostic categories. Using the RDoC framework, the proposed project will leverage five existing large, extensively phenotyped family-based and population-based cohorts from the US, the Netherlands, and Latin America in order to build an integrated database of multi-dimensional data. All of these studies collected extensive genetic, genomic, dimensional symptom and neurocognitive data, as well as neuroimaging measures. Cross-project data includes a broad range of constructs tapping multiple RDoC domains including positive and negative valence systems, cognitive systems, working memory, and arousal and regulatory systems. After assembling the integrated database, the project will test one of the central motivations of the RDoC project; the hypothesis that symptom dimensions that cut across diagnostic categories may be more closely linked to neural systems, as compared to categorical diagnoses. We will then use the extensive structural brain imaging data acquired across studies to identify neural circuits most relevant to both RDoC constructs and dimensional symptom expression, and thus represent the most promising biological pathways for subsequent genetic investigations.

PROJECT SUMMARY This is a proposal to renew a highly focused postdoctoral and predoctoral training program in Neurobehavioral Genetics. Elucidating the genetic basis of diseases of the nervous system promises to transform our understanding of some of the most prevalent, burdensome, and complex afflictions of humankind. The program bridges several longstanding dichotomies; between nervous system mechanisms and behavior, between neurology and psychiatry/psychology, between diseases and non-disease traits, and between humans and model organisms. The program provides exposure to the science of neurobehavioral phenotyping to individuals with basic or clinical science backgrounds And trainees, prior to their appointment, must commit to participate for such a duration. To establish a balanced cohort and reflect the merge of the two training grants in neurobehavioral genetics, which were previously funded separately by NIMH and NINDS, this program is designed support 6 predoctoral trainees and 3 postdoctoral trainees each year. With the yearly appointments of postdoctoral and predoctoral trainees and the two-year training of each participant, the overall group of trainees in the program at any time is 12. The program stresses the importance of, and provides unified training in, systematic delineation and assessment of nervous system phenotypes, including the integration of traditional clinical and cognitive evaluations with recently available phenotyping tools such as neuroimaging and gene expression profiling. The core curriculum of the program emphasizes phenotyping of the nervous system and advanced genetics, and is designed to promote interactions between the postdoctoral fellows and their predoctoral counterparts. A new curriculum element for this renewal is the support of a program faculty mentor with statistical and computational expertise who provides program-wide support to trainees. Furthermore, we are now aligning our training program with the highly successful UCLA Computational Genomics Summer Institute. In this way, all our trainees will receive practical training by mathematical and computational scientists, receive individual mentorship to advance their statistical and quantitative literacy, and obtain a thorough understanding of rigorous scientific research of neurobehavioral genetics, which includes bioinformatics analysis of high- throughput sequencing data and issues involved in large-scale data sharing. The program gains cohesion by a neurogenetics seminar series and an annual program retreat. Intensive research experience with a mentor chosen by the trainee constitutes the heart of the program. The ambitious goals of the program are achievable because the program faculty is very strong in virtually all of the areas that are relevant to neurobehavioral genetics, and because the faculty members have long embraced, in their research and teaching, the integrative and cross-disciplinary approach that is at the heart of the program.

PROJECT SUMMARY/ABSTRACT This proposed project aims to use genetics to help develop an approach for classifying severe mental illness (SMI) that has a stronger scientific foundation than the systems currently used in both research and clinical practice. These classification systems have, for more than a century, divided the bulk of SMI into dichotomous diagnostic categories: psychotic disorders (including schizophrenia [SCZ]) and mood disorders (including bipolar disorder [BP] and major depressive disorder [MDD]). However the overlap of symptomatology across mood and psychotic disorders, and growing evidence for the genetic correlation between these categories, demonstrate that they imprecisely represent the biological underpinning of SMI. It has been proposed that frameworks based on symptom-level and dimensional (quantitative) information, such as the NIMH Research Domain Criteria (RDoC), would better reflect the genetic contribution to SMI and would therefore provide a more useful framework for their classification. However the evidence supporting this hypothesis remains sparse, in large part because we lack the right datasets to test it. In this project we will generate a unique SMI dataset, using electronic health records to ascertain individuals who have received inpatient treatment at a single psychiatric hospital that serves the entire 1 million inhabitants of the state of Caldas, Colombia. All of the individuals whom we will investigate are members of the ?Paisa?, a genetically and culturally homogeneous population that comprises the majority in this region of Colombia. By recruiting 8,000 participants across the full range of severe mood and psychotic disorders (as well as 2,000 demographically-matched controls); performing uniform phenotyping of these 10,000 individuals using diagnostic and quantitative assessments; and genome wide genotyping, we will establish dimensional phenotypes that index core deficits of SMI and that reference multiple RDoC domains. We will then conduct genetic analyses of symptom-level and quantitative phenotypes, evaluating their relationship to known SMI loci and to polygenic risk scores (PRS) that represent the overall contribution of common genetic variation to these disorders; the SCZ, BP, and MDD workgroups of the Psychiatric Genomics Consortium (PGC) will provide us with up-to-date genetic data for each diagnosis. Additionally, we will conduct genome wide association analyses of the quantitative traits, including meta-analyses for traits that have been assessed in other study populations. We will also contribute our data (including genotypes available to us for an additional 6,000 Paisa controls) to the case-control meta-analyses of the PGC workgroups, contributing to the diversity of their datasets by adding a substantial number of samples from a previously underrepresented (Hispanic) population. .

PROJECT SUMMARY The International Consortium on Brain and Behavior Copy Number Variants (IBBC-CNVs) is a collaborative effort of 9 institutions with complementary experience and expertise in phenomics and genomics. The 22q11.2 and 16p11.2 loci are associated with significant risk for neuropsychiatric disorders across the lifespan. The clinical presentations are heterogeneous, manifesting in a range of developmental neuropsychiatric disorders, including Attention Deficit Hyperactivity, Anxiety, Autism Spectrum, and Psychosis Spectrum Disorders. Taking a `genetics first' approach of ascertaining patients based on known, homogeneous genetic etiologies will allow us to overcome barriers posed by the genetic and phenotypic complexity of idiopathic developmental neuropsychiatric disorders. We postulate that CNVs exert a large main effect on psychopathology, but the nature and degree of psychopathology observed in CNV carriers is multifactorial, with contributions from additional rare and common genetic variants, as well as environmental factors. Therefore, dissecting the effects of major CNV hits as well as additional rare and common variants on dimensional measures of psychopathology can elucidate the combined contribution of genetic mechanisms to psychiatric conditions and build models of risk prediction. Notably, the presentation and course of psychopathology in the CNVs resemble these features in idiopathic disorders. Therefore, beyond the specific genetic syndromes investigated, such a cross-CNV effort will identify convergent risk mechanisms for developmental neuropsychiatric disorders that are of relevance to the broader population. We propose to dissect dimensional measures of psychosis, social-emotional processing and neurocognition, and their genetic and environmental modifiers, to elucidate the architecture of risk for neuropsychiatric disorders in CNV carriers. Prospective evaluation with dimensional measures relevant to neuropsychiatric disorders will be applied to a cohort of 2000 individuals with 22q11.2 and 16p11.2 deletions and duplications (500 per group) and their relatives as feasible. In addition, categorical psychiatric diagnoses will be assessed in CNV carriers. Recruitment for prospective phenotyping will leverage existing large cohorts that carry these reciprocal CNVs, many of whom have already been ascertained and characterized with a range of phenotypic measures. New whole genome sequencing (WGS) will be performed in CNV carriers that have not yet been sequenced. We will also utilize existing genetic data from the largest available case-control samples diagnosed with SZ, ASD, and ADHD in the PGC. Finally, analysis of common variants for a subset of family members will allow us to complement our primary analysis by exploring models of complex genetic inheritance in extended pedigrees that carry CNVs. Our ability to conceive such a large scale study capitalizes on our existing successful collaborations, complementary expertise, and institutional commitments to achieve these goals.

ABSTRACT Developmental neuropsychiatric disorders are increasingly viewed as `developmental dysconnectivity' disorders characterized by pathological patterns of neural connectivity. However, to date investigational approaches to unravel the elusive pathophysiological basis of these phenomena are limited. Modeling specific copy number variants (CNVs) that are strongly associated with distinct neurodevelopmental outcomes offers an extraordinary opportunity to investigate the same genetic defect across species. The 22q11.2 microdeletion (22q11DS) is a well-established potent risk factor for psychosis, conferring at least 25 times the general population base rate. This CNV offers a particularly valuable investigational model, given that large patient cohorts have been identified and extensively characterized at both behavioral and neuroanatomic levels. Importantly, the close homology between human Chromosome 22 and portions of mouse chromosome 16 allows for precise modeling of the causal CNV. Mouse models allow direct assessment of brain mechanisms associated with CNVs while reducing variability due to genetic and environmental factors. The identification of analogous functional connectivity hubs in preclinical species like the mouse may provide critical insight into the elusive biological underpinnings of these connectional alterations. Yet, to date, truly translational studies in which the same genetic defect is modeled in animals and human patients are almost non-existent. Here, we propose to elucidate the cellular underpinnings of structural and functional large-scale connectivity alterations, in the context of this specific well-characterized genetic etiology, using novel methodologies in parallel mouse and human studies. In particular, we aim to: 1) Map macroscale networks, and their developmental trajectories, in human 22q11.2 deletion carriers and the 22q11DS mouse model, in comparison to typically developing controls and wild-type mice, order to investigate the cellular correlates of disrupted long-range connectivity; 2) Investigate developmental rescue of macroscale connectivity defects, at both the neural and behavioral levels; and 3) Investigate social behavioral correlates of connectivity alterations, using parallel tasks of social preference and social reward across species. Collectively, this work will provide a key proof of principle for future translational studies of neurodevelopmental genes and their contribution to large-scale connectivity alterations, and will inform whether neural connectivity may be a viable biomarker (complementary to behavior) for evaluation of novel treatments.

Project Summary This proposal responds to RFA-MH-18-707, ?Confirmatory Efficacy Clinical Trials of Non-Pharmacological Interventions for Mental Disorders (R01).? Adolescents and young adults at clinical high risk (CHR) for psychosis, characterized by recent onset or worsening of attenuated positive symptoms (APS), have a 16%-30% risk of converting to a psychotic disorder in 2 years. In a prior randomized trial in the North American Prodrome Longitudinal Study (NAPLS) network, we showed that family-focused therapy for clinical high-risk persons (FFT- CHR) was more effective than brief family education in (a) improving family (offspring/parent) communication and (b) reducing APS over 6 months, particularly among CHR youth with high baseline scores on a measure of individual risk of psychosis conversion. Both treatments were associated with reductions in young people's perceptions of criticism from parents, which in turn were associated with decreases in APS over 12 months. These findings led us to hypothesize enhanced family communication as a mechanism of action of FFT-CHR. FFT-CHR consists of 18 sessions in 6 months of psychoeducation, communication training, and problem-solving skills training. In the present study conducted in 7 NAPLS sites, we will randomly assign 220 CHR individuals (ages 13-25) and their parent(s) to FFT-CHR or a 6-month Enhanced Care (EC) treatment, consisting of 3 family educational sessions followed by 5 months of individual support and case management. CHR individuals will be interviewed and fill out questionnaires regarding APS (primary outcome) and social functioning (secondary) every 6 months over 18 months. We will examine behavioral targets indicative of improved family relationships: reductions in proportion of critical-conflictual statements and increases in proportion of calm-constructive statements of parents and CHR offspring in laboratory family interactional assessments conducted at baseline and end of treatment (6 months). We will also capture granular changes in targets and outcomes through remote monitoring: CHR participants in both conditions will enroll in a newly developed mobile phone app to facilitate weekly proband ratings of perceived criticism, appraisals of family interactions, and primary and secondary outcomes. We hypothesize that (1) youth/young adults in FFT-CHR will show greater improvements in APS than those in EC in 6 months; (2) improvements in parent and offspring communication by 6 months will be associated with downstream improvements in APS and social functioning over 18 months; and improvements in parent and offspring communication by 6 months will mediate the relationship between treatment condition and changes in primary and secondary outcomes over 18 months. We hypothesize that individuals who are at higher baseline risk of psychosis conversion will show more improvement in targets and primary and secondary outcomes in FFT-CHR than EC, compared to those at lower conversion risk. The involvement of 7 collaborative NAPLS sites with complementary expertise will assure accelerated recruitment of the sample, diagnostic reliability, sample diversity, and treatment exportability.

PROJECT SUMMARY It has now been two decades since the clinical high risk for psychosis (CHR) criteria were first formulated in service of the goal of preventing psychotic disorders, one of the most urgent unmet clinical needs in behavioral health if not in all of medicine. As with most psychiatric patients, CHR patients benefit from psychotherapies but are also often left with important treatment needs not fully addressed. Despite the critical public health need, drug development for CHR is viewed in many quarters as risky. The most daunting obstacle may be the heterogeneity of CHR course. In Aim 1 we will deeply pheno- type 1040 CHR patients across the ProNET network of 26 international sites with multi-modal biomarkers that span brain structure-function (MRI and EEG), psychopathology and cognition, genetics, body fluid analytes, natural speech/language, and passive/ecological momentary digital phenotyping, and map these biomarkers onto a core set of clinical outcome mea- sures and trajectories over a treatment-relevant time window at eight timepoints over 24 months. Biomarkers will be collected at two timepoints to map brain-behavior trajectories. Healthy volunteers (N=260) will complete a baseline assessment to quan- tify typical variation. We will also conduct exploratory studies to assess real-time behavioral data from smartphone sensors and symptom reports from surveys; novel repetition positivity and alpha-desynchronization measures derived from standard EEG paradigms; and pilot an evaluation of excitatory/inhibitory imbalance with MR spectroscopy for glutamate, glutamine, and GABA at 7 Tesla. In Aim 2 we will partner with the NIMH-selected Data Processing, Analysis, and Coordinating Center for rapid data integration and NIMH Data Archive (NDA) uploads with the proposed informatics platform. We will implement ProNET-wide standardized and near real-time data integration with the DPACC architecture to facilitate on-site monitoring, unification of standard operating procedures, and rapid data aggregation across ProNET for seamless DPACC to NDA transfer. In Aim 3 we will test the hypothesis that data-driven variation assessed by multivariate neural, genetic, and behavioral measures within the CHR syndrome predicts individualized clinical trajectories, expanding CHR stratification for broad clinical endpoints encompassing affect, anxiety, cognition, and APS with the goal of identifying behavioral and biomarker-driven patterns that can refine the CHR syndrome and promote personalized treatment decisions. These analy- ses will yield expanded outcome stratification calculators for the CHR syndrome that can predict actionable mental health trajectories in individual patients. The stratification calculators will allow future clinical trial designers to select optimal samples for determining whether a novel compound improves the particular CHR outcome of interest and pave the way for phase-specific and safe new interventions to benefit patients and their families and communities.