2009 |
Mccarley, Robert W |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Biological Basis of Schizotypal Personality Disorder
DESCRIPTION (provided by applicant): The biological basis of schizotypal personality disorder (SPD) is of intrinsic interest and also important because it bears closely on the nature of schizophrenia (SZ) and "SZ spectrum disorders". SPD and SZ are genetically linked, but SPD may offer a clearer picture of the SZ spectrum, since SPD does not have the potentially confounding features of SZ, including chronic illness, medication, and hospitalization. This 5-year study will evaluate 80 right-handed, DSM-IV diagnosed SPD subjects, half males and half females, who will be unmedicated, neuroleptic-naive and drawn from the community, but not from clinical treatment settings. They will be contrasted with 80 age-, sex-, handedness- and parental SES-matched normal controls. We are fortunate to be able to use the same common core methodology for SPD evaluation that we use for our separately funded evaluation of SZ, including neuropsychological, Event-Related Potential (ERP), structural and functional magnetic resonance imaging (MRI), and Diffusion Tensor Imaging (DTI), thereby making valid comparisons possible. We believe that this systematic approach will enable us to discover which features are common to SPD and SZ, thereby defining the core deficits of the SZ spectrum, as well as determining which are found only in SZ. Those features found only in SZ may underlie the more severe, psychotic aspects of SZ, while features abnormal in SZ, but normal in SPD, may be protective. 2 major novel findings have emerged from our previous funding period: 1) overall, there are marked gender differences, with abnormalities generally less prominent in women;2) abnormalities in SPD are likely to be primarily referable to temporal lobe systems {auditory &language processing) and to the frontal-striato-thalamic system (FST, working memory, set shifting), where structural abnormalities are present in the caudate but not in prefrontal cortex. Our proposed functional measures are specifically tailored to these 2 systems, with each system also having MRI &DTI anatomic measures. For example, temporal lobe systems will be studied with: Dichotic listening to complex tones, sentences, &emotion-laden words;ERP measures spanning early to late auditory/language processing;and Mismatch and Level of Processing fMRI tasks. The FST system will be studied with: delayed alternation and auditory working memory tasks, and the fMRI 2-back task. More generally, we expect negative symptom/working memory deficits to be associated with abnormalities in the FST and positive symptoms with the temporal lobe systems. For example, we expect a smaller Heschl's gyrus MRI volume will be associated with poorer performance on dichotic sentence tasks &complex tones, as well as abnormalities in the mismatch protocol (ERP and fMRI). As a FST system example, we expect decreased caudate volume/abnormal shape to be associated with perseveration, abnormal verbal working memory, &increased prefrontal activation in the 2-back fMRI test. Preliminary Data indicate DTI abnormalities -"system disconnections"- of the uncinate fasciculus (UF) white matter links between frontal &temporal lobes, which we predict will show strong associations with cognitive/clinical SPD features, i.e., left UF abnormalities will be associated with impaired cognitive performance while right UF abnormalities will be associated with increased psychopathological SPD symptoms. We believe the feasibility of our ambitious goal of linking biology with cognitive and clinical symptoms is validated by our group's extensive experience with these methods in schizophrenia and in SPD.
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1 |
2009 — 2011 |
Mccarley, Robert W |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Core 1: Operations and Clinical Assessment @ Beth Israel Deaconess Medical Center
This application requests five years of support to establish an NIMH Center for Intervention Development and Applied Research ("CIDAR") entitled "Vulnerability to Progression in Schizophrenia". The Operations and Clinical Assessment (OCA) Core (Seidman, PI) is responsible for location and recruitment of research participants, selection of all clinical (e.g., diagnostic and neuropsychological) instruments, training and quality control of the use of the instruments, and supervision of recruiters, diagnosticians, raters and of testers. The OCA is responsible for maintaining the subject flow, maintaining all records of study participants and ensuring that IRB, HIPAA and other regulatory procedures are followed. The OCA is also responsible for data management and statistical analysis. The OCA is the operational hub of a complex study involving five other
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0.922 |
2009 — 2011 |
Mccarley, Robert W |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neurophysiological Studies of Schizophrenia
DESCRIPTION (provided by applicant): Schizophrenia and bipolar disorder are major mental illnesses that cause their victims and their families much anguish and are a major source of lost productivity and medical care expenses to our nation. Yet too little is known about them, especially about the most effective time of treatment intervention during the course of illness. The main goal of this competing R01 renewal application, which uses a prospective longitudinal study design, is to advance our knowledge of the neurophysiology of schizophrenia (SZ) (and affective psychosis) by: 1) evaluating functional abnormalities in EEG event-related potentials (ERPs) that span both early and late stages of processing, with a special focus on early auditory processing;2) integrating this information with structural MRI anatomy;and 3) integrating both ERP and MRI measures with clinical features. Findings from our work, as well as others, suggest the importance of understanding the course of the disorder. Initial data from our prospective longitudinal study of first psychotic episode subjects (FE, operationally defined as first hospitalization)have shown which demonstrate post onset progression of MRI/ERP features deficits, including brain gray matter loss and concomitant reduction of ERP functional measures. Progression is very rapid in the first 1.5 years after initial hospitalization, but much slower or even absent in chronic patients. The present application adds a second longitudinally studied population, subjects who are clinically prodromal for psychosis (PRO) in whom we propose to track progression and biopredictors of conversion to psychosis, especially SZ psychosis. Unifying our approach is our neurobiological model of a fundamental cellular defect in recurrent inhibition, based on an NMDA neurotransmission abnormality. Specifically, we hypothesize that such an abnormality may be responsible for both the developmental abnormalities observed in this disorder as well as the prodromal and post-onset progression. This cellular- based model and our preliminary data have led to an increasing focus on early-stage brain processing, especially auditory processing, as results from early processing paradigms appear to be especially amenable to correlation with brain anatomical deficits and with documentation of progression of the disorder. Finally, we will use these measures to evaluate specificity to FE schizophrenic psychosis versus FE Affective Psychosis (90% biopolar). In terms of significance, it hardly needs emphasis that, should our prediction of progression of ERP/MRI abnormalities in prodromes be confirmed and constitute predictor(s) of conversion, such findings would likely form a rational basis for psychosocial and medication therapeutic interventions. Moreover, should our preliminary findings be confirmed -rapid post-onset progression in the early course of schizophrenia with lesser changes occurring later-this would immediately form a scientific foundation for emphasis on early treatment, and perhaps prevention of progression of illness over time.
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1 |
2009 — 2011 |
Mccarley, Robert W |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Project 3: Electrophysiological &Gray Matter Markers &Predictors of Progression @ Beth Israel Deaconess Medical Center
Project 3. Electrophysiological and MRI gray matter markers and predictors of progression. Increasing evidence, including that from our CIDAR investigators, points to a post-onset progression of event-related potential (ERP) and MRI markers of pathology in schizophrenia (SZ), including a conjoint progression of gray matter loss in Heschl gyrus and abnormalities of pitch mismatch negativity (MMN). However, the relative merit of each of the many putative markers in SZ is not clear, while markers in the prodromal period are not at all or only minimally defined. Accordingly, this project will study a selected set of putative biomarkers of vulnerability to progression in 3 sets of subjects,each with an equal number of control subjects, group matched for age, gender and parental socioeconomic status: 1) 75 subjects with prodromal manifestations of SZ (PRO), studied at entry, at one year longitudinal follow-up, and, for converters to SZ, immediately post conversion when they will enter the first episode protocol. 2) The first episode schizophrenia (FESZ) protocol will include the projected 24 converters and 80 new subjectswith first episode schizophrenia, operationally defined as first hospitalization for the disorder. FESZ &controls will be studied at entry (t1), 6 months post-entry (t2) and 18 mo post-entry (t3), timing based on our preliminary data showing the maximal rate of progression is immediately post-onset. 3) The chronic schizophrenia group (CSZ) will be 42 individuals with a history of 3 or more hospitalizations and a minimum 5 year post-onset duration who will be studied on one occasion to determine if the putative progression markers are, as needed in this model, present in the fully developed illness, near the end stage of progression. We will use ERPs of gamma band oscillations, mismatch negativity (pitch and duration) and P300, with MRI measuresof neocorticalgray gray matter, sulcal and ventriciular CSF, as well as specific regions of interest, including superior temporal gyrus, Heschl gyrus, and prefrontal cortex. We predict progression of reduced ERP amplitude, decreased neocortical gray matter and increased CSF in both prodromes (duration mismatch, P300, gamma, gray matter measures) first episode (pitch mismatch, gamma, gray matter measures). We predict a gradient of degree of progression in both prodromes and FESZ with superior (STG) >middle >inferior temporal gyri, and with STG progression greater than neocortical gray matter. We predict lesser progression in hippocampus than neocortical areas. In conjunction with the genetics core we will determine association of change measures with particular genes. In conjunction with the post-mortem core we will determine if expression data in parvalabumin GABA neurons and pyramidal cells are consistent with our model of the source of gamma oscillation abnormality in the interaction of these two cell types.
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0.922 |
2009 — 2016 |
Mccarley, Robert W |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Synaptic Basis of Sleep Cycle Control
DESCRIPTION (provided by applicant): Why do we get sleepy after being awake? Why does the sleep drive have such preemptive effects on behavior and performance? Formulating better answers to these simple questions is the purpose of this proposal. We use an animal model in our quest to understand the mechanisms mediating the homeostatic sleep drive (HSD), the drive that mediates the sleepiness following sleep loss or sleep deprivation (SD). Our earlier findings in animal models pointed to elevated extracellular levels of the neurochemical adenosine (AD) as a homeostatic sleep factor acting potently in the cholinergic basal forebrain (CBF) to increase sleepiness after as little as 3 to 6h of sleep deprivation (short term SD). We now think that with progressively longer periods of SD (6 or more h of SD), the HSD effects are progressively more mediated by non-CBF cortical regions. We note that "adenosine and sleep" is a scientific hot topic, with a February 2008 PubMed search revealing some 31 articles in the past year alone. To help advance our understanding, we propose the following studies relevant to the molecular, cellular, and behavioral mechanisms underlying the HSD. Specific Aim 1). We will test whether changes in AD production and extracellular levels occur first in CBF and then, with longer SD, in cortical areas. We predict an increase in adenosine A1 receptor binding (number of active receptors) with 24h SD. We will test our preliminary data-derived hypothesis indicating that inducible nitric oxide synthase (iNOS)-produced nitric oxide (NO) is an immediate mediator of AD increases during SD, and we predict that iNOS and NO activity will show the same temporal-spatial distribution as AD. Specific Aim 2). Using in vitro slice in a novel genetically modified mouse that expresses green fluorescent protein (GFP) in GABAergic neurons, we will investigate the cellular actions of NO to confirm preliminary data that NO initially excites cortically projecting CBF cholinergic and GABAergic neurons, and then produces an inhibition that is dependent on AD produced by NO. We further will study the intrinsic neurophysiological properties and pharmacology of identified cellular components of the CBF. Specific Aim 3). We will investigate the effects and interaction of SD, AD and NO in the CBF on sleepiness and vigilance using a novel rodent version of the human multiple sleep latency test (rMSLT) and a rodent version of the human psychomotor vigilance task (rPVT). In summary, this project proposes to use what we view as state-of-the-art molecular, electrophysiological and behavioral methods, including several which are unique to our lab within the sleep field. These include the use of a novel dye (DAF) to identify the cellular sources of NO production;the use of genetically modified GFP mice which allow identification of GABAergic neurons prior to electrophysiological recordings and finally the use of rodent analogues of human tests measuring sleepiness (rMSLT) and vigilance (rPVT). We thus see this application as using state-of-the art technology to answer critical questions about the homeostatic sleep drive. PUBLIC HEALTH RELEVANCE Sleep loss from disease (including insomnia and depression) and vocational demands (shift work, doctors, emergency workers) is known as a major contributor to diminished quality of life, to accidents and to decreased work and school efficiency. This proposal uses an animal model to enable understanding of the biological mechanisms mediating the sleepiness following sleep loss or sleep deprivation. By doing this we hope to lay the foundation for a rational treatment of insomnia and other sleep disorders.
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1 |
2009 — 2011 |
Mccarley, Robert W |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Vulnerability to Progression Schizophrenia @ Beth Israel Deaconess Medical Center
DESCRIPTION (provided by applicant): The central theme of the application for a Boston Center for Intervention Development and Applied Research (CIDAR) is "Vulnerability to Progression in Schizophrenia". We see two major strengths of the proposal. First we study subjects who are at various stages of progression of the disorder, prodromal, first episode and chronic, giving us a broad perspective and large database on phenotypic markers and predictors of progression. Moreover, prodromes and first episode individuals will be evaluated in a prospective longitudinal study. A second major strength, in our view, is our plan to link clinical, cognitive, neuroimaging, electrophysiological, hormonal and genetic markers of SZ disease progression to the understanding of how the underlying neural circuits may be disturbed. We do this by investigating the expression of genes of interest in specific cellular populations in post-mortem material and evaluating genetic association of the relevant genes with progression indices from each Project. Four projects, each with an experienced investigator as PI, all evaluate the same group of subjects so as to bring multiple perspectives on the markers and predictors of progression. Project 1. "Functional anatomy of neurocognitive deterioration in schizophrenia", uses neuropsychological and fMRI evaluations. Project 2, "Hormones, memory &sex effects in illness progression in schizophrenia", evaluates hormones and gender differences in schizophrenia. Project 3, "Electrophysiological and MRI gray matter markers and predictors of progression", uses event-related potentials (ERPs) and MRI gray matter measures to evaluate progression, often conjoint, in these two domains. Project 4, "Vulnerability to white matter progression in schizophrenia" uses diffusion tensor imaging evaluations of white matter. A long-standing history of previous successful collaborations and work on joint projects by these project PIs will facilitate the synergistic interactions essential for knitting together data from the different methodological and conceptual domains. The Center mechanism brings added value to this work since no single R01 award could support: 1) the translational gene expression and genetics endeavor in the cores that specifically links to each Project's clinical research findings;2) the large-scale subject recruiting needed for each project;3) the extensive neuroimaging work;4) the linking together of the Project's diverse technologies and levels of analysis on the same subjects, affording a rich opportunity to understand interrelationships of findings from different domains.
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0.922 |
2013 — 2015 |
Li, Huijun Mccarley, Robert W Seidman, Larry J |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Validating Biomarkers For the Prodrome and Transition to Psychosis in Shanghai @ Beth Israel Deaconess Medical Center
DESCRIPTION (provided by applicant): Validating Biomarkers for the Prodrome and Transition to Psychosis in Shanghai 7. Project Summary/Abstract: The identification of people at risk of developing psychosis is central to the development of early intervention and prevention strategies for schizophrenia. There is a worldwide movement in the study of populations at the putatively prodromal, clinical high-risk (CHR) stage led mainly by researchers in Australia, Europe, and North America (North American Prodrome Longitudinal Studies/NAPLS). Within the Asian Network for Early Psychosis, Taiwan and Singapore have started to address the putatively prodromal population. To our knowledge, we are the only group carrying out a CHR study, an R21 in collaboration with the Shanghai Mental Health Center (SMHC), MH093294 (Fogarty/NIH, Broadening the Investigation of Psychosis Prodrome to Different Cultural Groups). The preliminary study, which has already begun, contains four major components: a) clinical assessment of prodromal subjects using the Structured Interview for Prodromal Syndromes and Scale of Prodromal Symptoms (SIPS/SOPS) (translated into Chinese by the PI of the R21, Dr. Li); b) neurocognitive assessment with the MATRICS battery, c) stigma, and d) event related potentials. In addition, blood samples will be collected and stored for future genetic analyses. Our current proposal, in response to the RFA-AI-12-021: U.S.-China Program for Biomedical Collaborative Research (R01) will build upon and extend the R21 at the SMHC by expanding the sample substantially and bring in structural, DTI and resting state measures of magnetic resonance imaging (MRI). We will work collaboratively with researchers at the SMHC to design and initiate a sustainable CHR to psychosis longitudinal program of research in China. The SMHC, a World Health Organization designated research center for mental health, has excellent clinical and biomedical research technical resources that can carry out a first-rate study in collaboration with the US team. Our specific aims are to: 1. Identify clinical and biomarker abnormalities in CHR vs. Controls; 2. Replicate prediction of psychosis algorithms from the NAPLS study and; 3. Demonstrate increasing brain abnormalities with conversion to psychosis. Two hundred CHR and 100 controls, age 15-45, will be assessed at baseline and followed for one year, resulting in an estimated 40 converters to psychosis. With an estimated retention rate of 75%, 30 CHR who become psychotic, 120 who do not become psychotic and 75 controls will be assessed at conversion or 1 year follow-up with an extensive battery of clinical and biological measures.
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0.922 |
2015 — 2019 |
Mccarley, Robert W |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Project 3 Hms - Va Sub @ Beth Israel Deaconess Medical Center
ABSTRACT Obstructive sleep apnea (OSA) is characterized by frequent arousals from sleep due to closure of the upper airway, producing hypercapnia (increased carbon dioxide levels) and hypoxia (decreased oxygen levels). The consequences of OSA include excessive daytime sleepiness, cognitive deficits, as well as respiratory, metabolic, and cardiovascular disorders. Despite its importance in OSA-induced arousals and sleep fragmentation, very little is known about the neural mechanisms that mediate arousals during OSA. Recent work indicates that the brainstem glutamatergic neurons of the parabrachial complex (PB), which receive visceral and respiratory input, are important for hypercapnic arousal. We hypothesize that the PB projections to the basal forebrain (BF), a region containing cortically projecting & wakefulness promoting neurons, mediate the cortical arousal response to the hypercapnia. Sleep apnea will be modeled in mice by exposure to hypercapnia during sleep, termed repetitive carbon dioxide-mediated arousals (RCA). Optogenetic techniques will be used to investigate the roles of three neurotransmitter-defined subpopulations of cortically-projecting BF neurons in apnea-induced arousals: GABAergic parvalbumin positive (PV), cholinergic, and glutamatergic neurons. For each identified BF neurotransmitter phenotype we will address the criteria of: 1) sufficiency for arousal by optogenetic excitation using Channelrhodopsin 2 (ChR2); 2) necessity for arousal by optogenetic inhibition of RCA using Archaerhodopsin (ArchT); and 3) relevance of our optogenetic findings to natural physiological conditions by recording the electrical activity of RCA -related BF neurons whose neurotransmitter phenotype has been defined by short latency excitation by ChR2. Each neuronal BF population will be evaluated as mice are exposed to RCA or acoustic stimuli; we predict both stimuli will arouse, as our data point to the BF as a final common pathway leading to cortical arousal from both visceral and external sensory stimuli. Our preliminary data point to PV GABergic neurons as the most important for RCA and acoustic arousals: 1) ChR2 excitation of BF PV neurons causes arousal and EEG activation including high frequency oscillations; 2) PV ArchT inhibition markedly prolongs the latency to RCA arousal; and 3) PV unit recordings show activation in concert with cortical activation. In contrast, ChR2 stimulation of BF cholinergic neurons shows more modulatory, less powerful and less immediate effects on cortical activation than PV neurons. We predict that glutamatergic BF neurons will play a role in promoting arousal, but not high frequency oscillations. If successful, these experiments would suggest that blocking BF activation, especially that from GABAergic PV neurons, would increase the cortical arousal threshold, and thus would treat the sleep fragmentation evident in apnea and responsible for many of the symptoms of OSA. Improved understanding of the neural mechanisms controlling cortical arousals in OSA will guide therapeutic treatment aiming to decrease cortical arousals while maintaining airway patency.
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0.922 |
2016 |
Li, Huijun Mccarley, Robert W Seidman, Larry J Shenton, Martha E. Wang, Jijun Whitfield-Gabrieli, Susan |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
A Psychobiological Follow-Up Study of Transition From Prodrome to Early Psychosis @ Beth Israel Deaconess Medical Center
7. Project Summary/Abstract: There is a worldwide movement in the early intervention for adolescents and young adults appearing to develop early signs of psychosis or described as at clinical high risk (CHR) for psychosis, led mainly by researchers in Australia, Europe, and North America. Within the Asian Network for Early Psychosis, Taiwan and Singapore have started to address the CHR population. To our knowledge, we are the first research group carrying out CHR studies in a low-middle income country in Asia. Since 2012, supported by NIMH/Fogarty 1R21MH093294-01A1 and an NIMH R01 MH101052-01, we have worked closely with the Shanghai Mental Health Center (SMHC), to develop a CHR research program in Shanghai, China. The completed R21 and on-going R01 projects aim at identification of the risk factors for CHR conversion over approximately one year. In our current proposal, in response to NIH FOA PAR-14-332, Global Brain and Nervous System Disorders Research across the Lifespan (R01), we will continue to enhance research capacity building at SMHC, and collaboratively carry out an extensive follow-up study of clinical outcomes such as conversion to psychosis and level of disability, and we will evaluate the evolution of biomarkers such as event related potentials, resting state functional magnetic resonance imaging (MRI), white matter as assessed by diffusion tensor imaging MRI, and neurocognition. We will follow-up 300 well characterized CHR and Healthy Control (HC) participants between the ages of 15-45 for two more follow-up assessments. The longitudinal nature of the project is novel in China and worldwide as this will be the first study to comprehensively examine biopsychosocial parameters predictive of psychosis conversion and illness progression for up to 6 years, including two new follow-ups of the biomarkers (4 assessments including baseline). Moreover, unlike many studies in the West, virtually 100% of the participants are psychotropically naïve when they enter the study, and the assessments are done at one site (SMHC), reducing confounds associated with medications and multiple sites. Our goal is to work collaboratively with researchers at the SMHC to establish a sustainable CHR longitudinal program of research in China and to lay a solid foundation for CHR early intervention.This project aims to: 1). Develop predictors for conversion to psychosis, 2). Investigate clinical and biomarker progression in CHR, 3). Demonstrate an association between clinical features, biological measures and disability in CHR, and 4). Explore the feasibility of early intervention with CHR subjects. Capacity building and research training will be conducted during and beyond the proposed project to facilitate sustainable research at SMHC.
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0.922 |