Tyrone D. Cannon - US grants

Over 150 post-mortem, computed tomography, and magnetic resonance imaging (MRI) studies have documented the presence of structural brain pathology in schizophrenic patients. Several empirical studies suggest that many of the structural deviations observed in schizophrenics reflect genetic and/or teratogenic disruptions of brain development during gestation and birth, and that these neurodevelopmental abnormalities may play a role in the etiology and pathophysiology of some forms of schizophrenia. Studies which have examined the role of prenatal and perinatal factors in schizophrenia have used two sources for the obstetric information: 1) retrospective maternal recall, and 2) hospital or midwife records produced at the time of the delivery. The hospital and midwife records have the advantage of being unbiased and prospective. However, these records are incomplete; there is rarely any information concerning complications during pregnancy. This study will make use of a total birth cohort on which we have previously collected detailed information concerning pregnancy and delivery complications. The cohort consists of all children born in the city of Helsinki, Finland in 1955 (N=6,789). The existing data bank on this cohort includes complete, standard records of pregnancy and delivery complications produced during the pregnancies and at the time of deliveries by Finnish obstetricians and midwives. We have also previously collected information on neurological and behavioral disorders during infancy and childhood in the cohort offspring. We now wish to search the Finnish psychiatric hospitalization register and hospital archives to obtain the adult psychiatric diagnoses of all of the cohort members and all of their parents. Cohort members with schizophrenic parents and matched controls whose parents are free of mental illness will be interviewed and given an MRI scan. This information will be used to test the following primary hypotheses: 1) cohort offspring who became schizophrenic will have suffered a higher rate of severe obstetric complications (OCs) than those with other disorders and no mental illness; 2) high-risk (HR) subjects will evidence increased signs of cortical dysgenesis on MRI scan compared to low-risk (LR) subjects; 3) genetic risk for schizophrenia and OCs will interact in the prediction of subcortical pathology (i.e., ventriculomegaly, reduced hippocampal and thalamic volumes) and adult schizophrenia; and 4) genetic risk for schizophrenia, OCs, and developmental brain changes will be related to neurological and behavioral abnormalities during infancy and childhood and the type of schizophrenic symptom pattern displayed in adulthood.

Over 150 post-mortem, computed tomography, and magnetic resonance imaging (MRI) studies have documented the presence of structural brain pathology in schizophrenic patients. Several empirical studies suggest that many of the structural deviations observed in schizophrenics reflect genetic and/or teratogenic disruptions of brain development during gestation and birth, and that these neurodevelopmental abnormalities may play a role in the etiology and pathophysiology of some forms of schizophrenia. Studies which have examined the role of prenatal and perinatal factors in schizophrenia have used two sources for the obstetric information: 1) retrospective maternal recall, and 2) hospital or midwife records produced at the time of the delivery. The hospital and midwife records have the advantage of being unbiased and prospective. However, these records are incomplete; there is rarely any information concerning complications during pregnancy. This study will make use of a total birth cohort on which we have previously collected detailed information concerning pregnancy and delivery complications. The cohort consists of all children born in the city of Helsinki, Finland in 1955 (N=6,789). The existing data bank on this cohort includes complete, standard records of pregnancy and delivery complications produced during the pregnancies and at the time of deliveries by Finnish obstetricians and midwives. We have also previously collected information on neurological and behavioral disorders during infancy and childhood in the cohort offspring. We now wish to search the Finnish psychiatric hospitalization register and hospital archives to obtain the adult psychiatric diagnoses of all of the cohort members and all of their parents. Cohort members with schizophrenic parents and matched controls whose parents are free of mental illness will be interviewed and given an MRI scan. This information will be used to test the following primary hypotheses: 1) cohort offspring who became schizophrenic will have suffered a higher rate of severe obstetric complications (OCs) than those with other disorders and no mental illness; 2) high-risk (HR) subjects will evidence increased signs of cortical dysgenesis on MRI scan compared to low-risk (LR) subjects; 3) genetic risk for schizophrenia and OCs will interact in the prediction of subcortical pathology (i.e., ventriculomegaly, reduced hippocampal and thalamic volumes) and adult schizophrenia; and 4) genetic risk for schizophrenia, OCs, and developmental brain changes will be related to neurological and behavioral abnormalities during infancy and childhood and the type of schizophrenic symptom pattern displayed in adulthood.

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Deficits in long-term memory are thought to mark processes associated with the pathophysiology of schizophrenia and to participate in the development of impaired social and work functioning in these patients. A key limitation of prior work is that it has relied on clinical neuropsychological tasks that are poorly suited to address whether particular aspects of long-term memory are impaired. Here we propose a novel behavioral science strategy probing the functional architecture of long-term memory. The aims are to evaluate proposed functional dissociations between episodic and familiarity-based retrieval and between retrieval and encoding processes in long-term memory in healthy subjects and their possible differential relevance to symptom onset and functional deterioration in schizophrenia. Prodromal and FE schizophrenic patients, along with matched controls, will be examined with functional magnetic resonance scans in a longitudinal design, using a paradigm previously shown to discriminate between episodic and familiarity based retrieval in activating the hippocampus. We will also extend basic research by obtaining functional scans during the encoding phase of this experiment. We expect to detect prefrontal, parahippocampal, and hippocampal activity at encoding that predicts subsequent episodic memory in healthy subjects. We expect the patient groups to show impairments in behavioral and physiologic indices of episodic (as compared with familiarity-based) memory at encoding and retrieval, deterioration in which over time will be associated with an increased likelihood of schizophrenia onset and with poorer social and work outcome. The findings should help to clarify whether the long-term memory deficits in schizophrenia reflect a failure to encode contextual information at the study phase, a failure to utilize contextual information at the retrieval phase, or both, whether patients show abnormal activation of key components of the long-term memory circuit, and whether these behavioral and physiologic deficits predict the onset of schizophrenia over and above behavioral indicators of prodromal status and are differentially predictive of poor functional outcome. The findings could be used in future prodromal research to identify those at greatest risk and to develop interventions to prevent, attenuate or compensate for impairments in social and work functioning in schizophrenia.

model design /development

The primary goal of the Prevention Research Program is to provide prodromal participants with a structured, high quality clinical care setting within which the proposed Center research can take place. The objectives are 1) to recruit patients with prodromal symptoms and demographically comparable healthy controls; 2) to conduct diagnostic and screening evaluations of potential participants to determine study eligibility and to coordinate their participation in the following TRCBS research projects: Long-Term Memory Processes, Development of Automaticity, Attention and Dual-Task Interference, Associative Learning and Emotional Regulation, Social Cognition, and Stress and Emotional Reactivity; 3) to sustain subjects' participation in the TRCBS research protocols for a period of at least 12 months by providing extensive case management, psychological, and (when appropriate) psychiatric services; 4) to conduct repeated standardized assessments of diagnosis, clinical symptoms and functional status and to ascertain cases who convert to schizophrenia and other psychotic disorders within 1 year. To achieve the first objective, we will engage in community outreach activities and partner with community mental health sites to generate referrals of patients with prodromal symptoms. Staff will attend disposition planning meetings at local mental health sites to ascertain cases and give talks to educate local community mental health programs, high schools, colleges, and relatives' groups about the schizophrenia prodrome and our services. To achieve the second objective, we will conduct diagnostic and screening interviews of established reliability and predictive validity and continue to develop efficient screening instruments to diagnose the prodrome. To achieve the third objective, we will provide prodromal patients with case management, social and life skills training, family education, ongoing monitoring of symptoms and functional outcome, psychiatric evaluation and, when clinically indicated, psychiatric treatment. By offering ongoing evaluation and case management to participants, we hope to detect conversion to psychosis earlier than would otherwise be typical. Intervention early after onset of psychosis is associated with better treatment response and long-term prognosis. To achieve the fourth objective, we will repeat diagnostic and symptom assessments at 1-, 3-, 6-, and 12-month follow-ups and assessments of functional status at 6- and 12-months. Each TRCBS research project will evaluate a set ofneurocognitive and/or emotional processes in order to determine whether baseline functioning in these systems, and deterioration over time, are associated with onset of psychosis. This information could improve theoretical specification of the mechanisms underlying psychosis onset and improve the sensitivity and specificity of prediction of schizophrenia, so that future primary prevention efforts can be targeted to the individuals who need it most.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Schizophrenia and bipolar disorder are among the most chronic and debilitating of psychiatric syndromes and, with a lifetime prevalence of about 1% each, represent major public health concerns. While traditionally viewed as distinct from each other, recent work has revealed substantial familial co-aggregation and overlap in the genomic regions showing linkage and association with these two disorders. Elucidating the specific genetic and neural mechanisms influencing susceptibility to and expression of these illnesses, and explaining the nature of the overlap between them, is critical to understanding the necessary and sufficient conditions for overt psychosis and to the development of more effective treatment and prevention strategies. To gain traction on these issues, we propose to investigate the inheritance of neural dysfunctions in schizophrenia and bipolar disorder in population-based samples of monozygotic (MZ) and dizygotic (DZ) twin pairs concordant and discordant for these two conditions along with healthy control pairs recruited from the Swedish Twin Registry. Participants will be evaluated with structured clinical interviews, magnetic resonance imaging (MRI) scans of the brain, and a comprehensive neuropsychological test battery, and we will obtain blood samples for DNA extraction and genotyping. This information will be used: 1) to elucidate neural traits that vary in dose-dependent fashion with genetic liability to schizophrenia and bipolar disorder among unaffected MZ and DZ co-twins and control twins and to clarify the extent of overlap in these features between the two syndromes;2) to investigate genomic regions previously linked to schizophrenia and/or bipolar disorder for association with these neural endophenotypes and overt psychosis;and 3) to isolate non-genetic neural changes that are unique to or more severe in individuals who manifest overt schizophrenia or bipolar disorder compared with their unaffected MZ co-twins and determine the contributions of obstetric complications and other non-genetic influences to these neural changes.

Schizophrenia (SZ) and bipolar disorder (BP) are the most chronic and debilitating of psychiatric syndromes, each with lifetime prevalence of about 1%. Existing pharmacologic treatments are partially effective in reducing symptom severity but do not ameliorate the underlying disease processes, cognitive deficits, or functional disabilities associated with these syndromes. Given that both SZ and BP are substantially heritable, gene discovery represents our best hope for identifying new molecular targets for interventions. However, the highly polygenic and heterogeneous nature of these syndromes substantially reduces the effectiveness of traditional genetic linkage and association designs. In addition, recent evidence suggests that some genetic overlaps between these conditions. Our approach is based on the premise that SZ and BP are best conceptualized as sets of quantitative traits that reflect intermediate phenotypes between predisposing genes and syndromal expression (CEendophenotypes1). Here we will screen 300,000 SNP markers - distributed so as to enable the detection of linkage disequilibrium in most parts of the genome - for association with memory and sociability phenotypes previously associated with risk for SZ and BP in a sample of 2,000 subjects from the greater Los Angeles area (LA2K sample). Followup studies of patients with SZ and BP will be performed to specify the impact of the genes identified in the LA2K sample on neuroanatomical and neurophysiological indicators of the pathophysiology of SZ and BP. Because nearly half of the genome is expressed in the brain, and considering the central importance of memory and sociability to adaptive behavioral function, there are likely dozens to hundreds of genes of small to moderate effect influencing these phenotypes in the general population. We hypothesize that many of these genes contribute to susceptibility to SZ and BP through their impacts on the brain systems mediating memory systems and social function and that most of these have been undetected by previous studies using syndromal status as the phenotypic target. In parallel with this whole genome strategy, and to illustrate our translational approach, we will use rodent transgenic models of two promising candidate genes DISC1 and Dysbindin to specify the cellular mechanisms underlying the associations of these genes with memory, sociabiliy, and susceptibility to SZ and BP.

DESCRIPTION (provided by applicant): Schizophrenia and other forms of psychosis affect approximately 3% of the population with a disorder that is usually chronic and disabling. The peak age of onset is between ages 18-30, occurring just as life's most productive years are beginning. Although genetic liability and abnormal brain development are known contributing factors, the etiology and pathophysiology of schizophrenia and related syndromes is largely unknown. To date, prospective observation of onset, i.e., the transition from vulnerability to disorder has not been possible because most persons at true risk cannot be identified premorbidly. This has hampered efforts at prevention. However, recent progress in risk ascertainment methodology has enabled reliable identification of help-seeking persons with pre-psychotic or prodromal clinical syndromes who develop psychosis within 1-2 years at rates between 20%-50%. Thus, clinical high-risk populations are now available for tracking prospectively the development and emergence of psychosis. However, because of the low incidence of schizophrenia and the heterogeneity of outcomes in clinical high-risk cases, single site studies cannot efficiently exploit the risk criteria in identifying predictors and mechanisms of psychosis. The NAPLS consortium was created to solve this problem. Eight NIMH-funded sites in North America studying prodromal patients using a common prodromal assessment instrument pooled data to create the largest sample of such persons worldwide (N=291), 35% of whom converted to psychosis after 2 years. An algorithm of baseline data was generated predicting psychosis with about 80% positive predictive power and 40% sensitivity. In this revised proposal, we describe a collaborative prospective study for which we will recruit 800 cases and 400 appropriate controls over 5 years using common, standardized clinical and neurobiological measures. The aim is to collect a sample with sufficient size and power to rigorously test elements critical to the liability for and development of psychosis in the biomarker domains of brain structure, electrophysiology, stress hormones, and genomics, and in the clinical domains of prodromal presentation and epidemiology. The revised proposal addresses reviewers' concerns, including the integration of the research plan and measures into a unifying framework. The findings will enhance our ability to identify persons at high risk for imminent psychosis, by refining predictors of conversion, and expanding our understanding of the underlying neural mechanisms. Such knowledge is critical for future efforts at early detection, intervention and prevention of psychotic disorders.

DESCRIPTION (provided by applicant): This application addresses Broad Challenge Area 4 (Clinical Research) and Specific Challenge Topic 04- MH-105 (Developing interventions and service delivery models for the transition to adulthood). The goal of our research is to conduct a four-site (UCLA, Emory, North Carolina, Yale) pilot randomized trial (N = 96), to determine the efficacy of a 6-month Family-Focused Treatment (FFT) in comparison with Treatment-As-Usual (TAU) in enhancing functional outcomes, stabilizing symptoms, and preventing or delaying the onset of full psychosis in youth aged 12-25 years who meet criteria for a prodromal risk syndrome according to the Structured Interview for Prodromal Syndromes (SIPS). Our primary, secondary, and tertiary hypotheses, respectively, are that at-risk probands will respond better to FFT than TAU at 6- and 12-month follow-ups, in terms of (1) school and social functioning, family functioning, and parental distress, (2) symptom trajectories (SIPS scores), and (3) time to first onset of full psychosis. Subjects will be drawn from the participants in a currently funded prospective, longitudinal study elucidating predictors and mechanisms of conversion to psychosis (North American Prodrome Longitudinal Study, or NAPLS), on which the four sites collaborate. Subjects will be interviewed every 6 months for 2 years to assess positive and negative symptoms, academic and social functioning, family functioning, and conversion to psychosis. A major advantage of our proposal is that the costs of recruitment and clinical evaluation will be borne by the NAPLS grant, which allows the resources of the Challenge Grant to be concentrated on performing the proposed Treatment Study. Recent progress in risk ascertainment methodology has enabled reliable identification of persons with prodromal or "clinical high-risk" syndromes, 35% of whom develop psychosis within 2 and 1/2 years. This paradigm provides an opportunity for developing and testing interventions in the prodromal phase, before the onset of full psychosis and accumulation of substantial functional disability. Psychosocial interventions appear to be well suited to address issues of motivational deficits and functional disability in the psychosis prodrome. Given our present state of knowledge regarding the mechanisms of psychosis onset, and given that initial studies of antipsychotic drugs in prodromal patients have produced discouraging results in terms of prevention, a reduction in functional disability may represent a more achievable target in the short term than a reduction in psychosis incidence. We have developed and piloted a version of FFT for prodromal youth (FFT-PY) consisting of psychoeducation, communication training, and problem-solving skills training. In randomized trials, adults and adolescents with bipolar disorder and children at-risk for bipolar disorder undergoing FFT improved symptomatically and functionally compared to patients in brief psychoeducational control conditions. Further, an open trial of family psychoeducation for youth at risk for psychosis demonstrated symptomatic and functional improvements relative to baseline scores. However, no randomized controlled study has examined the efficacy of FFT for reducing functional disability and preventing functional deterioration or onset of full psychosis. In view of the improvements in quality of life and the reductions in costs of care that have occurred with preventive approaches to cardiovascular disease, diabetes, and certain forms of cancer, the field of psychiatry is in need of a major commitment to an early detection/prevention framework for its most debilitating syndromes - the psychotic disorders. The prodromal risk syndrome criteria have resulted in clinical algorithms that are highly effective in predicting onset of full psychosis. However, such knowledge will be of limited utility if we lack the means of intervening in the pre-onset phase in a way that either reduces the likelihood of progression to full psychosis, the accumulation of functional disability, or both. There are currently no cost- effective, evidence-based psychosocial approaches to psychosis prevention. Preventing the neurotoxic effects of early episodes, before these illnesses become chronic, and minimizing the psychosocial sequelae of early episodes, may do much to prevent the long-term disability caused by psychosis and thereby have a major impact on public health. Our study will take the critical next step by performing an initial efficacy test of a highly promising family-focused intervention designed to stabilize symptoms and improve social and role functioning in at risk youth. PUBLIC HEALTH RELEVANCE: Preventing psychotic disorders such as schizophrenia and associated functional disability could relieve an enormous burden of personal and family suffering and economic losses to society. This 4-site project aims to conduct a pilot randomized trial to determine the efficacy of a family-focused treatment in comparison with treatment-as-usual in enhancing functional outcomes, stabilizing symptoms, and preventing or delaying the onset of full psychosis in transitional age youth with prodromal symptoms. The results of this study will be crucial for the development of cost-effective, evidence-based psychosocial approaches to psychosis prevention and thus will have major implications for public health.

DESCRIPTION (provided by applicant): We propose a novel program for post-doctoral training in early detection and prevention of psychotic disorders, mood disorders, and anxiety disorders. Because these disorders strike relatively early in life and tend to be chronic and debilitating, individuals with these conditions utilize a disproportionate share of public funds for medical services and disability. Existing treatments are only partially effective in reducing symptom severity, generally requiring on-going maintenance therapy to do so (with accumulating side effect burden), and do not ameliorate the deficits in occupational and social functioning associated with these syndromes or the vulnerability to future episodes. In addition, for some of these conditions, the earlier treatment is initiated after the onset of illness, the better the long-term outcome, suggesting that progressive aspects of the underlying disease processes make these illnesses increasingly less responsive to interventions. This program will integrate didactic coursework, seminars, and supervised research training in early detection and prevention of psychiatric disorders. We integrate mechanisms to evaluate trainees and the program in relation to four objectives. First, progress toward effective prevention programs for these disorders will be more rapid if the next generation of researchers is armed with the tools needed both to ascertain risk markers and mechanisms and to develop and test preventive interventions. Second, given that these forms of psychopathology are complexly determined phenomena, involving biological and psychosocial processes, the next generation of researchers must be able to integrate effectively across these different levels of analysis in their approach to risk detection and preventive intervention. Third, our focus on transitional age populations will help to overcome the traditional boundaries between research in adolescent and adult forms of psychopathology, facilitating the integration of a developmental perspective. Finally, exposure of trainees to early detection and prevention approaches to multiple domains of psychopathology will provide useful points of comparison and contrast and will stimulate cross-fertilization between areas.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The Staglin Family Music Festival Center for the Assessment and Prevention of Prodromal States (CAPPS) is a research clinic at UCLA that provides preventative services for people between the age of 12-35 who are at risk for developing psychosis. CAPPS is the lead site for the North American Prodromal Longitudinal Study (NAPLS), an 8-site collaborative U01 project.

PROJECT 1: ENCODING AND RETRIEVAL PROCESSES IN DECLARATIVE MEMORY In the prior funding period, patients with and at risk for schizophrenia were found to show a differential deficit in recollection that scaled with phase of illness, while familiarity was intact. This deficit was correlated with reduced hippocampal and parahippocampal activity at retrieval on items for which associative memory was evident. There are two (not mutually exclusive) possible sources ofthese deficits: 1) disrupted structural connectivity, resulting from aberrant developmental changes in gray and/or white matter during peri-adolescence;and 2) failure of patients to disengage default mode network (DMN) activity during memory encoding and/or retrieval. The first hypothesis is suggested by our preliminary work indicating a steeper rate of gray matter reduction in prefrontal regions and a lack of normal age-related increase in medial temporal white matter tracks in FE and prodromal patients who convert to psychosis. The second hypothesis is based on recent evidence of reduced suppression of DMN activity and less task-related activity and functional connectivity during a working memory task in schizophrenia patients and their siblings. Increased DMN activation appears to accompany attention to internal thoughts and self-referential thinking;reduced suppression ofthe DMN may thus interfere with patients'ability to activate the episodic and associative memory circuitry at encoding and/or retrieval. In the next phase of the study we will pursue these two hypotheses in cross-sectional and short-term longitudinal studies of prodromal, FE and chronic patients and controls, using MRI and DTI to index structural connectivity and fMRI during an associative memory task and resting scans to index functional connectivity between memory-related and DMN regions. The findings will help to clarify the nature and neural underpinnings of declarative memory deficits in schizophrenia, whether behavioral and physiologic deficits predict the onset of schizophrenia over and above behavioral indicators of risk and are differentially predictive of poor functional outcome. Findings maybe used in prodromal research to identify those at greatest risk for schizophrenia.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. N/A

? DESCRIPTION (provided by applicant): Schizophrenia and other psychotic disorders are serious and debilitating mental illnesses that incur substantial suffering for patients and major challenges to our health care system. The clinical high-risk (CHR) prodromal phase is the period prior to the onset of psychosis when clinical symptoms gradually emerge and function declines. The presence of a CHR syndrome in young adults is associated with heightened risk (~30%) for the later development of psychosis. The North American Prodrome Longitudinal Study (NAPLS) and other CHR studies have made substantial progress towards predicting psychosis, and in showing an accelerated reduction in prefrontal cortex (PFC) gray matter (GM) density in CHR converters from pre- to post-psychosis onset, but the mechanisms driving conversion remain elusive, partly because no studies include repeated measures prior to the onset of psychosis. In NAPLS2, we found that disrupted resting-state (rs) thalamo- cortical functional connectivity prior to psychosis predicts conversion and correlates with rate of GM decline, but we do not know if rs-dysconnectivity is progressive during the prodrome. Furthermore, in NAPLS2, plasma markers of pro-inflammatory cytokines at baseline predicted the rate of GM loss in converters; these same markers also correlated with rs-dysconnectivity. We do not yet know whether these inflammatory markers drive the changes in brain structure/function or are consequences of these changes. Similarly, higher levels of cortisol, and lower mismatch negativity predicted psychosis and the rate of PFC GM decline and were correlated with each other and with measures of rs-connectivity and cytokines. This application is a competitive renewal for a nine-site, longitudinal study aimed at identifying the brain processes underlying the progression of the clinical syndromes that characterize the psychosis prodrome. The goals are: 1) to determine the pre-onset trajectories of GM decline and disrupted resting-state brain connectivity in CHR individuals who develop psychosis using MRI, and 2) to identify inflammatory and plasticity mechanisms associated with transition to psychosis. Over a two-year period, the study will repeatedly measure these indicators, and at the same time examine changes in physiological indices of brain function, social and cognitive functioning, and symptom progression. The multi-site collaboration will follow large CHR (n= 378) and demographically matched comparison (n= 162) samples that will undergo comprehensive assessments of biological and behavioral changes. This approach will answer important questions about the origins of the brain changes that give rise to psychosis and will provide insights into likely approaches to halting or mitigatig the pathological process and advance our understanding of risk prediction, both critical steps in prevention.

? DESCRIPTION (provided by applicant): Schizophrenia and other psychotic disorders are serious and debilitating mental illnesses that incur substantial suffering for patients and major challenges to our health care system. The clinical high-risk (CHR) prodromal phase is the period prior to the onset of psychosis when clinical symptoms gradually emerge and function declines. The presence of a CHR syndrome in young adults is associated with heightened risk (~30%) for the later development of psychosis. The North American Prodrome Longitudinal Study (NAPLS) and other CHR studies have made substantial progress towards predicting psychosis, and in showing an accelerated reduction in prefrontal cortex (PFC) gray matter (GM) density in CHR converters from pre- to post-psychosis onset, but the mechanisms driving conversion remain elusive, partly because no studies include repeated measures prior to the onset of psychosis. In NAPLS2, we found that disrupted resting-state (rs) thalamo- cortical functional connectivity prior to psychosis predicts conversion and correlates with rate of GM decline, but we do not know if rs-dysconnectivity is progressive during the prodrome. Furthermore, in NAPLS2, plasma markers of pro-inflammatory cytokines at baseline predicted the rate of GM loss in converters; these same markers also correlated with rs-dysconnectivity. We do not yet know whether these inflammatory markers drive the changes in brain structure/function or are consequences of these changes. Similarly, higher levels of cortisol, and lower mismatch negativity predicted psychosis and the rate of PFC GM decline and were correlated with each other and with measures of rs-connectivity and cytokines. This application is a competitive renewal for a nine-site, longitudinal study aimed at identifying the brain processes underlying the progression of the clinical syndromes that characterize the psychosis prodrome. The goals are: 1) to determine the pre-onset trajectories of GM decline and disrupted resting-state brain connectivity in CHR individuals who develop psychosis using MRI, and 2) to identify inflammatory and plasticity mechanisms associated with transition to psychosis. Over a two-year period, the study will repeatedly measure these indicators, and at the same time examine changes in physiological indices of brain function, social and cognitive functioning, and symptom progression. The multi-site collaboration will follow large CHR (n= 378) and demographically matched comparison (n= 162) samples that will undergo comprehensive assessments of biological and behavioral changes. This approach will answer important questions about the origins of the brain changes that give rise to psychosis and will provide insights into likely approaches to halting or mitigatig the pathological process and advance our understanding of risk prediction, both critical steps in prevention.