Larry J. Seidman - US grants

We propose to continue a line of research, enabled by an NIMH Merit Award, which has been testing hypotheses about neurobiologic manifestations of schizotaxia (the predisposition to schizophrenia) among schizophrenic patients and the nonpsychotic adult relatives of schizophrenic patients. Our work-showing that schizotaxia is associated with negative symptoms, neuropsychological dysfunction and structural brain abnormalities-converges with data from other centers to show that schizotaxia is a subtle brain disorder affecting about 20 to 50 percent of the nonpsychotic relatives of schizophrenic patients. The data collected during prior funding periods have allowed us to demonstrate a) neuropsychological deficits in schizophrenic patients and their relatives, b) gender differences in the expression of these deficits, c) stability of these deficits over time, d) structural brain abnormalities in patients and relatives, e) functional MRI abnormalities in patients and relatives, and f) how the psychometric features of neuropsychological tests make them useful for assessing phenotypes in genetic linkage studies of schizophrenia. We have decided to pursue three major aims in this continuation proposal that will help us better understand the neural substrates of schizotaxia and how they lead to schizophrenia. First, we will identify predictors of social dysfunction and psychopathology in adolescent children of schizophrenia patients. Second, we will better describe the neural substrate of schizophrenia prior to the onset of psychosis and lay the foundation for work that will examine if neurodegeneration occurs after illness onset. Third, we will establish the infrastructure required to monitor adolescents at risk for psychosis so that future proposals can select adolescents at risk for schizophrenia for prevention protocols. To accomplish these aims, we will assess 300 adolescent children of schizophrenic patients (ACSZ) and 50 normal controls with neuropsychological, psychosis proneness, psychosocial functioning, and family adversity measures. All controls and 150 randomly selected ACSZ will also be evaluated with magnetic resonance imaging. All 350 subjects will be monitored for adverse outcomes at six month intervals. Given the wide age range for the onset of schizophrenia, we plan to follow this sample for many years. Thus, we will also lay the foundation for future proposals that will monitor the incidence of psychosis in this sample through young adulthood. This will eventually allow us to assess 1)the predictive validity of schizotaxia measures and environmental adversity for subsequent psychosis and 2)longitudinal changes in neuro-psychological functioning and brain structure in subjects who do not become psychotic. Achievement of the second goal will help clarify which brain abnormalities in schizophrenic patients can be attributed to neurodevelop-mental events prior to onset and which are due to neurodegeneration after onset.

? DESCRIPTION (provided by applicant): We propose to take advantage of a unique opportunity to study cognition and its relation to other domains in a large untreated sample of individuals with psychosis (IWP), within an ethically appropriate context that is unlikely to continue to be available. After the onset of psychosis, studies of cognition in treated IWP suggest persisting deficits in many SCZ patients; these are present in bipolar affective psychoses to a somewhat lesser extent, indicating a continuum of severity in psychosis. To address this, we propose to study cognition among a large sample (n=500) of completely untreated IWP, assessed prior to AP treatment, within Ningxia Province who span a wide age range (21 to 65) and are community sampled. Ningxia is among the most poor and remote provinces in China, where the 686 Program has not fully penetrated but where identification of untreated cases is increasing. A community sampled comparison group of treated IWP's (n=500) (matched on locale, gender, age, and duration of illness) will also be recruited. Our goal is to illuminate the natural course of cognition and its relation to symptoms and functioning, in the absence of medication effects. We possess an unprecedented opportunity to do so within the 686 national treatment program. Our multidisciplinary research team is comprised of world-recognized experts from the fields of epidemiology, clinical psychology, and psychiatry. Building upon a history of successful collaborations, each investigator brings extensive capacity-building experience to execute this challenging project. A major goal is also to train a new cohort of investigators in Ningxia Province to increase capacity to intervene with untreated psychosis, thus serving as a model for scale-up for the 686 program.

?Enhancing Intervention of Attenuated Psychosis Syndrome with M-Health Technology? 7. Project Summary/Abstract: There is a worldwide movement in the early intervention of populations at the putatively prodromal or attenuated psychosis syndrome (APS) 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 first research group carrying out APS studies in a low-middle income country in Asia, an R21 in collaboration with the Shanghai Mental Health Center (SMHC) (1R21MH093294-01A1, Fogarty/NIMH, ?Broadening the Investigation of Psychosis Prodrome to Different Cultural Groups?), and an R01 ?Validating Biomarkers for the Prodrome and Transition to Psychosis in Shanghai? (1 R01 MH 101052-01, NIMH). The R21 and R01 studies aim at early identification of APS and the risk factors of APS. Our current proposal, in response to the NIH FOA (PAR-16-292) Mobile Health: Technology and Outcomes in Low and Middle Income Countries (R21), will focus on early intervention effort targeting neurocognitive function-memory and attention in particular, using mHealth technology. We will develop and implement a culturally sensitive smart phone application to engage patients with APS in improving neurocognitive and social functioning. Our goal is to work collaboratively with researchers at the SMHC to build their research capacity in establishing a sustainable APS longitudinal program of research in China and to lay a foundation for APS early intervention with mHealth technology. This project will be completed in two phases: Phase 1 (Month 1-7), Develop and test the Specific Memory Attention Resource and Training (SMART) application through a qualitative research approach-in- depth 1:1 interviews. Phase 2 (Month 8-24), we will firstly examine SMART feasibility and user engagement with a mixed method design. We will conduct a pilot study of 80 APS subjects (age 18-45). Forty subjects will get routine care (RC) and 40 matched by age, gender, clinical symptoms will receive add-on SMART for 3 months in addition to RC. At baseline and 3-month follow-ups, all subjects will complete questionnaires on app use habits and attitudes towards SMART feasibility and engagement, and MATRICS Cognitive Battery subtests measuring working memory and attention. The RC group will provide their attitudes addressing the likelihood of using SMART. In-depth interviews will be conducted at both time points to cross-validate the findings obtained from the questionnaires. Secondly we will examine cognitive and social function changes over time with the within and between group design. Thirdly, we strive to build mHealth research capacity at individual and organization levels during and beyond grant time.