Robert Asarnow - US grants

DESCRIPTION (Adapted from the Applicant's Abstract): This project addresses two major bottlenecks to progress in detecting susceptibility genes for schizophrenia: 1) the probable genetic heterogeneity of the schizophrenia disorders and 2) uncertainty over the boundaries of the schizophrenia phenotype. This project was stimulated by the hypothesis that early (childhood) onset schizophrenia is associated with increased genetic loading for this disorder. The proposed project will replicate and extend important findings from the first phase of this project indicating that there is a significantly increased familial aggregation of schizophrenia, schizophrenia spectrum personality disorders, and certain neurocognitive impairments in families of probands with childhood-onset schizophrenia compared to families of community control and adult-onset schizophrenia probands. The long-term stability and predictive validity of schizophrenia spectrum diagnoses and neurocognitive impairments detected during adolescence in the siblings of probands with childhood-onset schizophrenia will be determined. Hypotheses about the role obstetric complications play in triggering an early onset of schizophrenia and about the relation between history of obstetric complications and impaired functioning of the hippocampal/temporal lobes will be tested. The hypothesis that relatives of probands with childhood-onset schizophrenia who have neurocognitive impairments will show subtle signs of formal thought disorder impaired discourse and impairments in working memory will also be tested. The proposed project will test a number of genetic models of the familial transmission of putative measures of the extended schizophrenia phenotype, including analyses to examine the evidence for a single vulnerability factor versus two familial vulnerability factors (one influencing mainly neurocognitive measures and the other mainly schizophrenia spectrum diagnosis. Whether chromosomal regions found in prior research to be associated with susceptibility to schizophrenia are associated with susceptibility to childhood-onset schizophrenia and potentially associated phenotypes (including neurocognitive impairments) will be determined. These specific aims will be addressed by rediagnosing all previously studied (N = 50) probands and relatives with childhood-onset schizophrenia to confirm their original diagnoses, enrolling an additional 90 new families of probands with childhood-onset schizophrenia and 60 families of probands of community controls, and capitalizing on data from 120 families of adult-onset schizophrenia probands which has already been collected. We will conduct a genetic linkage analysis to determine whether putative susceptibility genes identified in prior research are associated with the presence of schizophrenia spectrum disorders and/or neurocognitive impairments in families of probands with childhood-onset schizophrenia. DNA will be retained for use in future linkage, linkage disequilibrium, association and other studies.

neuropsychology; nervous system disorder epidemiology; mental health epidemiology; trauma; child behavior disorders; brain injury; gender difference; psychomotor function; language development; middle childhood (6-11); adolescence (12-20); prognosis; attention; longitudinal human study; memory; neuropsychological tests; human subject;

The major objectives of this study are to: 1) confirm reports that cases with onset of schizophrenia prior to 13 years of age have an increased aggregation of schizophrenia and schizophrenia spectrum personality disorders in their families as compared to cases of adult onset schizophrenia, 2) test the hypothesis that certain measures of attention/information processing (AIP) index a genetic liability to schizophrenic disorder, 3) determine if the distribution of AIP impairments amongst the first degree relatives of schizophrenic children is consistent with a simple model of genetic transmission, and 4) test the hypothesis that performance on certain AIP tasks provides a useful basis for sub-typing schizophrenic patients by determining if schizophrenic children with and without AIP impairments differ in their short term response to neuroleptic treatment, incidence of minor physical anomalies, familial aggregation of schizophrenic spectrum disorders and in ratings of formal thought disorder and the frequency of parental communication deviance. Seventy five families in each of three groups will be studied: 1) families with a schizophrenic child, 2) families with an attention deficit disorder child, and 3) families with children who have no history of psychiatric disorder. Children with an attention deficit disorder provide a test of the diagnostic specificity of the above relations. Proband will be diagnosed with a structured diagnostic interview and rated on a measure of formal thought disorder. AIP performance will be evaluated and minor physical anomalies measured in all proband and their first degree relatives. First degree relatives will be administered structured diagnostic interviews to make DSM III axis I diagnoses and diagnoses of schizophrenic spectrum personality disorders, and psychometric measures of psychosis proneness. Family history of schizophrenic disorders will be determined for second and third degree relatives. All assessments of first degree relatives will be conducted by staff blind to the proband's diagnosis.

The major objectives of this study are to: 1) confirm reports that cases with onset of schizophrenia prior to 13 years of age have an increased aggregation of schizophrenia and schizophrenia spectrum personality disorders in their families as compared to cases of adult onset schizophrenia, 2) test the hypothesis that certain measures of attention/information processing (AIP) index a genetic liability to schizophrenic disorder, 3) determine if the distribution of AIP impairments amongst the first degree relatives of schizophrenic children is consistent with a simple model of genetic transmission, and 4) test the hypothesis that performance on certain AIP tasks provides a useful basis for sub-typing schizophrenic patients by determining if schizophrenic children with and without AIP impairments differ in their short term response to neuroleptic treatment, incidence of minor physical anomalies, familial aggregation of schizophrenic spectrum disorders and in ratings of formal thought disorder and the frequency of parental communication deviance. Seventy five families in each of three groups will be studied: 1) families with a schizophrenic child, 2) families with an attention deficit disorder child, and 3) families with children who have no history of psychiatric disorder. Children with an attention deficit disorder provide a test of the diagnostic specificity of the above relations. Proband will be diagnosed with a structured diagnostic interview and rated on a measure of formal thought disorder. AIP performance will be evaluated and minor physical anomalies measured in all proband and their first degree relatives. First degree relatives will be administered structured diagnostic interviews to make DSM III axis I diagnoses and diagnoses of schizophrenic spectrum personality disorders, and psychometric measures of psychosis proneness. Family history of schizophrenic disorders will be determined for second and third degree relatives. All assessments of first degree relatives will be conducted by staff blind to the proband's diagnosis.

DESCRIPTION: (Adapted from Applicant's Abstract) This project is a continuation of an earlier study. The earlier study was the largest, community-based investigation of the neurobehavioral sequelae of mild closed head injuries (CHI) in children and adolescents. Using a case-finding system of 25 emergency rooms, the investigators identified groups of children with mild CHI (n=137) and mild injuries not involving the brain (n=132). A non-injury control group (n=114) was recruited through community schools. Evaluations were conducted one, six and twelve months post-injury to assess key neuropsychological, behavioral and academic outcomes. This case-finding system yielded a sample of children with very mild CHI. For example, 95 percent of the children with CHI had been unconscious for less than 10 minutes. The results indicate that children with this mild a CHI did not show functional morbidity relative to the other injury and non-injury groups. Left still unanswered is the question of the minimal acute CHI severity necessary to produce impairment in children and adolescents. The proposed project has been designed to address this issue by sampling a more severe range of CHI injury severity than the prior study, including a range of severity known from prior research to produce significant functional morbidity. The proposed study will capitalize on the large non-injury group and the normative data collected in the earlier study by using the identical outcome measures used in the earlier study. The proposed study will use a new case-finding system consisting of three neurosurgery centers included in the newly funded UCLA Brain Injury Research Center. Children and adolescents with Glasgow Coma scores 6-15 (with a minimal interruption of consciousness greater than one hour) will be assessed immediately prior to hospital discharge on a brief neuropsychological battery and as in the prior study one, six and twelve months post injury. A major objective of the proposed study is to determine the minimal threshold of acute CHI severity necessary to produce significant neuropsychological impairments and/or school and behavior problems during the one year post injury in children and adolescents who are hospitalized within 24 hours of sustaining a CHI. The investigators will determine if neuropsychological functioning at hospital discharge and/or at one month post-injury predicts which children show new school and behavior problems during the one year post injury. The investigators will test the hypothesis that certain factors (e.g., prior history of central nervous system impairment, presence of CT scan abnormalities, the age of the child when injured, the sex of the child and the presence of multiple traumas) modify the minimal threshold of acute CHI severity that is necessary to produce functional morbidity.

This project is a family genetic stud), comparing childhood onset schizophrenia and attention deficit hyperactivity disorder. The objective of this study is to identify genes associated with different facets of the schizophrenia phenotype. Specific Aims 1. To determine the rate of schizophrenia and Schizophrenic Spectrum Personality Disorder (SSPD) by direct interviews of first degree relatives, and by family history for second degree relatives, of children with onset of schizophrenia prior to thirteen years of age. To compare the rates of schizophrenia and SSPD among the first and second degree relatives of schizophrenic children to those observed in children with ADHD and normal control children. 2. To test the hypothesis that certain attention and information processing (AIP) Impairments index a genetic liability to schizophrenic disorder by determining if there is an increased aggregation of certain impairments among the first degree relatives of schizophrenic children as compared to the first degree relatives of children with ADHD and normal control children. 3. To replicate findings that schizophrenic probands have reduced total cerebral volume and reductions in the volume of the midsagittal thalamic area which exceeds the reduction in total cerebral volume, and enlargements of the caudate and putamen. 4. To identify genes associated with the presence of schizophrenia, SSPD, AIP. impairments and changes in volumes of brain structures in schizophrenic probands and their siblings.

Brain Modeling Challenges. Investigations into brain structure and function require a diverse array of tools to create. analyze, visualize, and interact with models of the brain. There is a rapidly growing need for brain models comprehensive enough to represent brain structure and function as they change across time,. as they change vary across large populations, in different disease states, across imaging modalities, across age and gender. and even across species. This mandates the development of 3D and 4D brain models that are adaptable to a wide variety of applications. including the detection and analysis of structural change and abnormality, in all their spatial and temporal complexity. The range and sophistication of these strategies will match the broad scope of studies that will focus on mapping and modeling the dynamically changing brain. Develop dynamic brain modeling tools, based on the concept of parameterization in 2, 3, and 4 dimensions, to represent and analyze brain structure as it changes in different disease states. across large populations, across age and gender, across imaging modalities, and across species. Computational brain modeling tools will be created to track and analyze complex patterns of three-and four-dimensional structural change in the brain during a variety of neurodevelopmental and degenerative disease processes. Tools will correlate structural indices with databases of clinical, behavioral and neuropsychiatric test data, to expand investigations of brain structure-function relationships to four dimensions. Specific Aim 2. Create mathematical strategies to analyze the structure of the cerebral cortex, as it changes across time in single subjects and groups. Novel computerized approaches will be developed to map temporal patterns of cortical development and degeneration, to encode patterns of cortical variation in human populations, and to detect abnormal gyral and sulcal patterns in individual patients and groups. Statistical anatomic models will map cortical change in four dimensions and detect anomalies in patient populations with Alzheimer's Disease, schizophrenia, and neurodevelopmental disorders. Specific Aim 3. Develop and extend software for automated extraction and analysis of brain structure models. Parameterization of anatomic models is critical for comparative neuroanatomy, as it makes models comparable at different time-points. Robust tools to extract surface models for a comprehensive range of neuroanatomic structures will accelerate and expand the scope of brain modeling projects and diagnostic applications in which brain structure models must be created rapidly and robustly. Specific Aim 4. Develop brain mapping tools and mathematical image analysis algorithms that adapt and learn from archives of three and four-dimensional neuroanatomic models. Immense archives of computational models resulting from in-house and collaborative modeling projects will be structured so that they can guide and inform mathematical algorithms which analyze future neuroanatomic data of the same type. Model-driven tools will include software for structure extraction. delineation of structural change and abnormality, analysis of functional brain image data, and nonlinear registration tools that integrate brain data from subjects and groups with brain structure differences.

This revised application addresses hypotheses developed from work that the investigators carried out in the initial UCLA Epilepsy Surgery Program concerning the extent and nature of functional plasticity in young children following early hemispherectomies. The proposed project addresses key questions concerning the capacity of the human brain for functional plasticity. The investigators will test hypotheses about the functional plasticity of language, certain cognitive functions, and social communication in a unique cohort of children who have received left or right hemispherectomies for medially intractable epilepsy prior to 10 years of age. They will attempt to better define the temporal "window" for functional plasticity. They will determine if age at seizure onset and age at surgery predict the extent to which children show functional plasticity for specific linguistic, cognitive, and social communication function. The effect of seizure etiology on functional plasticity will be examined by comparing 1) children with and without evidence of cortical dysphasia in the resected hemisphere and 2) children with Rasmussen encephalitis to children with cerebral infarcts within the non-cortical dysplasia groups. This project represents a singular opportunity to more fully integrate the work conducted in their respective laboratories in order to examine the interrelation between language, cognition, and social communication in the isolated right and left hemispheres of children receiving early hemispherectomies. These questions will be addressed at two, five and ten years of age in the UCLA Pediatric Epilepsy Surgery Program. The investigators are currently following almost 50 children starting from pre-surgical evaluation to follow-up intervals ranging from 1 to 12 years. During the follow-up evaluations, children will be administered a careful selected set of tasks which have been demonstrated in prior research to tap linguistic, cognitive and social communication function normally lateralized to either the left or right hemisphere. This will provide the investigators the opportunity to determine the extent to which an isolated left or right hemisphere can support functions normally supported by the resected hemisphere.

Key basic and clinical research questions that need to be answered to understand defective automaticity in schizophrenia will be addressed in five studies. A cross-sectional study of normal participants will test hypotheses that there is a general skill acquisition factor, and that the neostriatum is the common neural substrate in early stages of skill acquisition for a wide variety of tasks. The hypotheses that automation is associated with negative functional connectivity between the mesial temporal lobes and the neostriatum and that increased automatization of skills is associated with focalized fMRI activation in task specific cortical neural networks will also be tested. A second cross-sectional study will compare schizophrenia patients to normal participants on the same tasks used in the first study to test the hypothesis that patients with schizophrenia are slower to automate new skills. The hypothesis that defective automaticity in schizophrenia is associated with abnormal patterns of neural activity reflected in fMRI activation will also be tested. A third cross-sectional study will test hypotheses about conditions that facilitate skill acquisition by comparing the effect of random vs. blocked practice in schizophrenia patients and normal controls. A fourth study uses a longitudinal design to test the hypothesis that prodromal patients who convert to psychosis during the prodromal phase show a decreased rate of automation of new skills compared to prodromal patients who do not convert to psychosis and normal controls. These behavioral differences in prodromal patients who convert to schizophrenia are hypothesized to be reflected in abnormal patterns of fMRI activation. We will determine if rate of skill automation predicts functional outcomes, and changes over the course of the disorder in a fifth study. An important feature of these studies is the use of dual-task probes to provide independent indices of the level of automaticity achieved on different tasks. Elucidating the neural substrate for defective automaticity may contribute to the development of new somatic treatments for schizophrenia by identifying specific brain systems as potential therapeutic targets. Testing hypotheses about the effects of different training conditions on skill acquisition should offer insights into the design of novel behavioral rehabilitation programs for patients with schizophrenia.

[unreadable] DESCRIPTION (provided by applicant): This project will test the hypothesis that specific cortical-striatal circuits are dysfunctional in schizophrenia. While there is evidence of striatal dysfunction in the few relevant studies of schizophrenia patients, the effect of schizophrenia on striatal functioning was inextricably confounded with the effects of the anti-psychotic medications used to treat schizophrenia. This project will avoid this pitfall by studying two groups of adolescents with liability to schizophrenia (patients with prodromal symptoms of schizophrenia and siblings of patients with childhood onset of schizophrenia), but who are not psychotic and therefore not treated with anti-psychotic medications. Prior research, including ours, suggests that the cognitive DLPFC/Caudate and the "reward" anterior cingulate/ventral striatum and LOF/ventral caudate circuits are impaired in schizophrenia, while the motor cortex/putamen circuit is intact. A combination of skill learning tasks and fMRI will be used to test this hypothesis. In the first year of the grant we will develop a reward-processing task that separately evaluates the effect of reward magnitude and reward predictability on fMRI activation and develop cognitive habit and motor skill learning tasks with comparable psychometric properties. In the second and third years of the grant we will conduct a large-scale pilot study of 20 siblings of childhood onset schizophrenia patients, 40 patients with prodromal symptoms of schizophrenia, and 20 adolescent controls. We will test the hypothesis that skill learning performance and fMRI indices of dysfunction of different cortical-striatal dysfunction will correlate with distinctive clinical features, neuropsychological deficits, and functional outcomes in individuals with liability to schizophrenia, depending on the putative circuit affected. This is the first schizophrenia study to: 1) use the convergence of evidence from psychometrically matched tasks and fMRI activation to test hypotheses about impairments of specific striatal circuits, 2) separately evaluate the effects of reward magnitude and predictability on brain activity, 3) demonstrate that specific cortical-striatal impairments are not due to the effects of anti-psychotic medication by studying adolescents with vulnerability to schizophrenia who have never been psychotic and therefore are not treated with antipsychotic medications. [unreadable] [unreadable]

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. This project will test the hypothesis that specific cortical-striatal circuits are dysfunctional in schizophrenia. While there is evidence of striatal dysfunction in the few relevant studies of schizophrenia patients, the effect of schizophrenia on striatal functioning was inextricably confounded with the effects of the anti-psychotic medications used to treat schizophrenia. This project will avoid this pitfall by studying two groups of adolescents with liability to schizophrenia (patients with prodromal symptoms of schizophrenia and siblings of patients with childhood onset of schizophrenia), but who are not psychotic and therefore not treated with anti-psychotic medications. Prior research, including ours, suggests that the cognitive DLPFC/Caudate and the "reward" anterior cingulate/ventral striatum and LOF/ventral caudate circuits are impaired in schizophrenia, while the motor cortex/putamen circuit is intact. A combination of skill learning tasks and fMRI will be used to test this hypothesis. In the first year of the grant we will develop a reward-processing task that separately evaluates the effect of reward magnitude and reward predictability on fMRI activation and develop cognitive habit and motor skill learning tasks with comparable psychometric properties. In the second and third years of the grant we will conduct a large-scale pilot study of 20 siblings of childhood onset schizophrenia patients, 40 patients with prodromal symptoms of schizophrenia, and 20 adolescent controls. We will test the hypothesis that skill learning performance and fMRI indices of dysfunction of different cortical-striatal dysfunction will correlate with distinctive clinical features, neuropsychological deficits, and functional outcomes in individuals with liability to schizophrenia, depending on the putative circuit affected. This is the first schizophrenia study to: 1) use the convergence of evidence from psychometrically matched tasks and fMRI activation to test hypotheses about impairments of specific striatal circuits, 2) separately evaluate the effects of reward magnitude and predictability on brain activity, 3) demonstrate that specific cortical-striatal impairments are not due to the effects of anti-psychotic medication by studying adolescents with vulnerability to schizophrenia who have never been psychotic and therefore are not treated with antipsychotic medications.

DESCRIPTION (provided by applicant): Moderate to severe non-penetrating pediatric traumatic brain injury (TBI) compromises distributed neural networks by disrupting axonal connections contributing to cognitive impairments. Cognitive functioning improves significantly over the first year post-TBI relative to the post-acute period in the vast majority of pediatric TBI survivors. There is evidence of restitution of neural connectivity over the first year post-TBI. The central hypothesis of this proposal is that cognitive deficits after non-penetrating pediatric TBI reflect white matter injury and disconnection, and that cognitive recovery occurs in conjunction with the restoration of neural network connectivity. Connectivity will be assessed using both structural brain imaging (MRI and DTI) and functional (electrophysiological, fMRI and neuropsychological) methods. We will study the structure and function of brain systems that are particularly vulnerable to white matter (WM) disruptions caused by TBI. The corpus callosum (CC) and a frontal-temporal-parietal (FTP) network that subserves spatial working memory will be studied as exemplars of neural networks disrupted by TBI. Innovative methods from behavioral neuroscience and neuroimaging will be used to assess the function of these networks, including separate measures of anterior and posterior CC function. Structural measures, including MRI and DTI, will be used to assess regional WM changes. The functional and structural measures will be administered longitudinally in 60 children with moderate/severe TBI and 60 age and gender matched controls. Children will be studied post-acutely (2-4 months post-TB I) and chronically (12 months post injury) to test the hypothesis that neurocognitive recovery following TBI is associated with increased WM connectivity and volume. This project will develop methods for studying brain/behavior relations in the CC following TBI that can be translated into experimental studies of small animals to help develop novel therapies. By explicating mechanisms that underlie naturally-occurring white matter injury and repair, the proposed project will identify potential new targets for interventions designed to accelerate the process of neurocognitive recovery. PUBLIC HEALTH RELEVANCE: Children with moderate-severe traumatic brain injuries will be studied 2-4 months and at 12 months post-injury to test the hypothesis that neurocognitive recovery following TBI is associated with increased white matter connectivity and volume. Innovative brain imaging and behavioral neuroscience methods will be used to assess changes in brain structure and function following pediatric TBI. By explicating mechanisms that underlie naturally-occurring white matter injury and repair, the proposed project will identify potential new targets for interventions designed to accelerate the process of neurocognitive recovery.

Abstract This mechanistic, proof of concept study tests the hypothesis that augmentation of suppressed N-Methyl-D-aspartate Receptor (NMDAR) function following pediatric moderate/severe traumatic brain injury (TBI) with D-cycloserine (DCS) will increase neural activation, and when used in conjunction with cognitive training will enhance the effect of cognitive training on working memory (WM). Study participants will be children who completed our currently funded study of neurocognitive recovery during the first year post-TBI. In this double blind, parallel, placebo controlled study children with moderate and severe TBI will be randomized to one of two treatment arms. Both treatment arms will receive six weeks of cognitive training from a computer training program shown in prior studies to improve WM. Participants will receive DCS or a placebo in addition to cognitive training. At baseline participants in both treatment arms will undergo fMRI before and after administration of the first dose of drug to test the hypothesis that DCS increases neural activation. This pharmacological MRI paradigm may be a biomarker for the mechanism for the therapeutic effects of DCS on cognitive function. In the baseline evaluation neuropsychological tests of WM and executive functioning and parent's ratings of their child's WM and executive functioning will be administered to provide a basis for assessing generalization. After six weeks of training, the same battery of evaluations will be readministered, with the exception on only one fMRI evaluation, to determine whether children treated with DCS improved more on the trained WM tests and showed greater generalization than children receiving placebo. After treatment has been terminated for three months the children will complete one session of cognitive training and will be retested on the non-trained measures of WM and EF and their parents will complete questionnaires to assess the maintenance of training. This study will collect preliminary data to support attempts to identify a new target (NMDAR mediated neural plasticity) for developing drugs that enhance neurocognitive recovery and a biomarker (pharmocological fMRI) for that target.