Martha Elizabeth Shenton - US grants

This application is a competitive renewal of an R01 that is nearing the end of its 10th year of funding. Previously the focus of research was on gray matter abnormalities in schizophrenia. In the current five-year application, we now turn to the investigation of white matter abnormalities in schizophrenia, where we will use magnetic resonance diffusion tensor imaging (MR-DTI). MR-DTI is a relatively new neuroimaging technique that affords a unique opportunity to investigate white matter. Furthermore, unlike conventional MRI, where white matter appears uniform and homogeneous, MR-DTI is particularly revealing of the physical properties of white matter, as measured by the motion of water along axons. Hence, the density, size, and orientation of white matter can be explored. Of particular note, we consider it an exciting opportunity to be able to evaluate the empirically long-postulated hypothesis that many of the symptom features in schizophrenia may be due to disturbances in connectivity between brain regions. Accordingly, we plan to evaluate three fronto-temporal connections in the brain, including the uncinate, cingulate, and arcuate fasciculi. Additionally, we will evaluate the corpus callosum, the largest white matter fiber tract in the brain, mediating interhemispheric connections postulated to be abnormal in schizophrenia, as well as the anterior limb of the internal capsule, a fiber tract connecting medial dorsal thalamus with prefrontal cortex, and the anterior nucleus of the thalamus with the cingulate gyrus, regions also thought to be abnormal in schizophrenia. Moreover, we will evaluate specific cognitive functions thought to be associated with each of these brain regions. We will use MR-DTI to quantify diffusion (the degree of directionality of water movement, as measured by fractional and relative anisotropy) in the aforementioned major fiber connections in the brain, and for all five fiber tracts, we will measure gray matter regions of interest that are interconnected by these fiber tracts. We will also measure magnetization transfer ratio, thought to be indicative of myelin content, and we will explore the extent to which fiber tractography, a measure of the extent and direction of fiber tracts, reveals white matter abnormalities in schizophrenia. Over the 5-year period of the grant we will examine right-handed male and female patients with schizophrenia (n=50 first episode and n=100 chronic patients), as well as a contrast group of bipolar patients with psychotic features (n=50). The addition of a contrast group will allow us to evaluate the specificity of findings to schizophrenia. Additionally, we will include age, gender, and parental-socioeconomic status group matched controls (n=100). We will also test a subset of 50 patients with schizophrenia and 50 controls on both the 1.5T and 3T magnets. Finally, we will use structural equation modeling to evaluate the specific hypotheses of the study, where we will be able to determine whether or not they provide the best model for explaining the relationship among variables. Through the use of such advanced neuroimaging techniques, our long-term goal is to understand the neuropathology of schizophrenia.

The technology to extract objective, quantitative information from in vivo magnetic resonance (MR) images has not kept pace with the improved spatial and contrast resolution of MR images. With recent advances in image processing, however, it is now possible to exploit more fully information contained in MR images. The purpose of the present proposal is to apply newly developed MR image processing techniques to high spatial resolution MR images in order to quantify in vivo differences between the brains of normal control subjects and patients afflicted with schizophrenia. The application of these techniques to the investigation of schizophrenia is promising because brain anomalies are often subtle and may not be present in all patients. We have begun to apply these techniques and have some exciting and promising, albeit preliminary findings from a small sample in which schizophrenics, compared to normals, showed: 1) left lateralized volume reductions in anterior hippocampus, parahippocampal gyrus (also on the right), and neocortical superior temporal gyrus (STG); 2) a high correlation between left posterior STG volume and amount of thought disorder (r=0.81); 3) a non-statistically significant but interesting increase in white matter in anterior cingulate gyrus that might be consistent with an increase in vertical axons reported by Benes in a post-mortem study of schizophrenics; and 4) a more disorganized, non-parallel gyral pattern in the temporal lobe. These findings are, however, preliminary and the inclusion of a larger sample is essential to increase the statistical power. We now propose to broaden our studies and to apply computerized image processing techniques to MR scans obtained from 75 male, right-handed, ch ronic schizophrenics (15 per year) and 75 age- sex- and parental social class- matched normal controls.

The goals of our brain atlas are: to develop it as a tool for education; use it for pre-surgical planning and reference; and apply the anatomy as a template for segmentation by matching 1. We plan to continue to add to the number of structures in the atlas. We will also develop further tools for enhancing the shading, texture, depth, and coloration of structures. 2. We will continue to utilize these tools in the clinical environment. This will require substantial engineering work. some of which has already begun, to reduce the computational times for the elastic matching algorithms and improve the ease of setting up the correspondences between the atlases and new studies. 3. We will incorporate new matching technologies to obtain greater accuracy and automation. 4. The use of the digitized 3D atlas for surgical planning will be integrated with 3D visualization tools, along with the warping of the atlas for surgical cases. This integrated system will be used for both the planning and the intraoperative support of surgery.

Although considerable progress has been made in delineating MRI gray matter abnormalities in schizophrenia, relatively little progress has been made in evaluating white matter abnormalities, or the white matter fiber tract connections between gray matter regions, particularly those that connect the frontal and temporal lobes. These tracts that have long been thought to be abnormal in schizophrenia. Many subsequent investigators have hypothesized some type of connectivity deficit or disconnection model of schizophrenia. We plan to explicitly investigate such anomalies in this proposal. The overarching aim of this three-year proposal is to investigate abnormalities of connectivity at an anatomic and functional level in schizophrenia. Accordingly, we plan to employ a novel and integrative approach to investigating abnormal brain connectivity in schizophrenia, including an analysis of white matter fiber tract abnormalities, as well as the network nodes that these pathways interconnect. As a Driving Biological Project (DBP), this integrative aim will require the highly advanced computational strategies and robust software implementation provided by other subprojects in this grant. This project will emphasize MR Diffusion Tensor Imaging (DTI), a relatively new MR imaging technique that affords a unique opportunity to investigate and quantify white matter abnormalities in the brain. It will also include functional MRI (fMRI) probes of working, episodic, and semantic memory systems known to be abnormal in schizophrenia. Our use of fMRI will focus specifically on connectivity among regions implicated in the pathophysiology of schizophrenia using memory activation tasks to bring out the hypothesized abnormalities. An event related verbal episodic encoding and recognition memory task will target prefrontal and medial temporal sites. This task was developed based on our prior fMRI experience in normals and in patients with known seizure foci undergoing surgical treatment. Earlier evidence using electrophysiological methods suggested sensitivity of similar experiments to frontal vs. temporal lobe lesion location and numerous PET and fMRI studies have implicated these regions in schizophrenia. We will investigate the working memory system with fMRI using the n-back paradigm which has been shown by our group to robustly activate the prefrontal and parietal cortex in neurological patients and controls. Similar results in healthy controls have been widely reported in the PET and fMRI literature. In the present study, this task will afford us an opportunity to examine fronto-parietal connectivity and basal ganglia sites of interest that are also often activated. Finally, an event-related semantic memory task patterned after our earlier blocked design experiments will be used to activate left inferior prefrontal and left superior temporal regions of interest (ROIs). The broader PET and fMRI literature typically implicates these sites for language and semantic memory retrieval. These leading edge technologies will be integrated with volumetric and shape analyses of implicated gray matter structures as well as clinical and neurocognitive assessments to fully characterize the sample. In addition, although not the focus of this project, we will also collect blood from all subjects for genetic analysis.

DESCRIPTION (provided by applicant): This is a request for an NIMH Senior Scientist Award (K05). The candidate has been funded previously by two K02 Independent Scientist Awards (1994-1999 and 1999-2004) and by a Mentored Research Scientist Development Award (1988-1993). The candidate's long-term objective is to investigate clinical symptoms, cognitive impairments, and structural and functional brain abnormalities in schizophrenia and other psychiatric disorders. She is also committed to the further technical training and development needed to incorporate new advances i n n euroimaging and t he p ostprocessing of neuroimaging data into her research program. Her short-term objective is to apply for a K05 Award to support her research efforts at a crucial time in her career development. The main goal of the Research Plan is to develop further Diffusion Tensor Imaging measures and their application to schizophrenia. Here, frontal-temporal white matter connections will be evaluated, including the uncinate, arcuate, and cingulate fasciculi, where it is predicted that impairments in decision making and in episodic/verbal memory will be associated with uncinate abnormalities, that semantic priming abnormalities will be associated with arcuate abnormalities, and that error detection and self monitoring abnormalities will be associated with cingulate abnormalities. Additionally, the corpus callosum and the anterior limb of the internal capsule will be evaluated, where it is predicted that abnormalities will be associated with interhemispheric abnormalities (Dichotic Listening Fused Rhymed Task) and impairments in verbal and spatial working memory tasks, respectively. Other career enhancement plans include: (1) to develop further shape analysis tools that include more local rather than global measures of shape deformation midline structures including caudate nucleus, thalamus, amygdala-hippocampal complex, and corpus callosum -brain regions likely influenced by neurodevelopmental factors; (2) to develop further cortical thickness measures of the brain, in vivo. Here, longitudinal studies of prefrontal and temporal lobe thickness are planned in patients with first episode schizophrenia, first episode affective psychoses, chronic schizophrenia, and in controls. (3) To develop further automated segmentation methods for identifying small brain regions of interest such as the superior temporal gyms. Non-rigid registration methods that incorporate atlas information will be used, and this method will be extended to other brain regions. (4) To develop further collaborative PTSD studies with Drs. Pitman, Gilbertson, and Shalev, including an examination of nurses deployed in the Gulf War with PTSD; (5) to develop further collaborative studies with Dr. Deutsch investigating brain abnormalities and their association with facial dysmorphology; (6) to develop a new area of investigation with Dr. Gon[unreadable]alves investigating narrative productions and cognitive anomalies and their association with brain abnormalities in language related areas in William's Syndrome patients. Finally, (7) to test MR and MR DTI protocols on 1.5T and 3T magnets in order to confidently move protocols to the 3T over the next 3 to 5 years.

disease /disorder proneness /risk; pathologic process

[unreadable] DESCRIPTION (provided by applicant): Clinical Research in Biological and Social Psychiatry","10124180"," The Clinical Research Training Program (CRTP), now in its twenty-eighth year, offers intensive, interdisciplinary postdoctoral training in clinical research to outstanding psychiatrists (MDs) and biological and behavioral scientists (PhDs). Our primary objective is trainees developing a sophisticated understanding of the research tools relevant to clinical research in psychiatry and in behavioral sciences. Trainees study experimental design, contemporary statistics, relevant assessments, and computer processing approaches in order to implement their own research. The multidisciplinary nature of the program (e.g. developmental psychology, neurophysiology) emphasizes varied perspectives in designing, conducting, and interpreting research findings. The CRTP is oriented towards developing clinical investigators who will in two-years be ready to conduct their own independent clinical research, or join already established clinical research teams as junior colleagues. Specific components of the CRTP are: 1) placement of each Fellow in a funded clinical research training site; 2) a weekly interdisciplinary research training seminar. Led by the training Directors, and attended by Fellows, visiting faculty, and other outstanding researchers in the area; 3) attendance at relevant courses within the Harvard University complex and other Boston universities and hospitals. The multiple research areas included in the program build upon the research resources present within the Department of psychiatry at Harvard, and include 42 research training sites. We have added 12 new training sites. 5 female and two minority (African American) training faculty. Core aspects of training are through the weekly seminar and Fellows' ongoing work with their research preceptor. A new aspect of the CRTP is our four-point strategic plan to enhance the number of under-represented minority trainees. This plan will include a newly-formed Diversity Advisory Board, and strong alliances with other organizations (e.g., APA) with ongoing Minority Fellowship and related programs. Trainees have continued to obtain full-time and tenured positions at major universities, have shown a strong publication record, and received over 100 research grants, including 17 NIH/NIMH Career Development Awards. We believe that the strength of our program will continue, and that the field of psychiatry will greatly benefit from this rigorous, multidisciplinary training of a new generation of clinical research investigators. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The Psychiatric Imaging Laboratory at the Brigham and Women's Hospital (Dr. Shenton, Director;PI, NIMH R01 5R01MH050740-13), in collaboration with the ICOHRTA Research Training Program in International Mental Health &Developmental Disabilities (MH/DD) at the Children's Hospital Boston (Dr. Munir;PI;Fogarty D43 TW005807), is applying for an International Research Collaboration - Behavioral, Social Sciences (FIRCA-BSS) [R03] grant for Dr. Ozgur Oner of Ankara Diskapi Children's Hospital in Turkey. Dr. Oner has been a highly successful international ICOHRTA fellow. The research goal of this proposal is to facilitate the further development of collaborative research between NIH supported U.S. biomedical scientists and investigators in Turkey, a FIRCA eligible country. The scientific objectives include: (1) studies of prefrontal, hippocampus-amygdala, caudate and superior temporal gyrus volumes measured by Magnetic Resonance Imaging (MRI) in adult subjects with schizophrenia and their "high-risk" (HR) first-degree relatives, stratified with and without ADHD, compared to subjects with ADHD, and normal controls;and (2) studies of the relation of neuropsychological executive, and attentional characteristics with the aforementioned brain structures in each group. Previous studies have shown that HR relatives of subjects with schizophrenia have attentional problems predictive of the emergence of schizophrenia, which are concomitant with structural and functional brain abnormalities and dysregulation in the dopaminergic systems, which may, in turn, involve the presence of symptoms resembling the ADHD phenotype. Subjects with ADHD themselves present with functional and structural brain variations, particularly in right prefrontal cortex and caudate, and may have dopaminergic transmission abnormalities, as reflected by imaging and genetics studies. We will study 4 groups: (i) index subjects with DSM-IV schizophrenia (n=30);(ii) their non-psychotic first-degree relatives --the high-risk HR group stratified as HR with ADHD (HR-A) (n=20) and without HR-NA (n=20) DSM-IV ADHD;(iii) subjects with DSM-IV ADHD (n=30);and (iv) normal controls of similar age, gender, and parental education (n=30). Weschler Adult Intelligence Scale-Revised, Wisconsin Card Sorting Test, Trailmaking Test A and B, Continuous Performance Test, and Weschler Memory Scale will be used to evaluate executive, memory and attention functions. The proposed study aims involve innovative approaches in comparative schizophrenia and ADHD risk research, as well as use of neuroimaging and psychological research methodologies and expertise under the direction of a leading center in the US that supports and builds upon already established and productive international research collaboration in Turkey. 7. PUBLIC HEALTH RELEVANCE: The proposed aims will provide access for a promising international investigator to new perspectives, innovative concepts and technologies in neuroimaging at a leading NIH supported US center. The proposed study will investigate important scientific topics relevant to global health, schizophrenia and ADHD, both of which cause significant burden on society globally.

? DESCRIPTION (provided by applicant): The Human Connectome Project (HCP) was initiated to accelerate progress in understanding the organization of the human brain. To accomplish this goal, the original HCP Washington-University-Minnesota and MGH/Harvard-UCLA Projects have focused on acquiring and sharing data relevant to structural and functional connectivity in 1200 healthy twins and their siblings. The main aims have been to use advanced 3T imaging to develop advanced data acquisition and scanning sequences, to develop novel algorithms for post-processing of white matter fiber structure and brain connectivity, and to develop novel graphical techniques for brain connectomes. The purpose of the new funding opportunity announcement, PAR-14-281 for Connectomes Related to Human Diseases (U01), is to build upon the original HCP by extending it to the study of human brain diseases in order to acquire the same high quality data as in the original HCP, but with the goal of accelerating knowledge of brain diseases in a manner heretofore not possible. Importantly, progress has been slow and frustrating in translating knowledge of the brain to new and more effective treatments for human brain diseases such as severe mental disorders. In fact, severe mental disorders, which include psychotic disorders, are brain diseases that are not only devastating because they result in severe disruptions that occur early in life, but, for many, the course of illness is progressive, leading to chronic debilitation and early mortality. Thus the need to accelerate knowledge of dysfunctions in structural and functional brain connectivity in these disorders, and to translate this knowledge to treatment, is critical. The primary goal of the proposed Human Connectome Project on Early Psychosis is to acquire high quality data consistent with data acquired by the original HCP. To this end, we will acquire imaging data on Prisma 3T magnets at two sites, one in Boston and one in Indianapolis, using the HCP Lifespan Prisma protocol. This imaging protocol was developed to be of similar high quality to the original HCP, but with reduced scan time, the latter important in a psychosis cohort. We will also use behavioral measures from the HCP as well as additional measures specific to early psychosis. We will acquire blood to be stored at the Rutgers University Cell and DNA Repository (RUCDR)(Aim 1), and we will use the Washington University HCP post-processing pipeline to process imaging data (Aim 2). Additionally, we will include new imaging tools for signal drop detection, multi-tensor tractography, diffusion magnetic resonance imaging (dMRI) models, i.e., free-water imaging, and a new harmonization protocol for diffusion images (Aim 3). We will also perform, as a representative example, a study comparing brain networks of affective and non-affective psychosis groups with controls (Aim 4). The main goals are thus to acquire high quality imaging, behavioral, cognitive, and genetic data on an important cohort of early psychosis patients, in a manner consistent with the HCP, which will be made available to the research community for future studies. Such data will provide a unique opportunity to characterize the pathological substrates of early psychosis.

The ?clinical high risk? (CHR) for psychosis syndrome is an antecedent period characterized by attenuated psychotic symptoms that are marked by subtle deviations from normal development in thinking, motivation, affect, behavior, and a decline in functioning. Early intervention in this CHR population is critical to prevent psychosis onset as well as other adverse outcomes. However, the presentation of symptoms and subsequent course is highly variable, and there is a paucity of biomarkers to guide treatment development. Thus, to improve predictive models that are clinically relevant, several issues need to be addressed: 1) focusing on outcomes beyond psychosis; 2) taking into account heterogeneity in samples and outcomes; and 3) integrating data sets with a broad array of variables using innovative algorithms to overcome variability across studies. To address these challenges, the proposed ?Psychosis Risk Evaluation Data Integration and Computational Technologies: Data Processing, Analysis, and Coordination Center? (PREDICT-DPACC) brings together a multidisciplinary team of highly experienced researchers with proven capabilities in all aspects of large-scale studies, CHR studies, as well as computational expertise. The ultimate goal is to identify new CHR biomarkers, and CHR subtypes that will enhance future clinical trials. To do so, the PREDICT-DPACC will 1) aggregate extant CHR- related data sets from legacy datasets; 2) provide collaborative management, direction, data processing and coordination for new U01 multisite network(s); and 3) develop and apply advanced algorithms to identify biomarkers that predict outcomes, and to stratify CHR into subtypes based on outcome trajectories, first from the extant data and then refined and applied to the new data. The PREDICT-DPACC team has the broad, comprehensive, and robust infrastructure that is sufficiently flexible to accommodate the inclusion of multiple data types and to optimally address the needs of the CHR U01 network(s). Carefully selected extant data will be rapidly obtained, processed, and uploaded to the NIMH Data Archive (NDA). Proposed analysis methods are powerful and robust, leveraging the expertise and experience of computer scientist developers, and experienced clinical researchers. The U01 network(s) will be coordinated by a team that is experienced in managing large studies, familiar with the needs of such studies, flexible, and is knowledgeable in all aspects of CHR studies, including measures, outcomes, biomarkers, and cohorts. Upon meeting the goals of this U24, and the supported U01 network(s), the expected outcomes of the PREDICT-DPACC will be new predictive biomarkers for CHR outcomes, new definitions of CHR subtypes that are clinically useful, and new curated and comprehensive CHR datasets (extant and new) as well as processing tools and prediction algorithms that are shared with the research community through the NIMH Data Archive.