Nancy C. Andreasen - US grants

The NIMH Collaborative Program on Psychobiology of Depression addresses two major substantive areas: 1) Nosology: To evaluate the comparative validity of alternative systems for clinical classification. 2) Genetics: To evaluate recent hypotheses that genetic factors are involved in the evolution of certain types of depressive disorders. In addition, this study also addresses a variety of other areas, including personality factors, life events, social supports, sociodemographic variables, and phenomenology. In addition to the comprehensive genetic study, family history variables are investigated in each proband. Finally, a large-scale follow-up investigation will also be completed on each subject.

DESCRIPTION (provided by applicant): This application is a request for a competitive renewal of our research on the diagnosis and phenomenology of schizophrenia. To our knowledge, this is the largest ongoing study of first-episode schizophrenia in existence. This study is currently following 293 first-episode patients, some of whom have been followed for as long as 15 years. The study emphasizes understanding the phenomenology of schizophrenia by examining the lifetime trajectory of the illness and its long-term outcome. Since the disorder is characterized by a prolonged lifetime course, longitudinal study of a large group of informative patients is one of the most powerful strategies for examining measures that will illuminate its mechanisms or refine the definition of its phenotype. This study examines 4 domains of variables: Symptoms, psychosocial function, brain morphology as measured by morphometric magnetic resonance imaging, and cognition as measured by both standard neuropsychological tests and a group of experimental tests. We have found that, although symptoms stabilize relatively quickly after initial onset in the majority of patients, the other domains tend to worsen throughout the first decade after onset. This suggests that the disorder may have a worse prognosis, despite adequate treatment, than originally anticipated. We also will divide the patients into groups based levels of recovery and determine the predictors of recovery group. In order to understand the long-term outcome of schizophrenia at the clinical, neural, and cognitive levels, it is important that we continue to study this large group of patients longitudinally on into the second decade of the illness so that we can examine the interrelationships between these four domains and determine whether the downward trends persist or stabilize.

The application requests funding for a Research Scientist's Award. The basic theme behind the research proposed for the next five year period is to study the neural mechanisms that produce the abnormal mental phenomena observed in psychotic patients. The work proposed consists of two major types. One group of studies focuses on diagnoses and phenomenology; the second group involves the study of brain anatomy, metabolism and neurochemistry, using the tools of neuroimaging. The studies of diagnosis and phenomenology have emphasized instrument development and have produced a series of linked instruments that are suitable for providing a comprehensive assessment of diagnoses and phenomenology: the Comprehensive Assessment of Symptoms and History (CASH), Scale for the Assessment of Negative Symptoms, and Scale for the Assessment of Positive Symptoms, (SANS and SAPS), and instruments suitable for longitudinal follow-up assessments (PSYCH-UP and CASH-UP). Thorough reliability and validity studies have been done with these instruments. They are currently being used on a prospective longitudinal study of first episode and 'young chronic' patients in order to monitor outcome and to identify predictors of good and poor outcome. Other studies include the evaluation of phenomenology and diagnosis in monozygotic and dizygotic twins in order to explore gene/environmental interactions as they shape clinical presentation. These various studies explore the possibility that schizophrenia is heterogeneous group of disorders and that rigorous evaluation of the clinical presentation may give us some leverage on separating patients into more homogeneous groups that may share an underlying pathophysiology or etiology. Studies using neuroimaging draw on the tools of magnetic resonance (MR), Single Photon Emission Computed Tomography (SPECT), and Positron Emission Tomography (PET). The image analysis component of the MR studies has led to the development of a variety of new techniques, including segmentation algorithms, methods for volumetric analysis and three-dimensional reconstruction, shape analysis, and techniques for overlaying structural and functional images. These techniques are being applied to a large, sample of schizophrenic patients and healthy volunteers in order to determine whether differences in grey and white matter structures exist and whether these evolve over time. Studies using SPECT have focused primarily on the prefrontal cortex; they use a variety of cognitive challenge tasks (e.g., the Tower of London, Wisconsin Card Sorting Test, Porteus Mazes, Continuous Performance Test) in order to study frontal executive functions in normal individuals, drug naive patients and chronic patients both on and off medications. A series of PET studies will be applied to the measurement of D2 receptor density in drug naive patients and in patients with tardive dyskinesia. The proposed studies will evaluate the relationship between drug dose, clinical response, and blood levels; they will also explore the phenomenon of receptor induction and super sensitivity. These studies are conducted within the context of the University of Iowa Mental Health Clinical Research Center; Dr. Andreasen serves as the principle investigator of this center. This center coordinates the efforts of 23 different investigators who conduct 18 different protocols. It also runs an active training program.

This study will build on our previous work exploring CT scan abnormalities in schizophrenia and their relationship to various clinical correlates. This work has demonstrated that some schizophrenic patients have indices of brain atrophy, such as ventricular enlargement. The present study would extend this work through the use of NMR scanning. We propose to examine 100 schizophrenic patients, 100 patients suffering from affective disorder (50 with mania, 50 with severe depression), and 90 control subjects. In addition to examining various indices of atrophy, we are also interested in using the improved resolution of NMR to look for possible changes in other structures, particularly structures in the frontal system or the temporolimbic system. We plan to use both area and ratio measurements of structures visualized on the scans, as well as measures based on NMR signal intensity and calculated T1 and T2 relaxation times. We plan to relate abnormalities noted on the basis of NMR scanning to important clinical correlates, such as the types of symptoms present, course and onset of illness, and indices of cognitive impairment. In particular, we will attempt to determine whether patterns of symptoms or cognitive impairment can be related to specific regional brain abnormalities. In addition, we will continue our exploration of the validity of the distinction between positive versus negative schizophrenia.

major depression; bipolar depression; psychobiology; human subject;

This study will build on our previous work concerning the phenomenology and classification of schizophrenia. Its basic and primary aim is to explore and develop new approaches to the classification of schizophrenia that unite neurobiological, phenomenological, longitudinal, and etiological aspects of the disorder. We postulate that the schizophrenic syndrome is heterogeneous and that it includes a spectrum of disorders. In this proposal, we will examine 60 first-episode patients drawn from the schizophrenia spectrum and 90 "young chronic" patients (patients under 30 years of age who have been ill less than five years). These subjects will be drawn from the entire schizophrenia spectrum. They will be evaluated at baseline with a comprehensive clinical assessment, indicators of motor function (smooth pursuit eye movements and finger tapping), neuropsychological assessment, and magnetic resonance imaging. Thereafter they will be followed at six-month intervals in order to identify predictors of outcome and indicators of good vs. poor prognosis. We also propose to explore the heterogeneity of schizophrenia by examining at least fifteen multiplex families. We have identified approximately five such families in which at least two members suffer from schizophrenia. The assessment of these family members will include evaluation, including psychometric measures of schizotype in addition to clinical evaluation, magnetic resonance imaging, neuropsychological evaluation, and smooth pursuit eye movements. Detailed birth history will also be obtained. The study will permit us to evaluate the schizophrenia spectrum and to explore the possibility that this spectrum of disorders represents an additive accumulation of multiple risk factors that determine the clinical presentation of the disorder. A final aspects of the study involves instrument development. In addition to the Scale for the Assessment of Negative Symptoms (SANS) and the Scale for the Assessment of Positive Symptoms (SAPS), which are now widely used, we have developed a full interview for the assessment of schizophrenia and affective disorders, the Comprehensive Assessment of Symptoms and History (CASH). We propose extensive reliability and validity studies using this instrument.

This MHCRC will have as its major emphasis the study of schizophrenia and its related spectrum disorders. Its unifying concept will be the goal of linking the clinical picture of the illness with its underlying neurobiology. This CRC will be composed of seven research units. These units will conduct the integrative and interdisciplinary research that is needed to advance our knowledge concerning the clinical presentation of schizophrenia and its relation to pathophysiology, etiology, prevention, and treatment. The DIAGNOSIS AND PHENOMENOLOGY UNIT will examine clinical issues, including evaluation, nosology, longitudinal outcome, and instrument development. The BRAIN IMAGING UNIT will focus on structural and functional brain abnormalities, using CT scanning, MRI, SPECT, and PET; these studies will attempt to integrate our understanding of the clinical symptoms, such as hallucinations, with the neural mechanisms that underlie them. The GENETICS UNIT will take a comprehensive approach to the genetics of schizophrenia, using multiplex family studies, twin studies, adoption studies, and molecular genetics. Multiple biological measures will also be obtained in order to attempt to identify markers. The NEUROENDOCRINOLOGY UNIT will examine cortical-hypothalamic-pituitary-target organ axes in the major psychoses. The EPIDEMIOLOGY UNIT will explore mortality in schizophrenia, birth injury, and other risk factors; this unit will work closely with the GENETICS UNIT in order to examine the environmental side of the genetic versus environmental interaction. The BASIC NEUROBIOLOGY UNIT will conduct research on animal models of psychosis, with particular emphasis on neurochemical systems. The NEUROPHARMACOLOGY UNIT will pursue the study of pharmacokinetics, drug dosage, target symptoms, and side effects. Three CORE UNITS will support these research units: ADMINISTRATIVE, ASSESSMENT AND TRAINING, and BIOSTATISTICS. This MHCRC will build on existing resources at Iowa, such as an excellent clinical population, a strong research tradition, and established collaborative relationships with Radiology, Internal Medicine, Preventive Medicine, and Pharmacology. In addition, we will continue to place a major emphasis on the training of young investigators in research careers in schizophrenia.

biomedical equipment purchase; image processing; computer graphics /printing;

DESCRIPTION (adapted from applicants abstract): Basic Aims: To achieve an increasingly fine resolution of the components of the cognitive processes that are disordered in schizophrenia (e.g., attention, memory, language); to relate them to the symptomatic manifestations of the disorder; to identify their neural substrates; to further refine a unifying concept of schizophrenia that will facilitate more basic research targeted toward identification of its cellular, molecular, and developmental mechanisms. Basic Hypothesis: Schizophrenia is characterized by a fundamental cognitive deficit, referred to as "cognitive dysmetria." This deficit is due to an underlying dysfunction of the neural circuits that provide interconnections and ongoing feedback between prefrontal cortex and the cerebellum, linked through the thalamus. In the healthy brain, these circuits facilitate the fluid coordination of mental functions--planning, initiation, timing, and monitoring of behavior. Patients with schizophrenia display impairments in both cognitive and motor behavior that reflect a dysfunction in this circuitry. The presence of this fundamental cognitive deficit leads to the very frequently observed phenomenon that patients with schizophrenia display a 'generalized deficit' on most cognitive tasks. It also explains the fact that schizophrenia is a polythetic disorder, that patients present with a diversity of symptoms, and that these symptoms cover the broad range of human cognitive, perceptual, emotional, and motor functions. Basic Methods: This hypothesis will be tested through convergent measures, using the techniques of MR imaging, PET imaging, experimental cognitive psychology, clinical psychopathology, and assessments of motor function. Interrelated experiments are proposed that permit the use of PET to dissect the components of cognitive operations and define their functional circuitry, complemented by the use of MR to localize these components anatomically and to determine whether they have gross anatomical substrates. During the five-year period of the grant, a total of 200 patients and controls will be studied. We have developed innovative MR sequences to measure the cerebellum and thalamic nuclei. We will also apply innovative image analysis techniques, either locally developed or obtained from experienced consultants, including neural nets, flat maps, and high dimensional transformations. These will be used to measure cortical surface anatomy and the volume of substructures such as caudate or hippocampus. Ten different groups of PET experiments will be completed, which are grouped into three general categories: motor rhythms and perception of time intervals, memory and temporal computation, and attention and executive function and temporal computation.

This MH-CRC has as its major emphasis the study of schizophrenia and related spectrum disorders. Its unifying concept is the goal of linking the clinical picture of the illness with its underlying neurobiology. The MH-CRC is composed of seven research units. These units conduct the integrative and interdisciplinary research that is needed to advance our knowledge concerning the clinical presentation of schizophrenia and its relation to pathophysiology, etiology, prevention and treatment. The Diagnosis and the Phenomenology Unit examines clinical issues, including evaluation, nosology, longitudinal outcome, and instrument development. The Brain Imaging Unit focuses on structural and functional brain abnormalities, using CT scanning, MRI, and SPECT; these studies attempt to integrate our understanding of the clinical symptoms, such as hallucinations, with the neural mechanisms that underlie them. The Genetics Unit takes a comprehensive approach to the genetics of schizophrenia, using multiplex family studies, twin studies, adoption studies, and molecular genetics. Multiple biological measures are obtained in order to identify markers. The Epidemiology Unit explores mortality in schizophrenia, birth history and other risk factors; this unit works closely with the Genetics unit in order to examine the environmental side of the genetic versus environmental interaction. The Basic Neurobiology Unit conducts research on animal models of psychosis and neurotransmitter systems assessed using both central and peripheral measures. The Neuropharmacology Unit pursues the study of pharmacokinetics, drug dosage, target symptoms, and side effects. The Neurophysiology/Neuropsychology Unit examines cognitive processing in psychosis and conducts studies using a variety of electrophysiological techniques. Three core units support these research units: Administrative, Assessment and Training, and Biostatistics. The Administrative Core Unit is responsible for maintaining a five-to six- bed inpatient unit on which patients can be studied after a three-week medication washout, as well as while on medications. This inpatient unit is crucial to the conduct of a majority of studies conducted by the MH-CRC, since an important goal is establishing the validity of neurobiological measures without contamination by neuroleptic effects. The Assessment and Training Unit insures that all assessment procedures are conducted in a reliable manner and provides training to investigators at Iowa and visitors from other facilities. The Biostatistics Core Unit maintains rigorous quality control over data management and provides consultation to investigators on experimental design and data analysis.

This MHCRC emphasizes the study of schizophrenia and other major psychoses. Its unifying concept is the goal of linking the clinical presentation of illnesses with their underlying neurobiology. Specifically, most projects attempt to identify the neural or biological substrates that underlie abnormalities in mental phenomena. The CRC consists of four core units and six research units. The Administrative Core is responsible for maintaining centralized records of all protocols, managing a five bed inpatient research unit, and coordinating the efforts of investigators between themselves and with the institution as a whole. The Assessment and Training Core maintains a core assessment battery, provides a training and calibration program for the various instruments used in CRC protocols, conducts studies of reliability, and develops new assessment techniques. The Biostatistics Core provides biostatistical consulting and collaboration to investigators at all stages of the research effort and maintains a computer system; it also maintains a centralized core data base and provides quality assurance at all levels of core data processing. The Image Analysis Core provides a centralized resource for the analysis of imaging data, including the development of new software techniques, training on the use of workstations, and a quality assurance program. The Diagnosis and Phenomenology Research Unit examines clinical issues, including cross sectional description, dimensional versus Categorical approaches, comparative nosology, and longitudinal course. The MR Unit focuses on structural brain abnormalities and explores various aspects of brain anatomy in relation to a variety of disease processes, including schizophrenia, autism, and eating disorders; this unit also examines gender differences in brain structure. The PET unit emphasizes the use of 150 water technique in order to explore cognitive systems in normal individuals (i.e., attention, memory, language, and mood) in normal individuals and in various disease processes, including mood disorders and schizophrenia. The Cognitive Neuroscience Unit uses the techniques of experimental cognitive psychology and neuropsychology to focus on the relationship between cognitive systems and disease processes. The Genetics Unit takes a comprehensive approach to studying the genetics of major psychoses, using twin studies, multiplex family studies, and molecular genetics. Specific projects also target epidemiological factors, such as exposure to toxins or viruses. The Neuropharmacology Unit pursues the study of pharmacokinetics, drug dosage, target symptoms, and side effects.

The application requests funding for a Research Scientist's Award. The basic theme behind the research proposed for the next five year period is to study the neural mechanisms that produce the abnormal mental phenomena observed in psychotic patients. The work proposed consists of two major types. One group of studies focuses on diagnoses and phenomenology; the second group involves the study of brain anatomy, metabolism and neurochemistry, using the tools of neuroimaging. The studies of diagnosis and phenomenology have emphasized instrument development and have produced a series of linked instruments that are suitable for providing a comprehensive assessment of diagnoses and phenomenology: the Comprehensive Assessment of Symptoms and History (CASH), Scale for the Assessment of Negative Symptoms, and Scale for the Assessment of Positive Symptoms, (SANS and SAPS), and instruments suitable for longitudinal follow-up assessments (PSYCH-UP and CASH-UP). Thorough reliability and validity studies have been done with these instruments. They are currently being used on a prospective longitudinal study of first episode and 'young chronic' patients in order to monitor outcome and to identify predictors of good and poor outcome. Other studies include the evaluation of phenomenology and diagnosis in monozygotic and dizygotic twins in order to explore gene/environmental interactions as they shape clinical presentation. These various studies explore the possibility that schizophrenia is heterogeneous group of disorders and that rigorous evaluation of the clinical presentation may give us some leverage on separating patients into more homogeneous groups that may share an underlying pathophysiology or etiology. Studies using neuroimaging draw on the tools of magnetic resonance (MR), Single Photon Emission Computed Tomography (SPECT), and Positron Emission Tomography (PET). The image analysis component of the MR studies has led to the development of a variety of new techniques, including segmentation algorithms, methods for volumetric analysis and three-dimensional reconstruction, shape analysis, and techniques for overlaying structural and functional images. These techniques are being applied to a large, sample of schizophrenic patients and healthy volunteers in order to determine whether differences in grey and white matter structures exist and whether these evolve over time. Studies using SPECT have focused primarily on the prefrontal cortex; they use a variety of cognitive challenge tasks (e.g., the Tower of London, Wisconsin Card Sorting Test, Porteus Mazes, Continuous Performance Test) in order to study frontal executive functions in normal individuals, drug naive patients and chronic patients both on and off medications. A series of PET studies will be applied to the measurement of D2 receptor density in drug naive patients and in patients with tardive dyskinesia. The proposed studies will evaluate the relationship between drug dose, clinical response, and blood levels; they will also explore the phenomenon of receptor induction and super sensitivity. These studies are conducted within the context of the University of Iowa Mental Health Clinical Research Center; Dr. Andreasen serves as the principle investigator of this center. This center coordinates the efforts of 23 different investigators who conduct 18 different protocols. It also runs an active training program.

schizophrenia; magnetic resonance imaging; neurophysiology; neuroanatomy; brain imaging /visualization /scanning; gender difference; anorexia nervosa; neurologic manifestations; hippocampus; developmental neurobiology; memory; cognition; autism; hallucinations; human subject;

The focus of The University of Iowa Mental Health Clinical Research Center is on understanding the neurobiology of mental phenomena and disease processes, with the long-term goals of translating our findings "back" to the basic level of mechanisms and causes, and "forward" to the clinical level of treatment. Our primary emphasis is on schizophrenia spectrum disorders. Because the boundaries between schizophrenia and many other major mental illnesses are not clear, however, we also seek to gain insights about the neural mechanisms of normal and abnormal mental phenomena by studying other conditions with known mechanisms that can serve as "model syndromes" such as Huntington's disease or conditions with shared phenomenology and neurodevelopmental origins such as autism. The CRC consists of four core units and six research units. The Administrative Core is responsible for maintaining centralized records of all protocols, managing a five bed inpatient research unit, and coordinating the efforts of investigators between themselves and with the institution as a whole. The Assessment and Training Core maintains a core assessment battery, provides a training and calibration program for the various instruments used in CRC protocols, conducts studies of reliability, and develops new assessment techniques. The Biostatistics Core provides biostatistical consulting and collaboration to investigators at all stages of the research effort, maintains a centralized core data base, and provides quality assurance at all levels of core data processing. The Image Analysis Core provides a centralized resource for the analysis of imaging data, including the development of new software and image analysis techniques, training on the use of workstations, and a quality assurance program. The Diagnosis and Phenomenology Unit examines approaches to improving the definition of the phenotype. The Structural Imaging Unit examines anatomical aspects of schizophrenia and related disorders, with an emphasis on identifying neural circuits and linking MR findings to basic neurobiology through neuropathology studies. The Functional Imaging Unit emphasizes the use of 150 water technique in order to explore cognitive systems in normal individuals (i.e., attention, memory, language, and mood) and in various disease processes, including schizophrenia, autism, and substance abuse. The Cognitive Neuroscience Unit uses the techniques of experimental cognitive psychology and neuropsychology to focus on the relationship between cognitive systems and disease processes. The Basic and Clinical NeuroPharmacology Unit studies genetic regulation of drug metabolism, pharmacokinetics, and the effects of medications on cognition and blood flow through the use of PET and fMR.

A Postdoctoral Fellowship Training Program in Clinical Neuroscience is proposed. This is a multidisciplinary program, particularly designed to train young investigators in clinical neuroscience areas relevant to the study of major psychoses. All trainees will be required to develop a set of core skills (biostatistics and standardized clinical assessment), but they will also develop expertise in a special skills area: e.g., one of the imaging modalities, molecular genetics or neuropsychological assessment. This training program will build on existing research facilities such as our MHCRC, which consists of four core units (Administrative, Assessment and Training, Biostatistics and Image Analysis) and six research units (Diagnosis and Phenomenology, Structural Neuroimaging, Functional Neuroimaging, Cognitive Neuroscience, Genetics, and Neuropharmacology). Trainees will be encouraged to identify a mentor as early as possible to develop an area of special expertise; each trainee will be expected to design and complete at least one research protocol during the second year of the training program.

Overall aims 1. To use MR to identify and study the neuroanatomic abnormalities that occur in disease states, such as schizophrenia or autism. 2. To use MR to examine neuroanatomic measures that may provide information about neurodevelopmental processes, such as gyrification patterns. 3. To use MR to study and measure specific subregions, hypothesized to be involved in dysfunctional anatomic/functional circuitry in schizophrenia, such as prefrontal cortex, thalamus, and cerebellum. 4. To use MR to examine anatomic circuitry directly through the use of diffusion anisotropy. 5. To use MR to study factors that could confound measurements of brain structure in schizophrenia, such as hydrational status. 6. To identify and develop new methods that will facilitate these aims, such as novel scanning sequences or new approaches to image analysis (e.g., neural nets, global pattern matching). 7. To confirm MR findings and improve their spatial resolution through the study of postmortem tissue.

schizophrenia; cognition disorders; neuroanatomy; brain circulation; brain mapping; brain imaging /visualization /scanning; time perception; memory; cerebellum; thalamus; cerebral cortex; intercellular connection; neuromuscular disorder; attention; clinical research; human subject; positron emission tomography;

[unreadable] DESCRIPTION (provided by applicant): A Postdoctoral Fellowship Training Program in Clinical Neuroscience is proposed. This is a multidisciplinary program, particularly designed to train young investigators in clinical neuroscience areas relevant to the study of major psychoses. All trainees will be required to develop a set of core skills (biostatistics and standardized clinical assessment), but they will a Iso develop expertise in a special skills area: Neuroimaging, Cognitive Neuroscience, Neuroanatomy, Neurobiology or Molecular Biology/Genetics. This training program will build on existing research facilities such as our Schizophrenia Research Center (SRC), which consists of four core units (Administrative, Assessment and Training, Biostatistics and Image Analysis) and six research units (Diagnosis and Phenomenology, Structural Neuroimaging, Functional Neuroimaging, Cognitive Neuroscience, Genetics, and Neuropharmacology). Trainees will be encouraged to identify a mentor as early as possible to develop an area of special expertise; each trainee will be expected to design and complete at least one research protocol during the second year of the training program. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This project will test the specificity of cortico-cerebellar-thalamic-cortical circuit (CCTCC)/cognitive dysmetria construct by comparing patients with schizophrenia to healthy volunteer subjects. This construct proposes that schizophrenia is characterized by an underlying dysfunction of the neural circuits that provide interconnections and ongoing feedback between key cortical regions and the cerebellum, linked through the thalamus. We refer to this circuit as the CCTCC. This relatively novel model emphasizes the importance of studying connectivity in schizophrenia, in addition to regional cortical abnormalities, and it stresses that the cerebellum plays a key role in both normal cognition and in the cognitive and symptomatic disturbances observed in schizophrenia. A malfunctioning CCTCC produces a fundamental cognitive deficit, which we refer to as a "cognitive dysmetria." In the healthy brain, the CCTCC facilitates the fluid coordination of mental functions-planning, initiation, timing and monitoring of behavior. Patients with schizophrenia display impairments in both cognitive and motor behavior that reflect a dysfunction in this circuitry. Our interest in the CCTCC, and particularly in subcortical regions (i.e., thalamus and cerebellum), is based on considerable empirical work conducted during the previous funding period of this anatomic MR grant, as well as our functional imaging studies. Basically, we have observed consistent functional and anatomic abnormalities in thalamus and cerebellum: We have also amassed evidence for white matter abnormalities in schizophrenia-the substrate of connectivity. It is also based on the pioneering viral tract-tracing studies conducted during the past decade, primarily by Peter Strick, which demonstrate closed cortical-cerebellar-thalamic-cortical feedback loops between "high cortical regions" (e.g., frontal and parietal cortex), which suggest that the cerebellum is likely to be playing a role in "higher cortical functions." Therefore, we propose to continue to explore the role of the CCTCC in schizophrenia. The proposed studies will build on our previous methodological advances in the use of anatomic MR, which has provided us with a powerful array of reliable and well-validated tools for measuring a variety of brain regions in a relatively rapid and automated way. We propose to use these tools in the current project, complemented with two new methods: structural equation modelling (SEM) and diffusion tensor imaging (DTI). These two approaches will provide convergent methods for comparing the CCTCC in patients with schizophrenia and healthy volunteers. We will compare our CCTCC model to an alternative model that is widely hypothesized to be important, the Cortical-Striatal-Thalamic circuit (CST), which will assist us in further testing our hypothesis that cerebellar malfunction (within a circuit model) contributes to the manifestations of schizophrenia. In addition, we will explore the CCTCC/cognitive dysmetria model using a group of experimental "cognitive dysmetria tests" designed to assess the various functions mediated by the CCTCC, such as timing or eyeblink conditioning, as well as several control experimental tasks. The control tasks were chosen in order to address the "generalized deficit problem." These are tasks that patients with schizophrenia are able to do at a normal or superior level. This group of tasks will give us an additional test of the specificity of the CCTCC/cognitive dysmetria construct.

DESCRIPTION (provided by applicant): This application uses functional imaging to examine cerebellar dysfunction in schizophrenia. It builds on our previous work, which has consistently shown that patients with schizophrenia have functional abnormalities in regional cerebral blood flow (rCBF) in distributed circuits (including cortical regions, thalamus, and cerebellum) in many types of cognitive tasks. We have described the resulting behavioral/cognitive abnormality as "cognitive dysmetria." In this application we propose to focus primarily on the cerebellum, based on our work during the past four years. During this time we examined a variety of tasks, which ranged from "classic cerebellar" (eyeblink conditioning) to "higher" cognitive and emotional tasks. All types of tasks showed cerebellar activations in normals and decreased flow in schizophrenia. Therefore, in the present application we plan to extend this work by examining three different models of cerebellar function in the normal brain: associative learning, timing and psychomotor integration, and multipurpose microcomplexes. We will examine these three models by using eight different PET protocols in healthy normal volunteers. These models are hierarchical, in that models 1 and 2 are encompassed in model 3. We hypothesize that we will confirm all three models, and that model 3 provides the best characterization of the role of the cerebellum in cognition. The eight protocols include studies of "classic cerebellar" functions (e.g., associative learning and psychomotor integration) and "higher cortical" functions (e.g., working memory, emotion, and social cognition). We will use these protocols to study these functions in eight different groups of patients suffering from schizophrenia. We hypothesize that the patients will show decreased cerebellar blood flow in all eight groups of tasks (as compared to the healthy volunteers), thereby confirming that the cerebellum is dysfunctional in schizophrenia in a broad range of tasks and suggesting that the importance of the cerebellum in both normal mental function and in schizophrenia has been underestimated.

DESCRIPTION (provided by applicant): Identifying the neural substrates of schizophrenia is a key step in developing more targeted treatments or identifying molecular mechanisms. The tools of neuroimaging have substantially facilitated this search. For approximately the past decade, we have been exploring the hypothesis that patients with schizophrenia suffer from a "misconnection syndrome": a disturbance in a widely distributed network of brain regions. This misconnection leads in turn to impairment in the ability to integrate information ("thought disorder") that is the hallmark of schizophrenia. The proposed project examines both structural connectivity (using diffusion tensor imaging, or DTI) and functional connectivity using functional magnetic resonance imaging (fMR) to examine the "default network" during random episodic silent thought ("REST"). We will employ both a cross-sectional and a longitudinal design in order to examine whether impairments in structural and functional connectivity progress over time, based on our preliminary work suggesting that this is the case. We will collect MR data at baseline in first episode patients, chronic patients, and healthy normal volunteers. A subset of the first episode patients will be studied when they are still neuroleptic naive. Follow-up MR data will be obtained at two time points. Only a few studies to date have examined first episode patients. Ours will be one of the first to compare first episode patients and chronic patients, using a matched control group. There are very few studies examining the issue of progression or of medication effects with DTI. Neuroleptic naive subjects have never been examined, nor has DTI been applied in a longitudinal design. DTI and fMR provide different and complementary data about the brain;additional power is provided if this information can be integrated in a single analysis. We will use novel statistical techniques for "data fusion" to integrate the information from DTI measures of structural connectivity with fMR measures of functional connectivity. Thus the proposed work with is highly innovative.

DESCRIPTION (provided by applicant): This application requests continuation of funding for a very successful and well-established post-doctoral training program (dating back to 1991) in Major Psychoses and Translational Clinical Neuroscience. It seeks to integrate training in translational clinical neuroscience with an emphasis on the study of schizophrenia and other major psychoses using a lifespan trajectory perspective. That is, trainees may study illnesses during their characteristic age of onset, but they may also examine them from the perspectives of neurodevelopmental and/or aging processes. This program in integrative translational clinical neuroscience will place strong emphasis on all three aspects: integrative, translational/clinical, and neuroscience. The ultimate goal is to train a group of young investigators who will combine a high level of sophistication about the complexities of clinical phenomena with a firm grounding in some specific area of neuroscience, such as neuroimaging, cognitive neuroscience, and genetics/genomics/molecular biology. The program supports five trainee slots/year. Trainees remain in the program for a minimum of two years, and many elect to continue their training for a total of three years because of the complexities inherent in doing sophisticated integrative translational clinical neuroscience. The minimum experience required for entry into the program is a doctoral degree (M.D., Ph.D.), but many of our trainees have also completed residency training and have M.D./Ph.D.s. Relevance An integration of basic and clinical science will, we hope, help identify the mechanisms and causes of the major psychoses and to suggest improved methods for treating or preventing them. The disorders studied through this program (schizophrenia, depression, and bipolar illness) are three of the top ten contributors to the global burden of disease, according to a recent study by the World Health Organization. Thus it is crucial that we train a young generation of investigators who will advance knowledge about these diseases over the coming decades.

DESCRIPTION (provided by applicant): Identifying the neural substrates of schizophrenia is a key step in developing more targeted treatments or identifying molecular mechanisms. The tools of neuroimaging have substantially facilitated this search. For approximately the past decade, we have been exploring the hypothesis that patients with schizophrenia suffer from a misconnection syndrome: a disturbance in a widely distributed network of brain regions. This misconnection leads in turn to impairment in the ability to integrate information (thought disorder) that is the hallmark of schizophrenia. The proposed project examines both structural connectivity (using diffusion tensor imaging, or DTI) and functional connectivity using functional magnetic resonance imaging (fMR) to examine the default network during random episodic silent thought (REST). We will employ both a cross-sectional and a longitudinal design in order to examine whether impairments in structural and functional connectivity progress over time, based on our preliminary work suggesting that this is the case. We will collect MR data at baseline in first episode patients, chronic patients, and healthy normal volunteers. A subset of the first episode patients will be studied when they are still neuroleptic naive. Follow-up MR data will be obtained at two time points. Only a few studies to date have examined first episode patients. Ours will be one of the first to compare first episode patients and chronic patients, using a matched control group. There are very few studies examining the issue of progression or of medication effects with DTI. Neuroleptic naive subjects have never been examined, nor has DTI been applied in a longitudinal design. DTI and fMR provide different and complementary data about the brain; additional power is provided if this information can be integrated in a single analysis. We will use novel statistical techniques for data fusion to integrate the information from DTI measures of structural connectivity with fMR measures of functional connectivity. Thus the proposed work with is highly innovative.