John A. Sweeney - US grants

The NIMH sponsored Treatment Strategies in Schizophrenia (TSS: Appendix A) Collaborative Study involves five sites and provides an opportunity for a single large study of up to 486 patients with schizophrenia for morphological abnormalities using computed tomography (CT). Patients from different sites are expected to provide a socio-economically, ethnically and geographically heterogenous population of schizophrenics representative of patients who live in the community and periodically require hospitalization. Each patient in the TSS study who gives informed consent will be CT scanned and followed every two weeks for two years with standardized clinical assessments to assess the response to a combination of pharmacological treatment and family management. The nature, magnitude and frequency of the atrophic changes observed on CT scanning in schizophrenia and their relationship to treatment response will be explored in detail in the TSS study.

Eye tracking abnormalities seem to be the most robust and sensitive (55-85%) psychobiological marker for schizophrenia. Although they are being used widely in high risk and genetic studies, their basic methodological underpinnings and validity as a marker for schizophrenia are not well established. The purposes of this study are to: 1) identify specific components of oculomotor functioning that are deviant; 2) establish diagnostic specificity; 3) assess stability over time; 4) evaluate effects of neuroleptics; and 5) determine clinical and neuroanatomic correlates of tracking deficits. To develop the eye tracking methodology and establish its validity, we will undertake studies with the following aims: 1) to precisely characterize the parameters of oculomotor deficits in schizophrenia we will use computer analysis of infrared eye movement recordings to replicate and extend previous findings of abnormalities in pursuit gain and the saccadic eye movement system; 2) to assess diagnostic specificity we will compare the performance characteristics of the test with schizophrenics, bipolars, psychotic unipolars, nonpsychotic unipolars, and normal controls; 3) to evaluate stability over time, we will test patients at admission, at weeks 2 & 4 of hospitalization, and at 6 month followup; 4) to assess neuroleptic effects, we will test unmedicated patients at hospitalization, and compare outpatient schizophrenics after 2 years of randomly assigned high, low or intermittent dose fluphenazine with known blood levels. An unmedicated subset of stabilized outpatients will be followed longitudinally; 5) to characterize patients with tracking deficits, we will assess relationships between tracking performance and premorbid adjustment, ventricular enlargement, thought disorder (TDI), positive and negative symptoms, and cognitive deficits. This investigation will be the first systematic assessment of eye tracking impairment in schizophrenia. It will allow us to learn about its sensitivity, stability and diagnostic specificity, and thereby develop the methodology and ascertain the degree to which tracking impairment has certain necessary characteristics of a valid psychobiologic/genetic marker.

Eye tracking abnormalities seem to be the most robust and sensitive (55-85%) psychobiological marker for schizophrenia. Although they are being used widely in high risk and genetic studies, their basic methodological underpinnings and validity as a marker for schizophrenia are not well established. The purposes of this study are to: 1) identify specific components of oculomotor functioning that are deviant; 2) establish diagnostic specificity; 3) assess stability over time; 4) evaluate effects of neuroleptics; and 5) determine clinical and neuroanatomic correlates of tracking deficits. To develop the eye tracking methodology and establish its validity, we will undertake studies with the following aims: 1) to precisely characterize the parameters of oculomotor deficits in schizophrenia we will use computer analysis of infrared eye movement recordings to replicate and extend previous findings of abnormalities in pursuit gain and the saccadic eye movement system; 2) to assess diagnostic specificity we will compare the performance characteristics of the test with schizophrenics, bipolars, psychotic unipolars, nonpsychotic unipolars, and normal controls; 3) to evaluate stability over time, we will test patients at admission, at weeks 2 & 4 of hospitalization, and at 6 month followup; 4) to assess neuroleptic effects, we will test unmedicated patients at hospitalization, and compare outpatient schizophrenics after 2 years of randomly assigned high, low or intermittent dose fluphenazine with known blood levels. An unmedicated subset of stabilized outpatients will be followed longitudinally; 5) to characterize patients with tracking deficits, we will assess relationships between tracking performance and premorbid adjustment, ventricular enlargement, thought disorder (TDI), positive and negative symptoms, and cognitive deficits. This investigation will be the first systematic assessment of eye tracking impairment in schizophrenia. It will allow us to learn about its sensitivity, stability and diagnostic specificity, and thereby develop the methodology and ascertain the degree to which tracking impairment has certain necessary characteristics of a valid psychobiologic/genetic marker.

The aim of this study is to define the functional neuroanatomy of brain regions subserving the control of eye movements in humans at high spatial resolution with fMRI. Single-cell recording studies in nonhuman primates during performance of saccadic eye movement tasks have found increased activation in cortical regions including the frontal eye fields, supplementary motor area, posterior parietal cortex and dorsolateral prefrontal cortex, as well as in several subcortical structures. In humans, a small number of PET, fMRI, stroke and lobectomy studies provide evidence for a generally similar mapping of the eye movement control system in humans. However, detailed delineation of the functional anatomy of this circuitry, and discrimination of the unique computational activities performed by its component structures, has not yet been achieved in humans. Using high-field echo-planar fMRI, established behavioral tasks, and stimulus-synchronized MR image analysis, we will undertake studies to characterize this neuronal network at unprecedented spatial and temporal resolution. The specific aims are to: 1) establish the functional neuroanatomy of reflexive saccadic eye movements, including efforts to characterize inter-and intra-subject consistency of activations, 2) differentiate task-related activations in specific brain regions during particular task conditions (e.g. pursuit vs. saccades, small vs. large saccades, reflexive vs. voluntary saccades) and 3) develop novel methodologies for using the temporal resolution of fMRI for characterizing time courses of activation effects and functional connectivity in vivo. These studies were designed to address important questions about elementary cognitive processes and oculomotor control systems in humans, and to lay the groundwork for fMRI studies of clinical disorders associated with eye movement abnormalities.

This is for the PI to develop his skills in the area of functional neuroimaging. The advent of high-field ultra-fast echo-planar fMRI and 3D PET provides the opportunity to conduct in vivo functional neuroimaging studies with unprecedented spatial and temporal resolution. The informed application of these technologies has great potential for delineating the nature, progression and treatment- responsiveness of brain dysfunction in psychiatric disorders at the level of individual patients. The PI requests support for a training program designed to develop the skills needed to initiate novel and sophisticated neuroimaging studies as a central element of his established program of schizophrenia research. The scientific aims to be pursued represent a systematic extension of the PI's ongoing studies of eye movement abnormalities in schizophrenia, in which newly-available neuroimaging strategies will be used to directly characterize neurophysiologic abnormalities associated with these established neurobehavioral deficits. The proposed program of neuroimaging studies is rooted in the well- developed understanding of oculomotor neurophysiology provided by extensive single-cell recording studies of behaving monkeys. The training and scientific aims described in this application will be accomplished in the context of: 1) exceptional technical and scientific resources at the MR and PET Centers at the "University of Pittsburgh, 2) ongoing collaborative work with neuroradiologists, statisticians, engineers and physicists focused on neuroimaging methodologies, 3) an integrated program of schizophrenia research including both basic and clinical investigators, and 4) linkages to senior investigators actively studying oculomotor systems in monkeys at the single cell level.

Current neurobiological theories of autism propose that the disorder results from developmental abnormalities in neocortex, limbic system and/or cerebellum. Neuropsychological evidence of impaired executive function, and evidence of disturbed metabolism, blood flow and functional connectivity, indicate that abnormalities in neocortical systems may be primary to this condition. In order to directly examine the functional integrity of neocortical and subcortical neural systems in autism, we will conduct funcitonal magnetic resonance imaging (fMRI) studies of the reflexive and voluntary control of eye and hand movements. The brain systems controlling both types of movement are well-delineated neuroanatomically and neurophysiologically, and we have previously established edficits in both domains of functioning in autism. These systems are therefore ideal targets for clinical functional neuroimaging studies. Using high-field echo-planar fMRI and well-validated behavioral paradigms, we will undertake studies to characterize the physiology of neocortical and subcortical systems in autism with unprecedented spatial and temporal resolution. We will examine developmental aspects of executive functions by assessing relevant behavioral and neurophysiological parameters during the ages when executive functions mature to adult levels. This will be done through annual behavioral testing of pediatric autistic patients and matched controls recruited between the ages of 8 and 13, and a follow-up fMRI study of these cases conducted 4 years after initial imaging studies. The proposed investigations are designed to directly establish clinico-pathological relationships and thereby clarify the neurophysiologic basis of disturbed executive functions in autism, and to examine underlying cortical neural circuitry abnormalities within a developmental framework.

Project proposes in vivo functional and structural neuroimaging, neurobehavioral studies, and postmortem histologic studies of schizophrenic patients designed to delineate the neural substrate of disturbed frontal lobe function in schizophrenia. We will focus on problems of spatial cognition and volition using oculomotor tasks for which the neurophysiologic substrates in dorsolateral prefrontal cortex (DLPFC) have been well-characterized by unit recording studies in non- human primates. We will focus on the integrity of the frontal eye fields (FEF), which receive substantial associational projections from DLPFC and which are believed to be a site of abnormalities causing eye movement dysfunctions in schizophrenia. Project is closely linked to Project-Lewis (which proposed postmortem histologic studies of DLPFC that parallel both our in vivo neuroimaging studies of that region as well as our histologic studies of FEF), Project-Levitt (which will conduct gene expression studies of FEF in postmortem tissue from schizophrenic patients), Project 6-Olson (which proposes unit recording studies of behaving monkeys performing the identical oculomotor tasks to be used in our clinical studies), and Project-Cohen (which proposes fMRI and cognitive studies of working memory disturbances in schizophrenia that parallel those proposed in this project).

DESCRIPTION: (Verbatim from the Applicant's Abstract) Abnormalities of eye movement control and spatial cognition are well-established deficits in schizophrenia. However, the regional disturbances in brain function causing these deficits are not yet known. This application proposes a series of integrated behavioral and fMRI studies designed to identify causes of pursuit eye movement and spatial working memory deficits in schizophrenia. We will determine whether there are intrinsic functional disturbances in extrastriate regions that process visual motion information (Area MT) using both optic flow and motion aftereffect paradigms. We will parametrically manipulate attentional enhancements during pursuit tracking to clarify the causes of what appears to be a reduced influence of extra retinal signals on the control of pursuit eye movements in schizophrenia. We will use an oculomotor delayed response (ODR) task to study spatial working memory impairments in schizophrenia. We will parametrically manipulate the rate of "distractor" information presented during the delay period of this prototypic spatial working memory task in order to model changes in dorsal brain regions of interest across a range of processing load conditions. Fifty schizophrenic patients will be recruited, 25 first episode antipsychotic-naive patients and 25 unmedicated chronic patients. In addition to matched healthy subjects, 50 patients with non-bipolar depression will be recruited as a clinical comparison group. Depressed patients are of interest because our group and others have demonstrated relevant disturbances of eye movement control and spatial cognition in this disorder. Subjects will be restudied after 3 months, during which all patients will receive controlled treatment, in order to assess the extent of normalization of brain function associated with treatment and clinical recovery. The results of these studies will clarify the neurobiological basis of one of the most robust and promising biological markers of risk for schizophrenia, and of working memory disturbances known to be a prominent component of the neuropsychological profile of the disorder. Findings will also clarify the diagnostic specificity of regional brain disturbances causing these abnormalities, and the impact of known effective treatments upon them.

space perception; schizophrenia; short term memory; neurophysiology; eye movements; neural information processing; visual tracking; cognition disorders; mental disorder chemotherapy; emotions; patient oriented research; functional magnetic resonance imaging; human subject; behavioral /social science research tag; clinical research;

[unreadable] DESCRIPTION (provided by applicant): Recent studies provide considerable evidence that schizophrenia (SZ) and psychotic bipolar disorder (BP) may share overlapping etiologic determinants. Identifying disease-related genetic effects is a major focus in SZ and BP research, with enormous implications for diagnosis and treatment for these two disorders. Efforts have been multifaceted, with the ultimate goal of describing causal paths from specific genetic variants, to changes in neuronal functioning, to altered brain anatomy, to behavioral and functional impairments. Parallel efforts have identified and refined several alternative endophenotypes that are stable, heritable, have (partly) known biological substrates, and are associated with psychosis liability. Although many such endophenotypes have been individually studied in SZ, and to a lesser extent in BP, no study has comprehensively assessed a broad panel of these markers in the two disorders with parallel recruitment, and the extent to which they mark independent aspects of psychosis risk, or their overlap in the two disorders. This line of investigation will potentially impact our conceptualization of psychotic disorders, help us make critical strides to identify the pathophysiology of psychosis, and guide development of new specific treatments targeting particular deficits. The overall goal of the proposed research is to examine a broad panel of putative endophenotypes in affected individuals with schizophrenia and bipolar and their unaffected relatives in order to: 1) characterize the degree of familial phenotypic overlap between SZ and psychotic BP; 2) identify patterns of endophenotypes unique to the two disorders, and 3) contrast the heritability of endophenotypes across the disorders. To achieve these goals, we will recruit 500 SZ and 500 BP I (with psychosis) probands, ~1700-2000 1st degree relatives of these probands, and 500 unrelated non-psychiatric controls from five centers. We will obtain measures of neurophysiology (e.g., eye tracking, P50 gating, PPI, and P300), neurocognition (e.g., attention/vigilance, episodic and working memory), and brain structure (e.g., volumes of gray and white matter in specified brain regions). We will collect blood for future genetic studies. We will assess the degree of familial aggregation of endophenotypes in SZ and BP relatives. Establishing similarities and differences in the endophenotypic signatures within SZ and BP families will provide important insights for future genetic studies, and clarify concepts about common and distinct aspects of pathophysiology, potentially meaningful heterogeneity within disorders, and the clinical boundaries of the two commonest psychotic disorders in adult psychiatry. This research will be conducted by 5 experienced research groups, with a long history of close and productive collaboration. [unreadable] [unreadable] Public Health Relevance: This multisite project will identify endophenotypes (or liability markers) that are shared and different in schizophrenia and bipolar disorder. Findings from these studies will provide important insights for future genetic studies, and clarify concepts about common and distinct aspects of pathophysiology, potentially meaningful heterogeneity within disorders, and the clinical boundaries of the two commonest psychotic disorders in adult psychiatry. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]

3-(2-Aminoethyl)-1H-indol-5-ol; 5-HT; 5-Hydroxytryptamine; 5HT; 5HT transporter; 5HTT protein; Acute; Affect; Affective; Animal Model; Animal Models and Related Studies; Area; Autism; Autism, Early Infantile; Autism, Infantile; Autistic Disorder; Behavior; Behavioral; Behavioral Model; Behavioral Paradigm; Biochemical; Brain; Causality; Classification; Clinic; Clinical; Clinical Research; Clinical Study; Clinical Trials; Clinical Trials, Unspecified; Cognition; Cognitive; Common Rat Strains; Complement; Complement Proteins; Condition; Dimensions; Disease; Disorder; Distress; Dysfunction; Encephalon; Encephalons; Enteramine; Escitalopram; Etiology; FLR; Failure (biologic function); Flexibility; Functional Magnetic Resonance Imaging; Functional disorder; Gene variant; Genes; Genetic Diversity; Genetic Variation; Goals; High Prevalence; Hippophaine; Human; Human, General; Impairment; Intervention; Intervention Strategies; Investigation; Kanner's Syndrome; Knowledge; Laboratories; MRI, Functional; Magnetic Resonance Imaging, Functional; Mammals, Rats; Mammals, Rodents; Man (Taxonomy); Man, Modern; Matched Group; Measurement; Mission; Modeling; Molecular; Nature; Nervous; Nervous System, Brain; Neurochemistry; Neurology; Outcome; Patients; Pharmacology-Psychopharmacology; Physiopathology; Play; Pliability; Process; Programs (PT); Programs [Publication Type]; Psychiatry; Psychopharmacology; Psychopharmacology / Toxicology; Rat; Rattus; Receptor Protein; Recruitment Activity; Research; Rodent; Rodent Model; Rodentia; Rodentias; SSRI; Science of neurochemistry; Science of neurophysiology; Selective Serotonin Reuptake Inhibitor; Selective serotonin re-uptake inhibitor; Serotonergic Agents; Serotonergic Drugs; Serotonin; Serotonin Agents; Serotonin Drugs; Severities; Speed; Speed (motion); Stress; System; System, LOINC Axis 4; Systematics; Testing; Translational Research; Translational Research Enterprise; Translational Science; Variation (Genetics); Week; Work; allelic variant; autism spectrum disorder; base; behavioral pharmacology; clinical effect; clinical investigation; cognitive neuroscience; cognitive system; comparison group; design; designing; disease causation; disease etiology; disease/disorder; disease/disorder etiology; disorder etiology; drug development; endophenotype; fMRI; failure; gene discovery; improved; interventional strategy; model organism; neural; neurobehavioral; neurobehavioral test; neurochemistry; neurophysiology; pathophysiology; programs; psychopharmacologic; psychopharmacological; receptor; recruit; relating to nervous system; response; serotonin reuptake inhibitor; serotonin transporter; sodium-dependent serotonin transporter; success; translation research enterprise; treatment effect