Brian P. Keane, PhD - US grants

DESCRIPTION (provided by applicant): Contour integration (CI)-for the purposes of the present application-refers to the ability to represent spatially segregated edges as a single continuous contour. Numerous studies suggest that people with schizophrenia (SZ) are impaired at contour integration, but the mechanisms, time-course, and clinical implications of the impairment are just beginning to be explored. To shed light on this issue, we conduct a two phase psychophysical investigation. In the first phase, we will satisfy NIMH Strategy 1.1, and clarify the neural mechanisms behind the deficit (Aim 1). Clinical CI studies to date have almost exclusively employed lower spatial frequency contour elements (<7 cycles/deg), but converging evidence suggests that schizophrenia is characterized by magnocellular dysfunction and, correspondingly, impaired processing of lower spatial frequencies (<8 cycles deg). To determine whether spatial frequency processing can account for CI deficits in SZ, a later-episode patient group and a matched healthy control group will perform 4 different tasks. The spatial frequency structure of the stimuli for each task will be varied to either include or not include low spatial frequencies. If CI deficits arise even with elements defined by high spatial frequencies, then impaired lateral interactions in early visual cortex would be evidenced as a core feature of schizophrenia. By contrast, if CI dysfunction arises only when lower spatial frequencies are available, then that would add to the growing evidence for magnocellular dysfunction in SZ, and would provide a new interpretation of results stemming from CI tasks. In the second data collection phase, we will satisfy NIMH Strategy 2.1 and examine the development of CI deficits from first-episode onward (Aim 2). Newly recruited subjects will be either healthy controls, first- episode patients, or later-episode patients. The tasks in this second phase will be the same as those that revealed between-group differences (p<0.05) in the first phase. Importantly, this phase will provide the first data on whether CI deficits exist among people with schizophrenia who recently experienced their first psychotic episode. At the end of data collection, we will combine data across phases to make two determinations. First, we will assess if CI deficits-at either high or lower spatial frequencies- correlate with clinical variables such as: functional outcome, disorganized symptoms, positive/negative symptoms, and premorbid social functioning (Aim 3). Second, we will compare the four tasks on the basis of: between-group effect sizes, capacities to predict illness features, total duration, and drop-out rate (Aim 4). Evaluating the tasks in this way will guide future larger-scale studies aiming to further establish, explain, or make use of contour deficits in schizophrenia. In summary, the four aims achieved over two data collection phases will elucidate the neural mechanisms, time course, clinical correlates, and optimal measures of contour integration dysfunction in schizophrenia. PUBLIC HEALTH RELEVANCE: In accord with NIMH Strategy 1.1 ("Develop an integrative understanding of basic brain-behavior processes...for understanding mental illness"), the proposed research will clarify the brain mechanisms that underlie the reduced ability to connect spatially separated contour elements in schizophrenia. Furthermore, consistent with NIMH Strategy 2.1 ("Define the developmental trajectories of mental disorders"), the proposed research will describe the developmental trajectory of perceptual dysfunction in schizophrenia, and provide the first substantive data on whether contour integration impairments are present as early as the first episode of psychosis.

Project Summary/Abstract [public] Candidate's short and long-term goals. The candidate's ultimate career goal is to become a tenured university professor who explores aspects of visual object perception using clinical science, neuroscience, and behavioral psychophysics. Overarching questions central to the research include: How does the brain construct and maintain coherent object representations despite a spatiotemporally fragmented retinal image? How do these integration processes break down when the brain is afflicted with serious mental illness? And what can we learn about mental disorders by looking at these processes? During the award period, four knowledge areas will be developed or deepened so as to increase the chances of long-term career success. First, basic methods in fMRI experimental design and analysis will be acquired such as functional connectivity and ROI analyses. A second goal is to develop expertise in basic neuroscience, including psychopharmacology and functional neuroanatomy. A third goal will be to improve knowledge of psychopathology, especially in regards to bipolar disorder. A final objective is to gain exposure to recent methods in vision and visual neuroscience such as eye movement analyses or neurostimulation. Training environment. A major component of the research and training will take place at the Center for Molecular and Behavioral Neuroscience (CMBN) on the Newark campus of Rutgers, which includes the Rutgers University Brain Imaging Center (RUBIC). The candidate has had hardly any exposure to faculty, staff or research on the Newark campus and is just at the very beginning of learning fMRI. Therefore, the activities at CMBN and Rutgers?Newark Psychology will provide exposure to new professors, new students, and new methodologies in cognitive neuroscience, underscoring the training potential of this application. Moreover, Rutgers University Behavioral Health Care (UBHC) is one of the largest academically-affiliated mental health providers in the United States, offering ample opportunity to find willing patients with schizophrenia or bipolar disorder. The infrastructure for finding and running patients at Rutgers has been intact for many years, indicating that rapid progress on the proposed research can be expected. The co-sponsors, as a group, are well-published, well-funded, have a history of mentorship, and have overlapping interests with my own. The union of their areas of expertise span vision research, cognitive neuroscience, fMRI, and psychopathology, which correspond to the four training areas identified above. Description of research. Perceptual organization (PO) refers to the ability to represent spatially segregated elements as unified wholes or inter-related parts. Numerous studies suggest that people with schizophrenia (SZ) are impaired at PO, but the neural mechanisms and clinical implications of the impairment are just beginning to be explored. Addressing this issue is valuable because PO deficits arise as early as the prodromal or first episode stages in SZ, and because they at times predict more severe disorganization and functional disability. To gain insight into the neural basis and diagnostic scope of PO deficits, a two-phase fMRI investigation will be conducted. In the first phase, the aim is to understand the neural basis for why PO deficits arise in SZ (Aim 1). Recent studies have suggested that PO deficits originate in early visual cortex, perhaps because of impaired lateral connectivity in this area. At the same time, SZ is characterized by prefrontal cortical dysfunction, and this has recently been shown to be relevant for perceptual organization. To determine whether prefrontal cortical contributions best explain PO deficits in SZ, I will learn recent functional imaging techniques?including functional connectivity, ROI, and multivariate pattern analyses?to compare SZ patients and matched healthy controls on three PO tasks. If PO dysfunction arises even at the earliest visual grouping stages, then this would broaden our conception of SZ and support prior studies that argue for integrative abnormalities in V1/V2. By contrast, if PO dysfunction arises only at late stages over prefrontal cortical areas, then that would give a new interpretation of previous studies, and add to the growing evidence for prefrontal cortical dysfunction in SZ. Regardless of the outcome, new insights will be had about the underlying pathophysiology of SZ, fulfilling NIMH Strategy 1.1. In the second phase of the study, it will be examined to what extent PO deficits arise in bipolar disorder, which shares a common genetic etiology with SZ (Aim 2). There are very few PO studies of bipolar disorder, and perhaps none that have used fMRI. Therefore, this investigation will provide entirely new insights into the nature and perceptual consequences of this related illness, fulfilling again NIMH Strategy 1.1. Once data collection ends, patient data will be combined across phases to assess whether the behavioral and neural signatures of PO co-vary with other clinical variables across disorders, such as levels of functioning, and conceptual disorganization (Aim 3). The investigation will clarify whether previously documented PO abnormalities in SZ are best attributed to diagnostic category or symptom dimensions (psychotic/mood), a question that is deemed high priority by the NIMH Strategy 1.4 (RDoC Initiative). It will also examine whether there are patient subgroups that exhibit similar degrees of perceptual dysfunction but that do not share a diagnosis. In summary, the three aims achieved over two data collection phases will elucidate the neural mechanisms and clinical implications of PO dysfunction across the schizo-bipolar spectrum.