Steven L. Small - US grants

The individual projects outlined in this proposal are aimed at the description of an overall processing architecture of the human neurolinguistic system. As research progresses toward this goal, theoretical notions motivated by empirical studies will be tested with connectionist network models, and concomitantly, predictions from network models will be tested with empirical studies. The desired result is the development of a general theory of cognitive neurolinguistic processing that is both testable and falsifiable. The proposed research and training uses research methods from experimental psychology, speech and language pathology, neuroanatomy and neuropathology, and computer modelling to construct useful cognitive theories of language disorders. Specifically, the project described here proposes to (a) organize a language disorders registry and database and implement it at Presbyterian-University Hospital (PUH); (b) design and execute a study of semantic priming in patients with language disorders; (c) extend an existing prototype connectionist simulator (DYSNET) to permit network lesions of both diffuse and focal types, in order to simulate neurological damage; and (d) perform computer modelling experiments leading to predictions for the design of empirical studies and suggestions for language therapy. Initial modelling experiments will be based on semantic priming data from a study of language disorders in diffuse brain disease. It will first account for the data from normal subjects (independent of age) that supportive context makes sentence completion tasks easier (i.e., faster); subsequently, it will be systematically disrupted (lesioned) to account for the results in the patients with language disorders, and lastly, the model will be examined for approaches to repairing lesioned networks, with attempts to correlate computational strategies and clinical language therapy. In the final two years of the project, the laboratory framework for building computer models should be sufficiently operative to initiate experiments in individualized patient models, with full-scale attempts to use the results of such tests in specific individually tailored language rehabilitation efforts.

psychomotor function; neuroanatomy; rehabilitation; stroke; brain imaging /visualization /scanning; functional ability; fingers; motor cortex; cerebellar cortex; limb movement; bioimaging /biomedical imaging; medical rehabilitation related tag; magnetic resonance imaging; human subject; clinical research;

Both functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) can be helpful in characterizing the neurophysiological status of patients with aphasia. Such measurements can be used to develop treatment approaches, select patient-specific treatments, and gauge the effectiveness of treatment. However, brain imaging in aphasia must be improved. Both fMRI and DTI are highly sensitive to both head motion and oropharyngeal motion, and these artifacts are exacerbated in patients with non-fluent aphasia, who have a more difficult time producing speech. Stroke is often precipitated by and/or accompanied by alterations in vasculature, which can affect the MRI signal. Hemodynamic redistribution leads to ambiguity about the source of MRI signals presumed to indicate neural reorganization and/or remodeling. Artifacts from reperfusion hemorrhage leads to susceptibility artifact in the vicinity of lesions. The proposed work will specifically address each of these technical issues to facilitate the use of neurophysiological (functional imaging) measures in patients with aphasia. For fMRI and DTI to guide therapeutic decision-making, there must be formal ways to characterize the physiological state of individual patients and to correlate biological and behavioral parameters. In this proposal, we develop two classes of measures, scalar indices and network activation maps, and investigate their relationship to measures of speech and language. Scalar indices reduce an entire pattern of activation into a single number, such as degree of brain lateralization or integrity of callosal white matter. Network maps include structural equation models and Euclidean distance maps, and we develop methods to compare such large-scale models between individuals or groups (e.g., patients who do and do not benefit from therapy). This component of the research aims to develop rational neurophysiological measures for aphasia research. Finally, these methodological improvements will be applied to a treatment study for patients with chronic non-fluent aphasia and left frontal lesions. The therapeutic intervention is based on (a) neurobiological observations that the brain has circuits particularly active in motor imitation through observation-execution matching, including oral motor imitation; (b) behavioral observations that imitation is a cornerstone of many treatments for non-fluent aphasia; and (c) treatment data that favor intensive approaches and graded incremental learning. Outcomes are assessed by both physiological and behavioral measures, which are collected every three weeks starting six weeks before treatment and ending six weeks after completion of treatment.

Neoclassical economic theory underlies almost all modern economic policy analyses. Nevertheless, several important deviations from standard assumptions of the theory have been robustly documented in laboratory experiments on economic decision-making. Two such important behavioral deviations are the "endowment effect" and the prevalent display of altruism/social preferences. A multidisciplinary team of researchers from economics, psychology, and neurology will examine the sources of these experimental findings. In this research, the economic decision-making experiments - spanning both laboratory and field treatments - used to detect these deviations will be complemented by neuroimaging techniques to provide insights into the neural mechanisms underlying the behavioral responses. An important hypothesis that will be tested in the context of the endowment effect is whether the effect survives in competitive trading settings. To test this hypothesis, a subject pool with varying degrees of experience as traders in real-world markets will be utilized. Neuroimaging techniques will be used to examine the neural responses of experienced versus inexperienced subjects. The experimental subjects will also be tracked over the course of several years to examine the persistence of behavioral patterns, and whether market experience attained during the survey period is reflected in neural activation patterns. In order to isolate the sources of social preferences/altruism displayed in laboratory games, an experimental design with variations in giving contexts will be used to test among competing explanations for the observed behavioral responses. Neuroimaging will play a crucial role in discriminating between alternative hypotheses and predicting behavior in novel situations. To collect neural measurements with high spatial and temporal accuracy, both fMRI and event-related electroencephalography (ER-EEG or ERP) techniques will be utilized, allowing a more complete understanding of the gains achieved from combining these two measurement modalities. The research is expected to have broader impact through several channels. The economic decision-making contexts studied in the research are ubiquitous in daily life. Assessing the effects of market experience and context variations on decision-making are necessary steps to extend the predictive domain of behavioral theories beyond the laboratory. The multidisciplinary nature of the project is expected to promote the flow of knowledge across the economic, psychology, and neurology/neuroscience disciplines, and will produce trainees (at the post-doc, graduate and undergraduate levels) who will further the communication between these fields.

DESCRIPTION (provided by applicant): Program Description: Many academic neurologists and neurosurgeons have noted a downward trend over the past decade in the numbers of trainees in residency programs who are interested in pursuing careers in academic medicine. This could adversely affect the future of basic and applied research in neurobiology, particularly with respect to (a) generation of new knowledge in the neurosciences;(b) understanding the relationships between basic neuroscience and clinical medicine;and (c) development of tools for diagnosis and treatment of diseases of the nervous system. It is our premise that neuroscientists and epidemiologists, also trained in clinical neurology or neurosurgery, represent our best hope for the future in developing and translating knowledge to expand treatment options in clinical neuroscience. This application proposes to develop an organizational structure and educational program for training neurology and neurosurgery residents at The University of Chicago in the day-to-day conduct of research, the ethical considerations that lead to honest science that is respectful of humans and animals, experimental design and statistical analysis that lead to interpretable results with impact, and the writing of grant proposals that contain important questions and clearly stated methods of answering them. Research training will be offered to select residents based on identification of an appropriate mentor and development of a promising research proposal. During a first phase of research education, neurology residents will perform 6-12 months of mentored research in a clinical or basic neuroscience laboratory within their PGY3 and PGY4 years. Neurosurgery residents will perform 12 months of mentored research during their PGY4 year. The second phase of research training will occur during the neurology fellowship years or the PGY5 year of the neurosurgery residency. A weekly evening seminar course during phase I will cover issues of experimental design, research implementation and ethics, and biostatistics. A year-long seminar course in grant-writing and a one-quarter course in the responsible conduct of research, accompanied by optional neuroscience and/or epidemiology coursework will accompany the Phase II research experience. All participants are expected to have an NIH research application, probably a K08 or K23 application, completed by the end of Phase II. Public Health Relevance: The recent downward trend in the numbers of neurological and neurosurgical trainees entering academic medicine could adversely affect the development of new knowledge in the neurosciences and the development of new tools for diagnosis and treatment of diseases of the nervous system. We aim to ameliorate this situation by teaching trainees in clinical neurology and neurosurgery the principles, practices, and ethics of effective research.

DESCRIPTION (provided by applicant): The primary goal of this application is to promote research and training in the neurobiology of speech and language via support for an annual scientific conference, the Neurobiology of Language Conference (NLC). The NLC fills a much-needed gap in scientific meetings on the neural basis of language by emphasizing the strongest work on the integration of neuroscience research and communication disorders with cognitive, linguistic, psycholinguistic, perceptual, and motor control models of speech and language. We have the following five specific aims. (1) To support an annual meeting on the Neurobiology of Language with the aim of providing a forum for the interaction of researchers in the full range of allied areas including neuroscience, genetics, communications disorders, cognitive psychology, linguistics, psycholinguistics, neurolinguistics, perception, motor control, computational modeling, and neural and psychophysical methods. (2) To expand the breadth of knowledge of researchers in the field by bringing in distinguished keynote speakers in neuroscience and biology. (3) To advance the training and education in the neurobiology of language by providing student scholarships for conference attendance. (4) To promote diversity in the field by providing scholarships for conference attendance to under-represented groups. Because the NLC meeting brings together a broad range of language scientists who don't normally interact regularly, we believe the meeting will lead to valuable new interactions, collaborations, and novel ideas in the Neurobiology of Language, including both basic scientific findings and applied findings in physiologically-based therapies for neurogenic language disorders. PUBLIC HEALTH RELEVANCE: Language disorders affect millions of people in the United States. There is an extensive research community, with much of this research funded by NIDCD, which targets both basic and clinically-oriented research on the neural basis of language and language disorders. By providing a forum for the communication of new research findings and emerging trends, the Neurobiology of Language Conference will play a pivotal role in scientific progress aimed at understanding, diagnosing, and treating language disorders.

In concert with Projects 1-3. this revised Project 4 probes the effects of fragmented early life experience on neuronal network structure and function using magnetic resonance brain imaging (MRI) of rats (with Project 1) and humans (with Projects 2-3). The results will be integrated with parameters generated by the other projects to accomplish the Center's goal of generating predictive models and markers of adolescent mental vulnerabilities. We will start by examining whether fragmented early-life experience influences the structure of brain regions and networks that are salient to cognitive and emotional functions. We then define a trajectory of these structural and functional alterations with development, and their correlation with cognitive and emotional behavior, resulting in potential biomarkers of vulnerability to overt cognitive and emotional pathology. The goal of this project is to employ MRI-derived measures to establish predictors of regional brain connectivity (as well as structural changes) that best correlate with developmental and cognitive vulnerabilities as a function of early life exposure to fragmented maternal signals. This novel analysis will identify a series of pathological changes that occur at varying intervals in the pre-symptomatic period that might guide the timing of future interventions and provide insights into intrinsic compensatory mechanisms. Its significance derives from the crucial importance of the clinical hypothesis: that fragmented patterns of sensory input modulate the function and connectivity of brain networks. The Project innovation stems from (a) The concept of developmentally evolving neuronal networks as the target of fragmented/unpredictable maternal input, (b) from the use of novel methodologies (e.g.. Structural Equation Modeling); (c) from the use of analysis of distributed hippocampal connectivity using multiple modalities across species, and (d) from inclusion of MRI parameters in multivariate models orchestrated by the Computational Core, to generate potentially predictive models for adolescent vulnerabilities.

? DESCRIPTION (provided by applicant): The primary goal of this application is to promote research and training in the neurobiology of speech and language via support for an annual scientific conference, the Annual Meeting of the Society for the Neurobiology of Language (SNL). SNL fills a much needed gap in scientific meetings on the neurobiological basis of language by emphasizing the strongest work on the integration of neuroscience research and communication disorders with cognitive, linguistic, psycholinguistic, perceptual, and motor control models of speech and language. In this proposal, we aim (1) to support an annual meeting on the Neurobiology of Language, providing a forum for the interaction of researchers in the full range of allied areas including (a) basic scientific fields of neuroscience, genetics, psychology, linguistics, mathematics, computation, and physics; and (b) clinical scientific fields of neurology, neurosurgery, speech/language pathology, and psychiatry; (2) to expand the breadth of knowledge of researchers in the field by bringing in distinguished keynote speakers in both general neuroscience and language neuroscience; (3) to advance training and education in the neurobiology of language by awarding travel and registration scholarships to students and postdoctoral fellows, and by holding special trainee workshops; and (4) to promote diversity in the field by providing scholarships for conference attendance to members of groups that are under- represented in the relevant disciplines. Because the SNL meeting brings together a broad range of active scientists, clinicians, and students who do not normally interact regularly, we believe these meetings will lead to valuable new interactions, collaborations, and novel ideas in the neurobiology of language, including both basic scientific findings and clinical applications in physiologically-based therapies for neurogenic language disorders.