David Smith - US grants

The research will describe the neuroanatomical and neurochemical bases of ketamine's (Ketalar; Ketaject) analgesic effect. It will be accomplished by an evaluation of the presence and function of opiate receptor sub-types in neuroanatomical loci (i.e., sites known to be loci of morphine's analgesic action); a description of opiate receptor sub-types with which ketamine interacts; and a determination of the consequences of an interaction of ketamine at these receptors. The research is divided into five scientific approaches. Each is designed to provide component information important to the project as a whole and/or to test the same proposal under different conditions. The methods are: 1) a pharmacological comparison of the analgesic action in rats of various sub-classes of opiate drugs presumed to be specific for sub-types of opiate receptors, and an evaluation of the participation of monoaminergic and opiate neuronal processes in these analgesias; 2) an in vitro comparison of the receptor binding characteristics of ketamine and other opiate drugs, specific for different receptors, using opiate binding assays; 3) an in vivo evaluation of the ability of ketamine to interact with opiate receptors that may mediate its special pharmacological actions; 4) local administration of ketamine and opiate drugs, specific for different opiate receptors, into central nervous system loci (i.e., those sites responsible for morphine analgesia) and an analysis of the neurochemical and neuroanatomical bases for the resulting analgesia and 5)*an in vitro and in vivo analysis of the participation of opiate or non-opiate mechanism(s) in the spinal analgesic action of ketamine, a site of action of established differences between ketamine and morphine. The study should define ketamine's opiate receptor preference and action (agonistic-antagonistic) on various sub-types of receptors found in areas of the central nervous system associated with morphine's analgesic action. The possibility that ketamine uses neuronal circuitry activated by morphine is being tested. Ketamine may be found to be dissimilar to morphine and share components of analgesic mechanisms associated with other classes of opiate drugs. Differences in the analgesic mechanisms associated with various types of analgesic drugs will begin to be defined which is consistent with our long term goal to determine pathways and neurotransmitters of analgesia.*

This project will develop ethical guidance for presymptomatic testing for autosomal dominant, late onset diseases for which genetic probes are available (familial Alzheimer disease, amyotrophic lateral sclerosis, Huntington disease, myotonic dystrophy, neurofibromatosis, adult polycystic kidney disease and retinitis pigmentosa). Our six-member working group offers expertise in genetic counseling, clinical medical ethics, genetic research, law, ethics and communication. We will collect and analyze case studies, beginning with Indiana University's extensive experience with Huntington disease (HD). Experience with HD research and presymptomatic testing provides a unique and informative historical model. Co-PI Kimberly A. Quaid will visit selected testing centers, and we will solicit supplementary cases from major centers that offer testing for diseases of interest. We will define the full range of ethical problems presented by presymptomatic testing for these disorders, and we will explore the salient questions from the varied perspectives represented by the working group, considering ethical principles (autonomy, beneficence, justice); clinical practicality; administrative feasibility; changing research findings; religious beliefs and institutions; and political, cultural and economic contexts. Consultants P. Michael Conneally, Robert Burt, Albert Jonsen and Thomas Murray will read drafts of our cases, analyses and guidelines and provide regular feedback on our work throughout the project. In addition, we will solicit input from genetic counselors and others experienced with presymptomatic testing, and we will invite patients and families at risk to review our materials in progress to assess their sensitivity, adequacy and feasibility. Our final product, a book published by Indiana University Press, will include guidelines for presymptomatic testing of autosomal dominant, late onset disorders; annotated cases; and the description of a method for resolving ethical issues our guidelines do not address directly.

This project utilizes behavioral and physiological techniques in the same animals to determine the functional role of olivocochlear bundle (OCB) efferents in auditory perception. Subjects will be monkeys (Macaca fascicularis). These will tie trained to respond on perceptual tasks using operant conditioning techniques applied in a standard yes-no adaptive tracking procedure. Perceptual processes to be examined are (1) monaural thresholds in quiet and under conditions of broadband noise masking, (2) frequency selectivity, (3) dynamic range and growth of loudness, and (4) central masking. These tasks were selected for study because they allow hypotheses of OCB function previously described in the auditory research literature to be evaluated. Baseline data for normal performance on one or more perceptual tasks will be collected for each animal. The animal will then undergo either a unilateral vestibular neurectomy (to remove the entire OCB projection to one ear) or near-midline section at the floor of the fourth ventricle (to eliminate only the crossed OCB projections). Following a recovery period, animals will be re-tested on the same tasks as earlier to determine the perceptual consequences of OCB loss. After behavioral testing has been completed, each animal will become the subject of an acute electrophysiological experiment to record single auditory nerve fiber responses, using the same stimuli and data collection paradigms that were used behaviorally. At the conclusion of the physiological recordings, the operated and unoperated cochleas of each animal will be injected with horseradish peroxidase and nuclear yellow, respectively, and light and electron microscopic techniques will be used to verify OCB transection (for the operated ear) and determine the number and condition of surviving OCB cells (for the unoperated ear).

9451165 Bart The field of geological education has changed dramatically in the past 2O years. Part of this progress is reflected in the incorporation of environmental and hydrogeologic courses in the curriculum. Undergraduates engaged in geologic study throughout our nation are moving into these endeavors because of the strong employment possibilities created by a growing industry. Until recently, environmental and hydrologic study were not part of the curriculum at La Salle University. The Department of Geology is hoping to correct this deficiency in our program by purchasing the necessary equipment to add hands-on environmental and hydrogeologic experiences to our curriculum. This equipment will be used by freshmen, sophomore, junior, and senior majors, in earth science teacher preparation, and freshmen introductory classes, and will serve as an important part of our curriculum in: Introductory Geology, Environmental Geology, Hydrogeology, Sedimentology, Environmental Geology, and Student Research. With this laboratory equipment our students will be complementing their intensive use of standard geologic investigation equipment and will be capable of investigating the earth in ways never before possible in our program. Subsurface interface radar will be used for conducting studies such as bedrock depths, soil profiles, water table information, fracture and fault mapping. Water studies will include water analysis for characterization of surface and subsurface quality. The gas vapor soil probe and organic vapor meter will be used for investigations of possible hydrocarbon contamination of soils. The radon detector will give students the chance to evaluate radon levels of soils throughout our region. If supported, this project will create a new and exciting dimension in geologic investigation at La Salle; and the students we serve will be better prepared for the challenges of graduate studies, teaching, employment in environmental sciences, and research.

This project is concerned with the behavioral analysis of the biophysical mechanisms underlying cochlear implant function. Behaviorally trained cats will be deafened unilaterally and implanted with one of two multi- contact intracochlear electrode arrays. Two classes of experiments are proposed. The first is to relate psychophysical performance to anatomic findings and several neurophysiological measures (EABRs, intracochlear- evoked potentials, and single-fiber discharge patterns) in response to the same stimuli, all in the same animals. Behavioral tasks include measures of absolute threshold, growth of loudness, dynamic range and channel interactions. In the second class, the goal is to characterize the effects of minute manipulations of intracochlear current fields on psychophysical performance. Using a dense, multicontact linear-array electrode, absolute thresholds for single and paired pulsatile stimuli will be measured as a pulse phase polarity and electrode position. Intracochlear-evoked potentials, EABR and electrical field mapping studies will be undertaken to characterize the growth in electrical field and activation, as a function of stimulus intensity, for the same stimuli as were used behaviorally. At the conclusion of the psychophysical and electrophysiological testing, animals from both classes of experiments will be sacrificed, and their cochleae harvested for histological analyses to determine the number and spatial position of surviving peripheral prncesses and spiral gang lion cells, relative to the electrode contacts. Data from both classes of experiments, combined with predictions of electrical fields from a finite element model, will form inputs into biophysically-based, neural behavioral models. The models will be evaluated in an attempt to account for behavioral performance on the basis of electrical field configuration, the resulting patterns of neural activity, and the anatomic condition of the spiral ganglion in the tested animal. In addition, the feasibility of conducting fine focal stimulation within the cochlea, both within and across a critical band length, will be evaluated in terms of measures of channel interactions and behavioral performance.

DESCRIPTION: (Adapted from the Investigator's Abstract) The ultimate goal of the proposed studies is characterization of the role of the medial efferent system in human perception of sound. It combines psychophysical and physiological measurements in the same subject, from both humans and monkeys. The PI proposes the development of psychophysical tasks that reflect known efferent processes. The characteristics of the distortion product otoacoustic emission (DPOAE) will be used to define the stimulus conditions for the specific aims. Based on psychophysical and anatomical studies of the two species, use of identical stimulus conditions allows direct comparison between the two species. The first study (Aim I) is designed to determine the relationship of "central masking" and efferent reduction of the DPOAE, both effects produced by contralateral acoustic stimulation. Psychophysical suppression will be measured parametrically by target frequency, contralateral noise bandwidth, intensity and frequency. In human subjects, the contralateral efferent effect on the DPOAE will determine the efferent involvement. Similar experiments, using identical stimulus conditions, will be performed with the monkey as the subject. The efferent involvement in perception, measured from the human, will be inferred from monkeys with discrete lesions. The experiments performed in Aim I will aid in the specification of stimulus conditions of subsequent Aims. In Aim II the PI proposes to characterize the role of the medial olivocochlear (MOC) in possible improvement in the perception of signals in noise. These studies are intended to determine the conditions in which enhanced perceptual acuity occurs. Aim III focuses on the role of the MOC in psychophysical adaptation. Recent physiological experiments suggest that some aspects of adaptation are related to MOC function. The DPOAE in response to sustained stimulation shows a rapid adaptation that is eliminated when the uncrossed efferent system is cut. The PI proposes to test, in parallel, psychophysical and physiological adaptation in humans and monkeys. The time course of the adaptation for each response measure will be compared. The involvement of the MOC in these two response measures will be evaluated by MOC lesions in the monkeys. The goal of Aim IV is to determine the role of the MOC tracts in auditory "selective" attention. Psychophysical and physiological evidence suggests that a control mechanism exists that can suppress extraneous or unattended signals. Parallel psychophysical and physiological studies in humans and monkeys are proposed to replicate the previous studies. The role of selective attention will be addressed by discrete MOC lesions and monitoring performance changes.

The medial olivocochlear (MOC) efferent system is known to exert significant effects on cochlear physiological activity, yet little is known about the function of the efferents in auditory perception or the behavioral response of hearing. The proposed functions of the MOC, relevant to the present work, include: 1) to unmask or decompress an auditory nerve fiber's I/O function by suppression of the neural representation of concurrent noise; 2) to increase the salience of transient signal onset by mediating the process of neural adaptation, which acts to decrease or suppress the representation of long-duration stimulation; and 3) to provide a peripheral, neural mechanism that underlies the process of "selective" auditory attention, by which the neural encoding of "unattended" stimuli are suppressed. This application proposes a unique experimental approach to characterizing the role of the efferent tracts in auditory perception in humans, combining psychophysical and physiological (DPOAE) measures in the same subjects. We propose to develop psychophysical tasks as analogs of known efferent physiological processes, focusing on psychophysical measures related to the above, purported efferent processes. Specific psychophysical tests will employ both human and non-human primate subjects as listeners, in parallel, under identical stimulus conditions. The DPOAE measures will serve to aid in specification of the precise stimulus conditions to be tested, being optimized for specific aims. It is assumed, based on previous psychophysical and anatomical studies, that the humans and monkeys will yield comparable data under similar stimulus conditions. The ultimate goal of this research program is characterization of the contribution of the medial efferent tracts to auditory perception in humans. Parallel testing of human and non-human subjects permits unequivocal determination of the contribution of the efferents to the different perceptual processes studied, in both monkeys and humans, through lesion studies in the monkey subjects. Without this parallel testing paradigm (and the ability to lesion tracts in the non-human primate subjects) the link between human perception and the underlying neural mechanism would not be direction obtainable.

The Mathematics and Science Partnership of Greater Philadelphia (MSPGP) focuses on improving secondary mathematics and science, grades 6-12, in an "open loop" environment typical of sprawling, densely-populated greater metropolitan areas containing hundreds of school districts and dozens of institutions of higher education. In an effort to build the required linkages that address issues such as bringing strong local successes to scale and preventing program erosion over time, the MSPGP brings together as core partners 46 school districts and 13 institutions of higher education in eight Pennsylvania and four New Jersey counties in the region outside of Philadelphia. The MSPGP model includes a "Core Connector" organizational structure that provides a way to facilitate and grow partnerships between grades 6-12 teachers and administrators and faculty from higher educational institutions. To assess the progress of mathematics and science programs and college/university preservice programs, the MSPGP uses five-stage "On the Road to Reform" rubrics and customizes project activities to each circumstance depending on where any particular partner is on the journey.

DESCRIPTION (provided by applicant): It would be difficult to overstate the magnitude of the burden depressive disorders pose, not only to society and to the friends and relatives of those afflicted, but especially to depressed people themselves. Marital discord is a substantial risk factor for major depression, and this investigation is designed to clarify the nature of the association between depression and discord through detailed examination of inter-spousal criticism. The purpose is two-fold. First of all, this investigation seeks to determine whether perceptions of excessive spousal criticism are due to depressed people's biased perceptions of otherwise benign communications or to their accurate perceptions of comments from genuinely hypercritical spouses. Secondly, this study seeks to clarify and contextualize various individual differences predisposing to sending and receiving criticism. Carefully diagnosed depressed and non-depressed married people and their spouses will participate in a laboratory session during which they each complete marital, symptom, and personality questionnaires as well as undertaking a dyadic criticism perception accuracy task. The stimulus interaction for the criticism accuracy task will be a social support discussion of something one spouse would like to change about themselves. Both spouses then review the interaction videotape. The target spouses indicate time-linked thoughts and feelings they recall having experienced during the original interaction. Non-target ("source") partners review these same moments and indicate the thoughts and feelings they perceived their spouse as having experienced as well as disclosing their own intentions as they recall having them during the original interaction. Signal detection analyses will be deployed to determine the accuracy and bias in inferring criticism as evidenced by discrepancies between the two spouses' reports. Outside observers will also provide criticality ratings for comparison purposes. The role of individual differences in perceiving and emitting criticism will also be examined.