Andrew Gordon - US grants

The long-term goals of the proposed research are to elucidate the role of bacteria in modifying metal ion (particularly copper) speciation in aquatic environments. Specifically, this study will further document the occurrence of the bacterial response to copper ion stress involving production of extracellular, proteinaceous metal chelators and their physiological role(s). Environmental health-related benefits of the research include an improved understanding of the response of aquatic environments to heavy metal contamination, influence of aquatic biota in "buffering" toxicity of heavy metals, and the influence of metals on lower members of the human food chain. In general, the research will contribute to our understanding of homeostatic mechanisms involved in trace metal metabolism and detoxification. The first phase of the study will focus on pinpointing the role of the copper binding proteins (CuBP) of Vibrio alginolyticus in metal detoxification. Tn5-l32 transductants will be screened for sensitivity to copper, and copper sensitive mutants will be screened for CuBP production. A copper sensitive Vibrio alginolyticus deficient in CuBP expression will provide a direct link between CuBP and copper detoxification. In addition, cultures will be screened for copper resistant mutants which overproduce CuBP. A Chesapeake Bay isolate of Vibrio alginolyticus will be tested for production of compounds similar to CuBP, as will Escherichia coli and Pseudomonasputida. The possibility that CuBP is induced by other environmental stresses, such as iron and carbon limitation, will also be examined. Specific methods employed in the study are polyacrylamide and agarose gel electrophoresis, immobilized metal ion affinity chromatography (IMAC) for characterization and quantitation of copper complexing supernatant proteins, and transduction by the transposable element Tn5-l32. Tangential flow filtration, IMAC, gel permeation chromatography and anion exchange chromatography will be used to concentrate and purify CuBP. Human health implications of the research regard the environmental fate of potentially toxic heavy metals, and, therefore, mechanisms by which they may be incorporated into the food chain.

Dissolved copper in surface seawater in many locations exists primarily in complexes with strong organic ligands, which are distinguished by their complexing strengths. However, these ligands have never been isolated and characterized; thus, almost nothing is known about their chemical nature. Isolation and characterization of these ligands is extremely important to our understanding of the biogeochemical cycling of copper and the ligands themselves, and perhaps that of other metals which may be similarly complexed. Recently, immobilized metal (Cu2+) affinity chromatography (IMAC) has been used to purify extracellular copper- binding proteins produced by marine bacteria, and also to isolate and partially characterize organic compounds with affinity for copper from estuarine, coastal, and open ocean waters. IMAC- isolated ligands have depth distributions similar to those of ligands that strongly complex Cu in the Atlantic and Pacific. This pilot project will determine whether IMAC, using either established or modified protocols, can isolate these ligands, ligands detected in seawater by differential pulse anodic stripping voltammetry (DPASV) and ligand competition/differential pulse cathodic stripping voltammetry (LC/DPCSV). The appropriate IMAC protocol will then be used in conjunction with DPASV and LC/DPCSV to characterize the ligands in coastal surface seawater with respect to: their concentrations, conditional stability constants, relative proportions of protein and polysaccharide comprising them, and molecular weight.

DESCRIPTION (Adapted from Applicant's Description): Impaired manual dexterity is often one of the most disabling motor symptoms of Huntington's disease (HD). The neural mechanisms underlying the impaired hand function are poorly understood. The investigators propose to address this issue by examining the fingertip forces employed during manipulation of an object between the thumb and index finger (precision grip). Patients with HD will be asked to grasp and lift a custom made instrument (whose weight will be varied) using the precision grip, while the grip (pinch) and vertical lift force will be measured with strain gauge transducers. Furthermore, kinematics of the hand will be recorded using an optoelectronic device. Both temporal and force amplitude measures will be compared to age-matched control subjects to determine whether impaired hand function in HD is attributed to problems with movement sequencing, anticipatory and sensory control of prehensile forces, and/or chorea intruding upon the hand motor function. The specific aims are: #1. To test the hypothesis that patients with HD have prolonged transitions between movement phases and an uncoupling of the normal parallel generation of grip and lift force during object manipulation. #2. To test the hypothesis that these patients are impaired in their ability to scale (plan) the fingertip force output based on predicted physical properties (e.g., weight) of the object. #3. To test the hypothesis that patients with HD are impaired in their ability to use sensory information to adapt the grip forces to the object's weight, and will use excessive forces to compensate for choreic movements. The investigators long-term objective is to understand the neural basis of hand impairment in HD in order to facilitate the development of therapeutic intervention.

LAY ABSTRACT Principal Investigator: Gordon, Andrew Proposal Number: IBN-97332679 The objective of this Faculty Early Career Development (CAREER) project is to understand how sensory information is used for the planning and control of hand movement. Professor Gordon and his students employ state-of-the-art techniques which allow precise measurement of hand and finger movements and forces during tasks such as typing, reaching and grasping. They study how tactile information contributes to the sequencing of movements (typing), how these sequences are learned, and the coordination between hand and eye movement during typing. They also study the contribution of tactile information to the regulation of fingertip forces during object manipulation and how tactile cues may provide information about the location of the limb in space. These studies provide insight into the nature of learning and organization of movement in the brain. The educational component of this CAREER project beyond involvement of students in this research is to form an interdepartmental cooperation with the Program in Science Education. This enhances teacher preparation by introducing Science Education doctoral students to research in systems neuroscience. Professor Gordon engages these students in research which foster an understanding of the methodology and rationale of science in order to facilitate exploration of the nature of science and scientific inquiry in the classroom and improve the learning process through the process of discovery.

DESCRIPTION (provided by applicant): Impaired hand function is one of the most disabling symptoms of hemiplegic cerebral palsy (CP). It significantly affects self-care activities such as feeding, dressing, and grooming, and may limit the use of assistive technology aimed at improving quality of life. During prior work in the investigators laboratory, they observed marked improvement in performance of the more affected upper extremity during the one-hour sessions in which hand function was tested. This improvement suggests that at least part of the disability may be due to nonuse of the more affected extremity, and that this specific disability may be amenable to intervention. A recent therapeutic intervention involving restraint of the less affected extremity and extensive functional task practice with the more affected extremity, constraint-induced (CI) therapy, has been developed for adults sustaining hemiplegic stroke. This highly innovative intervention has been found to be extremely effective in overcoming nonuse of the more affected extremity in these patients. These results have compelled us to test the efficacy of this intervention in children with hemiplegic CP. However, in its existing form, it may be too intrusive for children. Thus, the overall goal of this exploratory project is to develop, improve, and test a modified form of CI therapy that is suitable for use in the children with CP. The investigators will test the hypothesis that this intervention will result in an increased amount and improved quality of function in the more affected upper extremity compared to a delayed treatment control group (specific aim 1). They will also test the hypothesis that CI therapy will be more effective in younger children with hemiplegic CP than older children due to the increased plasticity in their developing central nervous system (specific aim 2). Finally, the investigators will determine whether CI therapy is effective when modified to fit usual and customary care therapeutic schedules (specific aim 3). To determine which outcome measures are appropriate, the researchers will examine a battery of clinical tests, some of which are analogous to the tests employed in adult stroke CI studies, and others that are specifically appropriate for children with disabilities. They will also employ state-of- the-art measurement techniques to quantify reach-to-grasp and force coordination during object manipulation to determine whether the intervention results in changes in movement/force patterns. The resulting data will be used to determine inclusion and exclusion criteria, develop estimates of effect size, and refine the methods and outcome measures for future grant applications.

With support from a National Science Foundation Major Research Instrumentation award Dr. Andrew Gordon, Dr. Peter Gordon, and colleagues at Teachers College, Columbia University, will establish a research facility containing state-of-the-art instrumentation to investigate neurophysiological mechanisms underlying language and movement and their interactions. Particular emphasis will be placed on processes underlying learning and development. The award will fund acquisition of a high-density electroencephalographic (256 channel EEG) system, which provides the best resolution available to study the structure and localization of neural activity associated cognitive function. Researchers at Teachers College will examine how the child and adult brain processes information during first and second language learning. Further studies will investigate neural information processing related to infants' perception of events in the world. These will include studies of how infants understand basic actions and sequenced events that will later be expressed verbally as they develop spoken language. The EEG system will also be used to investigate changes in brain activity as people use language to express their emotional reactions to life stressors. An eye-tracking system will also be acquired to study the relationship between eye-hand coordination during typing in adults, and the acquisition of reading in children and second language learners. Finally, a movement analysis system for tracking motion in three dimensions will be acquired to study facial and hand movements in children and adults as they develop language-related behaviors. These studies using state-of-the-art equipment will serve as a window into linguistic and cognitive development, explore brain-behavior relations in early perceptual development, identify relations between language and emotion, provide insights into the reading strategies and abilities of emerging readers, and gain deeper insights into the neural mechanisms underlying second language acquisition. The groundbreaking combination of language and movement sciences within this facility represents an exciting new approach to the study of human communicative learning and development.

The broader impacts of these activities include scientific discovery and understanding while promoting teaching, training and learning. The instrumentation will enable the investigators to create a well-equipped learning environment for integrating research and education. The research projects all involve students from Teachers College, which includes a high proportion of females and individuals from underrepresented groups, thus broadening their participation in science and its application to education. The instrumentation will be a centerpiece of a recently re-established multi-disciplinary Neurosciences and Education program that focuses on the neurological basis of learning and education. The benefits of these activities to society include developing the capacity to generate research that will aid our understanding of developmental and learning processes and impact pedagogy related to spoken, written and signed language. Students at Teachers College will become leaders of the educational establishment and will take the knowledge gained from exposure to the instrumentation and resulting research into the schools in their roles of leadership and practice.

How does the brain work with the human body to control behavior? This question holds many deep issues that are central to the behavioral and cognitive sciences. Some of them are more philosophical in nature (like the famous mind/body problem of Cartesian dualism), while others are more mechanical. One of the most general mechanical issues with behavioral control is often referred to as the "degrees of freedom" problem. The problem is that action goals may very often be reached by many different paths of action. To illustrate, imagine the act of picking up a cup of coffee. Healthy adults take this act for granted as trivially easy, but from the perspective of the human brain and body, there is non-trivial problem to be solved. The problem is that there is a vast number of distinct trajectories of the torso, arms, and fingers that may all suffice to accomplish the task of lifting the cup. How does the system choose among the vast array of possibilities so efficiently and effortlessly?

With support of the National Science Foundation, Dr. Santello and Dr. Gordon will conduct a series of experiments on human grasp behaviors to better understand the nature of behavioral control. The experiments will focus on the coordination of the fingers in response to the forces that are imposed upon them while maintaining the goal of holding an object and not allowing it to slip or tilt. Prior research suggests that grasping behaviors are governed in part by a tendency to simplify the control of the fingers, which helps to alleviate the degrees of freedom problem. However, there is also reason to believe that this tendency is itself a complex phenomenon because what is simple may depend on the particularities of the grasping task. The primary aim of this collaborative research project is to investigate the task-dependency of grasp control. Grasping serves as a simple laboratory task for more generally investigating the remarkably flexible and adaptive nature of human behavior. The knowledge to be gained in this research project may also inform the development of more dexterous robotic manipulators, as well as remotely operated machinery that is capable of handling fragile or dangerous objects.

The complexity of the human hand requires creative and multidisciplinary efforts aimed at understanding its control. The brain relies on strategies to simplify the control of complex movements such as those produced by the hands. However, most studies of these strategies have focused on limited tasks that may not generalize to natural grasping behaviors and that do not take into account the use of sensation. The overall aim of this collaborative research proposal is to test how grasp strategies depend on the behavior performed. The results will provide insight into how the brain controls and coordinates the complex architecture of the hand and how sensory information is used in this control.

The results of this project are potentially transformative in that understanding how the hand is controlled as well as how the brain controls complex movements has a wide variety of applications. Given the key role that the hand plays in our motor behavior, ranging from artistic expression to tool use, results may influence several fields, including neuroscience, robotic manipulation (e.g., space exploration, tele-operated surgery) and the development of 'smart' prosthetics. Furthermore, the projects will foster a rich learning environment for integrating research and education.

The ability to grasp and manipulate objects is an extremely complex motor behavior. When grasping an object such as a cup, people often vary their finger placements and the forces exerted by the fingers in order to ensure that the goal is attained (in this case, lifting the cup without spilling its contents). How humans do this so efficiently is not known, in part because previous research constrained subjects to place their fingers at pre-specified locations on the objects. This has led to a major gap in our understanding of how these complex motor behaviors are learned, planned, and executed. To address this gap, the proposed studies will investigate how subjects grasp and manipulate objects in tasks that allow them to choose their finger placements and applied forces and, importantly, to adjust the interaction between the two. Another function of grasping is to develop a representation of an object's weight and the distribution of weight within the object. How subjects develop this representation and refine their actions will be examined by studying the interaction between information extracted by grasping and memories of past manipulations of the object. The hypothesis that fingertip placement and forces are learned independently from each other will be tested by manipulating visual feedback of fingertip placement, varying visual shape and density cues, and through object rotation tasks that create a discrepancy between visual cues and memories of the same object from prior manipulations.

The proposed studies represent a major paradigm shift in the research on grasping by opening new and fundamental questions about how the brain learns to control the hand. Thus, the results of this work may inform the design of more dexterous robotic manipulators, brain-machine interfaces, and neuroprosthetic hands.

How people use their hands to interact with objects is one of the most complex and least understood sensorimotor skills. For example, when people pick up the same object multiple times they use different fingertip forces to compensate for differences in their fingertip positions. This compensation is important because it allows people to manipulate an object skillfully without having always to grasp it at the exact same points. Several important questions remain: What is the relative contribution of individual sensory modalities, such as touch and vision, in enabling the compensatory modulation of fingertip force and position? Are fingertip forces and positions represented separately by the central nervous system? What are the mechanisms underlying their generalization to different limbs or tasks? These questions represent a major gap in our understanding of how the central nervous system learns, plans, and executes complex motor behaviors. An understanding of how sensory modalities are seamlessly integrated to enable the development and implementation of high-level internal representations of hand-object interactions should inspire the design of more dexterous robotic manipulators endowed with sensory feedback, improve neuroprosthetics, and aid development of advanced bioengineering research tools to quantify biological control mechanisms.

The overall goal of this collaborative research is to elucidate the mechanisms responsible for building high-level representations of hand-object interactions accounting for end-effector position and force. The aims are 1) to quantify the mechanisms underlying the weighting of sensorimotor integration during hand-object interactions and 2) to determine the principles underlying generalization of a learned hand-object interaction to a new context. The investigators will test three hypotheses: 1) the weighting of different sensory modalities is time dependent according to its role within a given task epoch; 2) co-variation between end-effector force and position is a general feature of hand-object interactions, independent of the effectors used (fingertip, whole hand, or two-hands); and 3) generalization of learned hand-object interactions is sensitive to the frame of reference in which they were learned.

The objective of this Research Experiences for Undergraduates (REU) Site renewal is to engage 10 undergraduate students per summer at the University of Southern California's Institute for Creative Technologies, a unique multidisciplinary research community that combines leading academic researchers in computer science, psychology, communications, cinematic arts, and medicine. Participants will be immersed in collaborative research teams focused on the institute's core theme of interactive virtual experiences, with specific projects in areas such as virtual reality, narrative, virtual humans, natural language dialogue, and graphics. These activities will be combined with weekly interactive seminars for training in best research practices, mentorship support, and peer feedback.

The techniques and technologies developed by the researchers drive the creation of compelling synthetic environments and characters with immediate relevance to a broad range of application domains including training, education, rehabilitation, and medicine. The undergraduate students will become engaged in summer experiences that emphasize interdisciplinary research, with the goals of broadening participation from underrepresented populations in computing and exposing undergraduate students to opportunities in science and engineering graduate programs. This effort has the potential to prepare undergraduates to perform independent research, thereby increasing enrollment and retention in computing doctoral programs.

This project focuses on understanding how people learn, plan, and execute hand movements to grasp and use objects. For example, how does a person lift a cup of coffee without spilling or a factory worker line up a Phillips-head screwdriver with the grooves on a screw? Although we perform these tasks routinely without giving them too much thought, dexterous manipulation is one of the most complex and least understood human skills and one that still limits the utility of robots in industry. Of particular interest is understanding the brain mechanisms that allow people to learn to manipulate an object one way (e.g., to lift a mug by the handle) and then apply that knowledge differently (e.g., to lift the same mug by its sides). The investigators are working towards a comprehensive theory, at both the neural and behavioral levels, of how people learn and generalize these hand-object interactions. The results may inspire new robotic manipulators that are more dexterous, with human-like ability to generalize a learned motor behavior to novel contexts. The work may also influence development of more dexterous neuroprosthetics. The project's other broader impacts include a public lecture and discussion on the social and ethical implications of human-robot systems and participation in the "Science Cafe" series hosted by the Arizona Science Center.

Previous work by the investigators has provided evidence for two scenarios for learning how to manipulate objects. In one scenario, people build a high-level (i.e., task-level) representation of object manipulation, which allows them to generalize the learned manipulation to a different context. For example, people successfully manipulate an object even after a finger is removed from, or added to, the object's contact surface or when the object is manipulated by the contralateral arm. In a second scenario, people build an effector-level representation. In this case, they persist in generating the same finger placement and forces despite a new context that requires different solutions, as when an object with an asymmetric mass distribution is rotated. What are the neural mechanisms involved with promoting or interfering with generalization of learned hand-object interactions? Can neural representations at the task level - enabling generalization - be built following repeated exposure to a different manipulation context? These questions represent a significant gap in our understanding of skilled object manipulation. The overall goal of this collaborative research is to elucidate neural mechanisms underlying task- and effector-level representations of hand-object interactions. The studies will record finger position and forces utilized when grasping objects in order to probe the influence of the context in which a given hand-object interaction is learned. Electroencephalography (EEG) will be used to determine the neural correlates of successful and unsuccessful generalizations to new contexts. Quantification of these behavioral variables and the corresponding brain mechanisms will provide insights into how objects are mentally represented and how these representations underlie planning and execution of dexterous manipulation.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.