Scott T. Grafton - US grants

The objective of this research is to determine the functional organization of normal and pathologic motor pattern generation in humans in vivo with positron emission tomography imaging. Contrasting paradigms requiring locomotion, visual pursuit, and prehension will be studied with PET images of blood flow and glucose metabolism. We predict that a given type of patterned motor behavior will generate a specific distribution of active cerebral areas that can be used to define functional connectivity. We hypothesize that motor control can be effectively modelled with PET by characterizing the relative hierarchy of command centers and the degree to which they are distributed as a network of parallel cortical and subcortical processors. Cerebral plasticity associated with motor command centers. Measurable changes would include relocation of sites of cerebral response, alterations in the magnitude of each response, or redistribution of the functional connectivity between sites. Findings in normal subjects will form a basis for the study of CNS pathology. Locomotion, motor learning, and prehension will be examined in Parkinson's disease patients to delineate the metabolic anatomy of adaptation in response to a neurodegenerative process. Longitudinal studies of motor control in patients recovering from stroke will also be examined to characterize subacute functional reorganization of the motor system. By characterizing the potential configurations of connected and distributed networks of local neural responses that are active during motor performance, we will provide a broad view of motor organization. This view will have a significant impact on our understanding of the functional, as opposed to anatomic, defects that underlie nervous system injury and degeneration. Knowledge of the dynamic changes of the motor system during functional reorganization may ultimately guide therapy and predict outcome.

positron emission tomography; magnetic resonance imaging; cerebrovascular imaging /visualization; biomedical facility; human subject;

The re-emergence of surgical therapy for Parkinson's disease (PD) has provided major relief for patients who are no longer responsive to medical therapy. Deep brain stimulation (DBS) of either the internal segment of the globus pallidus (GPi) or the subthalamic nucleus (STN) is now being tested as an alternative surgical method to ablation. With DBS, an electrode is placed in the target nucleus and electrical current is applied with a subcutaneous stimulator device. The mechanisms by which DBS alters neural circuitry, culminating in symptom reduction, remains largely unknown. The overall goal of this project is to determine if there are relationships between DBS, the cardinal symptoms of PD, and patterns of brain activity measured at rest and during different types of movement. To do this, brain activity measured with positron tomography (PET) imaging of cerebral blood flow (CBF) will be assessed during GPi and STN DBS in PD patients. The specific aims will examine: 1. the effects of unilateral GPi and STN stimulation on "resting" brain activity. 2. the effects of unilateral GPi and STN stimulation on brain activity during different types of movement. Specific aims 1 and 2 will establish if GPi or STN DBS have similar effects on motor cortical circuits. The tasks are the same as those being used in PD patients studied before and after pallidotomy so that we will also be able to determine if GPi DBS and pallidotomy lead to similar changes of motor circuitry. 3. the clinical and functional (PET) effects of stimulation at different locations within the GPi. 4. the clinical and functional (PET) effect of GPi stimulation as a function of time. Specific aims 3 and 4 are designed to dissociate clinical symptoms with DBS to determine if there are anatomic correlates of the cardinal features of PD. These imaging studies using DBS provide a large-scale analysis of altered neural circuitry in the setting of neurodegeneration and reorganization that cannot be examined at the single neuron level or by behavioral assessment alone. The results of these experiments could have an impact on the development of surgical therapy for Parkinson's disease and could ultimately modify patient or stimulator selection.

image processing; biomedical facility; Parkinson's disease; bioimaging /biomedical imaging; human data;

human therapy evaluation; proprioception /kinesthesia; sensorimotor system; Parkinson's disease; basal ganglia; brain circulation; stereotaxic techniques; neurosurgery; antiparkinson drugs; noninvasive diagnosis; pathologic process; bioimaging /biomedical imaging; clinical research; human subject; electromyography; positron emission tomography;

The common goals of this program project are to understand how the basal ganglia contribute to the control of sensorimotor functions and to assess the pathophysiologic basis of human parkinsonism. The three research projects in this proposal are conceptually framed by the model of basal ganglia function formulated by DeLong and colleagues. In this model, widespread cortical inputs ultimately converge in the globus pallidus. Inhibitory pallidal output project to thalamus and brainstem. This concentrated will be an integrated investigation of basal ganglia sensorimotor function using two physiologic approaches (direct single unit recording at the neural level and PET functional imaging of regional brain activity) applied across four clinical states (normal, dopamine deficiency of Parkinson's disease (PD), dopamine replacement of PD, and surgical pallidotomy for PD). These groups will be assessed with consistent sensory, motor and control states. The experiments are distributed among three research projects, supported by two cores; one to manage subject recruitment and the other to orchestrate data analysis and modeling. The human imaging studies of this proposal form a critical bridge between the animal model of parkinsonism and clinical application of techniques such as pallidotomy to PD patients. They provide a large scale perspective of adaptation in the setting of neurodegeneration and reorganization after surgical pallidotomy that cannot be examined at the single unit level, by imaging on-human primates or behavioral assessment alone. The results could directly impact on the rational design of surgical therapies for patients with movement disorders. Integration of the imaging and physiologic data could be used to optimize lesion localization in surgical pallidotomy. Correlation of the physiological data could be used to optimize lesion localization in surgical pallidotomy. Correlation of the physiological data could be used to optimize lesion localization in surgical pallidotomy. Correlation of the physiological data with clinic scores may establish if functional imaging or intraoperative recording are reliable predictors of patient outcome.

[unreadable] DESCRIPTION (provided by applicant): A central problem in motor control research is to characterize the changes of internal representations for action planning that occur with skill learning. Traditional behavioral measures of performance such as improving reaction time or accuracy establish that a skill is being learned but do not sufficiently characterize the internal processes that lead to an improvement. The first goal of the current proposal is to use specific kinematic measures of performance to characterize brain behavior relationships underlying learning. For continuous tracking we have developed a model for estimating the contribution of position, velocity and acceleration estimates of a hidden movement trajectory with measured performance using canonical correlation. These will be used to model changes in the brain during skill acquisition [unreadable] [unreadable] Specific Aim 1: Characterize the internal representation of a continuous motor skill as a function of feedback and control mechanisms. [unreadable] [unreadable] Specific Aim 2: Identify convergence of functional anatomy. It is hypothesized that with sufficient training there will be a convergence in the neural systems used to control a movement, irrespective of the differences in training. [unreadable] [unreadable] Specific Aim 3: Determine changes in functional anatomy with progression/regression of skill. How do control parameters change with distraction, fatigue or a change of task demands? [unreadable] [unreadable] These aims relate fundamental aspects of normal motor learning and underlying functional anatomy. The experiments demanding extensive practice are particularly relevant for developing rational pathophysiologic models of brain plasticity that are applicable to studies of functional recovery after stroke. [unreadable] [unreadable]

How the central nervous system of vertebrates handles the staggering number of mechanical variables involved in even the simplest movement is one of the central problems in motor control. The experiments described in this proposal derive from the investigations conducted in intact frogs, spinalized frogs, rats and cats and are based on the hypothesis that the Central nervous System (CNS) constructs movements from a limited repertoire of motor primitives. Specifically, our goal is to investigate the way in which the CNS controls the monkey's hand movements and the variety of complex motor behaviors of the hand makes the hand an ideal model system for testing the validity of the modularity hypothesis. 1). In the monkey, we will investigate whether the muscles controlling hand and finger movements are constrained to act as units. To this end, we will use a computational analysis to identify these units. The analysis will allow us to extract a small set of muscle synergies from the large range of muscle activations generated during the movements of the hand and fingers. We will then investigate whether the flexible combinations of these synergies can account for the large number of different motor patterns produced by the animal. 2). With the aid of a specially designed glove (cyberglove) we will record the angular position and motion of the hand and individual fingers of the monkey. The kinematic data obtained with the help of the glove will make it possible to correlate the distinct hand shape typical of a variety of grips with combinations with synergies extracted during hand and finger movements. 3). Our third goal is to investigate whether the hand motor areas of the frontal lobe (especially M1) are related to the muscle synergies we have extracted with our computational procedure. To this end we will utilize three complementary approaches: A) partial inactivation (muscimol) of areas within the M1 hand region. B). Micro-stimulation and NMDA iontophoresis of small regions of M1. C). Recording the activity of antidromically identified cortico-spinal neurons and interneurons from selected areas of M1. These areas will be selected according to the results obtained with the technique of muscimol inactivation and/or microstimulation. The question here is whether or not the discharge of cortico-spinal cells represents the amplitude and time coefficients of the muscle synergies we have extracted.

This award provides funds to the University of California at Santa Barbara to acquire a 3T magnetic resonance imaging (MRI) scanner for basic-science brain imaging research. This instrument will be housed in a dedicated MRI research facility in the new Psychology East building where it will support a primary group of 37 basic-science faculty at UCSB. Ongoing research success by this group depends critically on access to a high performance 3T MRI scanner. These multidisciplinary researchers originate from eleven different departments that include Psychology, Computer Science, Education, Speech and Hearing, Molecular, Cellular & Developmental Biology, Geography, Communications, Physics and Anthropology. Thus, this 3T facility will provide campus-wide support to neuroscience researchers in the Schools of the Arts and Sciences, Education, Engineering. It will also be a critical resource for researchers from other institutions in the central coast region of California.

Functional brain imaging (fMRI) is an essential research tool used to define how the brain is organized to enable thinking and behavior and how these functions may be affected by abnormal development or disease. The 3T MRI will be used in many fMRI experiments including studies of memory, language, vision, navigation, communication, reasoning and learning. MRI will also be used to investigate brain anatomy, focusing on how white matter (the connections that link brain areas together) changes with development, disease and aging.

The vision of the Imaging Center is that it will serve as a catalytic research center for a broad, campus-wide initiative in Mind Science, for the study of the psychological, biological, and computational processes that govern mental function. What sets the initiative apart from other programs in cognitive science is that it will embrace a diverse set of approaches to studying the mind. These include, but are not limited to emotion, stress, conflict resolution, decision-making, genetics of behavior, optimal control, understanding intentionality, impact of media and criminality. Such interdisciplinary efforts offer far-reaching explanations of a wide variety of human phenomena, including strategies for complex decision-making, social interactions, conflict resolution, classification and induction, and statistical reasoning. The initiative in Mind Science is complemented by research on Basic fMRI Methodology and Technology. This work includes methods to model the fMRI BOLD signal, to characterize individual subject differences of brain structure and function, to integrate fMRI and EEG based technologies and to create immersive virtual reality environments for fMRI. A third thrust is in Engineering and Computer Science. The effort includes development of content-based retrieval and analysis of brain imaging data, new methods of image analysis, improving brain-computer and methods for the secure and reliable delivery of large data sets. These efforts reflect a strong commitment by faculty and students at University of California at Santa Barbara to interdisciplinary science and education. The 3T facility will operate in this tradition, providing new opportunities for research, graduate and post-graduate training, educational outreach, recruitment of new faculty in neuroscience, and increasing involvement by female students and researchers, and those from underrepresented groups.

How the central nervous system of vertebrates handles the staggering number of mechanical variables involved in even the simplest movement is one of the central problems in motor control. The experiments described in this proposal derive from the investigations conducted in intact frogs, spinalized frogs, rats and cats and are based on the hypothesis that the Central nervous System (CNS) constructs movements from a limited repertoire of motor primitives. Specifically, our goal is to investigate the way in which the CNS controls the monkey's hand movements and the variety of complex motor behaviors of the hand makes the hand an ideal model system for testing the validity of the modularity hypothesis. 1). In the monkey, we will investigate whether the muscles controlling hand and finger movements are constrained to act as units. To this end, we will use a computational analysis to identify these units. The analysis will allow us to extract a small set of muscle synergies from the large range of muscle activations generated during the movements of the hand and fingers. We will then investigate whether the flexible combinations of these synergies can account for the large number of different motor patterns produced by the animal. 2). With the aid of a specially designed glove (cyberglove) we will record the angular position and motion of the hand and individual fingers of the monkey. The kinematic data obtained with the help of the glove will make it possible to correlate the distinct hand shape typical of a variety of grips with combinations with synergies extracted during hand and finger movements. 3). Our third goal is to investigate whether the hand motor areas of the frontal lobe (especially M1) are related to the muscle synergies we have extracted with our computational procedure. To this end we will utilize three complementary approaches: A) partial inactivation (muscimol) of areas within the M1 hand region. B). Micro-stimulation and NMDA iontophoresis of small regions of M1. C). Recording the activity of antidromically identified cortico-spinal neurons and interneurons from selected areas of M1. These areas will be selected according to the results obtained with the technique of muscimol inactivation and/or microstimulation. The question here is whether or not the discharge of cortico-spinal cells represents the amplitude and time coefficients of the muscle synergies we have extracted.

Project 2 Multiple Time Scales of Human Sequence Learning A hallmark of human behavior is the capacity to acquire and maintain motor skills throughout life, both in health and in the face of brain injury or degeneration. This project will focus on mapping changes in motor systems of the human brain as healthy subjects practice and solidify skills into long-term memory. The primary goal of this work is to determine if there exist multiple time scales of learning and if these are based on behavioral features supported by distinct underlying neural circuits. The work is motivated by the need for a comprehensive model that explains when different motor circuits are engaged as a function of time over the course of training, particularly for skills requiring extensive practice. This question is important clinically because current therapies for neurodegeneration or stroke, including forced use paradigms, demand extensive training whereas most learning models consider changes over minutes to hours. The current work will identify longitudinal and cross sectional changes in the brain over extended training periods during sequence learning. Functional magnetic resonance imaging (fMRI) will be used as a physiologic probe of neural circuit recruitment and to model interactions between cortical and subcortical networks that may drive cortical plasticity. To generate causal inferences, disruptive transcranial magnetic stimulation (TMS) will be used to selectively inactivate different areas that contribute to task performance. Specific Aim 1. Distinguish neural systems associated with multiple time scales of learning. The conceptual framework underlying this aim is that dissociable cortical-subcortical networks are engaged over the course of skill training, with these networks demonstrating distinct time scales of recruitment. Specific Aim 2. Use functional imaging to predict long-term skill retention. This will be tested by comparing brain activity in different subjects at the end of training and for sequences trained at different intensities. Specific Aim 3. Determine the time course and substrates associated with sequence generalization. It is hypothesized that generalization of a skill to the other arm is supported is acquired early and on short time scales. In contrast, effector specificity emerges with long-term practice and is associated with changes in neural systems occurring on a long time scale. This has implications for defining when intermanual transfer is effective. RELEVANCE (See instructions): The proposed work is central to the problem of understanding the mechansims where practice leads to to reorganization of the human motor system in the face of aging, neurodeneration, stroke or brain injury. Understanding these mechansims has an impact on the design of therapies directed at preserving function, developing compensator movements and ultimately, developing novel motor capacity.

Core A: Administrative The administrative core is organized to support the overall program project via three main components: Project Direction, Program Integration and the organization of aSatellite Conference on Motor Learning PROGRAM DIRECTION The program director, with the assistance of a project coordinator, will be responsible for the following duties: 1. Insure that the evolving plans of the four projects and modeling core are well integrated. 2. Arrange PPG meetings and facilitate weekly communication among the motor control groups. 3. Communicate with an External Advisory Board. 4. Disseminate information about PPG activities to the public sector. 5. Coordinate recruitment and career development of young investigators in the PPG. 6. Oversee shared efforts by post-doctoral fellows between laboratories. 7. Organize three satellite conferences on motor learning. PROGRAM INTEGRATION The single most important source of integration in this project is a common behavioral task used across projects. Maintenance of integration is achieved by: 1. Reorganization of team members. 2. Physical Proximity. 3. Group Videoconferences. 4. Group Meetings. 5. Shared Fellows. , 6. Communications with an External Advisory Board. 7. Dissemination of information to the public sector. 8. Recruitment and career development. SATELLITE CONFERENCE ON MOTOR LEARNING We will integrate our work from this program project grant with the larger motor science community by organizing three Conferences in Motor Learning. The goal is to bring together a broad range of expertise in motor skill learning, from computational modeling to empiric research. RELEVANCE (See instructions): The proposed work is central to the problem of understanding the mechansims where pracfice leads to to reorganizafion of the human motor system in the face of aging, neurodeneration, stroke or brain injury. Understanding these mechansims has an impact on the design of therapies directed at preserving function, developing compensator movements and ulfimately, developing novel motor capacity.

DESCRIPTION (provided by applicant): This grant will be done primarily in Argentina at the Department of Physiology, School of Medicine, University of Buenos Aires in collaboration with Valeria Della-Maggiore, as an extension of NIH Grant No. P01 NS044393. Our daily routine involves acting on objects in our vicinity to achieve different goals. Sudden, unpredictable modifications in the environment require immediate adjustment of these well-practiced movements by updating the initial motor plan online, while persistent perturbations can be adapted to through learning over a longer time scale. Both types of adjustments may partly rely on the nervous system's ability to predict the future state of the motor system. An intriguing possibility is that the same mechanism necessary to adjust skilled behavior may be used at a higher cognitive level to predict the outcome of actions performed by others. This phenomenon, known as action observation, may be the basis to understanding other people's actions and learning by imitation. The present research project is aimed at identifying the neural substrates of motor prediction in humans and evaluating its contribution to the production and perception of action. These issues will be approached experimentally using transcranial magnetic stimulation and functional magnetic resonance imaging to characterize the role and timing of dorsal premotor and posterior parietal cortices in the prediction of action during: 1) the online adjustment of movement;2) visuomotor learning;3) observation of actions performed by others. PUBLIC HEALTH RELEVANCE: A better understanding of the role of posterior parietal and dorsal premotor cortices during production and perception of action will be informative at many levels. It may provide clues to the mechanism by which children learn social cues from observing and predicting the actions of others and how or why such learning goes awry in disorders such as autism or schizophrenia. It is also relevant for understanding the deficits of patients with neurological damage affecting the processing of visuomotor transformations such as optic ataxia (deficit in accurately reaching to objects) and ideomotor apraxia (deficit in imitating gestures under command) and, thus, may guide the development of the appropriate therapy to treat these patients. Finally, due to their role in movement preparation and movement intention, the PMd and PPC appear as suitable brain regions for the control of human prosthetics. These devices are aimed at aiding paralyzed patients interact with their environment. Neurophysiological activity of the PPC or PMd, could be decoded into signals to activate stimulators imbedded in the muscles of a patient, initiate the movement of a prosthetic arm or operate external devices such as a computer (Andersen et al., 2004;Musallam et al., 2004,Bokil et. al., 2006). Knowing the time course of PPC and PMd processing may help guide the interpretation of neuronal signals during the redirection of movement intention, and train adaptive algorithms to predict the goal and consequences of other people's actions solely based on neuronal activity elicited during action rehearsal.

DESCRIPTION (provided by applicant): This proposal is a collaborative effort by a team of five motor systems groups at five institutions seeking to probe the mechanisms that underlie the brain's capacity for learning a new motor skill. The common thread for all groups is to focus on changes that occur within the primary motor cortex as a new skill is acquired. Changes in motor cortex will be characterized in relationship to critical input areas including premotor and parietal cortex and the role of subcortical circuits in learning will also be modeled. Both immediate and long-lasting changes of motor cortex representation will be investigated using a synthesis of molecular, cellular, systems and computational level of analysis. Project 1: Dr. Peter Strick (at the University of Pittsburgh) will combine flavoprotein optical imaging and single unit recording in monkey to characterize changes of activity in premotor and motor cortex as animals learn sequential behavior. Flavoprotein imaging allows for long-term cortical mapping over at least two years time, making it possible to look at dynamic alterations of cortical neuronal activity throughout the training period. Project 2: Dr. Scott Grafton (at University of California, Santa Barbara) will use functional MRI and transcranial magnetic stimulation in humans to study the neural substrates for off-line consolidation of three types of newly acquired motor skills: sequencing, visuomotor and dynamic adaptation. The tasks are similar to those in the other projects allowing for translation between monkey and human studies. Project 3: Dr. Emilio Bizzi (at MIT) will collaborate with experts in nanotechnology and conducting polymers at MIT to develop a new type of electrode based on fine wires of conducting polymers. With this he will perform chronic recordings of primary motor neurons in primates learning to move in novel dynamics. Project 4: Dr. James Houk (at Northwestern University) and Dr. Andrew Barto (at the University of Massachusetts at Amherst) will develop computational models of learning that are integral to the other projects of this PPG. These models will be used to explore critical behavioral and representational issues. Core A: Support for program administration and videoconferencing to achieve PPG integration. In addition, the core will support 3 satellite conferences on motor learning and mechanisms of cortical reorganization that are relevant for translational research. These interrelated projects, focusing on single anatomical substrate and common set of learning behaviors, should provide an integration of methodologies across multiple levels of analysis that are far beyond those achievable if each project were pursued separately. The collaborative effort can be expected to significantly advance our knowledge about mechanisms that support motor cortex plasticity.