Terence Sanger - US grants

DESCRIPTION (provided by applicant): The purpose of this research career development proposal is to extend Dr. Sanger's training beyond his current theoretical background into clinicallyoriented research on children with movement disorders. Dr. Sanger's past research has focused on computational models of movement and motor learning. This research plan proposes to apply this background in a clinical research setting by performing a quantitative investigation of increased upperextremity movement in children with hyperkinetic cerebral palsy (CP). It is not known whether abnormal movements result from random noise, decreased ability to modulate the amplitude of movements, or inappropriate planning of motor sequences. This proposal suggests two related hypotheses: (1) Hyperkinetic CP is a result of a restriction in the variability of motor commands such that desired smooth movements are not available, and (2) Progression of abnormal movements over time is reflected by an increasing restriction in the variability of motor commands and worsening energetic efficiency. To test these hypotheses, position sensors and surface electomyographic (EMG) recordings of reaching movements will be made at 6 month intervals in children of different ages with hyperkinetic CP. Kinematic and EMG data will be analyzed to determine energy expenditure, variability of the set of kinematic patterns, and total information content of movement. If the hypotheses are correct, then we expect progression of symptoms in dyskinetic CP to be reflected in decreasing dimensionality, information content, and energy efficiency of the patterns of movements. The results of this study may allow early identification of children at risk for hyperkinetic CP as well as prediction of the progression and ultimate severity of symptoms. Dr. Andriacchi, Dr. Mobley, and Dr. Hlatky will serve as mentors for Dr. Sanger's work on this project. Dr. Andriacchi will provide instruction on the measurement of kinematics and energetics in children, Dr. Mobley will provide instruction on the clinical evaluation of children with movement disorders, and Dr. Hlatky will guide the design and implementation of clinical trials and outcome measure validation. The proposal includes coursework in cellular and molecular neurobiology and in the design of clinical research studies.

The objective of this proposal is to establish a series of meetings of a multi-disciplinary Task Force for the ongoing study of childhood motor disorders. Relevant disorders will include cerebral palsy (CP) and other static or progressive central nervous system injuries affecting movement. The purpose of the task force is the selection and initial development of research proposals through a consensus of clinicians and researchers across multiple disciplines. The task force meet in invitational sessions in January and open sessions in July each year for four and one-half years. The specific aims of this proposal are: 1. Organization of a task force of approximately 40 clinicians and researchers from multiple fields involved in clinical and basic science research for children with motor disorders. 2. Initiation of ongoing meetings twice yearly, in July and January. The purpose of the July open meeting is to set research priorities for the design of pilot clinical trials, and the purpose of the January meeting is for the task force to evaluate the results of pilot clinical trials and initiate proposals for definitive multi-center clinical trials. 3. Publication of meeting results in the form of interim summary reports, formal summary statements, definitions, and practice recommendations. 4. Education of students, residents, and fellows who will be invited to meetings. The topics of the meetings will include discussion of long-term strategy, short-term research needs, consistent clinical terminology, standardized outcome sales, incorporation of basic science research, development of pilot clinical trials, prioritization of hypotheses and protocol development for large-scale clinical trials, and education. The ultimate objective is to improve the functional abilities and societal participation of children with motor disorders.

[unreadable] DESCRIPTION (provided by the applicant): Children with severe disorders of speech who use assistive communication devices become dependent upon their sensory-motor abilities to activate buttons or sensors on their devices. If such children also have deficits in the skilled use of their limbs, then their communication abilities are further limited. We propose to measure the components of upper extremity motor function that relate directly to information and communication rate. We hypothesize that motor disability is an important contributor to decreased communication rate, and communication rate can be improved if the number and spacing of buttons on a communication device are modified to reflect the child's information transfer abilities. [unreadable] To test this, we propose the following specific aims: 1. Measure the time required to contact different numbers of buttons of different sizes in 10 children age 6-18 years with severe disorders of verbal communication and impairments of arm movement. The data will be analyzed in terms of information rate according to Fitts' Law and Hicks' Law, and the optimal spacing and number of buttons will be calculated for each child. The contribution of movement time and reaction time to information rate will be compared to performance on the Melbourne test of upper extremity function. The information rate will also be compared to the performance of 20 control subjects of similar ages. 2. Design a touch-screen computer interface that is optimized for the measured movements of each child with impairment, and compare the child's performance on the interface to their current device using a sequence of words randomly selected according to the statistics of the child's actual vocabulary. Compare the communication rate on the two devices to the maximum motor information rate predicted from specific aim 1 to determine the contribution of the motor impairment to overall communication ability. [unreadable] If these experiments are successful, they will generate important pilot data for assessing the effect of separate elements of motor disorders on communication, and they will provide a new methodology for the design of communication interface devices for individual children with severe speech and motor impairments. [unreadable] [unreadable]

Children with dystonia do not improve their movement performance despite a lifetime of practice. Recent theoretical results suggest that this may be due to one of two types of failure of motor learning: Type 1: inability to recognize relevant errors, Type 2: inability to generate examples of correct behavior. We propose a set of experiments to demonstrate that failure of motor learning may contribute to poor motor control in children with dystonia. To test this hypothesis, 30 children with primary or secondary dystonia and 30 control children will use surface electromyographic activity of either 2 or 4 muscles to control the position of cursors on a computer screen. Type 1 failure can be induced artificially by obscuring visual information about muscle activity. Type 2 failure can be induced using a difficult task in which 4 muscles control 4 dimensions of movement through an unknown linear mixing transformation, and the children must discover exactly one specific pattern of activity. In specific aim 1, we will demonstrate that both control children and children with dystonia show increased co-activation of muscles when information about muscle activity is obscured, as predicted by type 1 failure of motor learning. In specific aim 2, we will demonstrate that both control children and children with dystonia are unable to learn a difficult task until a successful example is learned in a simplified version of the same task. A successful result of this study will show that failure of motor learning is necessary and sufficient to produce part of the motor deficits in childhood dystonia. It will also show strategies for improvement of dystonia. In particular, type 1 failure can be improved ifbio- feedback of an unobserved mode (in this case, co-contraction of biceps and triceps) is provided. Type 2 failure can be improved if the correct solution is presented to children in a simplified task, so that they can then remember and return to the correct solution at will. These experiments will demonstrate a potentially important contributor to motor symptoms in dystonia, and they will indicate specific new treatment opportunities.

[unreadable] DESCRIPTION (provided by applicant): We propose to organize a satellite meeting to the Neural Control of Movement Society annual meeting in 2006. The satellite will be on the topic of the Neural Control of Abnormal Movement, and it will address issues on the interface between the basic science and the clinical science of disorders of movement and motor control. The satellite meeting will occur over 3 days, and session topics will be: 1. injury and diseases of the spinal cord; 2. brainstem symptoms and deficits of oculomotor control, 3. cerebellar injury, 4. basal ganglia injury, 5. cortical injury, stroke, and seizures, 6. cortical plasticity and recovery from injury, 7. thalamic and somatosensory injury and deficits. Discussion will focus on the link between pathophysiology and abnormal behavior, with particular emphasis on the physiology, biomechanics, and psychophysics of abnormal movement. This satellite meeting will bring together basic scientists and clinical scientists to provide the first comprehensive meeting to address the fundamental mechanisms of motor systems and the way in which disease affects those mechanisms. We hope that it will identify areas in need of research, foster new collaborations between clinical and basic science researchers, and permit the development of new treatments for patients affected with disorders of the motor control system. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): We propose to organize a series of three yearly meetings devoted to definition and measurement of hyperkinetic movement disorders in childhood. The taskforce on childhood motor disorders has previously established consensus definitions and measurement technology recommendations for hypertonic disorders and negative signs. Hyperkinetic disorders represent the third major category of pediatric motor disorders. In the first of the three meetings, consensus definitions relevant to children will be established for the terms "chorea", "choreoathetosis", "hyperkinetic dystonia", and "tremor". In the second meeting, current scales and technology for diagnosis and quantification of these impairments will be discussed. In the third meeting, new scales and technology for diagnosis and quantification will be demonstrated. The result of this series of meetings will be a consensus statement on definitions, identification of gaps in current assessment tools, and specific recommendations for the development of new measurement tools. Definitions and measurement tools are essential for communication between clinicians, inclusion of children in clinical trials, and measurement of outcomes of treatment in the clinic and in clinical trials. This project will provide consensus definitions and work toward the development of measurement tools for children with hyperkinetic disorders. The result will be definitions and recommendations that will improve the effectiveness and success of clinical trials for children with disorders of movement.

DESCRIPTION (provided by applicant): Children who have serious speech or writing impediments struggle every day with the simplest of communication tasks most of us take for granted. Over 500,000 children in the US require assistive technology to communicate and 20-60% of these children may require special-purpose keyboards, screens, or software to communicate with computers and computer-controlled assistive devices. For children with dyskinetic cerebral palsy (CP and severe arm movement disorders, devices such as adapted keyboards, programmable touch-screens, and joystick interfaces may be their most important communication link to their families, friends, teachers, and caregivers. However, these devices are so difficult to use that communication is often extremely slow and laborious and often results in high levels of frustration for the children using them. Additionally, because every child with CP presents differently, no one device is optimized for a particular child's impairments. Therefore, our goal for this study is to address the critical need for improved assisted communication devices and to optimize the interface design for each individual child. Two of the most common computer-based interface devices are touch- screen and joystick controllers. We propose to use a set of recently-developed techniques based on information theory and Bayesian signal processing to optimize the design of touch- screen interfaces and joystick controllers for children with dyskinetic cerebral palsy that impairs hand movement. Optimization of the touch-screen device will be based upon measurement of the speed, accuracy, and error rate of individual children as they reach to targets of varying size, spacing, and number. Optimization of the joystick device will make use of the complete path of the joystick as the child approaches the target. We have developed a new algorithm that can efficiently use Bayesian nonlinear filtering to estimate the intended target of the joystick early in the movement. This estimation significantly improves performance, but it introduces a tradeoff between speed and accuracy when children have variable movements. Therefore we must measure speed, accuracy, and error rate as a function of target size and spacing for the joystick as well. Bradykinesia (slow movement) and Hyperkinesia (increased variable movement) are common impairments of children with dyskinetic cerebral palsy that will affect performance on both devices. We will quantify these impairments and determine their affect on communication device use and optimization. Finally, we will test whether implementation of improved interfaces can increase the rate of communication. This study will provide essential quantitative links between disorders of movement and disorders of assisted communication for children with the dyskinetic form of cerebral palsy. PUBLIC HEALTH RELEVANCE: Up to 60% of children with dyskinetic cerebral palsy depend on computer-based assistive communication devices to talk with parents or friends and to participate in school. There is currently no reliable method for determining the best touch-screen layout for individual children. We will perform detailed testing of individual children and combine the results with a model of information processing in order to find the best possible design of a touch-screen or joystick interface that will maximize the speed of communication in children with dyskinetic cerebral palsy.

When the brain is injured during development, there is an effect not only on immediate brain function but also on the future ability to learn and acquire skills. We propose to create and simulate multi-scale computational models of the effect of early structural injury on future motor function of the cortex and spinal cord. We will use programmable chips (FPGA's) and the new mathematical theory of Likelihood Calculus to build simulations of 300,000 neurons that run 500 times faster than real-time. The model will be fitted to electromyographic and kinematic data from children at two visits spaced one year apart, and predictions will be tested by comparison to a third visit one year later. High speed simulation of the effect of early injury has the potential to revolutionize the treatment of developmental neurological deficits because it can, in one week, simulate 10 years of future change. In doing so, it allows prediction of disease progression, prediction of the future effects of treatments, and detailed understanding of the interaction between brain injury and resulting disorders of movement, perception, and behavior. Because of these predictions, we can intervene much earlier with treatments customized to each patient's disease profile. With early intervention, it may be possible to attenuate or block the natural progression of their disease. With over 750,000 US children and adults affected by developmental brain disorders, early acquired brain injury, or childhood progressive brain disease, the applicability and potential impact of an early intervention and disease prediction technique are significant.

The operation of the brain is not 'clockwork', but rather probabilistic. The project will provide proof of concept data for a new theoretical and experimental framework that utilizes this feature, by using stochastic dynamic operators (SDOs). These new methods have potential to significantly improve predictions of dynamics from recordings of brain function, which in turn would have significant technological and medical impacts in areas including disease process diagnosis, disease control using stimulation, robot prostheses and brain machine interface designs, neural prostheses, and neurally-driven augmentation or replacement. The project brings together a collaboration between an applied mathematician/neurologist and a comparative neurophysiologist, and will provide interdisciplinary graduate and postdoctoral training at the cutting edge of neuroscience, stochastic methods and control.

Increasing sophistication of brain recording technology is not fully matched by an equally sophisticated mathematical approach that permits modeling and direct prediction of the relation between behavior and the activity of neural populations. For motor systems, the primary goal is control of dynamics in the environment. The methods under investigation avoid the usual neural separation into sensory and motor effects. They treat neural activity as representing probabilistic alterations of unfolding dynamics. More specifically, the SDO framework considers neural activity as causing a modification of the overall system dynamics, so that the resulting dynamics (including movement, compliance, and oscillatory behavior) achieve a desired result. This allows principled engineering solutions and use of 'big' neural activity to predict dynamics. The proof of concept proposal will test model prediction responses during trajectory formation and perturbation in reflex behavior, prediction of real-time effect of single spikes, and combined effect of multiple neurons/populations. On proof of concept project completion: (1) The SDO framework will be compared with classical techniques using novel data sets; (2) Basic feasibility of real-time robot control from spinal neural activity in a model system will be assessed. Together, these data will all add significantly to neural analysis, neurotechnology and understanding of the novel methods in relation to others.

? DESCRIPTION (provided by applicant): The immediate effects of brain injury in both children and adults are directly related to loss of function in injured regions. In children the effects of early brain injury are further magnified due to distortion of subsequent development, motor learning and skill acquisition. These complications provide a unique opportunity for treatment if changes due to plasticity and distorted learning can be reversed. We have previously shown that children with dystonia due to dyskinetic cerebral palsy (CP) have deficits of sensory processing. Our goal is to show that this deficit specifically interferes with motor learning. The opportunity for improved treatment arises from the potential for improved motor learning if we can increase sensory function or awareness through the use of augmented sensory feedback. We combine a newly-developed figure-8 drawing task from the laboratory of Alessandra Pedrocchi in Milan, with a new speed-accuracy learning paradigm from the laboratory of Pietro Mazzoni in New York to show that deficits of sensory and motor behavior interfere with motor learning. We also test a newly-developed self- feeding task where speed depends upon the ability to carry an object in a spoon. We will determine if model- based interventions can improve real-world function and motor skill many years after injury, using a wearable device that enhances sensory information about muscle activity. We propose the following experiments: 1. Perform a multi-center clinical trial to test the effect of one month of wearable sensory feedback on real-world skill learning in children with dyskinetic CP and primary dystonia. We hypothesize that such intervention will permit acquisition of skills in the child's natural environment that wee not previously achievable through unaided practice, but that these effects will be greatest in children with dyskinetic CP for whom sensory deficits are often present from birth. 2. Test the effect of enhanced sensory feedback during drawing movements and a self-feeding task in children with dyskinetic CP, primary dystonia, and controls. We compare 5 days of learning with augmented feedback to 5 days of learning without feedback. These experiments create a theoretical and experimental foundation for a new understanding of how early brain injury interacts with motor development and skill acquisition in childhood. They perform a multi- center clinical trial of a new noninvasive intervention with significant potential for improving function n this population. They provide a detailed quantification in the laboratory of daily changes due to learning, and the sensory-motor mechanisms responsible for these changes. This understanding will lead to new treatment approaches based on correcting deficits that prevent or distort motor learning. These experiments will provide a significant change in the paradigm for understanding childhood motor deficits, by shifting focus from the immediate effect of injury to the long-term effects on development, motor learning, and skill acquisition.

? DESCRIPTION (provided by applicant): Increasing sophistication of brain recording technology has not been matched by a similarly sophisticated mathematical approach that permits modeling and prediction of the relation between behavior and the activity of populations of cells deep within the nervous system. This is particularly true for motor systems, where the primary goal is control of the dynamics of the environment. Our goal is to create multiscale models of motor components of the spinal cord that can link at least four scales: (1) individual neuron firing, (2) local neural population activity, (3) topographic maps of activity across the spinal cord, and (4) behavior. We propose to use the spinalized frog as our testbed, because the biomechanics are well understood, proprioceptive feedback is simplified, the cord can be studied in isolation from cortical control, and repeatable complex movements can be generated in the absence of cortical control. We will use and further develop a new mathematical framework based upon superposition of stochastic dynamic operators. It is appropriate to consider neural activity as causing a modification of the system dynamics, so that the resulting dynamics (including movement, compliance, and oscillatory behavior) achieve a desired result. The new framework allows us to model the response to dynamic environments, compliant control, reflex behavior, the effect of single spikes, and the combined effect of multiple neurons in a population. We can examine oscillatory activity (such as found in the central pattern generator (CPG) for locomotion) and the role of proprioceptive feedback. Because this theory operates at the level of single spikes and all neural representations are local and can use local learning rules, it provides a much closer link to the actual biological computations and could provide insight into the mechanisms used by the spinal cord to generate complex and varied movement. To test our understanding of the behavior of populations of neurons in the intermediate layers of spinal cord, we will (1) read out the dynamics of ongoing movement including perturbation responses and compliance, (2) modify the dynamics of ongoing movement, (3) create topographic maps showing the distribution of control functions across the cord. These experiments will allow us to understand control by neural populations of the dynamics of movement in a detailed way that links the neural scale to the population scale to the motor behavioral scale. The mathematical framework provides a new model for understanding the function of populations of neurons and predicting their effect on behavior. It also provides a quantitative model that allows the prediction of the effect of modification of firig or injury on behavior. Finally, it will provide the basis for new treatments for spinal cord injuryby giving an understanding of functional electrical stimulation that can be used not just to generate forces in target muscles, but can be used to generate smooth compliant control of dynamics in the way naturally used by the body.

This grant will beneficially impact human health and quality of life by enabling new functionality and improving the state of the art in assistive upper-limb wearable robots to amplify the functional independence of people with movement disorders. Upper-limb wearable robots use body-mounted sensors and actuators to monitor the human user and predict intention to dynamically adapt and provide physical assistance. These devices are envisioned for long-term daily assistance, and could therefore become a primary treatment for a variety of mobility impairments, including cerebral palsy, the most common cause of serious physical disability in childhood. However, the advancement of wearable robots has been limited by critical knowledge gaps in the areas of actuator and control technologies, and such devices are not widely available. This award supports research to develop novel bio-inspired soft robotic actuators and human-robot control algorithms to enable comfortable, low-cost, high-power wearable robots that seamlessly interface with human users. The technologies developed will be adaptable to general use, including providing physical assistance to the elderly, and for deployment in manufacturing, nursing, and other industrial sectors. Through collaborations among academics and clinicians, this project will form linkages between science and engineering and technology development to enhance human health. The project integrates K-12 outreach events at the University of California, Riverside, a Hispanic Serving Institution, to broaden the participation of under-represented groups.<br/> <br/>Most tasks in daily life involve physical interaction with the environment, facilitated by direct modulation of joint impedances. Upper-limb wearable robots arranged parallel to the joints therefore require impedance modulation capabilities. However, constraints on the morphology prohibit the use of sophisticated controllers for physical interaction, including impedance control with high bandwidth motors. This research will harness biological principles to design novel wearable robots with direct impedance modulation capabilities, including leveraging muscle topology, sensorimotor coupling, and exploiting the passive properties of actuators for stability. The research team will develop novel soft actuators with impedance modulation capabilities, proprioceptive reflex loops for actively modulating impedance, and human-in-the-loop controllers to regulate robot impedance through a non-invasive neural interface. A series of human experiments will evaluate the efficacy of the prototype devices. This project will contribute methods and theories in the area of assistive wearable robots with a focus on pediatric movement impairments, resulting in insight into muscle coordination, skill acquisitions, and object manipulation in individuals with motor impairments and neurotypical participants, with and without robotic assistance.<br/><br/>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.