Simon F. Giszter - US grants

The discovery of structural and functional elements of motor behavior is one of the key issues in motor control. It is very likely that he kinds of units available in the spinal cord may constrain athe types and organization of descending controls, intermediate representations and sensorimotor transformations. Recently a new type of unit has been suggested, based on combined physiological and biomechanical data. This unit has been called a 'force- field primitive'. A force-field is a function that maps the forces generated ina the limb to the limb's configuration. The relationship between force-field primitives and other spinal mechanisms is not well understood. Primitives could represent general purpose promotor elements: the site of convergence of signals from descending, pattern generator and coordinating systems.. Alternatively, they could be elements associated exclusively with spina pattern generators. The types of force-field primitives corresponded closely to force-fields that could be measured during wiping, burning and flexion behaviors elicited in spinal frogs. It is thus clearly important to understand how force-field primitives are related to these reflex behaviors. To begin to relate force-field primitive descriptions to spinal pattern generators we propose the following; (1) We will record the kinematics, and electromyographic activity (EMG) of reflex behaviors and using accurate dynamic models we will relate these to the static force-field measurements and their EMGs recorded from tahe same behaviors. The reflex behaviors examined will be wiping, flexion withdrawal and aversive turning movements. (2) To examine interlimb coordination. (3) To address control and modulation of reflexes by descending systems, we will examine athe effects of bulbospinal control of afferents on the force-field structures, the EMGs and the kinematics in the wiping, flexion and turning behaviors. (4) Identified pathways associated with the turn and strike will be stimulated in reduced preparations to examine how these interact with the spinal reflex behaviors. The notion that a small number of 'primitives' may form a large part of the support of spinal behaviors, and, perhaps, descending control, is interesting for the following two reasons; First, it offers hope of a simple experimental understanding of spinal cored function. Second, it suggests that functional recovery from spinal injury may be possible in the future with only limited, but targeted, neural growth and connectivity. The experiments proposed will provide two critical sets of data to test this scheme of the organization of motor behavior; (1) a detailed understanding of the specific roles and organization of the force-field primitives in the known context of spinal behaviors, and (2) a description of how the force-field primitives in the known context of spinal behaviors, and (2) a description of how the force-field primitives used in spinal behaviors interact with de descending control.

SUBPROJECT ABSTRACT NOT AVAILABLE

Recent data suggests the spinal cord of tetrapod vertebrates may be organized into circuits that control forcefield primitives. Recent data from my laboratory shows the temporal dynamics of primitives in spinalized frogs appear to have constant duration in many contexts, including rapid on-line trajectory corrections. We hypothesize this time scale is a conserved characteristic of the spinal circuits. If correct, this time scale defined by a primitive would impact on spinal trajectory formation, motor learning and the partitioning of control between spinal and supraspinal systems. To test the hypothesis in detail we have three specific aims: (1) We will test the hypothesis that all adjustments of trajectory formation in spinal wiping reflex can be understood as regulation of phase and amplitude of primitives but not the duration or temporal dynamics. (2) We will test the hypothesis that individual and ensemble sensory feedback circuits acting on force-field primitives are organized to preserve the temporal dynamics of primitives. (3) We will test how descending controls from medulla and tegmentum recruit and/or reorganize the timing properties of spinal primitives to build adaptable motor behaviors. Our data will bear on trajectory formation at the spinal level, interaction of descending and spinal motor control circuits, neural reorganization, design of neural repair and rehabilitation strategies following injury, design of neuroprostheses, and biomorphic robotics.

DESCRIPTION (provided by applicant): The goal of the proposal is to begin to develop and test a tool that can provide focal control of deep neural tissues including excitation, inhibition and modulation state in a fashion compatible with the range of physiological recording techniques. The tool we are designing and testing is a fiber optic light guide system, which is used for focal uncaging of caged neurotransmitters. This system will be coupled with neural recording and neurotransmitter measurement techniques. Such a combined system will allow rapid excitation, inhibition and/or modulation of target tissues, via post-synaptic mechanisms, while introducing no electrical noise for the recording components. There will also be the potential for feedback regulation of activity and of transmitter levels. To test the tool as it is iteratively prototyped we will use several animal models that are well established and understood in our laboratories. Our project has three Specific Aims: 1. Specific Aim 1 Construction and optimization of an implantable fiber optic uncaging system and recording device for use as an experimental tool, in deep brain stimulation and in other neuroprostheses. Specific Aim 2 Development of caged glycine, serotonin and dopamine for experimental and future clinical applications with the fiberoptic system. Specific Aim 3 Validation of developed devices and caged materials in mammalian CNS using physiological and behavioral assays, first in an acute preparation (cat spinal cord), and then in a chronic preparation (rat parabrachial nucleus).

The organization of movement is a complex and difficult problem, in part because of a "degrees of freedom problem" in motor control. The richness of an animal's movement possibilities makes its choice of movement controls complex. However, unlike current robots, animals cope efficiently with their degrees of freedom. A newborn wildebeest calf walks with the herd within a few hours of birth. A frog or a turtle, using just its spinal cord, can control complex goal-directed trajectories. The spinal cord can also rapidly correct such movements if they are perturbed. It has been argued that these remarkable capacities are modular, constructed with small sets of primitives or motor building blocks. How such primitives arise and are used is the focus of this project.

The concepts of modularity and motor primitives have provided useful descriptions of the organization of spinal motor systems. Modular organization has been shown to support spinal behaviors, and may help to "bootstrap" motor learning. Nonetheless, modularity is controversial at many levels. Spinal primitives might need to be supplanted or augmented in order to perform complex, voluntary behaviors. This project attacks this problem in frog prey strike behaviors, a voluntary and adapted behavior in a system that is fundamentally important to the animal, and has also been well characterized in previous studies of modularity. The neuromechanics of prey strike is examined from a multi-disciplinary perspective. The importance of modular organization in neuroscience and behavior extends well beyond biological motor control, with ramifications in evolutionary and cognitive psychology. Biological strategies and solutions are also highly relevant to future technologies and robotics.

A computer model of prey strike will be developed using a novel approach based on Cosserat strand-elements. The model will be developed by a team of four investigators: Simon Giszter (neurophysiology) and Jonathan Nissanov (anatomy, imaging) at Drexel University, Dinesh Pai (computer science, biomechanical modeling) at the University of British Columbia, and Kiisa Nishikawa (neuromechanics) at Northern Arizona University. Cryoplane microscopy will be used to reconstruct bullfrog sensorimotor anatomy in detail. These structures will be modeled using a strand-based approach to incorporate this detail. Experimental and model analyses of prey strike using these data will inform one another to establish the benefits and limits of fixed or adaptive modular mechanisms, and the biological implementation used in frogs.

DESCRIPTION (provided by applicant): The ultimate goal of this proposal is to utilize a neurobotics paradigm to assist trunk and limb controls by applying force at the pelvis during locomotion in normal and injured rats. We will also use more standard physiology. Together these two approaches provide tools to examine normal and post- injury corticospinal organization, and the control of trunk and hind-limbs. We seek to understand and improve trunk control after SCI, and to examine its development, modularity and its plasticity in intact and spinal cord injured (SCI) rats. We have three Specific Aims: Aim 1 : We will identify physiological and biomechanical differences in the use of trunk and leg muscles and the associated motor cortical activity between (1) adult rats with neonatal spinal transections with weight support and (2) adult rats with neonatal spinal transections without weight support and (3) normal rats. Aim 2: We will examine how normal rats alter neural and motor activity in response to neurorobotic interventions which generate lumbar actions. We will test (1) robot elastic force-field actions that are extrinsic or intrinsic but not contingent on neural activity, and (2) force-field actions directly contingent on features of neural activity (neurorobotic control). Aim 3: We will compare how neonatal injured SCI rats with good or partial weight support alter neural and motor activity in response to neurorobotic interventions which generate lumbar actions. We will test (1) robot elastic force-field actions that are extrinsic or intrinsic but not contingent on neural activity, and (2) force-field actions directly contingent on features of neural activity (neurorobotic control). The research here can contribute to the clinical mission of providing therapies for SCI and other trauma in a range of ways. First, by furthering our understanding of cortical and spinal integration, in normal and neonatal SCI rats with and without weight support (Aim 1) we will provide information on how best to assess and optimize recovery in rat models of injury and perhaps beyond. Second, by developing an animal model of pelvis interaction rehabilitation (Aim 2 and 3), we will provide basic data on what advantages or additional benefits this framework may have in a model where more invasive recording is feasible. This may be of fairly direct relevance to pelvic assistive devices under development for the clinic. Third, if the intact neonatal injured rat or the adult injured rats can learn to use a neurorobotic control of pelvis, we will have demonstrated a neural bypass strategy for trunk and legs which may be extended to intraspinal stimulation, FES or other higher degree of freedom control methods for the musculoskeletal and spinal systems in human SCI. PUBLIC HEALTH RELEVANCE Brain Machine Interfaces and novel prosthetics will in future require controls of the trunk as well as the limbs for injuries of spinal cord causing paraplegia or tetraplegia. Currently there is no animal model of rehabilitation and neurorobotics of the trunk. Trunk is essential for coordinated locomotion and action. We develop an animal model of trunk robotic rehabilitation and brain machine interface control.

DESCRIPTION (provided by applicant): Our goal is to obtain stable multielectrode recordings from spinal cord below a spinal transection in rats and follow the neural changes that occur after spinal cord injury and as a result of rehabilitation processes. To do this we will use multielectrode neural recordings and microstimulation. The data will be unique and novel with major potential impacts on our understanding of spinal cord injury, and possible technology transfer to clinical applications. We will use and further develop novel electrode designs initiated in our laboratory to achieve our objectives. Specific Aim 1 : We will further develop a chronic intraspinal multielectrode probe with recording sites along its length, using novel braided composite electrodes. We will add recording sites distributed along the inserted probe length in order to sample neural activity across laminae. To do this we will add laser ablation techniques to our existing construction. We also plan to reduce component wire diameter by a factor of 2-3 (from current 13 micron wire plus insulation components), increasing wire and probe compliance by a factor of 16 to 81 times beyond current values. Specific Aim 2: We will use our electrodes to record activity patterns in spinal cord throughout the process of robot assisted rehabilitation in T9/10 spinalized (ST) rats (both neonatal and adult ST rat injuries). We hypothesize that robot rehabilitation after SCI causes within session dynamic alterations in neural activity, which persist day to day, and correlate with improving functional recovery and weight support. These experiments will provide completely novel data and insights into the rehabilitation process at spinal levels and new measures for assessing rehabilitation and neuroplasticity. Specific Aim 3: We will perform intraspinal microstimulation tests in T9/10 spinalized rats (both neonatal and adult ST rat injuries), either throughout, or after, robot assisted rehabilitation. Our hypothesis is that differences in microstimulation between the groups early and late in training will correlate to functional recovery and robot training effects. These new stimulation data are also expected to provide a set of novel outcome measures and circuit test tools for assessing the interaction of focal spinal stimulation, rehabilitation and neuroplasticity. This project has the potential to have enormous and possibly transformative impacts on our understanding of spinal cord function, injury, and rehabilitation processes using standard animal models. Further, the technologies being tuned in Aim 1 may have broad applicability in neural recording and stimulation in many brain areas, and thus enable new generations of neural recording tools and neuroprosthetics. PUBLIC HEALTH RELEVANCE: This project makes improvements in new electrodes useful for basic scientific and clinical applications, and uses these for recordings from spinal cord during rehabilitation that have never been made before. The information gained may help design better rehabilitation and therapies for spinal cord injury and help understand disease progression. The electrodes developed may have numerous basic and clinical applications beyond this project.

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): 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.

Abstract Our project represents a new collaboration of two laboratories with differing but complementary skills, with the goal of understanding plasticity of specific spinal circuits and the effects of epidural stimulation on these. The project is built on new observations and paradigms developed by both our laboratories. Although we understand increasingly more about both (a) spinal circuits at the level of molecular genetics identified developmental interneuron classes and (b) spinal plasticity in the context of spinal cord injury (SCI), these two types of information are only rarely integrated experimentally to fully leverage the power of their combination. We will use a novel paradigm which explores the combination of biological/viral, bionic and rehabilitation therapies in complete SCI in both the rat and the mouse in order to obtain the power of both approaches in analyzing spinal plasticity and pathology after SCI. In the rat model in this paradigm we already have new data showing that the combination of rehabilitation and virally derived BDNF treatment after complete SCI leads to significant gains in function as a result of this combination treatment. However, in 40% of the treated rats, after the initial high gains achieved, it was observed that a hyperreflexia developed, causing a large collapse in function. In contrast, it was observed that in rats which also receive epidural stimulation (ES) of lumbosacral spinal cord during treatment (in addition to the viral driven BDNF and rehabilitative treatments) no rats showed any such hyperreflexia. This project seeks to use this paradigm to understand plasticity of spinal circuits that support function, create hyperreflexia and collapse, and that prevent such collapse with ES. We do not yet know if there exist specific time windows for the ES efficacy in preventing collapse. The ES in some way steers the course of plasticity away from pathology in the model when applied in a timely way. Our overall Aims are to characterize the best timing of ES and to understand in detail many of the changes that result. We seek to determine if specific genetically identified circuits show plasticity, and are targets of ES, and how these circuits contribute and alter in order to support walking functions. We also seek to understand what goes awry to cause collapse of function in some animals without ES treatment. Our planned work is important and impactful because it will shed new light on circuit changes and function after SCI. It will test how identified interneuron populations and functional circuits in the spinal cord are altered. It will deepen and broaden our understanding of the actions of epidural stimulation in promoting and shaping spinal plasticity supporting walking, and identify the therapeutic targets, windows of action, and interactions of epidural stimulation with other therapies. ES is becoming a promising and broadly applicable therapy for SCI conditions, but our understanding of fundamental mechanisms of action and interaction with other therapies remains limited. This project begins to address this gap using precise physiological and genetic methods.