Jonathan Wolpaw - US grants

Activity-dependent spinal cord plasticity affects motor function in health and disease. It contributes to skill acquisition, underlies the abnormal function associated with spinal cord injury, and should be a key factor in the design of effective new therapies. Yet this plasticity and the processes that create it are not understood. Progress requires a simple laboratory model in which it is possible to identify the sites and explore the mechanisms of activity-dependent spinal cord plasticity and to describe its translation into behavior. The spinal stretch reflex (SSR), or tendon jerk, which is mediated by a wholly spinal and largely monosynaptic pathway, is a model that satisfies these requirements. Because this spinal pathway is influenced by descending activity from the brain, monkeys, humans, and rats can gradually increase or decrease the SSR or its electrical analog, the H-reflex, in response to an operant conditioning paradigm. The learning changes the spinal cord, since evidence of it remains even after all descending activity is removed. This laboratory is defining the complex activity-dependent spinal cord plasticity underlying this simple change in motor function, the mechanisms that create the plasticity, and the manner in which it translates into behavior. The central hypotheses, supported by previous results and preliminary data, are: (1) that the complex spinal cord plasticity produced by H-reflex conditioning affects other spinal cord reflexes including reciprocal inhibition and presynaptic inhibition of agonist and antagonist muscles; (2) that the corticospinal tract, contralateral (and probably ipsilateral) sensorimotor cortex, and cerebellar-cortical connections are essential for acquisition and maintenance of this spinal cord plasticity; and (3) that this spinal cord plasticity affects spinal cord function during locomotion. These hypotheses will be tested by studying the effects of H-reflex conditioning on other spinal cord reflexes, by studying the effects of specific supraspinal lesions on H-reflex conditioning, and by studying the effects of H-reflex conditioning on responses to calibrated afferent inputs during locomotion. The results should lead to new understanding of the complex plasticity underlying the acquisition of motor skills and the changes in spinal cord function associated with trauma and disease, and should contribute to the development and assessment of new methods for improving function after spinal cord injury.

Scalp-recorded evoked potentials permit sensitive, objective, and quantitative non-invasive examination of function in defined regions of the CNS. In recent years, they have become important clinical and research tools. At present, evoked potential evaluation of the auditory system is most successful on the brainstem and peripheral levels. Incomplete definition of the scalp-recorded activity, and uncertainties concerning proper electrode placements and referencing, have impeded auditory evoked potential (AEP) evaluation of auditory cortex. Recent studies provide basic data necessary for such development. They indicate that AEPs recorded over temporal scalp contain components produced in underlying auditory cortex and show how these components are best recorded and separated from concurrent activity originating elsewhere. These components display hemispheric differences consistent with the established anatomic and physiologic features of the auditory system and are sensitive monitors of acute and chronic CNS effects of several drugs and of subtle abnormalities in auditory pathways. They should be able to provide powerful non-invasive means for evaluating auditory cortex function. Achievement of this capability requires data concerning the dependence of these components on auditory cortex and on function elsewhere in the cortex. In order to fulfill these requirements, we will record from patients with focal cortical lesions involving auditory cortex or other cortical areas and from patients with focal cortical lesions involving auditory cortex or other cortical areas and from controls. We will use scalp, primarily temporal scalp, electrode placements, all referred to a balanced noncephalic reference electrode. Averaging and analysis will be performed off-line from digitized raw data. We will also record brainstem suditory evoked potentials (BAEPs) and perform audiometric studies. The control data should clearly define normal latencies and amplitudes of auditory cortex AEP components. The data from patients with focal cortical lesions should further establish the origins of these components, delineate their dependence on auditory cortex, and begin to establish their value in studying auditory cortex.

Learning and development are central problems of current neuroscience research. The rapid progress of recent years has made three important themes clear. First, learning and development are closely related. They depend to a considerable extent on similar or identical molecular and synaptic processes. Second, both are in large part driven by certain types of neuronal activity occuring at specific sites, and at crucial times. Third, it is now possible for the first time to discuss in a connected and logical fashion the full sequence of events responsible for learning and development. Furthermore, such treatment is essential to progress beyond the fragmentary knowledge that has prevailed up to the present. These three themes are the impetus and the framework for this conference, which is the third on this topic sponsored by SUNY since 1980. The sequence of six half-day sessions will parallel the progression from neuronal activity to altered behavior. Thus, the first describes activity- driven triggers of plasticity, the second treats subsequent molecular events, the third and fourth discuss the resulting synaptic changes, and the fifth and sixth describe the expression of these changes in altered behavior. Throughout the meeting, the close relations between learning and development will be emphasized and analysed. This logical and comprehensive treatment, which has become possible only very recently, should distinguish this meeting. The conference will bring together leading scientists working on each aspect o the problem, from the neurotransmitter receptors triggering change to the patterns of activity causing altered behavior. Its six sessions, each focusing on a specific level of analysis, are: I. Excitatory Amino Acid Receptors as Triggers of Plasticity II. Molecular Mechanisms of Activity-driven Plasticity III. Silent Synapses IV. Activity-driven Anatomical Changes V. Expression of Plasticity in the Behavior of Hippocampal Circuitry VI. Expression of Plasticity in the Behavior of Intact Animals The meeting is designed to have maximum educational impact. Participants, besides speakers, will consist primarily of postdoctoral fellows and graduate students. A poster session is included. Full proceedings will be published.

New prosthetic methods are giving people with motor impairments alternative communication and control channels. A logical culmination of these developments is a system that allows the brain to bypass completely its normal output pathways. Recent studies from this laboratory have shown that humans, including those with motor disabilities, can learn to change rapidly and accurately the amplitude of the 8-12 Hz mu rhythm in the electroencephalogram (EEG) recorded over sensorimotor cortex. Furthermore, they can use this control to move a cursor on a computer screen. Good single-channel control has been obtained, and initial data indicate that multichannel control is also possible. Thus, the mu rhythm, which recent work shows is detectable in nearly all adults, may support a multichannel brain-to-computer interface, and thereby provide a powerful new communication and control option for severely disabled individuals. This project's goal is a reliable multichannel brain-computer interface. The proposed approach is based on three well-supported hypotheses: that the scalp-recorded 8-12 Hz mu rhythm comprises a number of relatively independent components, that topographic analysis and frequency analysis techniques can distinguish between these components, and that humans can learn to control specific components and use them to operate a multichannel brain-computer interface. The first objective is to define by topography and frequency the separate 8-12 Hz components that are present when individuals are using the current interface. The second objective is to determine which components individuals are best able to control. The third objective is to incorporate these trainable components into a multichannel brain-computer interface that is rapid and reliable. These objectives will be achieved by combining online studies in which subjects learn to use the interface while extensive data are stored, and offline data analyses in which methods for improving the interface are defined. This project should produce an EEG-based brain-computer interface of significant value to individuals with disabilities. It should also lead to further work exploring the practical capabilities and theoretical implications of this new form of communication.

DESCRIPTION (Adapted from the Applicant's Abstract): This application requests support for continuing studies using novel EEG signal recording and analysis techniques as a control tool for communication or operation of prosthetic devices. Over the past five years, the applicants have demonstrated that, with appropriate subject training, coupled with a variety of methods for signal processing of the resulting EEG signals, that normal and impaired subjects can use brain electrical signals to control a computer interface to enhance communication. The applicants propose to continue this line of research, relying on their three initially enunciated hypotheses which were: Increasing online adaptability of the interface will improve its performance. Time-domain EEG components can augment control now provided by frequency-domain analyses. The interface can support cursor-based menu selection, and operate a neuroprosthesis. To test the first hypothesis, the online algorithm will be expanded to incorporate automatic selection of optimal EEG components, electrode locations and frequencies in these components, as well as optimal spatial filters and gain functions. The utility of these changes in improving the performance of the interface will be assessed. To test the second hypothesis, time-domain EEG components, such as slow cortical potentials and error-rated potentials will be added to the online algorithm and their capacity to supplement the control provided by frequency-domain components alone will be assessed. To test the third hypothesis, the interface will be applied to cursor- based letter or icon selection and to the operation of a neuroprosthesis designed and tested by the FES group at Case Western Reserve University. If successful, this work is likely to improve performance and versatility of EEG-based communication and interface systems.

[unreadable] DESCRIPTION (provided by applicant): Signals from the brain can provide a new communication channel - a brain-computer interface (BCI) - for those with severe neuromuscular disorders such as amyotrophic lateral sclerosis, brainstem stroke, and spinal cord injury. BCI technology can allow people who are completely paralyzed, or "locked in," to express wishes to caregivers, use word processing programs, access the Internet, or even operate neuroprostheses. [unreadable] [unreadable] Up to now, BCI research has demonstrated that a variety of different methods using different brain signals, signal analyses, and operating formats can convey a persons commands to a computer. Future progress that moves from this demonstration stage to practical applications of long-term value to those with motor disabilities requires a flexible general purpose BCI system that can incorporate, compare, and (if indicated) combine these different methods, and can support generation of standard protocols for the clinical application of this new communication and control technology. The development and clinical validation of a general purpose BCI system is the goal of this Bioengineering Research Partnership (BRP) application. [unreadable] [unreadable] Each of the investigators in this partnership has been in the forefront of research into one of the current BCI methods, and together they have extensive experience in the development of BCI systems. The aims of this proposal are: (1) to develop a flexible general purpose BCI system that can incorporate any of the relevant signals, analyses, and operating formats and can be configured for laboratory or clinical needs; (2) to use the system to compare, contrast, and combine relevant brain signals and signal processing options during BCI operation and thereby develop a standard protocol for applying BCI technology to the needs of individual users; (3) to apply the system and protocol to address specific communication needs of people with severe motor disabilities and show that BCI technology is both useful to and actually used by these individuals;(4) to apply the system and protocol to develop the use of neuronal activity recorded within cortex for communication and control, and to define the relationships between this intracortical activity and scalp-recorded signals that might be used to guide or supplement invasive methods. [unreadable] [unreadable] Achievement of these aims and dissemination of the resulting technology to other research groups should advance BCI research from its current stage of laboratory demonstrations to development and validation of a general purpose BCI communication and control technology that can incorporate all relevant brain signals and has clear practical value for those with motor disabilities.

DESCRIPTION (provided by applicant): Signals from the brain can provide non-muscular communication and control channels, or brain-computer interfaces (BCIs), to people with amyotrophic lateral sclerosis (ALS), brainstem stroke, cerebral palsy, or spinal cord injury. BCIs can allow people who are severely paralyzed, or even "locked in," to use brain signals to write, communicate with others, control their environments, access the Internet, or operate neuroprostheses. The realization of clinically useful BCI systems requires work in three areas: (1) acquisition of brain signals;(2) signal processing;and (3) clinical implementation. Because these areas involve very different disciplines, research groups usually focus on only one area. Thus, at the beginning of this BRP, despite the exciting achievements of researchers around the world, the field had progressed only to the point of laboratory demonstrations, in large part because achievements in one area were not integrated with those in others. In the past grant period, this BRP changed that landscape. First, it developed and disseminated to more than 160 research groups a general-purpose BCI software platform, called BCI2000, that facilitates all aspects of interdisciplinary BCI research and development, from laboratory to home. Furthermore, it used BCI2000 to develop the first BCI system designed for independent home use, and successfully tested this prototype in long-term home use by a small group of people severely disabled by ALS. Building on this work, the goal of this renewal proposal is to establish the first vertically-integrated BCI research and development program, and use it to produce BCI systems that are fully practical for independent use in clinical and home settings. The proposed program extends from signal acquisition, to signal processing, to application development and clinical implementation. By including and coordinating the activities and achievements in these different areas, this program will create and validate the first BCI systems suitable for widespread independent use by people with severe motor disabilities. Each BRP partner is in the forefront of one or more of the essential research areas, from hardware design to clinical testing. In limited ways, they already collaborate with one another. Working closely together and implementing new ideas, they will: (1) improve signal acquisition by developing more reliable, robust, and convenient chronic methods for recording electroencephalographic activity (EEG) and for exploring the BCI capabilities of electrocorticography (ECoG);(2) optimize adaptive feature extraction and translation algorithms for these signals;and (3) incorporate the results into BCI systems that are fully practical for home and clinical settings and establish the value of these systems for daily use by people with severe motor disabilities. By achieving these aims, disseminating the resulting technology, and providing other researchers access to its vertically-integrated framework, this BRP program should enable BCI research to produce BCIs that actually improve the lives of people with severe motor disabilities. PUBLIC HEALTH RELEVANCE Brain-computer interfaces (BCIs) can restore communication and control to people severely paralyzed or even "locked-in" by amyotrophic lateral sclerosis (ALS), brainstem stroke, cerebral palsy, or other devastating neuromuscular disorders. The goal of this Bioengineering Research Partnership proposal is to establish the first comprehensive BCI research and development program and use it to produce the first BCI systems suitable for widespread independent home use by people with severe motor disabilities.

DESCRIPTION (provided by applicant): Throughout life, the nervous system acquires and maintains many different motor skills. These skills depend on complex patterns of activity-dependent plasticity throughout the CNS, from the cortex to the spinal cord. The goal of this research program is to learn how this plasticity can be initiated and guided so as to improve motor function after injury or disease. This goal requires an experimental model based on a simple skill produced by defined and accessible neural circuitry. The spinal stretch reflex (SSR or tendon jerk) satisfies this requirement. Because its spinal pathway is influenced by the brain, monkeys, humans, rats, and mice can gradually increase or decrease the SSR or its electrical analog, the H-reflex, in response to an operant conditioning protocol. By the standard definition of "skill" as "an adaptive behavior acquired through practice," these reflex changes are simple motor skills. This laboratory is exploring the complex patterns of plasticity that underlie these skills, and is learning how reflex conditioning can be used to help restore motor function after injury or disease. Recent work shows that soleus H-reflex conditioning changes soleus behavior during locomotion, and suggests that appropriate conditioning can improve locomotion after a spinal cord injury. Based on this work, this project will test two hypotheses. The first hypothesis is that, in normal rats, the impact of soleus H-reflex conditioning on the soleus locomotor burst induces compensatory changes in the behavior of other muscles that preserve the symmetry of the step cycle, and that these changes in the locomotor behavior of other muscles are due to plasticity in their reflex pathways. The second hypothesis is that, in spinal-cord injured rats with abnormal locomotion, appropriate reflex conditioning can improve the step cycle and that the improvement persists after conditioning ends. These hypotheses will be tested by studying normal rats and rats with well-defined spinal cord injuries before, during, and after up- or down-conditioning of the soleus H-reflex or other spinal reflexes. The impact of conditioning on the locomotor EMG activity and reflexes of soleus and other leg muscles and on the parameters of the step-cycle will be assessed. To evaluate the impact of conditioning on brain and spinal cord interactions, concurrent effects on cortical motor and somatosensory evoked potentials will also be measured. The results should help to clarify the origin and functional impact of the complex plasticity underlying the acquisition and maintenance of motor skills. They should lead to novel methods that use reflex conditioning to improve function after spinal cord injury or other trauma or disease. Reflex conditioning protocols might be designed to target the pathways underlying the particular deficits of each individual, and could thereby complement other more general therapeutic methods such as locomotor training. PUBLIC HEALTH RELEVANCE: Motor skills are acquired and maintained throughout life by changes in the brain and the spinal cord. When skills are impaired by spinal cord injury or other disorders, their restoration requires methods for promoting and guiding these changes. Spinal reflex conditioning is a powerful and precise new therapeutic method that can changespecificnervoussystempathwayssoastohelprestorecomplexmotorskillssuchaslocomotion. The goal of this proposal is to clarify the mechanisms, impact, and long-term benefits of this new therapeutic method.

PROJECT SUMMARY (See instructions); Throughout life, the nervous system acquires and maintains many different motor skills. These skills rely on the spinal circuits that determine the interactions between the spinal cord, which excites the muscles, and the peripheral apparatus that produces movements and provides sensory feedback. It is now clear that the brain continually adjusts these circuits to support new skills, to maintain older skills, and to reduce the functional impact of aging, trauma, and disease. The goal of this project is to advance understanding of how the brain exerts the long-term control over these circuits that keeps the spinal cord and the periphery working together effectively, and to apply that understanding to develop new therapeutic methods. Animals and humans can gradually change the spinal stretch reflex (SSR) or its electrical analog, the Hreflex, in response to an operant conditioning protocol. These reflex changes are simple motor skills (i.e.,

NCAN Summary Engineers and scientists at the National Center for Adaptive Neurotechnologies (NCAN) are creating technologies that can guide CNS plasticity to enhance recovery for people with spinal cord injury, stroke, or other neuromuscular disorders. NCAN is producing new insights and novel therapies and disseminating them to engineers, scientists, and clinicians everywhere. This renewal application proposes to enhance NCAN technologies, apply them to critical problems, hasten their clinical translation, and increase their wider impact. Aim 1 will develop a wholly implanted wireless system for long-term 24/7 interactive studies in freely moving rats. It will use this new system for the first study of the molecular biology underlying spinal reflex operant conditioning, a promising new therapy that can enhance recovery after spinal cord injury or other disorders. This novel system will support many kinds of long-term real-time interactive interventions for NCAN and for other researchers. Aim 2 will develop a robust clinical system that supports a wide variety of protocols designed to target beneficial plasticity to key CNS sites and is suitable for widespread clinical use. It will optimize this new system in collaboration with clinical therapists and provide it for therapeutic studies focused on spinal cord injury, cerebral palsy, and stroke. Aim 3 will develop a clinically practical system that uses electrical stimulation via electrocorticographic/stereoencephalographic electrodes to map brain networks, define causality between areas, and ultimately, to target plasticity that restores function impaired by stroke or other disorders. It will thereby create a new imaging modality that can reveal point-to-point functional connections in the brain, relate them to behavior, and enable their therapeutic modulation. Aim 4 will provide training in and promote dissemination of NCAN neurotechnologies. It will enhance NCAN's 3-week short course curriculum, continue to offer many topic-specific workshops in appropriate venues, and provide materials and guidance that enable other institutions to create their own topic-specific courses. It will disseminate and support training materials and technologies through the NCAN website and other mechanisms. Aim 5 comprises the administration that supports all NCAN activities. This new grant period will include further development of major successes of the first grant period, initiation of new technologies and novel therapeutic protocols, strong synergistic interactions among the Aims, intensive collaborations with industry, and growing focus on clinical translation of NCAN technologies and protocols. In summary, NCAN will continue to create novel neurotechnologies, define their mechanisms, translate them into widespread use, and provide training and dissemination that enable and encourage other scientists, engineers, and clinicians to join in developing these technologies and applying them to major scientific and clinical problems. Thus, NCAN will continue to perform, encourage, and enable studies that elucidate CNS function and dysfunction, and that realize effective new therapies for devastating neurological disorders.

? DESCRIPTION (provided by applicant): Neurological disorders affect many millions of people in the United States and throughout the world. Recent advances enable the development of adaptive neurotechnologies, powerful new technologies that interact with the nervous system to promote functional recovery. These technologies are inherently multidisciplinary: they involve neuroscience, biomedical engineering, electrical and computer science, signal processing, and clinical, ethical, and commercial domains. Very few people can function effectively across all these ?elds. As a result, only a few of these technologies have been fully developed and translated into clinical practice, and still fewer are widely used. The goal of this Short Course s to address this problem by providing a new group of leaders with the broad multidisciplinary knowledge needed to plan, develop, and implement the next generation of adaptive neurotechnologies. The Wadsworth scientists and engineers of the newly established National Center for Adaptive Neurotechnologies propose to create and conduct, together with additional external faculty, a comprehensive four- week Short Course in the theory and practice of adaptive neurotechnologies. This Course has three aims. Aim 1 will provide lectures in the ?ve areas critical to understanding and implementing adaptive neurotechnologies: basic neuroscience (with emphasis on the most relevant regions and functions); engineering (how technologies monitor the nervous system and interact with it); current adaptive neurotechnologies (capabilities, limitations, future prospects); clinical translation (target populations, trial design); and commercial, regulatory, ethical, and other factors important to dissemination and use of these technologies. Aim 2 will complement the lectures of Aim 1 with hands-on Training Exercises in which participants use the principles conveyed in the lectures and the software platform BCI2000 to design and implement three representative adaptive neurotechnologies. Aim 3 will disseminate the curriculum to the larger research and development community by providing lecture syllabi and videos online and publishing video journal articles for the Training Exercises. It will also gather formal and informal feedback from participants and others to guide improvements in the Course. This uniquely focused multidisciplinary curriculum will enable the participants to become independent and active agents in developing, evaluating, and using adaptive neurotechnologies, and in bringing others into this rapidly growing ?eld. To enhance the long-term impact of the Course, wide publicity and a careful selection process will recruit 24 participants who are or are likely to become leaders of laboratory, clinical, or commercial research and development programs in this ?eld. In summary, this intensive Short Course will empower the next generation of scientists, engineers, and clinicians to transform promising laboratory developments and concepts into real-world systems, methods, and applications that address important scienti?c and clinical problems.

NCAN has three goals: to develop adaptive neurotechnologies; to translate them into important scienti?c and clinical applications; and to train others in their principles and use and promote their wide dissemination. The mission of the NCAN Administration is to manage NCAN personnel, budget, and activities so that these goals are achieved ef?ciently and effectively. In accord with this mission, the Administration has four aims. Aim 1 is to ensure that the three TR&Ds proceed smoothly. The administration: oversees project budgets and personnel time commitments; establishes procedures for ordering equipment and supplies, monitoring delivery, and obtaining replacements and repairs; manages interactions with the Institutional Animal Care and Use Committee and the Institutional Review Board; monitors completion of required personnel training; and oversees travel arrangements, publication processes, and intellectual property procedures. Aim 2 is to accelerate translation of NCAN technologies to research and clinical use by ensuring that the collaborative and service projects (CPs and SPs) proceed smoothly. For CPs, the administration: maintains facilities, procedures, and schedules for regular NCAN-CP interactions; oversees hardware/software and data transfers; ensures effective interactions with the other institutions; and supports formulation and submission of joint publications. For SPs, the administration: establishes procedures for providing NCAN services; ensures that questions from SP personnel are addressed quickly; and maintains records of SP achievements. The administration also oversees the establishment of new CPs and SPs. Aim 3 is to train others in using adaptive neurotechnologies and to promote their wide dissemination. The administration: oversees assembly of training curricula and dissemination materials; schedules, publicizes, and manages workshops and symposia; oversees arrangements for visiting scientists and students; recruits high- school and undergraduate student interns for research experiences at NCAN; monitors maintenance of the NCAN website to ensure that it is up-to-date and accessible; schedules and publicizes meetings and seminars; manages interactions with the scienti?c and general media; leverages training/dissemination resources with commercial, foundational, or governmental contributions; and manages budgets for workshops and symposia. Aim 4 is to enable productive and ef?cient participation of the External Advisory Committee (EAC) in de?ning NCAN objectives and procedures, evaluating outcomes, and making plans. The administration: schedules and manages EAC meetings; assists the EAC in assembling its evaluations and recommendations; ensures that the NCAN personnel respond promptly and appropriately to EAC input; keeps EAC members informed of NCAN progress; and oversees recruitment of replacements for EAC members as their terms end. In summary, the NCAN administration creates and maintains a working environment that enables NCAN personnel to pursue and achieve their ambitious goals.

Project Summary/Abstract Improved understanding of the brain processes underlying normal and abnormal function is necessary for devising better ways to diagnose, alleviate, or cure neurological or psychiatric disorders. It is clear that even for simple behaviors, such processes depend on interactions among multiple brain regions. However, these interactions themselves are less well understood. This inadequate understanding of inter-regional interactions impedes the generation of substantive models of brain functions and the new diagnostic or therapeutic possibilities that such models could introduce. These de?ciencies re?ect in part the limitations of the widely used imaging modalities. Detailed analysis of the operation of a network of brain regions requires comprehensive coverage, high spatial resolution, and high temporal resolution. However, existing techniques either lack high temporal resolution, high spatial resolution, or comprehensive coverage. Thus, they cannot track the spatial and temporal progression of inter-regional interactions. Intracranial recordings using electrocorticographic (ECoG) electrodes placed on the brain surface, or depth electrodes (stereoencephalography; SEEG) placed in regions and sulcal depths not accessible with ECoG, can provide wide coverage and high temporal and spatial resolution. Furthermore, electrical stimulation through these electrodes can assess causal roles and inter-regional connections. However, because intracranial electrodes are only available in patients awaiting brain surgery, intracranial studies are typically limited to small numbers of subjects with variable electrode coverage. In the research proposed here, our established and highly experienced ECoG/SEEG consortium will engage in a formalized research program that seeks to begin to reveal the detailed connectivity, causality, and dynamic neural processes supporting human speech perception. Research to achieve our two project aims will take full advantage of the opportunities afforded by intracranial electrodes. The proposed work will make use of an established interdisciplinary intracranial consortium, with four data collection sites providing access to dozens of subjects per year. The consortium will apply itself to answering new questions about dynamic inter-areal function underlying speech perception. If successful, the proposed work should not only add new neuroscienti?c understanding, but also formally validate a consortium structure as a model for intracranial research.

Spinal cord injury (SCI), stroke, cerebral palsy and other chronic neuromuscular disorders impair important functions such as walking. Current therapies are seldom fully effective. Recent advances enable powerful new therapies that target bene?cial change to key nervous system pathways. Among the ?rst of these therapies are operant conditioning protocols that modify a speci?c spinal re?ex pathway. The re?ex is elicited, and the person is rewarded if re?ex size satis?es a criterion. The person learns to modify the brain's control over the pathway to increase rewards. This control gradually changes the spinal pathway itself. Furthermore, the bene?cial change (i.e., plasticity) in this pathway leads to wider bene?cial plasticity elsewhere. This wider effect is predicted by the new negotiated equilibrium model of spinal cord function. The result is that, in rats or people with incomplete SCI, operant conditioning of a spinal re?ex increases walking speed and reduces limping. TR&D1 is developing and translating into clinical use operant conditioning protocols that induce bene?cial plasticity in the nervous system. It includes animal and human studies. The animal studies reveal mechanisms and principles that guide the human studies, which develop therapeutic protocols and translate them into clinical use. Aim 1 will develop a fully implanted telemetry-based system for long-term 24/7 operant conditioning in freely moving rats. By simplifying and facilitating operant conditioning and other long-term studies, this new lab system will make it possible for many other researchers to engage in these important studies. In addition, this aim will use this new system for the ?rst studies of the molecular biology of spinal re?ex conditioning. Aim 2 will develop and validate a general-purpose operant conditioning system suitable for widespread clinical use. Full achievement of the therapeutic promise of operant conditioning and related protocols requires a clinically practical system that supports a broad range of protocols and can change a variety of nervous system pathways. The new general-purpose clinical system will be tested, optimized, and validated with clinical collaborators. Additional collaborations with colleagues at major rehabilitation centers will explore the ef?cacy of re?ex operant conditioning for improving function in people with cerebral palsy, stroke, and other disorders. This work will de?ne dose-response curves for key functional measures and will include functional imaging studies to characterize the underlying plasticity. It will delineate the range of potential clinical applications and help improve the design and implementation of conditioning protocols. These studies are expected to lead to larger clinical trials to establish the value of speci?c conditioning protocols for enhancing recovery of function for speci?c groups of patients. By creating, validating, and disseminating these new animal and human systems, and by conducting studies with them, TR&D1 will accelerate development and clinical translation of operant conditioning and related protocols that can complement other therapies and enhance functional recovery for people with spinal cord injury, stroke, cerebral palsy, and other devastating neuromuscular disorders.

Project Summary/Abstract Because activity-dependent plasticity is ubiquitous in the CNS, brain stimulation may have long-term effects on areas to which the stimulated area connects. These effects have received little attention. Nevertheless, recent appreciation of the long-term role of cortex in shaping spinal cord pathways suggests that the long-term spinal effects of cortical stimulation are likely to be substantial. In fact, weak electrical cortical stimulation (ECS) of rat sensorimotor cortex has lasting spinal effects. Three months after ECS ends, GABA receptors in spinal motoneurons remain decreased and the H-re?ex (analog of the spinal stretch re?ex) remains increased. This proposal seeks to determine in rats how ECS produces these spinal effects and to characterize the effects on physiological, anatomical, and molecular levels. Preliminary studies support the hypothesis that the spinal effects occur because ECS excites corticospinal tract (CST) neurons that synapse on spinal GABAergic interneurons that synapse on soleus motoneurons, that this input reduces GABA metabotropic receptors and thereby modi?es motoneuron properties so as to increase the H-re?ex (and also affect other spinal circuits), and that speci?c gene activations underlie these effects. Two speci?c aims test this hypothesis. The ?rst aim is to determine how ECS parameters affect its impact on the spinal cord and to de?ne the responsible descending pathway. ECS will be given by epidural electrodes. Pathway lesions and anatomical tracers will identify the key pathway and its spinal targets. Based on initial data and other studies, the expectation is that the CST is the essential pathway and that it connects to spinal motoneurons via GABAergic interneurons. The second aim is to characterize the short-term and long-term effects of ECS on spinal neurons and circuits on physiological, anatomical, and transcriptional levels. These studies will: examine ECS impact on motoneuron properties (e.g., ?ring threshold) and on spinal re?ex pathways; explore immunohistochemically ECS impact on GABAergic and other (e.g., glutamatergic) spinal interneurons and synapses and their receptors in soleus and other spinal motoneurons; use next-generation sequencing methods (RNA-Seq) to identify ECS-induced changes in gene expression in spinal motoneurons that correlate with and are likely to account for the changes in neuronal properties, spinal circuit function, and immunohistochemical measures. In summary, this proposal uses a well-de?ned experimental model to explore the spinal effects of cortical stimulation. By characterizing the nature and mechanisms of the spinal cord plasticity produced by this stimulation, it should provide fundamental new insight into the wider effects of cortical stimulation, and also into how the cortex modi?es the spinal cord throughout life. Furthermore, the results should guide development of stimulation protocols to further explore these effects, and stimulation protocols that can induce bene?cial plasticity to enhance functional recovery after CNS trauma or disease.