Marc H. Schieber - US grants

DESCRIPTION (provided by applicant): The long-term goal of this project is to improve understanding of how the nervous system selects and executes individuated finger movements. Individuated movements are the first lost and last recovered when neurologic lesions affect the motor cortex or corticospinal tract. The resulting motor deficits impair use of the hand and fingers in everyday tasks. The present application proposes to examine the role of synchrony among primary motor cortex neurons in the learning and performance of skilled finger movements. Studies will focus on changes in synchrony in three, inter-related situations: 1) changes that relate to long-term training at a repertoire of skilled finger movements, 2) changes that depend on which particular movements are performed, and 3) changes that occur when a skilled subject attempts a novel movement. Such changes in synchrony could enable the nervous system to more efficiently activate the varied combinations of muscles needed for execution of skilled movements. Multiple neuron recording and spike-triggered averaging of electromyographic activity will be used together to examine synchrony both between pairs of motor cortex neurons, and among larger ensembles of neurons that provide inputs to spinal motoneuron pools. The proposed studies will address the following specific questions: 1) What is the time course of the increase in synchrony over long-term training? 2) Does synchrony occur during only a subset of finger movements or task time periods? 3) Do patterns of synchrony change when a fully trained subject practices a novel movement? 4) Does synchrony occur predominantly in corticospinal or non-corticospinal primary motor cortex neurons?

DESCRIPTION (Investigator's Abstract): The present application's long- term objective is to extend fundamental knowledge about the neural control of individuated movements, those in which one body part moves relatively independently of the motion or posture of other body parts. Individuated movements i) are the first lost and last recovered when lesions affect the motor cortex or corticospinal tract; ii) play an increasingly important role in the motor repertoire of higher mammals, especially primates, in particular man; and iii) are used in many modes of cognitive expression, such as speaking (mouth) or playing a musical instrument (fingers). The proposed studies of individuated finger movements specifically aim to test two hypotheses. First,that generation of each individuated finger movement involves the activity of neurons distributed throughout the motor cortex (M1) hand area. Second, that some, but all, non primary cortical motor areas (NPMA) participate in visually-cued finger movement with each participating AMA making a different contribution, distinct from that of M1. To test these hypotheses, rhesus monkeys will be trained to perform visually-cued individuated movements of each finger of the right hand and of the wrist. As a trained monkey performs these movements, single neuron activity will be recorded in Ml and in concurrently with EMG activity from a number of muscles involved in the production of finger - movements. Spike -triggered averaging (SpTA) of EMG activity will be used to infer the strength of connections from each neuron to each muscle. These data on) each neurons's activity during finger movements and on its inferred connections to muscles will be incorporated in a model of the neural control of finger movements. Single neuron activity in different -As will be compared to distinguish the roles of these areas. Finally, Ml and NPMAI each will be reversibly inactivated by intracortical injection of the GABA agonist, muscimol, to determine: i) whether inactivation of different regions of the MI hand area impairs movements of different fingers, and ii) whether inactivation of different has different effects on visually-cued finger movements.

Individuated movementsDthose in which one or more body parts move relatively independently of the movement or posture of other body partsDimpart a rich flexibility to the human behavioral repertoire. The individuated movements used in many forms of cognitive expression, such as speaking, dancing, or playing a musical instrument, contrast significantly with the phylogenetically older movements of the same body parts used, respectively, in eating, walking or grasping. In neurologic patients, individuated movements are the first lost and last recovered when lesions of any sort injure the motor cortex or corticospinal tract. Given the importance of individuated finger movements in so many aspects of human functionDfrom buttoning buttons to playing the pianosurprisingly few studies have quantitatively examined the ability of normal humans to individuate finger movements, or to recover this ability after nervous system injury. This reflects an underlying assumption that humans make perfectly independent movements of each finger, with any lack of independence being attributable to connections between the tendons to different fingers. Independent finger movements are assumed to be controlled by different parts of the primary motor cortex (Ml), and produced by separatemuscles moving each finger. Recent studies in non-human primates have shown, however, that individuated finger movements are controlled by overlapping neuronal populations in Ml, and are produced by multitendoned extrinsic muscles that put tension on more than one finger at a time. In humans, recent evidence indicates: (i) that Ml territories controlling different fingers overlap extensively; (ii) that motoneurons in different human finger muscles receive common input from the same premotor neurons; and (iii) that human multitendoned finger musclesDsuch as flexor digitorum profundusDmay not have separate functional subdivisions for each finger.

DESCRIPTION (Investigator's Abstract): The long term goal of this project is to understand how finger muscles produce individuated finger movements--those in which one or more fingers are moved without moving the others. Though each finger often is assumed to be moved by its own muscles, the extrinsic muscles that provide most of the flexing and extending power typically send tendons to multiple fingers. This anatomic fact presents a paradox: contractions of these multitendoned muscles should move multiple fingers simultaneously. Individuated flexion and extension of the fingers are hypothesized to be possible because: i) functional subdivisions within some multitendoned muscles may apply tension relatively selectively to some of the muscle's tendons, and ii) the forces produced by different multitendoned muscles may combine such that the net forces on each finger cause one digit to move while other digits are held still. The proposed studies specifically aim to address the following 6 questions: 1) Does each neuromuscular compartment in multitendoned finger muscles distribute tension to more than one tendon? 2) Do single motor units in these muscles distribute tension to multiple tendons? 3) Do mechanical interconnections between a muscle's tendons passively distribute tension to multiple fingers? 4) Do single motor units in human finger muscles act on multiple fingers? 5) Do humans co-contract several multitendoned finger muscles to produce individuated movement of one finger while holding other fingers still? 6) Can the mechanical action of several multitendoned muscles combine to move one finger while holding the other fingers still? These studies will result in an improved basic understanding of how multitendoned finger muscles function, which can translate into: i) production of useful finger movements by functional electrical stimulation of these muscles in patients with brain or spinal cord injury, ii) more accurate botulinum toxin injections for treatment of the hand's focal dystonias, and iii) more appropriate tendon transfers for reconstruction of a useful hand in patients debilitated by forearm trauma. Moreover, results of the proposed studies of muscles will have broad implications for understanding how finger movements are controlled by the central nervous system.

Our long-term objective is to understand the neural control of individuated movements, those in which one body part moves relatively independently of the motion or posture of other body parts. Individuated movements are the first lost and last recovered when neurologic lesions affect the motor cortex or corticospinal tract, and play an increasingly important role in the motor repertoire of primates, especially humans. Modern evidence contradicts the notion that movements of different fingers are controlled from distinct, somatotopically arrayed regions of the primary motor cortex (M1), is if labeled lines extended from separate cortical regions to each finger. We hypothesize instead that each finger movement is controlled by a network of neurons distributed throughout the M1 hand region, and that this network reorganizes during motor skill learning. To test these hypotheses experimentally, we will identify M1 neurons that provide direct connections to spinal motoneuron averaging of electromyographic (EMG) activity. Each CM neuron and its target muscles will be recorded simultaneously during performance of 12 individuated finger and wrist movements. By comparing the activity of CM neurons and their target muscles across these 12 movements, we will (Aim 1) examine where CM neurons lie along a spectrum of functional possibilities-from labeled-lines to diversified elements of a distributed network; and (Aim 2) the extent to which the activity of CM neurons combined through the physiologically identified connections to spinal motoneuron pools, can account for the patterns of EMG activity actually recorded. We also will use the identified CM neuron-target muscle connections to map the spatial distribution of output effects from M1 to muscles at the single neuron level to determine (Aim 3) whether outputs to selected muscles that act on radial versus ulnar digits are spatially segregated or entirely overlapping. Finally, we will map M1 repeatedly during motor skill learning to determine (Aim 4) whether any spatial segregation diminishes as the M1 territories that provide output to trained muscles progressively enlarge and increasingly overlap.

DESCRIPTION:(adapted from applicant's abstract) The long-term goal of the present project is to understand the neural substrates underlying motoric choices. In picking one of the many identical apples from a tree for example, the nervous system must choose whether to pick an apple on the right or left, up or down, whether to use the right hand or left hand, and whether to grasp the apple with a power grip or to pinch the stem. These choices have more to do with movement to be executed than the apple to be picked. Here we advance the novel hypothesis that the same cortical areas, in particular the PMV, SMA, that participate in selecting movements based on external and internal cues also participate in choosing among multiple equivalent movements particularly when perceptual and motivational factors are evenly balanced. Put simple, if all the apples are equal, motoric factors will influence the subjects movement choices. Because the striatum receives partially overlapping projections from PMv and SMA, as well as dopaminergic inputs signalling events predictive of a desirable reward, we hypothesize that striatal neurons also participate in motoric choices. We propose to study the related processes of movement selection and motoric choice by having subjects select movements specified by external cues on some trials (no-choice), while on other trials the subjects will have a choice between equally appropriate movements, unbiased by perceptual or motivational factors. We will examine our hypotheses with the following specific aims. (1) Do neuronal populations in the Pmv, SMA, and the striatum participate in the choices of which hand to use and on which side the responses are made? (2) Do neuronal populations in the PMv, SMA, and the striatum also participate in other non-lateralized choices, such as up and down, and pinch and power grasp? (3) How does reversible inactivation or microstimulation of the PMv, SMA, and striatum bias motoric choices? (4) How do the partially overlapping cortico-striatal projections from the PMv and SMA correlate with striatal regions participating in motoric choices?

DESCRIPTION (provided by applicant): How do interactions among motor structures contribute to the selection and execution of coordinated eye, head and hand movements? The present program addresses this question with a series of 5 inter-related projects: Project 1, Brainstem-Cerebellar Interactions in Gaze Control (Freedman, PI), asks how the rostral and caudal regions of the fastigial nucleus interact to coordinate eye and head movements in a continuum of possible combinations during targeted gaze shifts. Project 2, Spatial Interaction of Otolith Mediated Collic Reflexes (Gdowski, PI) asks how interactions between the vestibular nuclei and cervical motoneuron pools stabilize the head during linear whole-body translation. Project 3, Interactions in the Corticostriatal Network (Lee, PI), asks how neural interactions between the prefrontal cortex and the striatum incorporate choice and reward history to select the next movement from discrete alternatives. Project 4, Basal Ganglia - Cortical Interactions in Motor Control (Mink, PI) asks how interactions of the globus pallidus, pars interna, with the primary motor cortex and the supplementary motor area, suppress posture and permit movement, or suppress a prepotent movement when an alternative choice is correct. Project 5, Premotor Interactions in Motoric Choices (Schieber, PI), asks how interactions between the head and arm representations of the ventral premotor cortex contribute to discrete choices of which direction to look, which hand to use, and which target to take. Rather than taking the traditional approach of comparing the function of structures studied one at a time, the present program will improve understanding of how seamlessly coordinated motor behavior, influenced by choices made in various behavioral contexts, emerges from the neural interactions among multiple motor structures. Such an improved understanding of the motor system can lead to improved rehabilitative treatment, and improved functional recovery after nervous system injury from diseases such as stroke and head trauma.

Project 5 - Premotor Interactions in Motoric Choices: The behavioral act of reaching typically begins with a coordinated eye-head gaze shift. As gaze turns, one or the other hand reaches out to an available target. When multiple potential targets are present, we have observed previously that the direction of the initial gaze shift (right or left), the hand used (right or left), and the target taken (right or left) all are correlated with one another. Here we will study the neural interactions between the head and arm representations of the ventral premotor cortex (PMv) that underlie these correlations. We will test the general hypothesis that the PMv participates in mediating these correlations between gaze, hand and target with four Specific Aims. First, we will test the hypothesis that requiring the monkey to lateralize each of these three variables?gaze, hand and target?to one side or the other, biases the monkey's choices of the other two variables. Second, the hypotheses that gaze direction biases choices of which hand to use, and alternatively that hand preference biases choices of gaze direction, will be examined by inactivation or stimulation of the superior colliculus or M1 upper extremity representation, respectively. Third, the hypothesis that the lateral head representation in PMv participates in control of the head movement component of coordinated eye-head gaze shifts will be tested by recording PMv neurons during both an 8-direction target-acquisition task and a lateralized choice task. We will determine whether variation in PMv neuron activity during the choice task can be attributed simply to effector selectivity, directional tuning and kinematic relationships of the neuron, or whether choice-related discharge is present as well. Fourth, the hypothesis that neural interactions between the PMv head and arm representations participate in mediating gaze/hand and gaze/target correlations will be examined by recording local field potentials and single neuron activity simultaneously in the PMv head and arm representations, by recording in one while microstimulating the other, and by recording in one while inactivating the other. By examining interactions that underlie correlations between the simple choices of which way to look, which hand to use, and which food morsel to take, these studies will complement other programmatic studies of cortico-subcortical interactions in decision making and gaze control.

DESCRIPTION (provided by applicant): As you grasp your coffee cup, thousands of neurons in your motor cortex control the activity of some 40 muscles that move your hand's 22 skeletal degrees of freedom. The complexity of controlling such an everyday action seems daunting. But recent studies have shown that because the movements of many skeletal degrees of freedom in the hand are highly correlated, as much as 90% of the motion of the 22 degrees of freedom can be captured in only 2 to 7 principal components. In other words, the number of dimensions needed to describe most of the motion of the hand can be reduced from 22 down to 7 or fewer. Similarly, other studies in which electromyographic activity has been recorded simultaneously from 19 muscles have shown that up to 80% of the simultaneously recorded electromyographic activity can be expressed as 3 to 5 time-varying muscle synergies. The number of dimensions needed to describe muscle activity thereby can be reduced from 19 down to 5 or fewer. Might such dimensionality reduction simplify the complexity of controlling such everyday movements? Here we propose to test the general hypothesis that cortico-muscular control of the hand and fingers makes use of dimensionality reduction. By reducing dimensions at three different levels of simultaneously recorded data-neuronal, muscular and kinematic-we will take the novel, comprehensive approach of comparing the correspondence between the reduced spaces at all three levels. Through these comparisons, we will explore the previously unexamined hypotheses that: 1) the biomechanical structure of particular finger muscles produces certain principal components of hand and finger kinematics;2) time-varying muscle synergies correspond to principal components of hand and finger kinematics;3) time-varying neuron synergies represent principal components of hand and finger kinematics;and 4) time-varying neuron synergies represent time-varying muscle synergies. To test our hypotheses, we will acquire data simultaneously from 128 single neuron microelectrodes implanted in the primary motor cortex hand representation, from 16 electromyographic electrodes implanted in various muscles, and from 23 markers tracking finger kinematics, during grasping movements of 16 to 48 different objects. Using these data, we will extract time-varying neuron synergies, time-varying muscle synergies, and principle components of hand and finger kinematics. We will determine whether individual muscles, time-varying muscle synergies, and/or neuron synergies correspond to principal components of hand kinematics, and whether time-varying neuron synergies correspond to muscle synergies. Our hypotheses will be rejected if the spaces of reduced dimensionality at different levels-neuronal, muscular and kinematic-fail to correspond. In contrast, strong relationships between elements in the different reduced spaces would support the notion that cortico-muscular control of the hand and fingers actually utilizes dimensionality reduction. In addition to the long term benefit to society of an improved understanding of how the brain controls movement, the proposed project will have ramifications in the growing field of neuroprosthetics. Dimensionality reduction in the cortico-muscular system would provide a means of minimizing the on-line computational load carried by on-board computers that will control neurally driven prosthetic devices. More broadly, our approach may provide a model for computational reduction and interpretation of large, complex, behavioral and cognitive neuroscience datasets. Our proposal builds upon a relatively new collaboration between Schieber at the University of Rochester, who brings expertise in motor systems physiology, and Thakor at Johns Hopkins University, who brings expertise in biomedical engineering approaches to computation. Through frequent videoteleconferencing and 2-3 month exchange visits, these two labs will provide cross-disciplinary training for the co-PIs, graduate students, and undergraduates (including under-represented minorities) at both institutions. Biomedical engineers from Hopkins will learn to record physiological data while at Rochester. Motor physiologists from Rochester will learn advanced mathematical techniques for analysis while at Hopkins. The students from both groups will present their work at both neuroscience and engineering conferences, where the co-PIs will organize hands-on workshops for further dissemination of the findings per se, and of the project as a model for inter-disciplinary research. The co-PIs also will coordinate an innovative inter-institutional graduate level course.

DESCRIPTION (provided by applicant): Our overall goal is to demonstrate within two years human closed-loop control of the DARPA Revolutionizing Upper Limb Prosthesis, based on real-time decoding of electrocorticographic (ECoG) signals. Under visual feedback, our human subjects will achieve sufficient cortical control of the prosthesis to reach out, grasp, and manipulate real objects. Our collaborative team will build on its substantial experience in developing and testing neural control algorithms for the Modular Prosthetic Limb (MPL, developed by JHU- APL), which arose from participation in the DARPA-sponsored RP2009 program. Based on our unique combination of expertise and experience, we are poised to meet the RFA's Grand Challenge with an innovative approach using parallel experiments in human subjects and in animals. While we develop and test ECoG- based neural control algorithms in patients implanted for the clinical aims of epilepsy surgery, parallel studies in animals will afford more consistent and long-term experimental time to validate the control algorithms, and allow deeper investigation into electrode placement and configuration, including investigating the relationship between intra-cortically recorded spikes and local field potentials (LFPs) and surface-recorded ECoG. We will test the hypothesis that both open- and closed-loop control of the prosthetic limb can be achieved using ECoG spectral features at different time and frequency scales, e.g. low frequencies for slow and/or coarse movements and high frequencies (>70 Hz) for rapid and/or individuated movements. Based on these features, subjects will use the prosthetic limb to perform a center-out reach task in 3D space with coordinated grasping of objects requiring different hand conformations that incorporate both wrist and 5 finger actions. Brain control will be implemented with real-time signal processing of ECoG and actuation of the prosthetic limb under closed-loop visual feedback of object-targeted limb movements. Closed-loop control will be first demonstrated using a virtual reality model of the prosthetic limb and subsequently using the JHU-APL modular prosthetic limb itself. Outcomes will be assessed with measures of success rate, time to trial completion, trajectory/grasp-shape similarity to native limb movements, and overall learning/adaptation rate. PUBLIC HEALTH RELEVANCE: Project Narrative This project will demonstrate the feasibility of using the signals recorded from non-penetrating electrodes on the surface of the brain to allow patients who have lost arm and/or hand function to intuitively control a revolutionary new prosthetic limb with far greater versatility and life-like dexterity than previously available prostheses. This could have a profound long-term impact on the ability of future generations of patients seeking to restore lost upper limb function with a lifelike prosthesis.

Description (provided by applicant): The long-term goal of the present project is to understand factors that influence throughput from single neurons in the primary motor cortex to the motoneurons that drive muscles. The primary motor cortex, through its corticospinal projection, plays a major role in controlling movements of the body. Much of this control is achieved via direct connections from single motor cortex neurons to pools of spinal motoneurons. The throughput of these connections can be assessed in spike-triggered averages of rectified electromyographic activity recorded from muscles. By recording the activity of multiple motor cortex neurons and multiple muscles simultaneously during both natural and novel voluntary motor behaviors, and analyzing their spike-triggered average effects, the present application proposes to determine whether changes in neuron firing rate and ongoing electromyographic activity during voluntary behaviors produce systematic variation in the amplitude of throughput from the neuron to the muscle. Because the firing rate of motor cortex neurons and the electromyographic activity of their target muscles often are correlated, the extent to which M1 neurons can be dissociated from that of their target muscles also will be investigated. Improved understanding of how the motor cortex controls muscles to move the body will lead to improved diagnosis, treatment and rehabilitation to functional recovery for patients affected by numerous neurological diseases including stroke, amyotrophic lateral sclerosis, multiple sclerosis, traumatic brain or spinal cord injury and cerebral palsy. PUBLIC HEALTH RELEVANCE: The long-term goal of the present project is to understand factors that influence the throughput from single neurons in the brain's primary motor cortex to the groups of motor neurons in the spinal cord that drive muscles. The connections from single motor cortex neurons to groups of spinal motor neurons play a major role in allowing the brain to control movement of the body. Improved understanding of how motor cortex neurons control muscles to move the body will lead to improved diagnosis, treatment and rehabilitation toward functional recovery for patients affected by numerous neurological diseases including stroke, amyotrophic lateral sclerosis, multiple sclerosis, traumatic brain or spinal cord injury, and cerebral palsy.

DESCRIPTION (provided by applicant): The long-term goal of the present project is to understand the cortical control of voluntary movements used to reach out, grasp and manipulate. These movements typically are considered as distinct processes, controlled from proximal versus distal sub-regions of the upper extremity representation in the primary motor cortex, and influenced via distinct inputs from dorsal versus ventral areas of the premotor cortex, respectively. Here we propose to investigate the neurophysiological activity underlying the seamless integration of reaching, grasping, and manipulation into a single coordinated motor act. Specifically, the present proposal aims to: 1) determine whether single neurons and other neurophysiological activity in the primary motor cortex, dorsal premotor cortex and ventral premotor cortex are modulated in relation to reaching, to grasping, or to both; 2) determine how and where manipulative actions of the arm and hand are represented in the primary motor and premotor cortex; and 3) to determine how the grip forces and the load forces used in manipulation are represented and controlled. Improved understanding of these processes will lead to improved rehabilitation for functional recovery and to improved neuro-prosthetic devices for patients affected by numerous neurological diseases including stroke, amyotrophic lateral sclerosis, multiple sclerosis, traumatic brain or spinal cord injury, and cerebral palsy. PUBLIC HEALTH RELEVANCE: The long-term goal of the present project is to understand how the brain controls movements of the arm and hand used to reach out, grasp and manipulate objects. The present experiments will examine how neurophysiological activity in motor areas of the cerebral cortex integrates the seamless control of the multiple stages of reaching, grasping and manipulation. Improved understanding of these processes will lead to improved rehabilitation to functional recovery and improved neuro-prosthetic devices for patients affected by numerous neurological diseases including stroke, amyotrophic lateral sclerosis, multiple sclerosis, traumatic brain or spinal cord injury, and cerebral palsy.

? DESCRIPTION (provided by applicant): The long-term goal of the present project is to understand the neuronal activity underlying the process of voluntary control. Historically, investigating this process has been constrained largely by the fact that voluntary motor output is naturally coupled to motion of a body part, to the muscle contractions moving that body part, and to the sensory feedback produced by the motion of that body part. Now, as knowledge of these relationships is being harnessed to control brain computer interfaces (BCIs), BCIs themselves provide a new paradigm for directly examining the neuronal processes underlying voluntary control. As the brain controls a BCI, neuronal activity becomes dissociated from movement of the body and devoted instead to voluntary control of the interface. Movement of the native limb may cease, and EMG activity may be absent as neurons continue to control the BCI voluntarily. Hence proprioceptive feedback and visual observation of limb movement may be absent as well. Carefully chosen BCI paradigms thus provide an unprecedented opportunity to examine voluntary control of neuronal activity per se, dissociated from motor output and sensory feedback. Here we propose to investigate the neuronal processes underlying voluntary control using a simple BCI paradigm that assesses the single-session performance of neurons in voluntarily controlling a novel interface. Our BCI paradigm assesses the ability to coordinate the activity of small ensembles of arbitrarily-selected neurons in novel patterns. Specifically, th present proposal aims to determine whether the brain's ability to control neurons voluntarily depends: i) on the cortical area (motor, premotor, and parietal areas will be compared), ii) on the presence or absence of visual and/or somatosensory inputs, and iii) on output projections to different levels of the neuraxis (neurons with cortico-cortical axons, axons projecting to the brainstem, cortico-spinal axons, and cortico-motoneuronal connections will be compared). Current efforts at neuro-prosthetic control of artificial hands, while impressive, have not progressed as rapidly as might have been expected. In part this may reflect inadequate basic understanding of the neuronal activity underlying the process of voluntary control per se. Thus, improved understanding of this fundamental process will lead both to improved neuro-prosthetic devices for restoration of lost function and to improved neuro-rehabilitation for functional recovery in patients affected by a wide variety of neurological diseases including stroke, amyotrophic lateral sclerosis, multiple sclerosis, brain or spinal cord injury, and cerebral palsy.

? DESCRIPTION (provided by applicant): Spike-timing dependent plasticity (STDP) is a mechanism thought to underlie much of normal learning, as well as recovery from nervous system injury. The ability to manipulate STDP in selected neural circuits, and specifically during certain behaviors, therefore could have vast potential for enhancing normal learning as well as treating a wide variety of neurological disorders. Indeed, previous work has shown that changes consistent with STDP can be produced in normal humans and in patients with spinal cord injury. These studies have paired i) transcranial stimulation of the corticospinal system with ii) peripheral nerve stimulation, both of which stimulate thousands of neurons at each site, inducing plastic changes relatively nonspecifically in large populations of neurons. Recently, the development of technology for brain-computer interfaces has enabled studies in which spikes recorded from a single neuron in an awake subject can be used to trigger intracortical microstimulation (ICMS) at another electrode with delays appropriate for producing STDP. Three studies have suggested that such spike-triggered ICMS (SpTr-ICMS) can alter cortical output, increase connections between neurons, and modify behavior. But in each of these studies SpTr-ICMS has been delivered continuously over days, during which the subject engaged in a wide variety of unrestrained, natural behaviors. The present proposal therefore aims to address the following questions: 1) Can SpTr-ICMS alter neuronal activity and interactions during a specific behavior when the stimulation is delivered during only that one behavior? 2) Does SpTr-ICMS delivered during one behavior alter neuronal activity and interactions during another behavior? And 3) Does SpTr-ICMS delivered during one behavior produce improvement in that behavior without detrimental effects on another behavior? The high risk of the present R21 proposal lies in the possibility that SpTr-ICMS delivered for only a few hours each day during a specific behavior may be insufficient to induce any changes, or that the changes induced may be non-specific. The potentially high payoff lies in the possibility that SpTr-ICMS will provide a new tool for experimental manipulations that probe the nature and limits of neural plasticity. Such progress would open the way for translational development of SpTr-ICMS as new means of enhancing selected aspects of learning, as well as promoting recovery of specific functions after nervous system injury.

Project Summary/Abstract Mirror neurons constitute a distinct class of neurons in that their firing rates are modulated both during performance and during observation. We will investigate three aspects of mirror neuron physiology. First, given that mirror neurons are thought to mediate understanding of another individual?s actions, in Aim 1 we ask if mirror neuron activity during observation differs depending on whether or not the individual performing the movement is of the same species. We hypothesize H1A ? that mirror neuron activity is modulated more when the observing subject watches an individual from the same species than when the performer is from a different species. Furthermore, we hypothesize H1B ? that communication between a conspecific performer and observer enhances observation-related activity. Second, although most studies of mirror neurons have focused on modulation during movement per se, our preliminary studies suggest that mirror neuron populations represent entire sequences of multiple behavioral epochs, including epochs during which no movement occurs. In Aim 2 we ask whether mirror neuron populations represent behavioral epochs other than the movement per se. We hypothesize: H2A ? that mirror neurons are modulated during separate instruction and/or preparatory periods; H2B ? that mirror neuron populations represent entire sequences of multiple behavioral epochs whether the subject is performing or observing; and H2C ? that the representation of behavioral epoch sequences is similar during performance and observation in mirror neuron populations from the ventral or dorsal premotor cortex, but different in those from the primary motor cortex. Third, we introduce the novel notion that i) condition-dependent modulation of mirror neuron activity related to the location to which the arm must reach and to the object the hand must grasp is dissociable experimentally from ii) condition-independent modulation that represents the sequence of behavioral epochs. In Aim 3 we ask whether inactivation of the parietal reach region (PRR) and/or the anterior intraparietal area (AIP) reduces or eliminates condition-dependent information in the premotor and motor cortex, while leaving condition- independent modulation relatively unchanged. We hypothesize: H3A ? that during observation, inactivation of PRR and/or AIP will reduce or eliminate the location- and/or object-related modulation, respectively, of mirror neuron populations, H3B ? while leaving the condition-independent modulation relatively unchanged.

Project Summary: Efforts to develop neuroprosthetic devices that restore function for patients who have lost vision, hearing, or somatic sensation typically aim to stimulate the sensory pathways of the nervous system in a manner that mimics their normal function closely. Yet the well-known cochlear implant for deaf patients has been successful even though the subject?s brain must adapt to the artificial stimulation, learning to interpret sounds and discriminate speech. Is biomimetic stimulation of sensory pathways the only way to provide neuroprosthetic inputs to the nervous system? In preliminary studies, we recently found that subjects could learn to interpret intracortical microstimulation (ICMS) delivered through 1 of 4 different electrodes in the premotor cortex (PM) as instructions to perform 1 of 4 arbitrarily associated movements. Even though ICMS in PM is not thought to evoke sensory percepts, subjects learned to use PM-ICMS instructions at currents and frequencies too low to evoke any muscle contraction or movement. Moreover, after the assignment of electrodes to movements was shuffled randomly subjects relearned the task, indicating that low-amplitude ICMS did not simply bias the subjects to perform specific movements, but instead evoked percepts or other experiences that the subjects could distinguish and learned to interpret as instructions. Here we propose to investigate whether subjects can experience, distinguish and learn to interpret low- amplitude ICMS delivered through different single electrodes in other select areas of the frontal and parietal association cortex that receive sensory information only indirectly. In Aim 1 we will examine 5 frontal areas: the supplementary motor area, the frontal eye field, the dorsolateral and ventrolateral prefrontal cortex, and the dorsal anterior cingulate cortex. In Aim 2 we will examine 5 parietal areas: area 5, the medial intraparietal area (parietal reach region), the lateral intraparietal area, the anterior intraparietal area, and area 7a. In Aim 3 we will determine whether subjects can learn to interpret ICMS in these frontal and parietal areas not only as instructions, but alternatively as feedback. The results of this work will expand the territory available for delivering artificial inputs to the nervous system substantially. Neuroprosthetic devices then may be developed that use such inputs to help patients affected by a wide variety of diseases of the central and peripheral nervous system including visual loss, sensory neuronopathies, stroke, and multiple sclerosis.