1994 — 2002 |
Nicolelis, Miguel A. L. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Trigeminal System Plasticity During Facial Anesthesia |
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1999 — 2004 |
Garg, Devendra (co-PI) [⬀] Henriquez, Craig (co-PI) [⬀] Nicolelis, Miguel Wolf, Patrick (co-PI) [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Kdi: Brain-Machine Interfaces For Monitoring and Modeling Sensorimotor Learning in Primates
Despite advances in computer-controlled automation, the technological capabilities of robotic and 'smart' instruments are still far exceeded by the human brain. The next generation of intelligent devices will need to combine features such as the perceptual abilities, high learning rates and capability of generalization shown by the brain. To clarify a fundamental component of intelligent behavior, this project studies how cellular interactions within the cerebral cortex of the brain underlie problem-solving strategies in behaving primates. New technologies will be used for recording brain activity, for designing microchips, and for pattern recognition analysis. The objectives are to characterize the learning methods used to map sensory cues (from sight, sound and touch) into relevant motor behaviors (directed arm movements), to see how different learning strategies affect the dynamic relations among functional associations of groups of cortical nerve cells during learning, and to design a brain-machine interface that will sample and process neuronal activity in real time in behaving animals. Technological goals include the use of a special virtual reality environment for behavioral testing, the development of a wireless multichannel microchip for transmitting brain activity to a remote receiver, and the development of pattern-recognition algorithms to analyze complex patterns of brain activity among multiple cells. Results of this project from the Knowledge and Distributed Intelligence (KDI) initiative will have broad impact on fields such as neurobiology, bioengineering and computer science, will have potential applications in technology for intelligent interactive roboticsm, and will provide excellent cross-disciplinary training for a range of students and postdoctoral researchers.
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0.915 |
2001 — 2005 |
Nicolelis, Miguel A. L. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Corticofugal Modulation of Tactile Sensory Processing
DESCRIPTION: In every mammalian sensory system, descending corticothalamic projections, which originate in multiple cortical areas and reach several thalamic relay nuclei, far outnumber the terminals of parallel feedforward projections that carry information from the periphery to the same thalamic structures. Despite numerous studies and a series of theories which have attempted to illuminate the role of these massive descending feedback projections in sensory information processing, the functional relevance of these pathways remains largely unknown. Here, we propose to investigate the physiological contribution of somatosensory corticothalamic projections to the tactile responses of neurons located in the main thalamic relay nucleus of the trigeminal system, the ventral posterior medial nucleus. Based on extensive preliminary data, we propose that, by providing both excitatory and inhibitory influences to the somatosensory thalamus, corticofugal projections endow thalamic neurons with the ability to enhance the differences between orthogonal tactile stimuli and modify the type of information transmitted to the cortex according to the behavioral state of the animal. The functional roles of cortical feedback projections will be assessed by a series of experiments that combine simultaneous multi-site neural ensemble recordings and reversible cortical inactivation, in behaving animals. The activity of large populations of single cortical and thalamic neurons will be simultaneously recorded in the same rat, while its facial whiskers are stimulated with complex tactile stimuli generated either passively or during an active behavioral whisker-dependant discrimination task. Focal regions of the primary somatosensory cortex will be reversibly inactivated during these simultaneous thalamocortical recordings. This will allow us to evaluate how cortical projections contribute to the generation of thalamic sensory responses to complex tactile stimuli. We predict that in rats cortical feedback facilitates the thalamic responses to a whisker column stimulus, while suppressing responses to a whisker row. Modifications in the balance of these contrasting influences should also account for the observation that VPM neurons become capable of integrating rapid sequences of whisker column stimuli generated during active whisker exploration.
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1 |
2006 — 2010 |
Nicolelis, Miguel A. L. |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) R33Activity Code Description: The R33 award is to provide a second phase for the support for innovative exploratory and development research activities initiated under the R21 mechanism. Although only R21 awardees are generally eligible to apply for R33 support, specific program initiatives may establish eligibility criteria under which applications could be accepted from applicants demonstrating progress equivalent to that expected under R33. |
Method For in-Vivo Assessment of Neuronal Dysfunction
[unreadable] DESCRIPTION (provided by applicant): Project Summary: As human life expectancy gradually increases, it has become critical to understand the neural mechanisms by which brain function deteriorates in progressive neurodegenerative disorders. Mouse models of neurodegenerative disorders can be very useful to investigate the mechanisms underlying the sensorimotor and cognitive deficits associated with neurodegenerative disorders. Recent studies indicate that functional alterations in neuronal circuits may occur before neuronal degeneration and may underlie many of the behavioral symptoms associated with neurodegenerative disorders and may be reversible. We have been developing a new electrophysiological approach that allows us to obtain multi-site, long-term simultaneous recordings of the activity of large populations of single neurons in awake behaving mice. We implant arrays of isonel-coated tungsten microwires (35 or 5Q\an, up to 48 per mouse) in multiple brain areas of the same animal. Our preliminary experiments revealed that several well-isolated single units and multi-unit activity can be obtained from a very high number of implanted electrodes. Concomitantly, we have also measured local field potentials (LFP) in the same areas by low-pass filtering the data (0.1 to 400Hz range). Perhaps more importantly, we have demonstrated that these chronic implants are so well tolerated by the animal and its brain that often many single units can be recorded more than 6 months after the initial implantation surgery. To further corroborate this approach, we have already used it to investigate the neural plasticity underlying motor skill learning in WT mice. In the first section of this proposal, we plan to further develop this technique by: a) using high density arrays to increase the number of channels per mouse, b) testing several types of array design to optimize the number and quality of isolation of single neurons per channel and c) testing methodology and software for single unit isolation and visualization (with Pfexon, Inc., Texas). Relevance: Once fully developed, we propose to use this new methodology to test the hypothesis that physiological alterations at the cellular and circuit level (even before severe neurodegeneration) underlie the behavioral deficits in mouse models of neurodegenerative disorders. We believe that this unique approach will allow the integration of molecular, cellular, systems, and behavioral data in the same animal, in order to produce a more complete understanding of the progression of deficits associated with a variety of neurological disorders. [unreadable] [unreadable]
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2006 — 2010 |
Nicolelis, Miguel A. L. |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Mouse Models With Multi Electrode Arrays
Monoamines play a major role in depression. The present proposal will[unreadable] examine this idea by evaluating neural responses in the various mouse models of depression and it will[unreadable] complement the human imagining studies by providing a functional approach for identifying brain areas and[unreadable] neural circuits that may participate in depressive-like behaviors. It will also complement the human[unreadable] morphology experiments by targeting multi-electrodes in mice to cortical layers in frontal cortex that have[unreadable] been shown to change in depressed patients. To better understand the role of monoamines in depression,[unreadable] we will use multi-electrode arrays to investigate changes in cortical and subcortical neuronal activity in[unreadable] genetically-modified mice that have norepinephrine (NE) and/or serotonin (5-HT) dysfunction. Recently, we[unreadable] have developed a method to record activity simultaneously from multiple single neurons in various brain[unreadable] areas of freely-behaving mice. With this approach, cortical and subcortical neuronal activity will be monitored[unreadable] in several mouse models of depression and under different behavioral and treatment conditions. Briefly, we will study vesicular monoamine transporter 2 (VMAT2) heterozygotes, glycogen[unreadable] synthase kinase 3b (GSK) heterozygotes, and mice carrying a polymorphism in the Tph2 gene that has been[unreadable] identified in depressed patients. Wild type (WT) and mutant mice will be implanted with multi-electrode[unreadable] arrays targeted to the dorsomediofrontal and orbitofrontal cortices, nucleus accumbens (NAc), and central[unreadable] and basolateral amygdala (AMY) - the same sites that imagining studies have shown to be affected in[unreadable] human depressed patients. Multiple electrodes will be targeted to each of these areas simultaneously and[unreadable] neural activity will be assessed in freely-behaving mice under baseline conditions, after exposure to chronic[unreadable] stress, and following treatment with anti-depressants. In addition, as many depressed patients show[unreadable] disturbances in wake-sleep cycles, we will also analyze brain state dynamics throughout the cycle in mice[unreadable] under baseline, stress, and treatment conditions. The experiments we propose will allow for the first time the[unreadable] integration of molecular, cellular, systems, and behavioral data within the same animal and this approach[unreadable] should lead to a more complete understanding of the mechanisms underlying depression.
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1 |
2006 |
Nicolelis, Miguel A. L. |
P41Activity Code Description: Undocumented code - click on the grant title for more information. |
Mri Imaging of Electrode Tracks in Macaque Cortex |
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2007 |
Nicolelis, Miguel A. L. |
R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
Gne 2007: Global Neuroengineering 2007
[unreadable] DESCRIPTION (provided by applicant): The 2007 Global Neuroengineering (GNE 2007) conference will allow key members of the international neuroscience and technology community to come together to discuss recent advances, opportunities, and challenges in key thematic areas of modern brain research. In addition, GNE 2007 will provide a forum to explore the social, ethical, and societal implications of these advances, and to explore pathways that could facilitate and accelerate advances in fundamental neuroscience research, applied clinical medicine, and commercialization of resulting technologies. GNE 2007 will also serve as the inaugural event of the International Neuroscience Network, a project that aims at linking leading neuroscience institutes and centers around the world to help define a global agenda for brain research. One of the main goals of the INN project, sponsored by the recently created International Neuroscience Network Foundation (INNf), is fostering international collaborations that can address fundamental questions in basic and clinical neuroscience. The INNf also aims at helping the creation of world class neuroscience research centers and institutes in developing nations. As a way to demonstrate the commitment of the INNf to this cause, the GNE 2007 will be hosted by the newly created International Institute of Neuroscience of Natal (IINN), a new neuroscience research initiative put forward by a group of Brazilian neuroscientists who work in leading universities in the United States. Through a series of private donations and a partnership with the Brazilian government, the IINN has been created to serve as the "first node" of the International Neuroscience Network in Latin America. By holding the GNE 2007 in Natal, Brazil, the INNf will be able to invite students from all over Latin America to participate in a meeting that will bring together leading scientists working in many areas of modern neuroscience. Such an event, therefore, will allow students and faculty from Latin America and US based neuroscientists to interact and likely establish collaborations between leading US academic institutions and the best Latin American universities. The global explosion of neuroscience research and the resulting cutting edge technologies emerging from this multidisciplinary field have led to groundbreaking advancements in the fundamental understanding of normal brain function as well as to pathophysiological mechanisms underlying neurological disorders. These advances have the potential to impact millions of people worldwide by providing new treatments for serious illnesses such as Alzheimer's or Parkinson's disease, as well as other neural impairments induced by disease or injury. GNE 2007 will bring together leading neuroscientists from the US, Europe, and Japan, as well as students from all over Latin America, along with leading members of the private biomedical industry interested in contributing to the translational of new ideas and technologies to the clinical arena and set the stage for the establishment of a global brain research agenda and for the emergence of broad international collaborations that are likely to significantly impact the future of neuroscience. [unreadable] [unreadable] [unreadable]
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2007 — 2011 |
Nicolelis, Miguel A. L. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Trigeminal System Plasticity During Active Exploration
Understanding the phenomena of adult brain plasticity, triggered either by injury to the nervous system or by learning new skills, will likely provide a fundamental step towards establishing newtherapies for treating neurological disorders. However, the circuit mechanisms underlying neural plasticity remain mostly unknown. Elucidating this question is the central focus of our research program. During the previous funding period, we demonstrated that corticothalamic (CT) projections, originating in the rat primary somatosensory cortex (S1), significantly contribute to the definition of the spatiotemporal structure of the receptive fields of neurons in the ventroposterior medial nucleus (VPM) of the thalamus. Our data also revealed that, following a peripheral deafferentation, CT projections contribute to the ability of VPM neurons to exhibit plastic reorganization. Interestingly, we also found that both the magnitude and duration of tactile responses of S1 and VPM neurons change according to the animal's behavioral state. Together, these results indicate that sensory representations within the thalamocortical loop (TCL) are plastic, dynamically modulated constructs, which emerge from the asynchronous convergence of multiple ascending and descending excitatory and inhibitory afferents. Most recently, we have reported that tactile signal processing across S1 layers is fundamentally different during active versus passive tactile stimulation. For example, task-related modulation of firing rates can begin before tactile stimulation. To date, however, the circuit mechanisms to account for such gross changes in response properties remain largely unknown. Here we propose to test the hypothesis that, during active tactile exploration, multiple corticocortical and corticothalamic projections dynamically modulate the magnitude and duration of tactile responses of S1 and VPM neurons respectively, in order to optimize the discrimination of tactile stimuli. We also propose that learning of a new tactile discrimination task enhances the effects of these "top-down" projections on the TCL. In this project we propose to focus on two major inputs to S1: primary motor cortex (M1) and contralateral S1. Focal reversible inactivation of M1 or S1 would reveal their contribution to TCL responses during motivated discrimination behavior. Chronic recording methods would allow us to follow changes in response statistics over the course of learning the discrimination task. Moveable electrode technology, pioneered in our lab, enables us to correlate the layer structure of S1 responses with anatomically known projections. These experiments offer a window into the nervous system as it dynamically integrates widely distributed neural signals to carry out a non-trivial sensory-motor task, and promise significant revisions to current models of sensation based predominantly on electrophysiological responses to passively delivered stimuli.
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1 |
2009 — 2010 |
Nicolelis, Miguel A. L. |
RC1Activity Code Description: NIH Challenge Grants in Health and Science Research |
Sensorized Neural Prosthetic
DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (06) Enabling Technologies and specific Challenge Topic, 06-HD-101 Improved interfaces for prostheses to improve rehabilitation outcomes. Considerable progress has been made during the last decade in the development of BMIs -- devices that translate brain activity into the commands to artificial actuators, such as prosthetic limbs. Neuroprosthetics based on BMI technology aim to restore limb mobility in people suffering from brain injury, neurological diseases and limb loss. One significant unknown in BMI research is the issue of providing sensory feedback from neuroprosthetics to their users. This gap in the field's knowledge impedes the development of clinically relevant neuroprosthetics because normal motor behaviors, which neuroprosthetic systems strive to reproduce, critically depend on the sensory feedback from the skin, muscle and tendon receptors. To address this problem, we propose developing a sensorized neuroprosthesis in which the signals from touch and pressure sensors of a prosthetic hand are delivered to the brain as spatiotemporal patterns of ICMS of the primary somatosensory cortex. We are well positioned to conduct these experiments and achieve success because of our extensive experience with monkey models of BMIs and previous work in which we used spatiotemporal cortical stimulation to guide animal motor performance. The experiments will be conducted in rhesus macaques trained to grip objects initially using a virtual-environment arm and then a robotic exoskeleton encasing the monkey's own arm. These monkeys will be chronically implanted with multielectrode arrays in cortical motor and somatosensory areas. BMI decoding algorithms will extract motor commands from the neural activity recorded by motor cortex implants. These commands will be used to enact reaching and gripping performed by artificial actuators. Sensations of touch, pressure and texture will be mimicked by spatiotemporal patterns of ICMS delivered through the somatosensory cortex implants. PUBLIC HEALTH RELEVANCE: This study is expected to have a significant impact on the development of clinical neuroprosthetics because it will produce effective techniques for sensorizing prosthetic limbs, making them feel as parts of the body and improving the accuracy of manual operations.
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2010 — 2014 |
Nicolelis, Miguel A. L. |
DP1Activity Code Description: To support individuals who have the potential to make extraordinary contributions to medical research. The NIH Director’s Pioneer Award is not renewable. |
A Virtual Reality Simulator to Study Vlsba and Test Brain-Actuating Technologies
Abstract: For the past 25 years, my research has focused on the investigation of the basic neurophysiological principles that allow neural circuits in the mammalian brain to generate sensory, motor, and cognitive behaviors. To pursue this goal, my laboratory has developed a series of highly innovative experimental approaches that combine electrophysiological, genetic, pharmacological, behavioral, computational, and engineering tools. Utilizing those, our laboratory has pioneered a revolutionary paradigm known as brain-machine interfaces (BMIs). Using BMIs, we have demonstrated that non-human primates and human subjects can effectively use their brain-derived electrical activity to directly control the movements of complex artificial devices, such as computer tools and prosthetic limbs. Yet, BMI research has barely touched the enormous biomedical potential that brain-actuating technologies will likely have in the future of both basic and clinical neuroscience. To start probing this future, I propose to develop the first shared brain-controlled virtual reality environment (BC-VRE) designed to investigate the dynamic properties of very-large scale brain activity (VLSBA) and the full potential of brain-actuating technologies for treating neurological disorders. The core of this virtual reality simulator will be formed by interfacing modern electrophysiological, magnetoenecephalographic (MEG), and brain imaging devices to a supercomputer cluster capable of rendering a virtual reality environment in which all constituent elements, including a variety of computational and robotic tools, and even virtual bodies, can be directly controlled by the VLSBA of interacting subjects. Initially, VLSBA will be obtained using a new method for mega-channel (up to 100,000 single neurons) recordings in non-human primates. Later on, the BC-VRE will also accept local or remote MEG/MRI data from human subjects. The BC-VRE will be initially used to: (1) measure how artificial tools are assimilated by the brain[unreadable]s representation of the subject[unreadable]s body, and (2) test the design of a whole-body neuroprosthetic device for severely paralyzed patients.
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1 |
2010 — 2014 |
Nicolelis, Miguel A. L. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Dorsal Column Stimulation as a New Therapy For Motor Disorders
DESCRIPTION (provided by applicant): In Parkinson's disease (PD), degeneration of dopaminergic neurons enervating the striatum causes progressive impairment of motor function. Treatment strategies involve repetitive administration of dopaminergic precursors or agonists. Although very effective, these strategies decline in efficacy in the long- term. The electrical stimulation of subcortical areas of the brain (deep brain stimulation - DBS) is an effective alternative option, which is rather restricted due to its invasiveness and associated risks. Epidural electrical stimulation of the dorsal spinal cord (dorsal column stimulation - DCS) at the upper thoracic level can lead to a dramatic and instantaneous improvement of locomotion in acute and chronic rodent models of PD. This finding has the potential to translate into a minimally invasive, easy to perform, and inexpensive new treatment for PD, available to a broader group of patients. We propose a comprehensive study addressing the mechanisms and efficacy of DCS using different animal models of PD. Our first specific aim is to study the neuronal mechanisms through which DCS achieves its therapeutic effects;we will use Parkinsonian 6-hydroxydopamine striatal lesioned rats implanted with multi-electrode arrays in eight brain areas, including striatum, subthalamic nucleus, globus pallidus, motor and sensory cortices, thalamus, and substantia nigra pars compacta. The effect of DCS on brain activity will be analyzed in terms of neuronal firing rate and oscillatory and synchrony properties of neuronal populations. In the second specific aim, we will evaluate the long term efficacy of DCS. Mice with a genetic mitochondrial dysfunction, which develop progressive dopaminergic neurodegeneration and severe motor impairment through adult life, will be treated daily with DCS from age 8 weeks until the end of their lives (on average about 28 weeks). Open field activity, catalepsy tests and rotating rod tests will be used to evaluate their motor function and compare it to a sham treated group and a levodopa treated group. Other parameters, like lifespan and body weight will also be used as indicators of the long term efficacy of DCS. The third specific aim is to evaluate DCS in two nonhuman primate species, owl monkeys (Aotus trivirgatus) and rhesus macaques (Macaca mulatta), treated with 6-hydroxydopamine. Rhesus monkeys will provide unique information about the effects of DCS on fine motor bimanual reaching/grasping. Owl monkeys will be used to evaluate the effects of DCS and a DCS/L-dopa combination on general mobility and feeding and drinking behavior. Using the analysis of the electrophysiological recordings obtained from both primate species in cortical and subcortical brain areas related to motor control, we will study the neuronal mechanisms of DCS effects. Our laboratory has a unique expertise in multi-electrode electrophysiological recordings in rodents and primates;this expertise, in combination with our competence in dorsal column stimulation, will allow a comprehensive analysis of both the potential mechanisms through which DCS exerts its effects and whether DCS has potential as a viable future treatment for PD patients. PUBLIC HEALTH RELEVANCE: We propose a comprehensive three-stage study to evaluate electrical stimulation of the spinal cord as a treatment for Parkinson's disease. In the first stage, we will perform a mechanistic study using Parkinsonian rats to examine the effect of spinal cord stimulation on the activity of multiple brain areas;in the second stage, mice genetically programmed to develop Parkinsonian symptoms will be used to evaluate the long-term effect of stimulation on motor function;and in the third stage, the concept will be translated to a primate model, where monkeys will be used to test the efficacy of spinal cord stimulation to alleviate Parkinsonian symptoms.
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1 |
2011 — 2015 |
Nicolelis, Miguel A. L. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Interval Timing and Motor Programming by Cortico-Striatal Ensembles
DESCRIPTION (provided by applicant): Proper timing of movements is crucial for many behaviors of living organisms. Disorders of temporal processing have been linked to neurological diseases, such as aphasia, dyslexia and Parkinson's disease. Neurophysiological studies revealed the involvement of many brain areas in temporal processing, but the neural mechanism of behavioral timing remains poorly understood. This is in part because previous studies examined brain regions in isolation, whereas temporal processing may be fundamentally distributed. To address this problem, we propose a study in which we will apply the methods of multielectrode recordings and neural interfaces to elucidate the mechanisms of motor timing and their plasticity in corticostriatal ensembles. We hypothesize that corticostriatal ensembles simultaneously encode temporal and spatial parameters of motor activities and facilitate learning of new temporal contingencies. This hypothesis will be tested through three specific aims: 1. Identify neural modulations in corticostriatal ensembles underlying temporal programming of movements and their plasticity during learning. Rhesus macaques will be implanted with multielectrode arrays in multiple cortical areas and the striatum. Monkey arm-reaching motor tasks will require both interval timing and directional programming. Novel instructions will be used to introduce learning paradigms. We expect to find that spatial and temporal components of motor tasks are processed and modified conjointly by the corticostriatal system. 2. Develop neural decoders that extract spatial and temporal information from corticostriatal ensembles. We will use neural decoding algorithms (Wiener filter, Kalman filter, discriminant analysis and Markov chains) to extract both temporal and spatial characteristics of motor patterns from large populations of cortical and striatal neurons. We expect to find that overlapping populations of neurons contribute to the extraction of both temporal and spatial characteristics. 3. Develop a real-time paradigm in which temporal and spatial motor behaviors are learned and controlled through a neural interface. Rhesus macaques will perform the same tasks as in Aim 1, but through a neural interface which will use decoding algorithms developed in Aim 2. We expect that corticostriatal ensembles will plastically adapt to this direct brain control. As the outcome of the proposed study we expect to have uncovered essential features of corticostriatal control of temporal sequencing of movements and neural plasticity involved. Moreover, we expect to have created an interface that extracts temporal and spatial parameters of movements in real time. These findings will contribute to therapies of neurological disorders of temporal processing and to neural prosthetics that reproduce decoded motor patterns in assistive devices.
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