Karen A. Moxon - US grants

[unreadable] DESCRIPTION (provided by applicant): In 1999 we reported an important demonstration of a working brain-machine interface (BMI), in which recordings from multiple, single neurons in sensorimotor cortical areas of rats were used to directly control an arm to retrieve a water reward (Chapin, Moxon et al., 1999). Recent studies in humans with spinal cord injury have shown that recording from multiple, single neurons can be used by the patient to control the cursor on a computer screen. The promise is that one day it will be possible to use these control signals from neurons to re-activate the patient's own limbs. However, the ability to record from large populations of single neurons for long periods of time has been hampered because either the electrode itself fails or the immunological response of the tissue surrounding the microelectrode produces a glial scar, preventing single-neuron recording. While appropriate insulating materials have largely solved the problem of electrode failure, much less is known about the immunological response to insertion of a microelectrode, its effect on neuronal recordings and, of greatest importance, how it can be reduced. The long-term goal of our work is to develop a bioactive, multisite, single neuron recording electrode that can record at least one single neuron from 100% of the recording sites for more than one year in rat and ten years in primates. The objective of this proposal is to identify intervention strategies that, when combined, will allow high quality, single neuron recordings for one year in the rat. It is our central hypothesis that because the development of a glial scar is due to two separate mechanisms: mechanical damage to neurons due to electrode insertion and sustained immunological response to the foreign body (i.e., the microelectrode), multiple interventions are necessary to ensure long-term recordings of single neurons. The rationale for this proposal is that if both of these mechanisms that contribute to the glial scar are ameliorated, then it will be possible to record more single neurons, longer, with better signal-to-noise. We use immunohistochemistry and electrophysiology to assess the effect of different interventions on the formation of a glial scar and neuronal activity. We are well prepared to undertake this research because we have experience in 1) electrophysiological recordings for BMI, 2) electrode development, having developed a ceramic-based, multi-site microelectrode recording device (CBMSE array), with superior strength and insulating properties compared to silicon based microelectrodes, 3) immunohistochemical methods to study the effects of injury on neuronal tissue and 4) the study of the mechanisms of neural cell injury and the effects of repair agents on neuronal survival. There are three primary motivations for perfecting the ability to record single neurons for long periods of time from chronically implanted arrays of microelectrodes: 1) to better understand neuronal function, 2) to develop novel brain-machine interface devices and sensors and 3) for clinical applications in neurorobotics. While it has been demonstrated that chronically implanted microelectrodes can be used as the neural interface in a brain machine interface for the treatment of paralyzed and disabled patients, if the neural interface could be enhanced such that the neuronal recordings can be sustained for decades, then the maximum potential benefit can be realized. However, in the short term, even moderate improvements in the recording capabilities of microelectrodes will enhance our ability to understand how ensembles of neurons code for motor commands, the role of plasticity in these circuits and most importantly how these circuits in the brain are modified after disease or injury. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Exercise induces changes in somatotopic maps of the somatosensory or motor cortices of animals with brain or peripheral nerve injuries and these changes are related to functional recovery. In the case of spinal cord injury (SCI), exercise also improves recovery, but the effect of exercise on cortical organization after SCI is not well understood. The effect of SCI alone on cortical organization is well studied and SCI can alter somatotopic maps in two ways. The first is sometimes referred to as "silencing". This refers to the case when the region of the somatosensory cortex most affected by the injury does not respond to any cutaneous stimulation. The second possibility is that the affected region develops a novel somatotopic organization, such that the cells in this region respond to stimulation of peripheral areas innervated from spinal segments rostral to the injury. Cortical plasticity after spinal cord injury is likely to aid in learning novel sensorimotor strategies to maximize recovery. However, the effect of exercise on cortical organization after spinal cord injury is rarely addressed. Therefore, the relationship between changes in cortical organization and functional recovery after SCI remains unclear. The goal of this proposal is to determine if the cortical reorganization induced in response to therapeutic interventions after SCI contributes to improved functional recovery. To determine this, we will identify the relationship between cortical reorganization and functional recovery. Our central hypothesis is that reorganization of neuronal circuits in the cortex after mid-thoracic transection is necessary for functional recovery. Our preliminary data suggest that rats with mid-thoracic transection that receive therapeutic interventions to improve functional recovery demonstrate novel cortical organization in the brain such that deafferentated regions of the cortex are no longer silent after the spinalization. Moreover, in neonatally spinalized rats that achieve weight supported stepping, the novel cortical organization is correlated with functional recovery. We suggest, therefore, that reorganization of the cortex may play an important role in functional recovery. Our central hypothesis will be tested using two Specific Aims: Aim 1 Evaluate the role of reorganization in the sensorimotor cortex on the functional recovery of spinalized rats that receive exercise as a therapeutic intervention. Aim 2 Evaluate the role of reorganization in the sensorimotor cortex on the functional recovery of spinalized rats that receive exercise combined with serotonergic pharmacotherapy. PUBLIC HEALTH RELEVANCE: Brain reorganization after spinal cord injury Spinal cord injury affects more than 200,000 individuals in the United States and approximately 10,000 more patients sustain spinal cord injuries each year. When a person receives an SCI, the communication between the brain and other parts of the body is disrupted, and messages no longer flow past the damaged area. The goal of this project is to understand plasticity in the brain so that after injury, the brain can reorganize to improve function in patients.

PI: Moxon, Karen A.
Proposal Number: 1402984
Institution: Drexel University
Title: Sources of adaptation during BMI control

There are currently over 270,000 people who have sustained a debilitating spinal cord injury costing the nation $9.73 billion per year on healthcare and lost productivity. Most of these people are paralyzed from at least the waist down and restoring voluntary control of their legs is among their most desired outcomes. Importantly, significant advances have been made in developing improved stimulators that can activate nerves or muscles of the legs and restore movement. At the same time, scientists have demonstrated the ability to record the activity of neurons in the brain, decode information about the intention of a patient to move their limbs and then use that information to control a robotic device or exoskeleton. The goal of this project is to combine these technologies and develop optimal decoders that can "translate" the patterns of activity of neurons in the brain to information that could be used to control electrical stimulation and restore volitional control of the patients own legs. This work is important because it represents an innovative approach to restoring a patient?s autonomy after a debilitating spinal cord injury. A broader impact of this research is that this approach could likely be applied to other neurological disorders or diseases. Additional broader impacts include the fact that this work is part of a larger Neuroengineering Program at Drexel University that both trains students and develops outreach programs. This project will contribute to the program by raising awareness about spinal cord injury while providing opportunities for students to participate in engineering design and development at all levels of education (K-12, undergraduate, graduate). Importantly, this is an interdisciplinary program involving engineers, biologists and neuroscientists in a team effort to solve a complex problem and special emphasis will be placed on the education of women and other underrepresented groups in science, technology and engineering.

To date, most brain-machine interface (BMI) studies have been done in healthy animal models. While these data show extensive adaptation of neurons to "learn" to control an external device, the problem is that extensive plasticity and reorganization occur after injury and the effects of this on BMI are unknown. The long-term goal of this project is to design effective decoders as part of a closed-loop BMI system that could control functional electrical stimulation after spinal cord injury to restore volitional control of a patient's own limbs. The central goal of this proposed work is to assess the relative role of the decoding algorithm compared to that of task complexity on neural adaptation both before and after complete spinal cord injury. This goal will be accomplished by using an innovative BMI paradigm that allows a rat to continuously interact with the decoder while performing a task 1) they are highly motivated to perform, 2) does not require training and 3) they can perform even after a complete spinal transection. The task requires the animal to maintain its balance in response to unexpected perturbations of posture using neural control (i.e. BMI). Using this novel BMI paradigm, the central goal of this proposal will be addressed with two Aims. Aim 1 is to identify computational mechanisms used by primary motor cortex for the control of balance. This Aim will be accomplished by comparing encoding mechanisms utilized by healthy rats to those of rats with spinal transection in the tilting task by recording and analyzing the activity of populations of single neurons, electromyography from hindlimb flexors and extensors and ground reaction forces. Aim 2 is to compare the adaptability of neurons during BMI control using different decoders and tasks. This Aim will be accomplished by comparing the adaptability of neurons recorded from healthy animals to those recorded from rats with spinal transection using variations of the tilting task in a closed-loop BMI paradigm.

Project Summary It is becoming increasingly evident that plasticity within supraspinal networks, induced by therapeutic interventions, is necessary for optimal recovery of function after spinal cord injury. We have developed a novel combination therapy of motorized bike, 5-HT replacement therapy and treadmill training that can restore open-field weight-supported stepping (BBB score >9) in animals with complete spinal transection. Our preliminary data suggest that both supraspinal neuronal and glial plasticity modulated by therapy and that they influence each other. The central hypothesis of this proposal is that therapy combined with strategies to either promote beneficial neural/glial plasticity and/or attenuate deleterious plasticity (e.g., astrogliosis and inflammation) will enhance supraspinal remodeling and improve functional outcome. This Aim will be addressed with two Specific Aims. Aim 1: Investigate the impact of therapy on functional recovery and supraspinal plasticity after SCI as measured by changes in neurons and glial cells and their relationship to functional recovery. Aim 2: Determine if combining NCTherapy with: (A) strategies to enhance supraspinal plasticity (e.g. via brain-machine interface (BMI) training) and/or (B) inhibiting aspects of reactive gliosis (e.g. modulate TNF activity) is more effective than NCTherapy alone in improving functional recovery after SCI. The results of this work will aid in the development of therapies for recovery of volitional control of movement. Moreover, results could be used for translational research to develop assistive devices to maintain balance (e.g. cortical control of an exoskeleton or functional electrical stimulation). Glial plasticity is defined as a change in the number and or ?activation? of astrocytes and microglia in response to SCI or therapy after SCI. Neuronal plasticity includes changes in the organization of sensorimotor cortex and in neuronal firing patterns that carry information about sensory and motor events. The combined Bethea and Moxon labs have extensive experience measuring and manipulating glial and neuronal plasticity after spinal cord injury. By combining expertise, we can address, for the first time, how these two systems, neuronal and glial, interact to promote functional recovery. We will compare results from a series of 9 Experiments in animals with a complete spinal transection to those with a severe spinal contusion. These Experiments will assess electrophysiology changes (Experiments 1-4), the effect of lesioning the reorganized cortex (Experiment 5) and trace the source of this reorganization (Experiment 6). In Experiment 7, the impact of therapy on differences in spared fibers that cross the lesion will be measured. Finally, difference in the proteins/ genes associated with neuroplasticity and inflammation in the brains of animals will be compared between transected and contused animals (Experiments 8 and 9).