Chet T. Moritz - US grants

DESCRIPTION (provided by applicant): The proposed research aims to develop a brain-computer interface that uses chronically-implanted cortical electrodes in the monkey to control stimulation of arm muscles. Monkeys will be trained to match wrist torque targets, and cortical neurons will be identified that are modulated during wrist movements. Subsequently, we will test that these cortical units can be volitionally controlled by the monkey using an operant conditioning paradigm. After temporarily blocking peripheral nerve activity, we will connect the activity of these cortical neurons to control muscle stimulation, and allow animals to learn to produce wrist movements using this artificial circuit. In subsequent experiments, we will develop a small neurochip system that can be attached to the monkey and permit online discrimination of motor cortex activity and convert this activity into stimulation of wrist flexor and extensor muscles. This neurochip system will be completely autonomous, and represents a major step toward permitting artificial stimulating circuits to function during free behavior. The long-term goal of the proposed research is to develop an implantable brain-computer interface capable of bypassing spinal cord lesions and restoring movement to spinal cord injured patients.

DESCRIPTION (provided by applicant): The goal of this research is to develop and test a method to guide repair and regeneration of the central nervous system following injury or degeneration. We propose that by creating both a regenerative environment as well as directing intrinsic plasticity among neurons, we can achieve a new milestone in neural repair. If successful, this approach could be used to treat patients suffering from central nervous system damage such as traumatic brain injury, stroke, or spinal cord injury in order to reduce the burden of neurological disease on individuals and society. Our studies employ a novel combination of targeted electrical microstimulation and stem cell therapies to guide the formation of appropriate and functional connections bypassing an injury. We will test our approach in a rodent model of incomplete cervical spinal cord injury that is representative of insults throughout the central nervous system. It is known that during development of the nervous system, stem cells produce immature astrocytes that create an environment to support axon guidance and synaptic plasticity. Here, we hypothesize that neural plasticity and the repair of damaged neurons can be facilitated by re-creating the developmental phenotype of astrocytes surrounding an injury site. In a first of its kind approach, we will derive immature astrocytes from autologous adult stem cells and transplant them near a spinal cord lesion to create a supportive environment for plasticity and neural repair. We propose that providing environmental support alone has had limited success because it does not address the intrinsic drive of neurons to grow. Synchronous and appropriate neural activity is also needed to direct the formation of functional synaptic connections in the intact and injured nervous system. Here we will use a neuroprosthetic device to deliver microstimulation to targeted sites within the spinal cord below the injury that is synchronized with functionally related activity in the motor cortex. Targeted microstimulation will strengthen appropriate and functional connections via mechanisms of Hebbian plasticity. Rather than attempt long-tract regeneration in the spinal cord, our approach aims to promote the formation of indirect connections via spared pathways bypassing the lesion. The extent of recovery will be measured using behavioral tasks, and electrophysiological and histological methods. This will determine the ability of synchronous, targeted microstimulation to guide implanted stem cells in the formation of appropriate and functional connections following damage to the central nervous system. We contend that microstimulation will collaborate with the transplant environment to produce a multiplicative effect on local plasticity. PUBLIC HEALTH RELEVANCE: This research aims to develop a treatment for damage to the brain or spinal cord as occurs, for example, following traumatic brain injury, stroke, or spinal cord injury. Targeted electrical microstimulation will be applied across the injury in order to guide implanted stem cells to make appropriate connections and restore function following injury.

Over the last decade, the field of neural engineering has demonstrated to the world that a computer cursor, a wheelchair, or a simple prosthetic limb can be controlled using direct brain-machine and brain-computer neural signals. However, technologies that allow such accomplishments do not yet enable versatile and highly complex interactions with sophisticated environments. Today's intelligent systems and robots can neither sense nor move like biological systems, and devices implanted in or interfaced with neural systems cannot process neural data robustly, safely, and in a functionally meaningful way. Doing so requires a critical missing ingredient: a novel, neural-inspired approach based on a deep understanding of how biological systems acquire and process information. This is the focus of this proposal.

The NSF ERC for Sensorimotor Neural Engineering (ERC/SNE or "Center") will become a global hub for delivering neural-inspired sensorimotor devices. Using devices that mine the rich data in neural signals available from implantable, wearable, and interactive interfaces, the ERC/SNE will build end-to-end integrated systems. Examples include: implantable neurochips that can activate paralyzed limbs by electrically stimulating muscles or nerve roots; stationary robots that extract neural signals from a user's touch to provide home-based, post-stroke therapy; neural-controlled adaptive prosthetic limbs that provide sophisticated sensory feedback, and wearable caps that control external exploration devices. Unlike traditional approaches that stress accommodation to the needs of people with neurological disabilities, the ERC/SNE will focus on proactive technologies that provide seamless and adaptive person-machine interaction. It will accomplish this mission with three core engineering thrusts: (1) communication and interface design for devices and data management, (2) reverse and forward engineering of neural systems and neural-inspired devices, and (3) control and adaptation technologies that express sensorimotor functions for individual needs.

The ERC/SNE will nurture future global multidisciplinary leaders. It will develop middle and high school project-based curricula that introduce neural engineering principles to students underrepresented in engineering. It will create multi-institution, undergraduate and graduate Neural Engineering courses with new degree structures and develop vertical research mentoring chains to build a strong research culture from faculty to K-12. It will build long-lasting and deep relationships through faculty and student exchange programs across all disciplines and partnering institutions, with a goal of removing barriers in communication across different fields, countries, and diverse backgrounds. The neural engineering field creates new pathways from the less quantitatively-based biological sciences to the more quantitatively-based engineering fields as well as pathways for people with disabilities to work in an engineering field that addresses their own experience and needs. The women and underrepresented minorities who currently account for over 40% of the Center's leadership team will serve as role models for students and starting faculty. Further, the ERC/SNE will extend its impact by identifying key technologies according to market significance and technical risk. The Center's portfolio will be constructed to deliver a steady stream of innovations over the near and long term. Its industry partnership structure includes not only small and large firms that will help shape Center IPs, but also hospitals and investment firms that will ground research activities to technologies that will truly assist people in need and steer future neural engineering market directions.

The ERC/NSE will strive to enhance the human experience both for persons with neurological disabilities and for the coming generation of global and diverse engineering innovators. The Center's seasoned, multi-disciplinary team will transform healthcare, manufacturing, and the educational infrastructure to guarantee neural engineering global leadership.

Project Summary/Abstract Restoration of hand and arm function is the highest treatment priority for people with cervical spinal cord injury. The goal of this research is to develop and test a novel method to improve recovery of hand and arm function after spinal cord injury. We propose to use optogenetic stimulation of the cervical spinal cord to both improve function and to uncover the mechanisms by which spinal cord stimulation leads to recovery. Our preliminary data demonstrate both a rapid and near complete recovery of forelimb function when animals receive optogenetic spinal cord stimulation following a clinically-realistic cervical spinal cord contusion injury. Optogenetic light stimulation may provide benefits by both directly activating neural circuits and also by increase blood flow to the injured spinal cord. Here we propose to compare the functional recovery resulting from optogenetic and electrical spinal cord stimulation, as well as the combination of electrical and light stimulation delivered to naïve animals that do not express optogenetic proteins. Our experiments are enabled by a novel multifunctional electrode that permits both optical and electrical stimulation to be delivered to the surface of the spinal cord in rodents. These flexible polymer electrodes will be refined in Aim 1 to deliver chronic optogenetic and epidural electrical stimulation to the rat cervical spinal cord. Thus all animals will be implanted with identical hardware prior to being randomized into treatment groups to permit a direct comparison between optogenetic and electrical stimulation in Aim 2. We will use our established rat model of spinal contusion injury where animals are trained to perform precision forelimb reaching to accurately quantify recovery of function after injury. Our collaborative team has developed a reliable method of viral transduction of optogenetic proteins such that light-sensitive ion channels are expressed in neurons of the non-transgenic rat cervical spinal cord. Following 6-weeks of treatment with optogenetic and epidural electrical stimulation, we will explore the mechanisms by which each treatment leads to prolonged recovery of forelimb function in Aim 3. We will perform terminal electrophysiology and record the responses evoked by both optical and electrical stimulation in the same animals. Our preliminary data demonstrate an upregulation of axon growth following optogenetic stimulation. We will use retrograde trans-synaptic tracing and histology to quantify new circuit formation bypassing the injury. Labelled neurons will be co-localized with the neurons activated by optogenetic vs. epidural stimulation using combined in-situ hybridization and immunohistochemistry to illuminate mechanisms of recovery. In summary, we propose to uncover the mechanisms by which optogenetic spinal cord stimulation leads to nearly complete recovery of forelimb function following spinal cord injury. Once understood, we expect these mechanism to directly inspire treatments for a range of neurological traumas to the brain and spinal cord.