Research Overview

Spinal cord injury (SCI), stroke, multiple sclerosis, and other chronic neuromuscular disorders impair important motor functions such as locomotion. Current therapies are seldom fully effective. Recent advances introduce a powerful new class of neurotechnologies that can target beneficial plasticity to key CNS pathways. These systems deliver precisely calibrated and focused stimuli to the CNS, evaluate the responses in real-time, and give further stimuli that induce and guide CNS adaptive changes that restore more normal sensorimotor function. NCAN has developed one of the first of these new technologies—operant conditioning protocols that can modify (i.e., target) a specific spinal reflex pathway. The reflex is elicited and the subject is rewarded if reflex size satisfies a criterion. The subject learns to modify cortical control of the pathway to increase the likelihood of receiving a reward. We have shown that this conditioning changes spinal cord neurons and synapses anatomically and physiologically. Furthermore, we have shown that these protocols can be used in both animals and humans to improve behaviors such as locomotion that have been impaired by spinal cord injury or peripheral nerve injury. By targeting specific neuronal pathways, these operant conditioning protocols can address each individual’s particular deficits. They can thereby complement standard therapies for spinal cord injuries and other neuromuscular disorders and enhance the restoration of important motor functions such as locomotion. Thus, they provide a unique and important new approach to neurorehabilitation.

The overall goal of this project is to develop, optimize, and translate into clinical use targeted-plasticity protocols that can modify specific spinal and supraspinal pathways so as to induce and guide beneficial (i.e., rehabilitative) plasticity in the nervous system. The project includes studies in both animals and humans. The animal studies are the first step in the progression toward clinical dissemination; they provide basic science insight, pre-clinical data, and methodological guidance for the initial human studies. Our current animal studies seek to broaden the range and enhance the speed, efficacy, and precision of targeted-plasticity protocols in the treatment of spinal cord injury by combining spinal reflex conditioning with locomotor training to improve locomotion significantly more than either therapy alone. We are also exploring for the first time the molecular biological bases of targeted plasticity and its functional effects.

The human studies of this project seek to optimize the speed and efficacy of reflex conditioning protocols, explore the impact of reflex conditioning in other clinical populations, and create a robust reflex conditioning system suitable for clinical use. Specific projects include: developing, optimizing, and validating a compact, robust, and convenient spinal reflex operant conditioning system suitable for widespread clinical use in collaboration with the Medical University of South Carolina; identifying and using brain signal (EEG) features that drive operantly conditioned reflex change to increase the reliability, magnitude, and speed of reflex conditioning; exploring the efficacy of spinal reflex conditioning for reducing spasticity in adults with cerebral palsy in collaboration with Burke Neurological Research Institute of Cornell University; and developing novel multi-electrode arrays and associated hardware to automate EMG electrode placement and nerve stimulation in collaboration with Axion Biosystems.

In summary, the work of this project will extend the range and augment the reliability, rate, efficacy, and precision of targeted-plasticity protocols, explore their use in new clinical populations, and instantiate these protocols in systems suitable for widespread clinical dissemination.

The development and use of adaptive neurotechnologies is an inherently multidisciplinary endeavor, involving neuroscience, biomedical engineering, electrical and computer science, and clinical domains. The integration of knowledge and ideas from these diverse areas, and their implementation by highly sophisticated software/hardware systems, requires substantial time, effort, and multidisciplinary expertise. The lack of readily accessible and highly adaptable systems that can support scientific and clinical laboratories in their investigation of adaptive neurotechnologies slows progress in research and development and limits the number of groups that are successful in realizing and disseminating these technologies.

Over the past 18 years, we have developed and disseminated BCI2000, a software platform that supports complex real-time closed-loop interactions with the CNS, and can implement a wide range of adaptive neurotechnologies. To date, we have provided BCI2000 to more than 6,000 users worldwide; they have used it to support real-time experiments described in over 1,200 peer-reviewed publications. New support through the NIH ensures the continued development, validation, and dissemination of BCI2000; and thus ensures its continued ability to enhance the scientific productivity of its users.

This fortunate new environment, in which the continued viability and further development of BCI2000 is assured, enables NCAN to focus its efforts on providing highly adaptable BCI2000-based systems that address major categories of adaptive neurotechnology research and development. These systems are being developed in cooperation with NCAN’s other Technology Research and Development (TR&D) projects.

The first system will be a wholly-implanted and telemetry-based platform that supports long-term 24/7 interactions with the CNS in rats and other small laboratory animals. This system will enable implementation and exploration of a wide variety of protocols that can target plasticity to specific CNS pathways and thereby modify sensorimotor function, including those that use operant conditioning, vagal nerve stimulation, or other stimulation regimens. This new system is being developed, optimized, and validated in cooperation with TR&D 1. The system will support a broad spectrum of basic science endeavors and provide pre-clinical data for novel therapeutic interventions.

The second system will provide a robust platform for clinical researchers to explore targeted plasticity protocols that guide beneficial plasticity to enhance functional recovery for people with stroke, spinal cord injury, or other neuromuscular disorders. This highly adaptable real-time system will handle multimodal data (e.g., EMG, EEG, kinematic, video), perform online analyses, provide ongoing feedback, and store all data in a standard format through an interface between BCI2000, which handles all online operations, and the Blackfynn data management platform. This system will support a wide variety of single- and multi-site clinical studies exploring novel technology-based therapeutic interventions.

The third system will enable detailed functional analysis of cortical/subcortical connections and supports interventions that can target specific changes in these connections and the behaviors to which they contribute. We plan to develop a bedside-based system for mapping these functional connections by stimulating and recording through electrocorticographic (ECoG) and/or stereoencephalographic (SEEG) electrodes arrays and for targeting modifications in them using closed-loop feedback and other methods. This new system will be developed, optimized, and validated in cooperation with TR&D3.

By creating, optimizing, validating, and disseminating these three systems, NCAN’s system development will provide scientists, engineers, and clinicians with the ability to address important scientific and clinical problems, and it will thereby advance the creation, development, and use of valuable new neurotechnologies that can reduce the devastating impact of neuromuscular disorders.

Neurological and psychiatric disorders affect millions of people in the United States and worldwide. Improving diagnosis and treatment of these disorders requires real-time technologies that can interact with the processes underlying brain function. Recent work from NCAN and other laboratories has produced powerful new automated computer-based methods for learning how brain regions interact to produce specific behaviors and how brain processes modulate these interactions. While some methods have unprecedented precision (e.g., detection of intra-cortical interactions in individual trials), use of stimulation protocols to produce beneficial changes in these interactions remains very rudimentary, due in large part to a lack of understanding of the short- and long-term changes that result from targeted electrical stimulation of brain networks.

NCAN’s long-term goal is to develop and iteratively optimize a new generation of adaptive neurotechnologies that can introduce predictable changes in brain networks, and to clinically test the efficacy of those technologies for alleviating the devastating effects of neurological disorders such as stroke, Parkinson’s disease, or chronic pain. To achieve this goal, we are taking advantage of the spatial and temporal precision of stimulation and recording using brain surface (electrocorticographic (ECoG)) or depth (stereoencephalographic (SEEG)) electrodes to advance our understanding of the short- and long-term changes introduced by electrical stimulation. Using the BCI2000-based electrical stimulation and recording platform being developed at NCAN #link to TR&D2#, we are identifying brain regions that are involved in an auditory reaction-time task, and determining the short-term and persistent effects of electrical stimulation of discrete parts of this auditory and other connected cortical networks.

To validate and optimize the stimulation/recording platform and associated protocols, we are engaging in two collaborative projects. With NIH-funded scientists at the University of California (Berkeley), we will use the platform and its protocols to stimulate frontal cortical areas to produce predictable changes in gambling behavior. With NIH-funded scientists at MIT, we will use the device and specific protocols to map cortical functional connectivity, and we will compare the results to the anatomical connectivity derived by diffusion tensor imaging (DTI).

In summary, we expect that this project will produce new understanding of how electrical stimulation produces short-term and persistent changes in brain function. Together with the new stimulation system produced by TR&D2, this understanding should greatly increase our ability to produce specific beneficial changes in brain function that enable new treatment options for a wide range of neurological disorders.