Jaimie M. Henderson, M.D. - US grants

? DESCRIPTION (provided by applicant): Difficulty with communication is a widespread problem, reported by more than 2 million people in the US. Communication may be a particular challenge for people with total paralysis (Locked-in Syndrome or LIS) from disorders such as brainstem strokes or advanced Amyotrophic Lateral Sclerosis (ALS). People with these disorders rely on augmentative and alternative communication (AAC) technology that can be inefficient, often not designed with their unique access needs in mind, and therefore frustrating to implement successfully. Brain-computer interface (BCI) systems provide one promising avenue for restoring communication capabilities to people with LIS. However, these systems currently offer performance well below that achievable by able-bodied computer users. The overall objective of the proposed research is to evaluate advanced neural decoding methods and interfaces for a high-performance communication system for people with LIS. To accomplish this, we propose 3 Specific Aims as follows. Aim 1: We will evaluate whether advanced decoding techniques developed in the animal laboratory can improve continuous point-and-click control of a computer cursor from signals decoded from human motor cortex. Aim 2: We will optimize parameters for high-speed discrete target selection (i.e., typing) by decoding movement intent from pre-motor cortex. Aim 3: We will test new communication interfaces based on the results of Aims 1 and 2 against each participant's usual AAC system, with the goal of providing faster and easier communication. Finally, we will assess the ability of research participants to control a commercial computer GUI and typing interface while switching between continuous and discrete decoding.

? DESCRIPTION (provided by applicant): Severe to moderate traumatic brain injury (smTBI) annually afflicts many hundreds of thousands of Americans producing chronic cognitive disabilities that lack effective treatments. The present proposal will develop a critical first-in-an early clinical feasibility study to support a next generation device to provide central thalamic deep brain stimulation (CT-DBS). CT-DBS is proposed as a therapy for the survivors of smTBI who recover to independent functional levels but remain significantly limited in their activities b chronic cognitive impairment (difficulties with sustained attentional effort, working memory, processing speed and fatigue). Stakeholders, including patients identifying their cognitive difficulties as matched to the functions proposed to be supported by CT-DBS, have shown support for this approach and willingness to consider participation after having the concepts and risks of this approach presented to them. The working hypothesis for the present study is that the pattern of cognitive deficits seen after smTBI takes origin in a broad reduction of neuronal connections and cell loss produced by smTBI that will on average produce disproportionate down-regulation of frontostriatal systems and deafferentation of the central thalamus (which collectively support the range of executive cognitive functions typically impaired in smTBI), and that CT-DBS can activate these systems sufficiently to provide effective functional improvements. Preliminary studies including evidence of CT-DBS facilitation of cognitive function in a different, more severely brain-injured population of patients with traumatic brain injuries as well as pre-clinical behavioral, electrophysiological, and computational modeling studies in intact non-human primates (NHP) support the hypothesis and the approach. The present study will use bilateral placement of a research single- electrode system with sensing and recording capabilities to aid the electrophysiological mapping of the central thalamus. Our supporting data demonstrate that behavioral facilitation can be achieved with a single electrode system in both the human and NHP. In NHP studies we have found that a more reliable and robust therapeutic response can be achieved through the use of a multiple electrode system capable of targeted delivery of electric fields across a specific fiber tract in the central thalams. Here we will obtain and analyze neuroimaging, computational modeling, behavioral, and electrophysiological data from human subjects to advance the development of a next-generation system that may allow more flexibility and reliability of for the application of CT-DBS in patients with traumatic brain injuries. These studies will be carried out by an investigative team with multiple, long-standing collaborations aimed at the development of CT-DBS technologies and treatment of cognitive impairment following TBI; the team spans expertise in clinical trials, neurology, neurosurgery, neurophysiology, neurorehabilitation, neuropsychology, radiology, and computational modeling. The early feasibility study proposed has been through a presubmission review for an Investigational Device Exemption with the Food and Drug Administration.

PROJECT SUMMARY While current augmentative and alternative communication (AAC) devices present a variety of access methods for message generation to benefit people with complex communication needs, there still exists a group of literate adults with severe speech and motor impairments (SSMI) who cannot identify a functional means for typing, which is an important tool for computer-based communication. In prior NIDCD- supported research, our research team developed a high performance intracortical brain-computer interface (iBCI) that decodes movement intentions directly from brain activity. This technology has allowed people to control a cursor on a computer screen for communication simply by imagining movements of their own arm. The proposed R01 clinical research will extend this prior work on improving the performance of iBCI systems, as part of the multi-site BrainGate consortium, and utilizing a new fully- implantable, wireless system being developed under separate NIH BRAIN Initiative funded project. The goals of the project are to leverage the discovery of new motor and cognitive signals in human motor cortex to implement and evaluate three new methods for iBCI typing and general purpose computer use: (1) an automatic Error Detect and Undo (EDU) system that uses error-related signals from motor cortex, (2) decoding techniques that create continuous high degree-of-freedom control signals from motor cortex to increase rates of point-and-click iBCI typing in 3D and 4D as compared with 2D, and (3) decoding techniques that classify multiple different ?click? signals from motor cortex. A rigorous uniform experimental procedure with clear evaluation metrics will be utilized across all three Specific Aims, in all three research participants, and at each clinical site using a standardized suite of iBCI tasks, assuring consistency across sessions and participants. Upon completion, this project will advance both the capabilities of iBCIs for communication and our understanding of the function of human motor cortex.

PROJECT SUMMARY Augmentative and alternative communication (AAC) technology for people with severe speech and motor impairment (SSMI) continues to improve, with recent advances being made in the neural control of communication devices. In prior NIDCD-supported research, our research team developed a high-performance intracortical brain-computer interface (iBCI) that decodes arm movement intentions directly from brain activity. This technology has allowed people with SSMI to control a computer cursor with sufficient speed and accuracy to type at up to 8 words/min and has enabled full control of unmodified consumer devices using only decoded motor cortical activity. In the proposed U01 clinical research, performed as part of the multi-site BrainGate consortium, we will build upon decades of experience in studying the motor system in humans and non-human primates, with the end goal of advancing iBCI technology. The goals of this project are to study how speech is prepared and produced at the level of ensembles of single neurons in speech-related motor areas of the brain in people with amyotrophic lateral sclerosis (ALS), and to create a speech prosthesis that will allow communication at rates approaching conversational speech (120-150 words per minute). We will approach these investigations with a suite of advanced methods, including (1) newly-developed dynamical systems computational approaches that have provided fundamental insights into the function of the motor system, and (2) machine learning algorithms for decoding of movement intention and language modeling that have formed the basis of the fastest communication prosthesis yet reported. Finally, we will continue to evaluate the safety profile of Utah-array based iBCIs through the ongoing BrainGate2 pilot clinical trial. Upon completion, this project will advance both the capabilities of iBCIs for communication and our understanding of the detailed neural mechanisms of speech production.