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.