Brain-machine interfaces (BMIs) have the potential to restore independence in people with disabilities, yet a compromise between non-invasiveness and performance limits their translational relevance. Here, we demonstrate a high-performance BMI controlled by individual motor units non-invasively recorded from the biceps brachii. Through real-time auditory and visual neurofeedback of motor unit activity, 8 participants learned to skillfully and independently control three motor units in order to complete a two-dimensional center-out task, with marked improvements in control over 6 days of training. Concomitantly, dimensionality of the motor unit population increased significantly relative to naturalistic behaviors, largely violating recruitment orders displayed during stereotyped, isometric muscle contractions. Finally, participants' performance on a spelling task demonstrated translational potential of a motor unit BMI, exceeding performance across existing non-invasive BMIs. These results demonstrate a yet-unexplored level of flexibility of the peripheral sensorimotor system and show that this can be exploited to create novel non-invasive, high-performance BMIs.

Neurophysiological studies in humans and non-human primates have revealed movement representations in both the contralateral and ipsilateral hemisphere. Inspired by clinical observations, we ask if this bilateral representation differs for the left and right hemispheres. Electrocorticography (ECoG) was recorded in human participants during an instructed-delay reaching task, with movements produced with either the contralateral or ipsilateral arm. Using a cross-validated kinematic encoding model, we found stronger bilateral encoding in the left hemisphere, an effect that was present during preparation and was amplified during execution. Consistent with this asymmetry, we also observed better across-arm generalization in the left hemisphere, indicating similar neural representations for right and left arm movements. Notably, these left hemisphere electrodes were largely located over premotor and parietal regions. The more extensive bilateral encoding in the left hemisphere adds a new perspective to the pervasive neuropsychological finding that the left hemisphere plays a dominant role in praxis.

During motor learning, as well as during neuroprosthetic learning, animals learn to control motor cortex activity in order to generate behavior. Two different population of motor cortex neurons, intra-telencephalic (IT) and pyramidal tract (PT) neurons, convey the resulting cortical signals within and outside the telencephalon. Although a large amount of evidence demonstrates contrasting functional organization among both populations, it is unclear whether the brain can equally learn to control the activity of either class of motor cortex neurons. To answer this question, we used a Calcium imaging based brain-machine interface (CaBMI) and trained different groups of mice to modulate the activity of either IT or PT neurons in order to receive a reward. We found that animals learn to control PT neuron activity faster and better than IT neuron activity. Moreover, our findings show that the advantage of PT neurons is the result of characteristics inherent to this population as well as their local circuitry and cortical depth location. Taken together, our results suggest that motor cortex is optimized to control the activity of pyramidal track neurons, embedded deep in cortex, and relaying motor commands outside of the telencephalon.