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Treadmills are a convenient tool to study animal gait and behavior. Traditional animal treadmill designs often entail preset speeds and therefore have reduced adaptability to animals’ dynamic behavior, thus restricting the experimental scope. Fortunately, advancements in computer vision and automation allow circumvention of these limitations. Here, we introduce a series of real-time adaptive treadmill systems utilizing both marker-based visual fiducial systems (colored blocks or AprilTags) and marker-free (pre-trained models) tracking methods powered by advanced computer vision to track experimental animals. We demonstrate their real-time object recognition capabilities in specific tasks by conducting practical tests and highlight the performance of the marker-free method using an object detection machine learning algorithm (FOMO MobileNetV2 network), which shows high robustness and accuracy in detecting a moving rat compared to the marker-based method. The combination of this computer vision system together with treadmill control overcome the issues of traditional treadmills by enabling the adjustment of belt speed and direction based on animal movement.

While the movement of rodents can be paused by optogenetic stimulation of a brainstem nucleus, the pedunculopontine nucleus (PPN), it is unknown whether this response has a functional purpose. The arrest appears conspicuously similar to fear-induced freezing behavior and could constitute a general halting mechanism for movement without an emotional component. Further, it is unclear to what extent brain activity is affected by the evoked motor arrest. Here, we investigate this phenomenon by engaging a distinct brain activity, the hippocampal theta rhythm. The theta rhythm is prominent during locomotor activity, absent under normal immobile situations, yet present under vigilant states like fear-induced freezing. Specifically, we ask whether the PPN-induced motor arrest has the same effect on the theta rhythm as if the animal would perform a volitional arrest, which results in the disappearance of the theta rhythm, or whether it would cause a continuation of the theta rhythm as would be expected by a fear-induced motor arrest. An alternative hypothesis is that the theta rhythm represents an ongoing intention to move rather than the movement itself. To distinguish between these two possibilities, we recorded the hippocampal brain rhythm before and during movement arrest induced by optogenetic stimulation of the PPN in rats. The PPN-induced motor arrest was associated with a clear obstruction of the ongoing theta activity. The timescale of movement arrest was less than 200 ms, similar to the obstruction of the theta rhythm. Since fear and behavioral freezing are associated with hippocampal theta rhythm, which we did not see during PPN stimulation, we suggest that induced motor arrest occurs without an associated emotional component. Further, our experiments reveal that the theta rhythm during motor activity does not represent an intention, but rather the ongoing sensory-motor state.

A spinal cord injury interrupts the communication between the brain and the region of the spinal cord that produces walking, leading to paralysis 1 , 2 . Here, we restored this communication with a digital bridge between the brain and spinal cord that enabled an individual with chronic tetraplegia to stand and walk naturally in community settings. This brain–spine interface (BSI) consists of fully implanted recording and stimulation systems that establish a direct link between cortical signals 3 and the analogue modulation of epidural electrical stimulation targeting the spinal cord regions involved in the production of walking 4 – 6 . A highly reliable BSI is calibrated within a few minutes. This reliability has remained stable over one year, including during independent use at home. The participant reports that the BSI enables natural control over the movements of his legs to stand, walk, climb stairs and even traverse complex terrains. Moreover, neurorehabilitation supported by the BSI improved neurological recovery. The participant regained the ability to walk with crutches overground even when the BSI was switched off. This digital bridge establishes a framework to restore natural control of movement after paralysis. A reliable digital bridge restored communication between the brain and spinal cord and enabled natural walking in a participant with spinal cord injury.

Epidural electrical stimulation (EES) targeting the dorsal roots of lumbosacral segments restores walking in people with spinal cord injury (SCI). However, EES is delivered with multielectrode paddle leads that were originally designed to target the dorsal column of the spinal cord. Here, we hypothesized that an arrangement of electrodes targeting the ensemble of dorsal roots involved in leg and trunk movements would result in superior efficacy, restoring more diverse motor activities after the most severe SCI. To test this hypothesis, we established a computational framework that informed the optimal arrangement of electrodes on a new paddle lead and guided its neurosurgical positioning. We also developed software supporting the rapid configuration of activity-specific stimulation programs that reproduced the natural activation of motor neurons underlying each activity. We tested these neurotechnologies in three individuals with complete sensorimotor paralysis as part of an ongoing clinical trial ( www.clinicaltrials.gov identifier NCT02936453). Within a single day, activity-specific stimulation programs enabled these three individuals to stand, walk, cycle, swim and control trunk movements. Neurorehabilitation mediated sufficient improvement to restore these activities in community settings, opening a realistic path to support everyday mobility with EES in people with SCI. Implantation of a multielectrode paddle that allows personalized electrical stimulation to all regions of the spinal cord involved in leg and trunk movements rapidly restores motor function in patients with spinal cord injury with complete paralysis.

A spinal cord injury interrupts pathways from the brain and brainstem that project to the lumbar spinal cord, leading to paralysis. Here we show that spatiotemporal epidural electrical stimulation (EES) of the lumbar spinal cord 1 – 3 applied during neurorehabilitation 4 , 5 (EES REHAB ) restored walking in nine individuals with chronic spinal cord injury. This recovery involved a reduction in neuronal activity in the lumbar spinal cord of humans during walking. We hypothesized that this unexpected reduction reflects activity-dependent selection of specific neuronal subpopulations that become essential for a patient to walk after spinal cord injury. To identify these putative neurons, we modelled the technological and therapeutic features underlying EES REHAB in mice. We applied single-nucleus RNA sequencing 6 – 9 and spatial transcriptomics 10 , 11 to the spinal cords of these mice to chart a spatially resolved molecular atlas of recovery from paralysis. We then employed cell type 12 , 13 and spatial prioritization to identify the neurons involved in the recovery of walking. A single population of excitatory interneurons nested within intermediate laminae emerged. Although these neurons are not required for walking before spinal cord injury, we demonstrate that they are essential for the recovery of walking with EES following spinal cord injury. Augmenting the activity of these neurons phenocopied the recovery of walking enabled by EES REHAB , whereas ablating them prevented the recovery of walking that occurs spontaneously after moderate spinal cord injury. We thus identified a recovery-organizing neuronal subpopulation that is necessary and sufficient to regain walking after paralysis. Moreover, our methodology establishes a framework for using molecular cartography to identify the neurons that produce complex behaviours. Transcriptomic analysis following epidural electrical stimulation of the lumbar spinal cord during neurorehabilitation in mice identifies a population of neurons that orchestrates the restoration of walking following paralysis.

Spinal cord injury leads to severe locomotor deficits or even complete leg paralysis. Here we introduce targeted spinal cord stimulation neurotechnologies that enabled voluntary control of walking in individuals who had sustained a spinal cord injury more than four years ago and presented with permanent motor deficits or complete paralysis despite extensive rehabilitation. Using an implanted pulse generator with real-time triggering capabilities, we delivered trains of spatially selective stimulation to the lumbosacral spinal cord with timing that coincided with the intended movement. Within one week, this spatiotemporal stimulation had re-established adaptive control of paralysed muscles during overground walking. Locomotor performance improved during rehabilitation. After a few months, participants regained voluntary control over previously paralysed muscles without stimulation and could walk or cycle in ecological settings during spatiotemporal stimulation. These results establish a technological framework for improving neurological recovery and supporting the activities of daily living after spinal cord injury. Spatially selective and temporally controlled stimulation of the spinal cord, together with rehabilitation, results in substantial restoration of locomotor function in humans with spinal cord injury.

Spinal cord injury (SCI) induces haemodynamic instability that threatens survival 1 – 3 , impairs neurological recovery 4 , 5 , increases the risk of cardiovascular disease 6 , 7 , and reduces quality of life 8 , 9 . Haemodynamic instability in this context is due to the interruption of supraspinal efferent commands to sympathetic circuits located in the spinal cord 10 , which prevents the natural baroreflex from controlling these circuits to adjust peripheral vascular resistance. Epidural electrical stimulation (EES) of the spinal cord has been shown to compensate for interrupted supraspinal commands to motor circuits below the injury 11 , and restored walking after paralysis 12 . Here, we leveraged these concepts to develop EES protocols that restored haemodynamic stability after SCI. We established a preclinical model that enabled us to dissect the topology and dynamics of the sympathetic circuits, and to understand how EES can engage these circuits. We incorporated these spatial and temporal features into stimulation protocols to conceive a clinical-grade biomimetic haemodynamic regulator that operates in a closed loop. This ‘neuroprosthetic baroreflex’ controlled haemodynamics for extended periods of time in rodents, non-human primates and humans, after both acute and chronic SCI. We will now conduct clinical trials to turn the neuroprosthetic baroreflex into a commonly available therapy for people with SCI. An epidural spinal cord stimulation system regulates blood pressure in the acute and chronic phases of spinal cord injury.

Walking is fundamental to humans and animals, yet the neural principles underlying movement generation remain unclear. In particular, the relationship between neuronal cell types, networks, and functions has been difficult to establish. Here, we propose that the spatial organization of the spinal cord governs network-driven locomotor rhythms and patterns. An asymmetric “Mexican hat\" connectivity - local excitation with longer-range inhibition and a longitudinal skew - accounts for proper motor dynamics, while segregation of cell types in the transversal plane allows descending fibers to find appropriate targets and control network dynamics. We extract these principles via a model of the mouse spinal cord, where synaptic connections are sampled probabilistically from cell-specific projection patterns derived from single-cell RNA sequencing and spatial transcriptomics. Essential aspects of locomotion are induced and controlled without extensive parameter optimization. We additionally predict propagating activity bumps during rhythmic movement. This work reveals universal spatial principles linking cell types, connectivity, and behavior across species. Neural mechanisms underlying rhythmic motor behaviors are not fully understood. Here authors propose a theory of how the nervous system generates and controls walking, which entails a spatial layout of spinal nerve cells that form longitudinal connectivity patterns of a ‘Mexican hat’, i.e. local excitation and long-range inhibition.

Walking, stopping and maintaining posture are essential motor behaviors, yet the underlying neural processes remain poorly understood. Here, we investigate neural activity behind locomotion and its walk-to-stop transition. Based on a new theory of the lumbar spinal cord(1,2) we propose and predict that spinal population activity contains limit cycle dynamics to drive walking and fixed-point attractors for stopping. To test these predictions we record neural activity in lumbar cord of freely moving rats using Neuropixels probes3. To control stopping, we stimulate a brainstem nucleus, known to induce motor arrest(4-7). We find: During locomotion, the population activity of lumbar spinal neurons exhibits rotational dynamics(8-10). These dynamics unfold within a low-dimensional locomotor manifold(11,12), a looping set of trajectories that serves as the repeating signature of locomotion, that also behaves as a limit-cycle attractor. Shortly before stopping, the neural state rapidly changes from the locomotor manifold to a \"postural\" fixed point attractor. When kicking the state out of the fixed point using perturbations it shifts to a nearby albeit different fixed point. Repeated stoppings form a local quasi-continuum of fixed points representing various poses - i.e. a postural manifold. These observations are in agreement with our theory, which further indicates the mechanistic roles for subpopulations of spinal interneurons for controlling walking and stopping. Besides explaining the data, our theory makes further predictions to be tested in future experiments.Competing Interest StatementThe authors have declared no competing interest.Footnotes* Minor improved in the text. Supplementary data and methods section now included as separate files.Funder Information DeclaredLundbeck Foundation, https://ror.org/03hz8wd80, R366-2021-233Novo Nordisk (Denmark), https://ror.org/0435rc536, NNF23OC0082192Swiss National Science Foundation, https://ror.org/00yjd3n13, P500PB_206824European Innovation Council, https://ror.org/05cx8cy07, 101130161

Generation of locomotion is a fundamental function of the spinal cord, yet the underlying principles remain unclear. In particular, the relationship between neuronal cell types, networks and functions has been difficult to establish. Here, we propose principles by which functions arise primarily from spatial features of the cord. First, we suggest that projections of distinct cell types constitute an asymmetrical \"Mexican hat\" topology, i.e. local excitation and surrounding inhibition with dissimilar length of projection along the rostro-caudal axis. Second, this projection topology constitutes the mechanism of rhythm- and pattern generation of mammalian locomotion. Third, the role of segregation of cell types in the transversal plane is for descending fibers to find appropriate targets. Modulation of these targets allows control of motor activity by adjusting the symmetry of the projection topology. We extract these principles via a model of the mouse spinal cord, where networks are constructed by probabilistic sampling of synaptic connections from cell-specific projection patterns, which are based on previous studies. The cell-type distributions are derived from single-cell RNA sequencing combined with spatial transcriptomics. We find that essential aspects of locomotion are readily reproduced and controlled without requiring parameter optimization, and several experimental observations can now be explained mechanistically. Further, two main features are predicted: propagating bumps of neural activity during rhythmical activity and formation of static bumps during arrest and posture. Besides linking cell types, structure and function, we propose our approach as a new theoretical framework for motor control.Competing Interest StatementThe authors have declared no competing interest.Footnotes* Text improved and author added. Figures have been updated.