The Ancient Origins of Neural Substrates for Land Walking.

Walking is the predominant locomotor behavior expressed by land-dwelling vertebrates, but it is unknown when the neural circuits that are essential for limb control first appeared. Certain fish species display walking-like behaviors, raising the possibility that the underlying circuitry originated in primitive marine vertebrates. We show that the neural substrates of bipedalism are present in the little skate Leucoraja erinacea, whose common ancestor with tetrapods existed ∼420 million years ago. Leucoraja exhibits core features of tetrapod locomotor gaits, including left-right alternation and reciprocal extension-flexion of the pelvic fins. Leucoraja also deploys a remarkably conserved Hox transcription factor-dependent program that is essential for selective innervation of fin/limb muscle. This network encodes peripheral connectivity modules that are distinct from those used in axial muscle-based swimming and has apparently been diminished in most modern fish. These findings indicate that the circuits that are essential for walking evolved through adaptation of a genetic regulatory network shared by all vertebrates with paired appendages. VIDEO ABSTRACT.

Neural circuit mechanisms underlying context-specific halting in Drosophila.

Walking is a complex motor programme involving coordinated and distributed activity across the brain and the spinal cord. Halting appropriately at the correct time is a critical component of walking control. Despite progress in identifying neurons driving halting1-6, the underlying neural circuit mechanisms responsible for overruling the competing walking state remain unclear. Here, using connectome-informed models7-9 and functional studies, we explain two fundamental mechanisms by which Drosophila implement context-appropriate halting. The first mechanism ('walk-OFF') relies on GABAergic neurons that inhibit specific descending walking commands in the brain, whereas the second mechanism ('brake') relies on excitatory cholinergic neurons in the nerve cord that lead to an active arrest of stepping movements. We show that two neurons that deploy the walk-OFF mechanism inhibit distinct populations of walking-promotion neurons, leading to differential halting of forward walking or turning. The brake neurons, by constrast, override all walking commands by simultaneously inhibiting descending walking-promotion neurons and increasing the resistance at the leg joints. We characterized two behavioural contexts in which the distinct halting mechanisms were used by the animal in a mutually exclusive manner: the walk-OFF mechanism was engaged for halting during feeding and the brake mechanism was engaged for halting and stability during grooming.

Walking naturally after spinal cord injury using a brain-spine interface.

A spinal cord injury interrupts the communication between the brain and the region of the spinal cord that produces walking, leading to paralysis1,2. 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 signals3 and the analogue modulation of epidural electrical stimulation targeting the spinal cord regions involved in the production of walking4-6. 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.

Movement is governed by rotational neural dynamics in spinal motor networks.

Although the generation of movements is a fundamental function of the nervous system, the underlying neural principles remain unclear. As flexor and extensor muscle activities alternate during rhythmic movements such as walking, it is often assumed that the responsible neural circuitry is similarly exhibiting alternating activity1. Here we present ensemble recordings of neurons in the lumbar spinal cord that indicate that, rather than alternating, the population is performing a low-dimensional 'rotation' in neural space, in which the neural activity is cycling through all phases continuously during the rhythmic behaviour. The radius of rotation correlates with the intended muscle force, and a perturbation of the low-dimensional trajectory can modify the motor behaviour. As existing models of spinal motor control do not offer an adequate explanation of rotation1,2, we propose a theory of neural generation of movements from which this and other unresolved issues, such as speed regulation, force control and multifunctionalism, are readily explained.

Odour motion sensing enhances navigation of complex plumes.

Odour plumes in the wild are spatially complex and rapidly fluctuating structures carried by turbulent airflows1-4. To successfully navigate plumes in search of food and mates, insects must extract and integrate multiple features of the odour signal, including odour identity5, intensity6 and timing6-12. Effective navigation requires balancing these multiple streams of olfactory information and integrating them with other sensory inputs, including mechanosensory and visual cues9,12,13. Studies dating back a century have indicated that, of these many sensory inputs, the wind provides the main directional cue in turbulent plumes, leading to the longstanding model of insect odour navigation as odour-elicited upwind motion6,8-12,14,15. Here we show that Drosophila melanogaster shape their navigational decisions using an additional directional cue-the direction of motion of odours-which they detect using temporal correlations in the odour signal between their two antennae. Using a high-resolution virtual-reality paradigm to deliver spatiotemporally complex fictive odours to freely walking flies, we demonstrate that such odour-direction sensing involves algorithms analogous to those in visual-direction sensing16. Combining simulations, theory and experiments, we show that odour motion contains valuable directional information that is absent from the airflow alone, and that both Drosophila and virtual agents are aided by that information in navigating naturalistic plumes. The generality of our findings suggests that odour-direction sensing may exist throughout the animal kingdom and could improve olfactory robot navigation in uncertain environments.

The neurons that restore walking after 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 cord1-3 applied during neurorehabilitation4,5 (EESREHAB) 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 EESREHAB in mice. We applied single-nucleus RNA sequencing6-9 and spatial transcriptomics10,11 to the spinal cords of these mice to chart a spatially resolved molecular atlas of recovery from paralysis. We then employed cell type12,13 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 EESREHAB, 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.

Early versus delayed weight-bearing following operatively treated ankle fracture (WAX): a non-inferiority, multicentre, randomised controlled trial.

BACKGROUND: After surgery for a broken ankle, patients are usually instructed to avoid walking for 6 weeks (delayed weight-bearing). Walking 2 weeks after surgery (early weight-bearing) might be a safe and preferable rehabilitation strategy. This study aimed to determine the clinical and cost effectiveness of an early weight-bearing strategy compared with a delayed weight-bearing strategy. METHODS: This was a pragmatic, multicentre, randomised, non-inferiority trial including 561 participants (aged ≥18 years) who received acute surgery for an unstable ankle fracture in 23 UK National Health Service (NHS) hospitals who were assigned to either a delayed weight-bearing (n=280) or an early weight-bearing rehabilitation strategy (n=281). Patients treated with a hindfoot nail, those who did not have protective ankle sensation (eg, peripheral neuropathy), did not have the capacity to consent, or did not have the ability to adhere to trial procedures were excluded. Neither participants nor clinicians were masked to the treatment. The primary outcome was ankle function measured using the Olerud and Molander Ankle Score (OMAS) at 4 months after randomisation, in the per-protocol population. The pre-specified non-inferiority OMAS margin was -6 points and superiority testing was included in the intention-to-treat population in the event of non-inferiority. The trial was prospectively registered with ISRCTN Registry, ISRCTN12883981, and the trial is closed to new participants. FINDINGS: Primary outcome data were collected from 480 (86%) of 561 participants. Recruitment was conducted between Jan 13, 2020, and Oct 29, 2021. At 4 months after randomisation, the mean OMAS score was 65·9 in the early weight-bearing and 61·2 in the delayed weight-bearing group and adjusted mean difference was 4·47 (95% CI 0·58 to 8·37, p=0·024; superiority testing adjusted difference 4·42, 95% CI 0·53 to 8·32, p=0·026) in favour of early weight-bearing. 46 (16%) participants in the early weight-bearing group and 39 (14%) in the delayed weight-bearing group had one or more complications (adjusted odds ratio 1·18, 95% CI 0·80 to 1·75, p=0·40). The mean costs from the perspective of the NHS and personal social services in the early and delayed weight-bearing groups were £725 and £785, respectively (mean difference -£60 [95% CI -342 to 232]). The probability that early weight-bearing is cost-effective exceeded 80%. INTERPRETATION: An early weight-bearing strategy was found to be clinically non-inferior and highly likely to be cost-effective compared with the current standard of care (delayed weight-bearing). FUNDING: National Institute for Health and Care Research (NIHR), NIHR Barts Biomedical Research Centre, and NIHR Applied Research Collaboration Oxford and Thames Valley.

NeuroMechFly, a neuromechanical model of adult Drosophila melanogaster.

Animal behavior emerges from an interaction between neural network dynamics, musculoskeletal properties and the physical environment. Accessing and understanding the interplay between these elements requires the development of integrative and morphologically realistic neuromechanical simulations. Here we present NeuroMechFly, a data-driven model of the widely studied organism, Drosophila melanogaster. NeuroMechFly combines four independent computational modules: a physics-based simulation environment, a biomechanical exoskeleton, muscle models and neural network controllers. To enable use cases, we first define the minimum degrees of freedom of the leg from real three-dimensional kinematic measurements during walking and grooming. Then, we show how, by replaying these behaviors in the simulator, one can predict otherwise unmeasured torques and contact forces. Finally, we leverage NeuroMechFly's full neuromechanical capacity to discover neural networks and muscle parameters that drive locomotor gaits optimized for speed and stability. Thus, NeuroMechFly can increase our understanding of how behaviors emerge from interactions between complex neuromechanical systems and their physical surroundings.

Identifying essential factors for energy-efficient walking control across a wide range of velocities in reflex-based musculoskeletal systems.

Humans can generate and sustain a wide range of walking velocities while optimizing their energy efficiency. Understanding the intricate mechanisms governing human walking will contribute to the engineering applications such as energy-efficient biped robots and walking assistive devices. Reflex-based control mechanisms, which generate motor patterns in response to sensory feedback, have shown promise in generating human-like walking in musculoskeletal models. However, the precise regulation of velocity remains a major challenge. This limitation makes it difficult to identify the essential reflex circuits for energy-efficient walking. To explore the reflex control mechanism and gain a better understanding of its energy-efficient maintenance mechanism, we extend the reflex-based control system to enable controlled walking velocities based on target speeds. We developed a novel performance-weighted least squares (PWLS) method to design a parameter modulator that optimizes walking efficiency while maintaining target velocity for the reflex-based bipedal system. We have successfully generated walking gaits from 0.7 to 1.6 m/s in a two-dimensional musculoskeletal model based on an input target velocity in the simulation environment. Our detailed analysis of the parameter modulator in a reflex-based system revealed two key reflex circuits that have a significant impact on energy efficiency. Furthermore, this finding was confirmed to be not influenced by setting parameters, i.e., leg length, sensory time delay, and weight coefficients in the objective cost function. These findings provide a powerful tool for exploring the neural bases of locomotion control while shedding light on the intricate mechanisms underlying human walking and hold significant potential for practical engineering applications.

A simulation framework to determine optimal strength training and musculoskeletal geometry for sprinting and distance running.

Musculoskeletal geometry and muscle volumes vary widely in the population and are intricately linked to the performance of tasks ranging from walking and running to jumping and sprinting. As an alternative to experimental approaches, where it is difficult to isolate factors and establish causal relationships, simulations can be used to independently vary musculoskeletal geometry and muscle volumes, and develop a fundamental understanding. However, our ability to understand how these parameters affect task performance has been limited due to the high computational cost of modelling the necessary complexity of the musculoskeletal system and solving the requisite multi-dimensional optimization problem. For example, sprinting and running are fundamental to many forms of sport, but past research on the relationships between musculoskeletal geometry, muscle volumes, and running performance has been limited to observational studies, which have not established cause-effect relationships, and simulation studies with simplified representations of musculoskeletal geometry. In this study, we developed a novel musculoskeletal simulator that is differentiable with respect to musculoskeletal geometry and muscle volumes. This simulator enabled us to find the optimal body segment dimensions and optimal distribution of added muscle volume for sprinting and marathon running. Our simulation results replicate experimental observations, such as increased muscle mass in sprinters, as well as a mass in the lower end of the healthy BMI range and a higher leg-length-to-height ratio in marathon runners. The simulations also reveal new relationships, for example showing that hip musculature is vital to both sprinting and marathon running. We found hip flexor and extensor moment arms were maximized to optimize sprint and marathon running performance, and hip muscles the main target when we simulated strength training for sprinters. Our simulation results provide insight to inspire future studies to examine optimal strength training. Our simulator can be extended to other athletic tasks, such as jumping, or to non-athletic applications, such as designing interventions to improve mobility in older adults or individuals with movement disorders.

A dynamic foot model for predictive simulations of human gait reveals causal relations between foot structure and whole-body mechanics.

The unique structure of the human foot is seen as a crucial adaptation for bipedalism. The foot's arched shape enables stiffening the foot to withstand high loads when pushing off, without compromising foot flexibility. Experimental studies demonstrated that manipulating foot stiffness has considerable effects on gait. In clinical practice, altered foot structure is associated with pathological gait. Yet, experimentally manipulating individual foot properties (e.g. arch height or tendon and ligament stiffness) is hard and therefore our understanding of how foot structure influences gait mechanics is still limited. Predictive simulations are a powerful tool to explore causal relationships between musculoskeletal properties and whole-body gait. However, musculoskeletal models used in three-dimensional predictive simulations assume a rigid foot arch, limiting their use for studying how foot structure influences three-dimensional gait mechanics. Here, we developed a four-segment foot model with a longitudinal arch for use in predictive simulations. We identified three properties of the ankle-foot complex that are important to capture ankle and knee kinematics, soleus activation, and ankle power of healthy adults: (1) compliant Achilles tendon, (2) stiff heel pad, (3) the ability to stiffen the foot. The latter requires sufficient arch height and contributions of plantar fascia, and intrinsic and extrinsic foot muscles. A reduced ability to stiffen the foot results in walking patterns with reduced push-off power. Simulations based on our model also captured the effects of walking with anaesthetised intrinsic foot muscles or an insole limiting arch compression. The ability to reproduce these different experiments indicates that our foot model captures the main mechanical properties of the foot. The presented four-segment foot model is a potentially powerful tool to study the relationship between foot properties and gait mechanics and energetics in health and disease.

Springs vs. motors: Ideal assistance in the lower limbs during walking at different speeds.

Recent years have witnessed breakthroughs in assistive exoskeletons; both passive and active devices have reduced metabolic costs near preferred walking speed by assisting muscle actions. Metabolic reductions at multiple speeds should thus also be attainable. Musculoskeletal simulation can potentially predict the interaction between assistive moments, muscle-tendon mechanics, and walking energetics. In this study, we simulated devices' optimal assistive moments based on minimal muscle activations during walking with prescribed kinematics and dynamics. We used a generic musculoskeletal model with tuned muscle-tendon parameters and computed metabolic rates from muscle actions. We then simulated walking across multiple speeds and with two ideal actuation modes-motor-based and spring-based-to assist ankle plantarflexion, knee extension, hip flexion, and hip abduction and compared computed metabolic rates. We found that both actuation modes considerably reduced physiological joint moments but did not always reduce metabolic rates. Compared to unassisted conditions, motor-based ankle plantarflexion and hip flexion assistance reduced metabolic rates, and this effect was more pronounced as walking speed increased. Spring-based hip flexion and abduction assistance increased metabolic rates at some walking speeds despite a moderate decrease in some muscle activations. Both modes of knee extension assistance reduced metabolic rates to a small extent, even though the actuation contributed with practically the entire net knee extension moment during stance. Motor-based hip abduction assistance reduced metabolic rates more than spring-based assistance, though this reduction was relatively small. Our study also suggests that an assistive strategy based on minimal muscle activations might result in a suboptimal reduction of metabolic rates. Future work should experimentally validate the effects of assistive moments and refine modeling assumptions accordingly. Our computational workflow is freely available online.

Insights into muscle metabolic energetics: Modelling muscle-tendon mechanics and metabolic rates during walking across speeds.

The metabolic energy rate of individual muscles is impossible to measure without invasive procedures. Prior studies have produced models to predict metabolic rates based on experimental observations of isolated muscle contraction from various species. Such models can provide reliable predictions of metabolic rates in humans if muscle properties and control are accurately modeled. This study aimed to examine how muscle-tendon model individualization and metabolic energy models influenced estimation of muscle-tendon states and time-series metabolic rates, to evaluate the agreement with empirical data, and to provide predictions of the metabolic rate of muscle groups and gait phases across walking speeds. Three-dimensional musculoskeletal simulations with prescribed kinematics and dynamics were performed. An optimal control formulation was used to compute muscle-tendon states with four levels of individualization, ranging from a scaled generic model and muscle controls based on minimal activations, inclusion of calibrated muscle passive forces, personalization of Achilles and quadriceps tendon stiffnesses, to finally informing muscle controls with electromyography. We computed metabolic rates based on existing models. Simulations with calibrated passive forces and personalized tendon stiffness most accurately estimate muscle excitations and fiber lengths. Interestingly, the inclusion of electromyography did not improve our estimates. The whole-body average metabolic cost was better estimated with a subset of metabolic energy models. We estimated metabolic rate peaks near early stance, pre-swing, and initial swing at all walking speeds. Plantarflexors accounted for the highest cost among muscle groups at the preferred speed and were similar to the cost of hip adductors and abductors combined. Also, the swing phase accounted for slightly more than one-quarter of the total cost in a gait cycle, and its relative cost decreased with walking speed. Our prediction might inform the design of assistive devices and rehabilitation treatment. The code and experimental data are available online.

Foot callus thickness does not trade off protection for tactile sensitivity during walking.

Until relatively recently, humans, similar to other animals, were habitually barefoot. Therefore, the soles of our feet were the only direct contact between the body and the ground when walking. There is indirect evidence that footwear such as sandals and moccasins were first invented within the past 40 thousand years1, the oldest recovered footwear dates to eight thousand years ago2 and inexpensive shoes with cushioned heels were not developed until the Industrial Revolution3. Because calluses-thickened and hardened areas of the epidermal layer of the skin-are the evolutionary solution to protecting the foot, we wondered whether they differ from shoes in maintaining tactile sensitivity during walking, especially at initial foot contact, to improve safety on surfaces that can be slippery, abrasive or otherwise injurious or uncomfortable. Here we show that, as expected, people from Kenya and the United States who frequently walk barefoot have thicker and harder calluses than those who typically use footwear. However, in contrast to shoes, callus thickness does not trade-off protection, measured as hardness and stiffness, for the ability to perceive tactile stimuli at frequencies experienced during walking. Additionally, unlike cushioned footwear, callus thickness does not affect how hard the feet strike the ground during walking, as indicated by impact forces. Along with providing protection and comfort at the cost of tactile sensitivity, cushioned footwear also lowers rates of loading at impact but increases force impulses, with unknown effects on the skeleton that merit future study.

Low effective mechanical advantage of giraffes' limbs during walking reveals trade-off between limb length and locomotor performance.

Giraffes (Giraffa camelopardalis) possess specialized locomotor morphology, namely elongate and gracile distal limbs. While this contributes to their overall height and enhances feeding behavior, we propose that the combination of long limb segments and modest muscle lever arms results in low effective mechanical advantage (EMA, the ratio of in-lever to out-lever moment arms), when compared with other cursorial mammals. To test this, we used a combination of experimentally measured kinematics and ground reaction forces (GRFs), musculoskeletal modeling, and inverse dynamics to calculate giraffe forelimb EMA during walking. Giraffes walk with an EMA of 0.34 (±0.05 SD), with no evident association with speed within their walking gait. Giraffe EMA was about four times lower than expectations extrapolated from other mammals, ranging from 0.03 to 297 kg, and this provides further evidence that EMA plateaus or even diminishes in mammals exceeding horse size. We further tested the idea that limb segment length is a factor which determines EMA, by modeling the GRF and muscle moment arms in the extinct giraffid Sivatherium giganteum and the other extant giraffid, Okapia johnstoni. Giraffa and Okapia shared similar EMA, despite a four to sixfold difference in body mass (Okapia EMA = 0.38). In contrast, Sivatherium, sharing a similar body mass with Giraffa, had greater EMA (0.59), which we propose reflects behavioral differences, such as a somewhat increased capability for athletic performance. Our modeling approach suggests that limb length is a determinant of GRF moment arm magnitude and that unless muscle moment arms scale isometrically with limb length, tall mammals are prone to low EMA.

Relationship of device measured physical activity type and posture with cardiometabolic health markers: pooled dose-response associations from the Prospective Physical Activity, Sitting and Sleep Consortium.

AIMS/HYPOTHESIS: The aim of this study was to examine the dose-response associations of device-measured physical activity types and postures (sitting and standing time) with cardiometabolic health. METHODS: We conducted an individual participant harmonised meta-analysis of 12,095 adults (mean ± SD age 54.5±9.6 years; female participants 54.8%) from six cohorts with thigh-worn accelerometry data from the Prospective Physical Activity, Sitting and Sleep (ProPASS) Consortium. Associations of daily walking, stair climbing, running, standing and sitting time with a composite cardiometabolic health score (based on standardised z scores) and individual cardiometabolic markers (BMI, waist circumference, triglycerides, HDL-cholesterol, HbA1c and total cholesterol) were examined cross-sectionally using generalised linear modelling and cubic splines. RESULTS: We observed more favourable composite cardiometabolic health (i.e. z score <0) with approximately 64 min/day walking (z score [95% CI] -0.14 [-0.25, -0.02]) and 5 min/day stair climbing (-0.14 [-0.24, -0.03]). We observed an equivalent magnitude of association at 2.6 h/day standing. Any amount of running was associated with better composite cardiometabolic health. We did not observe an upper limit to the magnitude of the dose-response associations for any activity type or standing. There was an inverse dose-response association between sitting time and composite cardiometabolic health that became markedly less favourable when daily durations exceeded 12.1 h/day. Associations for sitting time were no longer significant after excluding participants with prevalent CVD or medication use. The dose-response pattern was generally consistent between activity and posture types and individual cardiometabolic health markers. CONCLUSIONS/INTERPRETATION: In this first activity type-specific analysis of device-based physical activity, ~64 min/day of walking and ~5.0 min/day of stair climbing were associated with a favourable cardiometabolic risk profile. The deleterious associations of sitting time were fully attenuated after exclusion of participants with prevalent CVD and medication use. Our findings on cardiometabolic health and durations of different activities of daily living and posture may guide future interventions involving lifestyle modification.

Simultaneous control of forward and backward locomotion by spinal sensorimotor circuits.

Mammals walk in different directions, such as forward and backward. In human infants/adults and decerebrate cats, one leg can walk forward and the other backward simultaneously on a split-belt treadmill, termed hybrid or bidirectional locomotion. The purpose of the present study was to determine if spinal sensorimotor circuits generate hybrid locomotion and if so, how the limbs remain coordinated. We tested hybrid locomotion in 11 intact cats and in five following complete spinal thoracic transection (spinal cats) at three treadmill speeds with the hindlimbs moving forward, backward or bidirectionally. All intact cats generated hybrid locomotion with the forelimbs on a stationary platform. Four of five spinal cats generated hybrid locomotion, also with the forelimbs on a stationary platform, but required perineal stimulation. During hybrid locomotion, intact and spinal cats positioned their forward and backward moving hindlimbs caudal and rostral to the hip, respectively. The hindlimbs maintained consistent left-right out-of-phase alternation in the different stepping directions. Our results suggest that spinal locomotor networks generate hybrid locomotion by following certain rules at phase transitions. We also found that stance duration determined cycle duration in the different locomotor directions/conditions, consistent with a common rhythm-generating mechanism for different locomotor directions. Our findings provide additional insight on how left-right spinal networks and sensory feedback from the limbs interact to coordinate the hindlimbs and provide stability during locomotion in different directions. KEY POINTS: Terrestrial mammals can walk forward and backward, which is controlled in part by spinal sensorimotor circuits. Humans and cats also perform bidirectional or hybrid locomotion on a split-belt treadmill with one leg going forward and the other going backward. We show that cats with a spinal transection can perform hybrid locomotion and maintain left-right out-of-phase coordination, indicating that spinal sensorimotor circuits can perform simultaneous forward and backward locomotion. We also show that the regulation of cycle duration and phase duration is conserved across stepping direction, consistent with a common rhythm-generating mechanism for different stepping directions. The results help us better understand how spinal networks controlling the left and right legs enable locomotion in different directions.

Vertebral level specific modulation of paraspinal muscle activity based on vestibular signals during walking.

Evoking muscle responses by electrical vestibular stimulation (EVS) may help to understand the contribution of the vestibular system to postural control. Although paraspinal muscles play a role in postural stability, the vestibulo-muscular coupling of these muscles during walking has rarely been studied. This study aimed to investigate how vestibular signals affect paraspinal muscle activity at different vertebral levels during walking with preferred and narrow step width. Sixteen healthy participants were recruited. Participants walked on a treadmill for 8 min at 78 steps/min and 2.8 km/h, at two different step width, either with or without EVS. Bipolar electromyography was recorded bilaterally from the paraspinal muscles at eight vertebral levels from cervical to lumbar. Coherence, gain, and delay of EVS and EMG responses were determined. Significant EVS-EMG coupling (P < 0.01) was found at ipsilateral and/or contralateral heel strikes. This coupling was mirrored between left and right relative to the midline of the trunk and between the higher and lower vertebral levels, i.e. a peak occurred at ipsilateral heel strike at lower levels, whereas it occurred at contralateral heel strike at higher levels. EVS-EMG coupling only partially coincided with peak muscle activity. EVS-EMG coherence slightly, but not significantly, increased when walking with narrow steps. No significant differences were found in gain and phase between the vertebral levels or step width conditions. In summary, vertebral level specific modulation of paraspinal muscle activity based on vestibular signals might allow a fast, synchronized, and spatially co-ordinated response along the trunk during walking. KEY POINTS: Mediolateral stabilization of gait requires an estimate of the state of the body, which is affected by vestibular afference. During gait, the heavy trunk segment is controlled by phasic paraspinal muscle activity and in rodents the medial and lateral vestibulospinal tracts activate these muscles. To gain insight in vestibulospinal connections in humans and their role in gait, we recorded paraspinal surface EMG of cervical to lumbar paraspinal muscles, and characterized coherence, gain and delay between EMG and electrical vestibular stimulation, during slow walking. Vestibular stimulation caused phasic, vertebral level specific modulation of paraspinal muscle activity at delays of around 40 ms, which was mirrored between left, lower and right, upper vertebral levels. Our results indicate that vestibular afference causes fast, synchronized, and spatially co-ordinated responses of the paraspinal muscles along the trunk, that simultaneously contribute to stabilizing the centre of mass trajectory and to keeping the head upright.

Reductions in functional muscle mass and ability to ambulate in Duchenne muscular dystrophy from ages 4 to 24 years.

Duchenne muscular dystrophy (DMD) results in a progressive loss of functional skeletal muscle mass (MM) and replacement with fibrofatty tissue. Accurate evaluation of MM in DMD patients has not previously been available. Our objective was to measure MM using the D3creatine (D3Cr) dilution method and determine its relationship with strength and functional capacity in patients with DMD over a wide range of ages. Subjects were recruited for participation in a 12 month, longitudinal, observational study. Here, we report the baseline data. A 20 mg dose of D3Cr dissolved in water was ingested by 92 patients with DMD (ages 4-25 years) followed later with a fasting urine sample. Enrichment of D3creatinine was determined by liquid chromatography-mass spectrometry analysis. The North Star Ambulatory Assessment (NSAA) total score was determined for ambulatory participants, and the Performance of Upper Limb (PUL 2.0) total score and grip strength for all participants. We observed a significant age-associated increase in body weight along with a substantial decrease in MM/body weight (%MM). MM and %MM were associated with PUL score (r = 0.517, P < 0.0001 and r = 0.764, P < 0.0001 respectively). The age-associated decrease in MM and %MM was strongly associated with ambulatory status. We observed very little overlap in %MM between ambulant and non-ambulant subjects, suggesting a threshold of 18-22% associated with loss of ambulation. MM is substantially diminished with advancing age and is highly related to clinically meaningful functional status. The D3Cr dilution method may provide a biomarker of disease progression and therapeutic efficacy in patients with DMD or other neuromuscular disorders. KEY POINTS: The non-invasive D3creatine dilution method provides novel data on whole body functional muscle mass (MM) in a wide range of ages in patients with DMD and reveals profoundly low functional MM in older non-ambulant patients. The difference in %MM between ambulant and non-ambulant subjects suggests a threshold for loss of ambulatory ability between 18 and 22% MM. The data suggest that as functional MM declines with age, maintaining a lower body weight may help to conserve ambulatory ability.

Increasing Activity After Stroke: A Randomized Controlled Trial of High-Intensity Walking and Step Activity Intervention.

BACKGROUND: Physical inactivity in people with chronic stroke profoundly affects daily function and increases recurrent stroke risk and mortality, making physical activity improvements an important target of intervention. We compared the effects of a high-intensity walking intervention (FAST), a step activity monitoring behavioral intervention (SAM), or a combined intervention (FAST+SAM) on physical activity (ie, steps/day). We hypothesized the combined intervention would yield the greatest increase in steps/day. METHODS: This assessor-blinded multisite randomized controlled trial was conducted at 4 university/hospital-based laboratories. Participants were 21 to 85 years old, walking without physical assistance following a single, unilateral noncerebellar stroke of ≥6 months duration, and randomly assigned to FAST, SAM, or FAST+SAM for 12 weeks (2-3 sessions/week). FAST training consisted of walking-related activities at 70% to 80% heart rate reserve, while SAM received daily feedback and goal setting of walking activity (steps/day). Assessors and study statistician were masked to group assignment. The a priori-determined primary outcome and end point was a comparison of the change in steps/day between the 3 intervention groups from pre- to post-intervention. Adverse events were tracked after randomization. All randomized participants were included in the intent-to-treat analysis. RESULTS: Participants were enrolled from July 18, 2016, to November 16, 2021. Of 2385 participants initially screened, 250 participants were randomized (mean [SE] age, 63 [0.80] years; 116 females/134 males), with 89 assigned to FAST, 81 to SAM, and 80 to FAST+SAM. Steps/day significantly increased in both the SAM (mean [SE], 1542 [267; 95% CI, 1014-2069] P<0.001) and FAST+SAM group (1307 [280; 95% CI, 752-1861] P<0.001) but not in the FAST group (406 [238; 95% CI, -63 to 876] P=0.09). There were no deaths or serious study-related adverse events. CONCLUSIONS: Only individuals with chronic stroke who completed a step activity monitoring behavioral intervention with skilled coaching and goal progression demonstrated improvements in physical activity (steps/day). REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02835313.