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Spinal cord injury leads to disruption in autonomic control resulting in cardiovascular, bowel, and lower urinary tract dysfunctions, all of which significantly reduce health-related quality of life. Although spinal cord stimulation shows promise for promoting autonomic recovery, the underlying mechanisms are unclear. Based on current preclinical and clinical evidence, this narrative review provides the most plausible mechanisms underlying the effects of spinal cord stimulation for autonomic recovery, including activation of the somatoautonomic reflex and induction of neuroplastic changes in the spinal cord. Areas where evidence is limited are highlighted in an effort to guide the scientific community to further explore these mechanisms and advance the clinical translation of spinal cord stimulation for autonomic recovery., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective. Electrical spinal cord stimulation (SCS) has emerged as a promising therapy for recovery of motor and autonomic dysfunctions following spinal cord injury (SCI). Despite the rise in studies using SCS for SCI complications, there are no standard guidelines for reporting SCS parameters in research publications, making it challenging to compare, interpret or reproduce reported effects across experimental studies. Approach. To develop guidelines for minimum reporting standards for SCS parameters in pre-clinical and clinical SCI research, we gathered an international panel of expert clinicians and scientists. Using a Delphi approach, we developed guideline items and surveyed the panel on their level of agreement for each item. Main results. There was strong agreement on 26 of the 29 items identified for establishing minimum reporting standards for SCS studies. The guidelines encompass three major SCS categories: hardware, configuration and current parameters, and the intervention. Significance. Standardized reporting of stimulation parameters will ensure that SCS studies can be easily analyzed, replicated, and interpreted by the scientific community, thereby expanding the SCS knowledge base and fostering transparency in reporting., (Creative Commons Attribution license.)

Objective. Spinal cord injury (SCI) leads to debilitating sensorimotor deficits that greatly limit quality of life. This work aims to develop a mechanistic understanding of how to best promote functional recovery following SCI. Electrical spinal stimulation is one promising approach that is effective in both animal models and humans with SCI. Optogenetic stimulation is an alternative method of stimulating the spinal cord that allows for cell-type-specific stimulation. The present work investigates the effects of preferentially stimulating neurons within the spinal cord and not glial cells, termed 'neuron-specific' optogenetic spinal stimulation. We examined forelimb recovery, axonal growth, and vasculature after optogenetic or sham stimulation in rats with cervical SCI. Approach. Adult female rats received a moderate cervical hemicontusion followed by the injection of a neuron-specific optogenetic viral vector ipsilateral and caudal to the lesion site. Animals then began rehabilitation on the skilled forelimb reaching task. At four weeks post-injury, rats received a micro-light emitting diode (µLED) implant to optogenetically stimulate the caudal spinal cord. Stimulation began at six weeks post-injury and occurred in conjunction with activities to promote use of the forelimbs. Following six weeks of stimulation, rats were perfused, and tissue stained for GAP-43, laminin, Nissl bodies and myelin. Location of viral transduction and transduced cell types were also assessed. Main Results. Our results demonstrate that neuron-specific optogenetic spinal stimulation significantly enhances recovery of skilled forelimb reaching. We also found significantly more GAP-43 and laminin labeling in the optogenetically stimulated groups indicating stimulation promotes axonal growth and angiogenesis. Significance. These findings indicate that optogenetic stimulation is a robust neuromodulator that could enable future therapies and investigations into the role of specific cell types, pathways, and neuronal populations in supporting recovery after SCI., (Creative Commons Attribution license.)

There is growing evidence on the efficacy of electrical stimulation delivered via spinal neural interfaces to improve functional recovery following spinal cord injury. For such interfaces, carbon-based neural arrays are fast becoming recognized as a compelling material and platform due to biocompatibility and long-term electrochemical stability. Here, we introduce the design, fabrication, and in vivo characterization of a novel cervical epidural implant with carbon-based surface electrodes. Through finite element analysis and mechanical load tests, we demonstrated that the array could safely withstand loads applied to it during implantation and natural movement of the subject with minimal stress levels. Furthermore, the long-term in vivo performance of this neural array consisting of glassy carbon surface electrodes was investigated through acute and chronic spinal motor evoked potential recordings and electrode impedance tests in rats. We demonstrated stable stimulation performance for at least four weeks in a rat model of spinal cord injury. Lastly, we found that impedance measurements on all carbon-based spinal arrays were generally stable over time up to four weeks after implantation, with a slight increase in impedance in subsequent weeks when tested in spinally injured rats. Taken together, this study demonstrated the potential for carbon-based electrodes as a spinal neural interface to accelerate both mechanistic research and functional restoration in animal models of spinal cord injury.

Spinal cord injuries lead to permanent physical impairment despite most often being anatomically incomplete disruptions of the spinal cord. Remaining connections between the brain and spinal cord create the potential for inducing neural plasticity to improve sensorimotor function, even many years after injury. This narrative review provides an overview of the current evidence for spontaneous motor recovery, activity-dependent plasticity, and interventions for restoring motor control to residual brain and spinal cord networks via spinal cord stimulation. In addition to open-loop spinal cord stimulation to promote long-term neuroplasticity, we also review a more targeted approach: closed-loop stimulation. Lastly, we review mechanisms of spinal cord neuromodulation to promote sensorimotor recovery, with the goal of advancing the field of rehabilitation for physical impairments following spinal cord injury., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Although there is currently no cure for paralysis due to spinal cord injury (SCI), the highest treatment priority is restoring arm and hand function for people with cervical SCI. Preclinical animal models provide an opportunity to test innovative treatments, but severe cervical injury models require significant time and effort to assess responses to novel interventions. Moreover, there is no behavioral task that can assess forelimb movement in rats with severe cervical SCI unable to perform antigravity movements., New Method: We developed a novel lever pressing task for rats with severe cervical SCI. We employed an automated adaptive algorithm to train animals using open-source software and commercially available hardware. We found that using the adaptive training required only 13.3 ± 2.5 training days to achieve behavioral proficiency. The lever press task could quantify immediate and long-term improvements in severely impaired forelimb function effectively. This behavior platform has potential to facilitate rehabilitative training and assess effects of therapeutic modalities following SCI., Comparison With Existing Methods: There is no existing assessment aiming to quantify forelimb extension movement in rodents without function against gravity. We found that the new lever press task in the antigravity position could assess the severity of cervical SCI as well as the compensatory movement in the proximal forelimb less affected by the injury., Conclusions: This study demonstrates that the new behavioral task is capable of tracking the functional changes with various therapies in rats with severe forelimb impairments in a cost- and time-efficient manner., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: This study investigated the effect of cervical and lumbar transcutaneous spinal cord stimulation (tSCS) combined with intensive training to improve walking and autonomic function after chronic spinal cord injury (SCI)., Methods: Two 64-year-old men with chronic motor incomplete cervical SCI participated in this single-subject design study. They each underwent 2 months of intensive locomotor training and 2 months of multisite cervical and lumbosacral tSCS paired with intensive locomotor training., Results: The improvement in 6-Minute Walk Test distance after 2 months of tSCS with intensive training was threefold greater than after locomotor training alone. Both participants improved balance ability measured by the Berg Balance Scale and increased their ability to engage in daily home exercises. Gait analysis demonstrated increased step length for each individual. Both participants experienced improved sensation and bowel function, and 1 participant eliminated the need for intermittent catheterization after the stimulation phase of the study., Conclusion: These results suggest that noninvasive spinal cord stimulation might promote recovery of locomotor and autonomic functions beyond traditional gait training in people with chronic incomplete cervical SCI., Impact: Multisite transcutaneous spinal stimulation may induce neuroplasticity of the spinal networks and confer functional benefits following chronic cervical SCI., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Physical Therapy Association.)

To date, relatively few studies have used optogenetic stimulation to address basic science and therapeutic questions within the spinal cord. Even less have reported optogenetic stimulation in the rat spinal cord. This is likely due to a lack of accessible optogenetic implants. The development of a device that can be fabricated and operated by most laboratories, requiring no special equipment, would allow investigators to begin dissecting the functions of specific neuronal cell-types and circuitry within the spinal cord, as well as investigate therapies for spinal ailments like spinal cord injury. Here, we describe a long-term implantable μLED device designed for optogenetic stimulation of the spinal cord in awake, freely moving rats that is simple enough to be fabricated, implanted and operated by most laboratories. This device, which sits above the dorsal cord, can induce robust movements for at least 6 weeks without causing physical or thermal damage to the underlying spinal cord. In this regard, the presented μLED device could help tease apart the complexities of the spinal cord and uncover potential future therapeutics., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Paralysis of the upper extremity severely restricts independence and quality of life after spinal cord injury. Regaining control of hand and arm movements is the highest treatment priority for people with paralysis, 6-fold higher than restoring walking ability. Nevertheless, current approaches to improve upper extremity function typically do not restore independence. Spinal cord stimulation is an emerging neuromodulation strategy to restore motor function. Recent studies using surgically implanted electrodes demonstrate impressive improvements in voluntary control of standing and stepping. Here we show that transcutaneous electrical stimulation of the spinal cord leads to rapid and sustained recovery of hand and arm function, even after complete paralysis. Notably, the magnitude of these improvements matched or exceeded previously reported results from surgically implanted stimulation. Additionally, muscle spasticity was reduced and autonomic functions including heart rate, thermoregulation, and bladder function improved. Perhaps most striking is that all six participants maintained their gains for at least three to six months beyond stimulation, indicating functional recovery mediated by long-term neuroplasticity. Several participants resumed their hobbies that require fine motor control, such as playing the guitar and oil painting, for the first time in up to 12 years since their injuries. Our findings demonstrate that non-invasive transcutaneous electrical stimulation of the spinal networks restores movement and function of the hands and arm for people with both complete paralysis and long-term spinal cord injury.

Brain-computer interfaces (BCIs) are an emerging strategy for spinal cord injury (SCI) intervention that may be used to reanimate paralyzed limbs. This approach requires decoding movement intention from the brain to control movement-evoking stimulation. Common decoding methods use spike-sorting and require frequent calibration and high computational complexity. Furthermore, most applications of closed-loop stimulation act on peripheral nerves or muscles, resulting in rapid muscle fatigue. Here we show that a local field potential-based BCI can control spinal stimulation and improve forelimb function in rats with cervical SCI. We decoded forelimb movement via multi-channel local field potentials in the sensorimotor cortex using a canonical correlation analysis algorithm. We then used this decoded signal to trigger epidural spinal stimulation and restore forelimb movement. Finally, we implemented this closed-loop algorithm in a miniaturized onboard computing platform. This Brain-Computer-Spinal Interface (BCSI) utilized recording and stimulation approaches already used in separate human applications. Our goal was to demonstrate a potential neuroprosthetic intervention to improve function after upper extremity paralysis.

Intraspinal microstimulation (ISMS) can effectively activate spinal motor circuits, but the impact on the endogenous respiratory pattern has not been systematically evaluated. Here we delivered ISMS in spontaneously breathing adult rats while simultaneously recording diaphragm and external intercostal electromyography activity. ISMS pulses were delivered from C2-T1 along two rostrocaudal tracts located 0.5 or 1 mm lateral to midline. A tungsten electrode was incrementally advanced from the dorsal spinal surface and 300μs biphasic pulses (10-90 μA) were delivered at depth increments of 600 μm. Dorsal ISMS often produced fractionated inspiratory bursting or caused early termination of the inspiratory effort. Conversely, ventral stimulation had no discernable impact on respiratory resetting. We conclude that ISMS targeting the ventral spinal cord is unlikely to directly alter the respiratory rhythm. Dorsal ISMS, however, may terminate the inspiratory burst through activation of spinobulbar pathways. We suggest that respiratory patterns should be included as an outcome variable in preclinical studies of ISMS., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Designing brain-computer interfaces (BCIs) that can be used in conjunction with ongoing motor behavior requires an understanding of how neural activity co-opted for brain control interacts with existing neural circuits. For example, BCIs may be used to regain lost motor function after stroke. This requires that neural activity controlling unaffected limbs is dissociated from activity controlling the BCI. In this study we investigated how primary motor cortex accomplishes simultaneous BCI control and motor control in a task that explicitly required both activities to be driven from the same brain region (i.e. a dual-control task). Single-unit activity was recorded from intracortical, multi-electrode arrays while a non-human primate performed this dual-control task. Compared to activity observed during naturalistic motor control, we found that both units used to drive the BCI directly (control units) and units that did not directly control the BCI (non-control units) significantly changed their tuning to wrist torque. Using a measure of effective connectivity, we observed that control units decrease their connectivity. Through an analysis of variance we found that the intrinsic variability of the control units has a significant effect on task proficiency. When this variance is accounted for, motor cortical activity is flexible enough to perform novel BCI tasks that require active decoupling of natural associations to wrist motion. This study provides insight into the neural activity that enables a dual-control brain-computer interface.

Objective: Recent advances in neural engineering have restored mobility to people with paralysis, relieved symptoms of movement disorders, reduced chronic pain, restored the sense of hearing, and provided sensory perception to individuals with sensory deficits., Approach: This progress was enabled by the team-based, interdisciplinary approaches used by neural engineers. Neural engineers have advanced clinical frontiers by leveraging tools and discoveries in quantitative and biological sciences and through collaborations between engineering, science, and medicine. The movement toward bioelectronic medicines, where neuromodulation aims to supplement or replace pharmaceuticals to treat chronic medical conditions such as high blood pressure, diabetes and psychiatric disorders is a prime example of a new frontier made possible by neural engineering. Although one of the major goals in neural engineering is to develop technology for clinical applications, this technology may also offer unique opportunities to gain insight into how biological systems operate., Main Results: Despite significant technological progress, a number of ethical and strategic questions remain unexplored. Addressing these questions will accelerate technology development to address unmet needs. The future of these devices extends far beyond treatment of neurological impairments, including potential human augmentation applications. Our task, as neural engineers, is to push technology forward at the intersection of disciplines, while responsibly considering the readiness to transition this technology outside of the laboratory to consumer products., Significance: This article aims to highlight the current state of the neural engineering field, its links with other engineering and science disciplines, and the challenges and opportunities ahead. The goal of this article is to foster new ideas for innovative applications in neurotechnology.

Innovations for creating somatosensation via direct electrical stimulation of the brain will be required for the next generation of bi-directional cortical neuroprostheses. The current lack of tactile perception and proprioceptive input likely imposes a fundamental limit on speed and accuracy of brain-controlled prostheses or re-animated limbs. This study addresses the unique challenge of identifying a robust, high bandwidth sensory encoding scheme in a high-dimensional parameter space. Previous studies demonstrated single dimensional encoding schemes delivering low bandwidth sensory information, but no comparison has been performed across parameters, nor with update rates suitable for real-time operation of a neuroprosthesis. Here, we report the first comprehensive measurement of the resolution of key stimulation parameters such as pulse amplitude, pulse width, frequency, train interval and number of pulses. Surprisingly, modulation of stimulation frequency was largely undetectable. While we initially expected high frequency content to be an ideal candidate for passing high throughput sensory signals to the brain, we found only modulation of very low frequencies were detectable. Instead, the charge-per-phase of each pulse yields the highest resolution sensory signal, and is the key parameter modulating perceived intensity. The stimulation encoding patterns were designed for high-bandwidth information transfer that will be required for bi-directional brain interfaces. Our discovery of the stimulation features which best encode perceived intensity have significant implications for design of any neural interface seeking to convey information directly to the brain via electrical stimulation.

Electrical intraspinal microstimulation (ISMS) at various sites along the cervical spinal cord permits forelimb muscle activation, elicits complex limb movements and may enhance functional recovery after spinal cord injury. Here, we explore optogenetic spinal stimulation (OSS) as a less invasive and cell type-specific alternative to ISMS. To map forelimb muscle activation by OSS in rats, adeno-associated viruses (AAV) carrying the blue-light sensitive ion channels channelrhodopsin-2 (ChR2) and Chronos were injected into the cervical spinal cord at different depths and volumes. Following an AAV incubation period of several weeks, OSS-induced forelimb muscle activation and movements were assessed at 16 sites along the dorsal surface of the cervical spinal cord. Three distinct movement types were observed. We find that AAV injection volume and depth can be titrated to achieve OSS-based activation of several movements. Optical stimulation of the spinal cord is thus a promising method for dissecting the function of spinal circuitry and targeting therapies following injury. NEW & NOTEWORTHY Optogenetics in the spinal cord can be used both for therapeutic treatments and to uncover basic mechanisms of spinal cord physiology. For the first time, we describe the methodology and outcomes of optogenetic surface stimulation of the rat spinal cord. Specifically, we describe the evoked responses of forelimbs and address the effects of different adeno-associated virus injection paradigms. Additionally, we are the first to report on the limitations of light penetration through the rat spinal cord.

Recent advances in neuroscience and devices are ushering in a new generation of medical treatments. Engineered biodevices are demonstrating the potential to create long-term changes in neural circuits, termed neuroplasticity. Thus, the approach of engineering neuroplasticity is rapidly expanding, building on recent demonstrations of improved quality of life for people with movement disorders, epilepsy, and spinal cord injury. In addition, discovering the fundamental mechanisms of engineered neuroplasticity by leveraging anatomically well-documented systems like the spinal cord is likely to provide powerful insights into solutions for other neurotraumas, such as stroke and traumatic brain injury, as well as neurodegenerative disorders, such as Alzheimer's, Parkinson disease, and multiple sclerosis. Now is the time for advancing both the experimental neuroscience, device development, and pioneering human trials to reap the benefits of engineered neuroplasticity as a therapeutic approach for improving quality of life after spinal cord injury.

Upper extremity function is the highest priority of tetraplegics for improving quality of life. We aim to determine the therapeutic potential of transcutaneous electrical spinal cord stimulation for restoration of upper extremity function. We tested the hypothesis that cervical stimulation can facilitate neuroplasticity that results in long-lasting improvement in motor control. A 62-year-old male with C3, incomplete, chronic spinal cord injury (SCI) participated in the study. The intervention comprised three alternating periods: 1) transcutaneous spinal stimulation combined with physical therapy (PT); 2) identical PT only; and 3) a brief combination of stimulation and PT once again. Following four weeks of combined stimulation and physical therapy training, all of the following outcome measurements improved: the Graded Redefined Assessment of Strength, Sensation, and Prehension test score increased 52 points and upper extremity motor score improved 10 points. Pinch strength increased 2- to 7-fold in left and right hands, respectively. Sensation recovered on trunk dermatomes, and overall neurologic level of injury improved from C3 to C4. Most notably, functional gains persisted for over 3 month follow-up without further treatment. These data suggest that noninvasive electrical stimulation of spinal networks can promote neuroplasticity and long-term recovery following SCI.

A complex propriospinal network is synaptically coupled to phrenic and intercostal motoneurons, and this makes it difficult to predict how gray matter intraspinal microstimulation (ISMS) will recruit respiratory motor units. We therefore mapped the cervical and high thoracic gray matter at locations which ISMS activates diaphragm (DIA) and external intercostal (EIC) motor units. Respiratory muscle electromyography (EMG) was recorded in anesthetized female spinally intact adult rats while a stimulating electrode was advanced ventrally into the spinal cord in 600μm increments. At each depth, single biphasic stimuli were delivered at 10-90μA during both the inspiratory and expiratory phase independently. Twenty electrode tracks were made from C2-T1 at medial and lateral gray matter locations. During inspiration, ISMS evoked DIA and EIC activity throughout C2-T1 gray matter locations, with mutual activation occurring at 17±9% of sites. During inspiratory phase ISMS the average latency for DIA activation was 4.40±0.70ms. During the expiratory phase, ISMS-induced DIA activation required electrodes to be in close proximity to the phrenic motoneuron pool, and average activation latency was 3.30±0.50ms. We conclude that appropriately targeted ISMS can co-activate DIA and EIC motor units, and endogenous respiratory drive has a powerful impact on ISMS-induced respiratory motor unit activation. The long latency diaphragm motor unit activation suggests the presence of a complex propriospinal network that can modulate phrenic motor output., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Paralysis due to spinal cord injury can severely limit motor function and independence. This review summarizes different approaches to electrical stimulation of the spinal cord designed to restore motor function, with a brief discussion of their origins and the current understanding of their mechanisms of action. Spinal stimulation leads to impressive improvements in motor function along with some benefits to autonomic functions such as bladder control. Nonetheless, the precise mechanisms underlying these improvements and the optimal spinal stimulation approaches for restoration of motor function are largely unknown. Finally, spinal stimulation may augment other therapies that address the molecular and cellular environment of the injured spinal cord. The fact that several stimulation approaches are now leading to substantial and durable improvements in function following spinal cord injury provides a new perspectives on the previously "incurable" condition of paralysis., (Copyright © 2017 the American Physiological Society.)

The number of clinical trials in regenerative medicine is burgeoning, and stem cell/tissue engineering technologies hold the possibility of becoming the standard of care for a multitude of diseases and injuries. Advances in regenerative biology reveal novel molecular and cellular targets, with potential to optimize tissue healing and functional recovery, thereby refining rehabilitation clinical practice. The purpose of this review is to (1) highlight the potential for synergy between the fields of regenerative medicine and rehabilitation, a convergence of disciplines known as regenerative rehabilitation; (2) provide translational examples of regenerative rehabilitation within the context of neuromuscular injuries and diseases; and (3) offer recommendations for ways to leverage activity dependence via combined therapy and technology, with the goal of enhancing long-term recovery. The potential clinical benefits of regenerative rehabilitation will likely become a critical aspect in the standard of care for many neurological and musculoskeletal disorders.

For brain-computer interfaces (BCIs) which provide the user continuous position control, there is little standardization of performance metrics or evaluative tasks. One candidate metric is Fitts's law, which has been used to describe aimed movements across a range of computer interfaces, and has recently been applied to BCI tasks. Reviewing selected studies, we identify two basic problems with Fitts's law: its predictive performance is fragile, and the estimation of 'information transfer rate' from the model is unsupported. Our main contribution is the adaptation and validation of an alternative model to Fitts's law in the BCI context. We show that the Shannon-Welford model outperforms Fitts's law, showing robust predictive power when target distance and width have disproportionate effects on difficulty. Building on a prior study of the Shannon-Welford model, we show that identified model parameters offer a novel approach to quantitatively assess the role of control-display gain in speed/accuracy performance tradeoffs during brain control.

Goal: To identify and overcome barriers to creating new neurotechnologies capable of restoring both motor and sensory function in individuals with neurological conditions., Methods: This report builds upon the outcomes of a joint workshop between the US National Science Foundation and the German Research Foundation on New Perspectives in Neuroengineering and Neurotechnology convened in Arlington, VA, USA, November 13-14, 2014., Results: The participants identified key technological challenges for recording and manipulating neural activity, decoding, and interpreting brain data in the presence of plasticity, and early considerations of ethical and social issues pertinent to the adoption of neurotechnologies., Conclusions: The envisaged progress in neuroengineering requires tightly integrated hardware and signal processing efforts, advances in understanding of physiological adaptations to closed-loop interactions with neural devices, and an open dialog with stakeholders and potential end-users of neurotechnology., Significance: The development of new neurotechnologies (e.g., bidirectional brain-computer interfaces) could significantly improve the quality of life of people living with the effects of brain or spinal cord injury, or other neurodegenerative diseases. Focused efforts aimed at overcoming the remaining barriers at the electrode tissue interface, developing implantable hardware with on-board computation, and refining stimulation methods to precisely activate neural tissue will advance both our understanding of brain function and our ability to treat currently intractable disorders of the nervous system.

Cervical spinal cord contusion is the most common human spinal cord injury, yet few rodent models replicate the pathophysiological and functional sequela of this injury. Here, we modified an electromechanical injury device and characterized the behavioral and histological changes occurring in response to a lateralized C4 contusion injury in rats. A key feature of the model includes a non-injurious touch phase where the spinal cord surface is dimpled with a consistent starting force. Animals were either left intact as a control, received a non-injury-producing touch on the surface of the cord ("sham"), or received a 0.6 mm or a 0.8 mm displacement injury. Rats were then tested on the forelimb asymmetry use test, CatWalk, and the Irvine, Beatties, and Bresnahan (IBB) cereal manipulation task to assess proximal and distal upper limb function for 12 weeks. Injuries of moderate (0.6 mm) and large (0.8 mm) displacement showed consistent differences in forelimb asymmetry, metrics of the CatWalk, and sub-scores of the IBB. Overall findings indicated long lasting proximal and distal upper limb deficits following 0.8 mm injury but transient proximal with prolonged distal limb deficits following 0.6 mm injury. Significant differences in loss of ipsilateral unmyelinated and myelinated white matter was detected between injury severities. Demyelination was primarily localized to the dorsolateral region of the hemicord and extended further rostral following 0.8 mm injury. These findings establish the C4 hemi-contusion injury as a consistent, graded model for testing novel treatments targeting forelimb functional recovery.

Background: Many persons post-stroke continue to have difficulty using their more involved upper extremity and home programs may be poorly adhered to limiting the amount of practice an individual receives. More information on the experience of traditional home program and the acceptability of a novel home intervention was sought., Objective: To qualitatively describe 1) upper extremity use at home, 2) previous home exercise or activity programs, and 3) the acceptability of a novel upper extremity home program, NeuroGame Therapy (NGT), that combines surface electromyography (sEMG) biofeedback and a commercial computer game., Methods: A purposeful sample of ten persons with moderate to severe upper extremity motor impairment used the NGT intervention in their home for four weeks and completed nested (pre and post) one-on-one interviews. Written transcripts from the interviews were coded and themes were identified to address stated objectives., Results: Participants reported that while use of their upper extremity in daily activities was recommended it occurred infrequently. Most participants described previous home programs as being non-specific, were often not carried out as recommended or were self-modified. Participants found NGT to be engaging and motivating, but reported minimal changes in the functional uses of their upper extremity., Conclusion: These findings suggest that after stroke upper extremity use may be infrequent and home program approaches could be re-examined. NGT was reported to be an acceptable home intervention, but it will require further development and study to understand its value and role in post-stroke rehabilitation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Toward expanding the population of potential BCI users to the many individuals with lateralized cortical stroke, here we examined whether the cortical hemisphere controlling ongoing movements of the contralateral limb can simultaneously generate signals to control a BCI. A monkey was trained to perform a simultaneous BCI and manual control task designed to test whether one hemisphere could effectively differentiate its output and provide independent control of two tasks. Pairs of well-isolated single units were used to control a BCI cursor in one dimension, while isometric wrist torque of the contralateral forelimb controlled the cursor in a second dimension. The monkey could independently modulate cortical units and contralateral wrist torque regardless of the strength of directional tuning of the units controlling the BCI. When the presented targets required explicit decoupling of unit activity and wrist torque, directionally tuned units exhibited significantly less efficient cursor trajectories compared to when unit activity and wrist torque could remain correlated. The results indicate that neural activity from a single hemisphere can be effectively decoupled to simultaneously control a BCI and ongoing limb movement, suggesting that BCIs may be a viable future treatment for individuals with lateralized cortical stroke.

Objective: To investigate the preliminary effectiveness of surface electromyography (sEMG) biofeedback delivered via interaction with a commercial computer game to improve motor control in chronic stroke survivors., Design: Single-blinded, 1-group, repeated-measures design: A1, A2, B, A3 (A, assessment; B, intervention)., Setting: Laboratory and participants' homes., Participants: A convenience sample of persons (N=9) between 40 and 75 years of age with moderate to severe upper extremity motor impairment and at least 6 months poststroke completed the study., Intervention: The electromyography-controlled video game system targeted the wrist muscle activation with the goal of increasing selective muscle activation. Participants received several laboratory training sessions with the system and then were instructed to use the system at home for 45 minutes, 5 times per week for the following 4 weeks., Main Outcome Measures: Primary outcome measures included duration of system use, sEMG during home play, and pre/post sEMG measures during active wrist motion. Secondary outcomes included kinematic analysis of movement and functional outcomes, including the Wolf Motor Function Test and the Chedoke Arm and Hand Activity Inventory-9., Results: One third of participants completed or exceeded the recommended amount of system use. Statistically significant changes were observed on both game play and pre/post sEMG outcomes. Limited carryover, however, was observed on kinematic or functional outcomes., Conclusions: This preliminary investigation indicates that use of the electromyography-controlled video game impacts muscle activation. Limited changes in kinematic and activity level outcomes, however, suggest that the intervention may benefit from the inclusion of a functional activity component., (Copyright © 2014 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: There is great interest in closed-loop neurostimulators that sense and respond to a patient's brain state. Such systems may have value for neurological and psychiatric illnesses where symptoms have high intraday variability. Animal models of closed-loop stimulators would aid preclinical testing. We therefore sought to demonstrate that rodents can directly control a closed-loop limbic neurostimulator via a brain-computer interface (BCI)., Approach: We trained rats to use an auditory BCI controlled by single units in prefrontal cortex (PFC). The BCI controlled electrical stimulation in the medial forebrain bundle, a limbic structure involved in reward-seeking. Rigorous offline analyses were performed to confirm volitional control of the neurostimulator., Main Results: All animals successfully learned to use the BCI and neurostimulator, with closed-loop control of this challenging task demonstrated at 80% of PFC recording locations. Analysis across sessions and animals confirmed statistically robust BCI control and specific, rapid modulation of PFC activity., Significance: Our results provide a preliminary demonstration of a method for emotion-regulating closed-loop neurostimulation. They further suggest that activity in PFC can be used to control a BCI without pre-training on a predicate task. This offers the potential for BCI-based treatments in refractory neurological and mental illness.

There is a pressing clinical need for responsive neurostimulators, which sense a patient's brain activity and deliver targeted electrical stimulation to suppress unwanted symptoms. This is particularly true in psychiatric illness, where symptoms can fluctuate throughout the day. Affective BCIs, which decode emotional experience from neural activity, are a candidate control signal for responsive stimulators targeting the limbic circuit. Present affective decoders, however, cannot yet distinguish pathologic from healthy emotional extremes. Indiscriminate stimulus delivery would reduce quality of life and may be actively harmful. We argue that the key to overcoming this limitation is to specifically decode volition, in particular the patient's intention to experience emotional regulation. Those emotion-regulation signals already exist in prefrontal cortex (PFC), and could be extracted with relatively simple BCI algorithms. We describe preliminary data from an animal model of PFC-controlled limbic brain stimulation and discuss next steps for pre-clinical testing and possible translation.

Neuroprosthetic approaches have tremendous potential for the treatment of injuries to the brain and spinal cord by inducing appropriate neural activity in otherwise disordered circuits. Substantial work has demonstrated that stimulation applied to both the central and peripheral nervous system leads to immediate and in some cases sustained benefits after injury. Here we focus on cervical intraspinal microstimulation (ISMS) as a promising method of activating the spinal cord distal to an injury site, either to directly produce movements or more intriguingly to improve subsequent volitional control of the paretic extremities. Incomplete injuries to the spinal cord are the most commonly observed in human patients, and these injuries spare neural tissue bypassing the lesion that could be influenced by neural devices to promote recovery of function. In fact, recent results have demonstrated that therapeutic ISMS leads to modest but sustained improvements in forelimb function after an incomplete spinal cord injury (SCI). This therapeutic spinal stimulation may promote long-term recovery of function by providing the necessary electrical activity needed for neuron survival, axon growth, and synaptic stability.

Transcranial ultrasound can alter brain function transiently and nondestructively, offering a new tool to study brain function now and inform future therapies. Previous research on neuromodulation implemented pulsed low-frequency (250-700 kHz) ultrasound with spatial peak temporal average intensities (ISPTA) of 0.1-10 W/cm(2). That work used transducers that either insonified relatively large volumes of mouse brain (several mL) with relatively low-frequency ultrasound and produced bilateral motor responses, or relatively small volumes of brain (on the order of 0.06 mL) with relatively high-frequency ultrasound that produced unilateral motor responses. This study seeks to increase anatomical specificity to neuromodulation with modulated focused ultrasound (mFU). Here, 'modulated' means modifying a focused 2-MHz carrier signal dynamically with a 500-kHz signal as in vibro-acoustography, thereby creating a low-frequency but small volume (approximately 0.015 mL) source of neuromodulation. Application of transcranial mFU to lightly anesthetized mice produced various motor movements with high spatial selectivity (on the order of 1 mm) that scaled with the temporal average ultrasound intensity. Alone, mFU and focused ultrasound (FUS) each induced motor activity, including unilateral motions, though anatomical location and type of motion varied. Future work should include larger animal models to determine the relative efficacy of mFU versus FUS. Other studies should determine the biophysical processes through which they act. Also of interest is exploration of the potential research and clinical applications for targeted, transcranial neuromodulation created by modulated focused ultrasound, especially mFU's ability to produce compact sources of ultrasound at the very low frequencies (10-100s of Hertz) that are commensurate with the natural frequencies of the brain.

Recent advances in intracortical brain-machine interfaces (BMIs) for position control have leveraged state estimators to decode intended movements from cortical activity. We revisit the underlying assumptions behind the use of Kalman filters in this context, focusing on the fact that identified cortical coding models capture closed-loop task dynamics. We show that closed-loop models can be partitioned, exposing feedback policies of the brain which are separate from interface and task dynamics. Changing task dynamics may cause the brain to change its control policy, and consequently the closed-loop dynamics. This may degrade performance of decoders upon switching from manual tasks to velocity-controlled BMI-mediated tasks. We provide experimental results showing that for the same manual cursor task, changing system order affects neural coding of movement. In one experimental condition force determines position directly, and in the other force determines cursor velocity. From this we draw an analogy to subjects transitioning from manual reaching tasks to velocity-controlled BMI tasks. We conclude with suggested principles for improving BMI decoder performance, including matching the controlled system order between manual and brain control, and identifying the brain's controller dynamics rather than complete closed-loop dynamics.

Objective: This case series examines the feasibility, specificity, and preliminary effectiveness of NeuroGame Therapy (NGT) for improving wrist control in four children with cerebral palsy (CP). NGT uses surface electromyographic (sEMG) signals routed through motivating computer games to improve motor control., Methods: Primary outcomes of NGT included feasibility (hours of play) and specificity (changes in sEMG activity during game play). Secondary outcomes included changes in co-contraction, range of motion, segmental alignment, and spontaneous upper extremity function following intervention., Results: Participants completed a mean of 8.8 hours of NGT over 5-6 weeks. Participants demonstrated dramatic improvement of the sEMG activity during game play. Several participants also showed improvements in range of motion, co-contraction, and spontaneous upper extremity function following NGT., Conclusion: This case series provides evidence for the feasibility, specificity, and effectiveness of NGT. Future studies will pair NGT with functional practice to improve transfer of learning to daily activities.

Neural progenitor cells (NPCs) have shown modest potential and some side effects (e.g. allodynia) for treatment of spinal cord injury (SCI). In only a few cases, however, have NPCs shown promise at the chronic stage. Given the 1.275 million people living with chronic paralysis, there is a significant need to rigorously evaluate the cell types and methods for safe and efficacious treatment of this devastating condition. For the first time, we examined the pre-clinical potential of NPCs derived from human induced pluripotent stem cells (hiPSCs) to repair chronic SCI. hiPSCs were differentiated into region-specific (i.e. caudal) NPCs, then transplanted into a new, clinically relevant model of early chronic cervical SCI. We established the conditions for successful transplantation of caudalized hiPSC-NPCs and demonstrate their remarkable ability to integrate and produce multiple neural lineages in the early chronic injury environment. In contrast to prior reports in acute and sub-acute injury models, survival and integration of hiPSC-derived neural cells in the early chronic cervical model did not lead to significant improvement in forelimb function or induce allodynia. These data indicate that while hiPSCs show promise, future work needs to focus on the specific hiPSC-derivatives or co-therapies that will restore function in the early chronic injury setting., (© 2013.)

Objective: Intraspinal microstimulation (ISMS) is a promising method for activating the spinal cord distal to an injury. The objectives of this study were to examine the ability of chronically implanted stimulating wires within the cervical spinal cord to (1) directly produce forelimb movements, and (2) assess whether ISMS stimulation could improve subsequent volitional control of paretic extremities following injury., Approach: We developed a technique for implanting intraspinal stimulating electrodes within the cervical spinal cord segments C6-T1 of Long-Evans rats. Beginning 4 weeks after a severe cervical contusion injury at C4-C5, animals in the treatment condition received therapeutic ISMS 7 hours/day, 5 days/week for the following 12 weeks., Main Results: Over 12 weeks of therapeutic ISMS, stimulus-evoked forelimb movements were relatively stable. We also explored whether therapeutic ISMS promoted recovery of forelimb reaching movements. Animals receiving daily therapeutic ISMS performed significantly better than unstimulated animals during behavioural tests conducted without stimulation. Quantitative video analysis of forelimb movements showed that stimulated animals performed better in the movements reinforced by stimulation, including extending the elbow to advance the forelimb and opening the digits. While threshold current to elicit forelimb movement gradually increased over time, no differences were observed between chronically stimulated and unstimulated electrodes suggesting that no additional tissue damage was produced by the electrical stimulation., Significance: The results indicate that therapeutic intraspinal stimulation delivered via chronic microwire implants within the cervical spinal cord confers benefits extending beyond the period of stimulation, suggesting future strategies for neural devices to promote sustained recovery after injury.

Objective: Intraspinal microstimulation (ISMS) is a promising method for reanimating paralyzed limbs following neurological injury. ISMS within the cervical and lumbar spinal cord is capable of evoking a variety of highly-functional movements prior to injury, but the ability of ISMS to evoke forelimb movements after cervical spinal cord injury is unknown. Here we examine the forelimb movements and muscles activated by cervical ISMS both before and after contusion injury., Approach: We documented the forelimb muscles activated and movements evoked via systematic stimulation of the rodent cervical spinal cord both before injury and three, six and nine weeks following a moderate C4/C5 lateralized contusion injury. Animals were anesthetized with isoflurane to permit construction of somatotopic maps of evoked movements and quantify evoked muscle synergies between cervical segments C3 and T1., Main Results: When ISMS was delivered to the cervical spinal cord, a variety of responses were observed at 68% of locations tested, with a spatial distribution that generally corresponded to the location of motor neuron pools. Stimulus currents required to achieve movement and the number of sites where movements could be evoked were unchanged by spinal cord injury. A transient shift toward extension-dominated movements and restricted muscle synergies were observed at three and six weeks following injury, respectively. By nine weeks after injury, however, ISMS-evoked patterns were similar to spinally-intact animals., Significance: The results demonstrate the potential for cervical ISMS to reanimate hand and arm function following spinal cord injury. Robust forelimb movements can be evoked both before and during the chronic stages of recovery from a clinically relevant and sustained cervical contusion injury.

Volitional control of cortical activity is relevant for optimizing control signals for neuroprosthetic devices. We explored the control of firing rates of single cortical cells in two Macaca nemestrina monkeys by providing visual feedback of neural activity and rewarding changes in cell rates. During 'brain-control' sessions, the monkeys modulated the activity of each of 246 cells to acquire targets requiring high or low discharge rates. Cell control improved more than two-fold from the beginning of practice to peak performance. Cell activity was modulated substantially more during brain control than during wrist movements. When recording stability permitted, the monkeys practiced controlling activity of the same cells across multiple days. The performance improved substantially for 27 of 36 cells when practicing brain control across days. The monkeys maintained discharge rates within each target for 1 s, but could maintain rates for up to 3 s for some cells, and performed the brain-control task equally well using cells recorded from the pre-central cortex compared to cells in the post-central cortex, and independently of any directional tuning. These findings demonstrate that arbitrary single cortical neurons, regardless of the strength of directional tuning, are capable of controlling cursor movements in a one-dimensional brain-machine interface. It is possible that direct conversion of activity from single cortical cells to control signals for neuroprosthetic devices may be a useful complementary strategy to population decoding of the intended movement direction.

When human hoppers are surprised by a change in surface stiffness, they adapt almost instantly by changing leg stiffness, implying that neural feedback is not necessary. The goal of this simulation study was first to investigate whether leg stiffness can change without neural control adjustment when landing on an unexpected hard or unexpected compliant (soft) surface, and second to determine what underlying mechanisms are responsible for this change in leg stiffness. The muscle stimulation pattern of a forward dynamic musculoskeletal model was optimized to make the model match experimental hopping kinematics on hard and soft surfaces. Next, only surface stiffness was changed to determine how the mechanical interaction of the musculoskeletal model with the unexpected surface affected leg stiffness. It was found that leg stiffness adapted passively to both unexpected surfaces. On the unexpected hard surface, leg stiffness was lower than on the soft surface, resulting in close-to-normal center of mass displacement. This reduction in leg stiffness was a result of reduced joint stiffness caused by lower effective muscle stiffness. Faster flexion of the joints due to the interaction with the hard surface led to larger changes in muscle length, while the prescribed increase in active state and resulting muscle force remained nearly constant in time. Opposite effects were found on the unexpected soft surface, demonstrating the bidirectional stabilizing properties of passive dynamics. These passive adaptations to unexpected surfaces may be critical when negotiating disturbances during locomotion across variable terrain.

A potential treatment for paralysis resulting from spinal cord injury is to route control signals from the brain around the injury by artificial connections. Such signals could then control electrical stimulation of muscles, thereby restoring volitional movement to paralysed limbs. In previously separate experiments, activity of motor cortex neurons related to actual or imagined movements has been used to control computer cursors and robotic arms, and paralysed muscles have been activated by functional electrical stimulation. Here we show that Macaca nemestrina monkeys can directly control stimulation of muscles using the activity of neurons in the motor cortex, thereby restoring goal-directed movements to a transiently paralysed arm. Moreover, neurons could control functional stimulation equally well regardless of any previous association to movement, a finding that considerably expands the source of control signals for brain-machine interfaces. Monkeys learned to use these artificial connections from cortical cells to muscles to generate bidirectional wrist torques, and controlled multiple neuron-muscle pairs simultaneously. Such direct transforms from cortical activity to muscle stimulation could be implemented by autonomous electronic circuitry, creating a relatively natural neuroprosthesis. These results are the first demonstration that direct artificial connections between cortical cells and muscles can compensate for interrupted physiological pathways and restore volitional control of movement to paralysed limbs.

Documenting the forelimb responses evoked by stimulating sites in primate cervical spinal cord is significant for understanding spinal circuitry and for potential neuroprosthetic applications involving hand and arm. We examined the forelimb movements and electromyographic (EMG) muscle responses evoked by intraspinal microstimulation in three M. nemestrina monkeys sedated with ketamine. Trains of three stimulus pulses (10-80 muA) at 300 Hz were delivered at sites in regularly spaced tracks from C6 to T1. Hand and/or arm movements were evoked at 76% of the 745 sites stimulated. Specifically, movements were evoked in digits (76% of effective sites), wrist (15% of sites), elbow (26%), and shoulder (17%). To document the muscle activity evoked by a stimulus current just capable of eliciting consistent joint rotation, stimulus-triggered averages of rectified EMG were calculated at each site where a movement was observed. Typically, many muscles were coactivated at threshold currents needed to evoke movements. Out of the 13-15 muscles recorded per animal, only one muscle was active at 14% of the effective sites and two to six muscles were coactivated at 47% of sites. Thus intraspinal stimulation at threshold currents adequate for evoking movement typically coactivated multiple muscles, including antagonists. Histologic reconstruction of stimulation sites indicated that responses were elicited from the dorsal and ventral horn and from fiber tracts in the white matter, with little somatotopic organization for movement or muscle activation. The absence of a clear somatotopic map of output sites is probably a result of the stimulation of complex mixtures of fibers and cells.

The Neurochip BCI is an autonomously operating interface between an implanted computer chip and recording and stimulating electrodes in the nervous system. By converting neural activity recorded in one brain area into electrical stimuli delivered to another site, the Neurochip BCI could form the basis for a simple, direct neural prosthetic. In tests with normal, unrestrained monkeys, the Neurochip continuously recorded activity of single neurons in primary motor cortex for several weeks at a time. Cortical activity was correlated with simultaneously-recorded electromyogram (EMG) activity from arm muscles during free behavior. In separate experiments with anesthetized monkeys, we found that microstimulation of the cervical spinal cord evoked movements of the arm and hand, often involving multiple muscles synergies. These observations suggest that spinal microstimulation controlled by cortical neurons could help compensate for damaged corticospinal projections.

On a range of elastic and damped surfaces, human hoppers and runners adjust leg mechanics to maintain similar spring-like mechanics of the leg and surface combination. In a previous study of adaptations to damped surfaces, we changed surface damping and stiffness simultaneously to maintain constant surface compression. The current study investigated whether hoppers maintain spring-like mechanics of the leg-surface combination when surface damping alone changes (elastic and 1000-4800 N s m(-1)). We found that hoppers adjusted leg mechanics to maintain similar spring-like mechanics of the leg-surface combination and center of mass dynamics on all surfaces. Over the range of surface damping, vertical stiffness of the leg-surface combination increased by only 12% and center of mass displacement decreased by only 6% despite up to 55% less compression of more heavily damped surfaces. In contrast, a simulation predicted a 44% decrease in vertical displacement with no adjustment to leg mechanics. To compensate for the smaller and slower compression of more heavily damped surfaces, the stance legs compressed by up to 4.1 +/- 0.2 cm further and reached peak compression sooner. To replace energy lost by damped surfaces, hoppers performed additional leg work by extending the legs during takeoff by up to 3.1 +/- 0.2 cm further than they compressed during landing. We conclude that humans simultaneously adjust leg compression magnitude and timing, as well as mechanical work output, to conserve center of mass dynamics on damped surfaces. Runners may use similar strategies on natural energy-dissipating surfaces such as sand, mud and snow.

The purpose of this study was to compare the influence of prolonged vibration of a hand muscle on the amplitude of the stretch reflex, motor unit discharge rate, and force fluctuations during steady, submaximal contractions. Thirty-two young adults performed 10 isometric contractions at a constant force (5.0 +/- 2.3% of maximal force) with the first dorsal interosseus muscle. Each contraction was held steady for 10 s, and then stretch reflexes were evoked. Subsequently, 20 subjects had vibration applied to the relaxed muscle for 30 min, and 12 subjects received no vibration. The muscle vibration induced a tonic vibration reflex. The intervention (vibration or no vibration) was followed by 2 sets of 10 constant-force contractions with applied stretches (After and Recovery trials). The mean electromyogram amplitude of the short-latency component of the stretch reflex increased by 33% during the After trials (P < 0.01) and by 38% during the Recovery trials (P < 0.01). The standard deviation of force during the steady contractions increased by 21% during the After trials (P < 0.05) and by 28% during the Recovery trials (P < 0.01). The discharge rate of motor units increased from 10.3 +/- 2.7 pulses/s (pps) before vibration to 12.2 +/- 3.1 pps (P < 0.01) during the After trials and to 11.9 +/- 2.6 pps during the Recovery trials (P < 0.01). There was no change in force fluctuations or stretch reflex magnitude for the subjects in the Control group. The results indicate that prolonged vibration increased the short-latency component of the stretch reflex, the discharge rate of motor units, and the fluctuations in force during contractions by a hand muscle. These adjustments were necessary to achieve the target force due to the vibration-induced decrease in the force capacity of the muscle.

Time- and frequency-domain measures of discharge times for pairs of motor units are used to infer the proportion of common synaptic input received by motor neurons. The physiological mechanisms that can produce the experimentally observed peaks in the cross-correlation histogram and the coherence spectrum are uncertain. The present study used a computational model to impose synchronization on the discharge times of motor units. Randomly selected discharge times of a unit that was being synchronized to a reference unit were aligned with some of the discharge times of the reference unit, provided the original discharge time was within 30 ms of the discharge by the reference unit. All time-domain measures (indexes CIS, E, and k') were sensitive to changes in the level of imposed motor-unit synchronization (P < 0.01). In addition, synchronization caused a peak between 16 and 32 Hz in the coherence spectrum. The shape of the cross-correlogram determined the frequency at which the peak occurred in the coherence spectrum. Further, the magnitude of the coherence peak was highly correlated with the time-domain measures of motor-unit synchronization (r2 > 0.80), with the highest correlation occurring for index E (r2 = 0.98). Thus the peak in the 16- to 32-Hz band of the coherence spectrum can be caused by the time that individual discharges are advanced or delayed to produce synchrony. Although the in vivo processes that adjust the timing of motor-unit discharges are not fully understood, these results suggest that they may not depend entirely on an oscillatory drive by the CNS.

The goal of this study was to improve the ability of a motor unit model to predict experimentally measured force variability across a wide range of forces. Motor unit discharge characteristics were obtained from 38 motor units of the first dorsal interosseus muscle. Motor unit discharges were recorded in separate isometric contractions that ranged from 4 to 85% of the maximal voluntary contraction (MVC) force above recruitment threshold. High-threshold motor units exhibited both greater minimal and peak discharge rates compared with low-threshold units (P < 0.01). Minimal discharge rate increased from 7 to 23 pps, and peak discharge rate increased from 14 to 38 pps with an increase in recruitment threshold. Relative discharge rate variability (CV) decreased exponentially for each motor unit from an average of 30 to 13% as index finger force increased above recruitment threshold. In separate experiments, force variability was assessed at eight force levels from 2 to 95% MVC. The CV for force decreased from 4.9 to 1.4% as force increased from 2 to 15% MVC (P < 0.01) and remained constant at higher forces (1.2-1.9%; P = 0.14). When the motor unit model was revised using these experimental findings, discharge rate variability was the critical factor that resulted in no significant difference between simulated and experimental force variability (P = 0.22) at all force levels. These results support the hypothesis that discharge rate variability is a major determinant of the trends in isometric force variability across the working range of a muscle.

During hopping in place and running, humans maintain similar center of mass dynamics by precisely adjusting leg mechanics to compensate for moderate changes in surface stiffness. We investigated the limits of this precise control by asking humans to hop in place on extremely soft elastic surfaces. We found that hoppers drastically altered leg mechanics and maintained similar center of mass dynamics despite a sevenfold change in surface stiffness (11-81 kN m(-1)). On the stiffest surfaces, the legs compressed in early stance and then extended in late stance in the pattern that is typical for normal bouncing gaits. On the softest surfaces, however, subjects reversed this pattern so that the legs extended up to 8 cm in early stance and then compressed by a similar distance in late stance. Consequently, the center of mass moved downward during stance by 5-7 cm less than the surface compressed and by a similar distance as on the stiffest surfaces. This unique leg action probably reduced extensor muscle pre-stretch because the joints first extended and then flexed during stance. This interpretation is supported by the observation that hoppers increased muscle activation by 50% on the softest surface despite similar joint moments and mechanical leg work as on the stiffest surface. Thus, the extreme adjustment to leg mechanics for very soft surfaces helps maintain normal center of mass dynamics but requires high muscle activation levels due to the loss of the normal extensor muscle stretch-shorten cycle.

Humans running and hopping maintain similar center-of-mass motions, despite large changes in surface stiffness and damping. The goal of this study was to determine the contributions of anticipation and reaction when human hoppers encounter surprise, expected, and random changes from a soft elastic surface (27 kN/m) to a hard surface (411 kN/m). Subjects encountered the expected hard surface on every fourth hop and the random hard surface on an average of 25% of the hops in a trial. When hoppers on a soft surface were surprised by a hard surface, the ankle and knee joints were forced into greater flexion by passive interaction with the hard surface. Within 52 ms after subjects landed on the surprise hard surface, joint flexion increased, and the legs became less stiff than on the soft surface. These mechanical changes occurred before electromyography (EMG) first changed 68-188 ms after landing. Due to the fast mechanical reaction to the surprise hard surface, center-of-mass displacement and average leg stiffness were the same as on expected and random hard surfaces. This similarity is striking because subjects anticipated the expected and random hard surfaces by landing with their knees more flexed. Subjects also anticipated the expected hard surface by increasing the level of EMG by 24-76% during the 50 ms before landing. These results show that passive mechanisms alter leg stiffness for unexpected surface changes before muscle EMG changes and may be critical for adjustments to variable terrain encountered during locomotion in the natural world.

Humans hopping and running on elastic and damped surfaces maintain similar center-of-mass dynamics by adjusting stance leg mechanics. We tested the hypothesis that the leg transitions from acting like an energy-conserving spring on elastic surfaces to a power-producing actuator on damped surfaces during hopping due to changes in ankle mechanics. To test this hypothesis, we collected surface electromyography, video kinematics, and ground reaction force while eight male subjects (body mass: 76.2 +/- 1.7 kg) hopped in place on a range of damped surfaces. On the most damped surface, most of the mechanical work done by the leg appeared at the ankle (52%), whereas 23 and 25% appeared at the knee and hip, respectively. Hoppers extended all three joints during takeoff further than they flexed during landing and thereby did more net positive work on more heavily damped surfaces. Also, all three joints reached peak flexion sooner after touchdown on more heavily damped surfaces. Consequently, peak moment occurred during joint extension rather than at peak flexion as on elastic surfaces. These strategies caused the positive work during extension to exceed the negative work during flexion to a greater extent on more heavily damped surfaces. At the muscle level, surface EMG increased by 50-440% in ankle and knee extensors as surface damping increased to compensate for greater surface energy dissipation. Our findings, and those of previous studies of hopping on elastic surfaces, show that the ankle joint is the key determinant of both springlike and actuator-like leg mechanics during hopping in place.

Fast-moving legged animals bounce along the ground with spring-like legs and agilely traverse variable terrain. Previous research has shown that hopping and running humans maintain the same bouncing movement of the body's centre of mass on a range of elastic surfaces by adjusting their spring-like legs to exactly offset changes in surface stiffness. This study investigated human hopping on damped surfaces that dissipated up to 72% of the hopper's mechanical energy. On these surfaces, the legs did not act like pure springs. Leg muscles performed up to 24-fold more net work to replace the energy lost by the damped surface. However, considering the leg and surface together, the combination appeared to behave like a constant stiffness spring on all damped surfaces. By conserving the mechanics of the leg-surface combination regardless of surface damping, hoppers also conserved centre-of-mass motions. Thus, the normal bouncing movements of the centre of mass in hopping are not always a direct result of spring-like leg behaviour. Conserving the trajectory of the centre of mass by maintaining spring-like mechanics of the leg-surface combination may be an important control strategy for fast-legged locomotion on variable terrain.