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Objective To provide precise description of the dorsal and ventral roots orientation along with the main spinal cord anatomical measurements and their segment-specific variations. Patients and Methods We collected and analyzed the measurements of the spines, spinal cords, and dorsal and ventral roots (C2-L5) of nine adult cadavers (five males and four females). Results This study for the first time provides analysis of the dorsal and ventral roots orientation along with spinal cord anatomical measurements and their segment-specific distribution. The results of this study showed less variability in rostral root angles compared with the caudal. Dorsal and ventral rootlets were oriented mostly perpendicular to the spinal cord at the cervical level and had more parallel orientation to the spinal cord at the thoracic and lumbar segments. The number of rootlets per root was greatest at dorsal cervical and lumbar segments. Spinal cord transverse diameter and width of the dorsal columns were largest at cervical segments. The strongest correlation between the spinal cord and vertebrae structures was found between the length of intervertebral foramen to rostral rootlet distance and vertebral bone length. Conclusion These results demonstrate consistent variation in spinal cord anatomical features across all tested subjects. The results of this study can be used to locate spinal roots and main spinal cord landmarks based on bone marks on computed tomography or X-rays. These results could improve stereotactic surgical procedures and electrode positioning for neuromodulation procedures.

Integrating multiple assessment parameters of motor behavior is critical for understanding neural activity dynamics during motor control in both intact and dysfunctional nervous systems. Here, we described a novel approach (termed Multifactorial Behavioral Assessment (MfBA)) to integrate, in real-time, electrophysiological and biomechanical properties of rodent spinal sensorimotor network activity with behavioral aspects of motor task performance. Specifically, the MfBA simultaneously records limb kinematics, multi-directional forces and electrophysiological metrics, such as high-fidelity chronic intramuscular electromyography synchronized in time to spinal stimulation in order to characterize spinal cord functional motor evoked potentials (fMEPs). Additionally, we designed the MfBA to incorporate a body weight support system to allow bipedal and quadrupedal stepping on a treadmill and in an open field environment to assess function in rodent models of neurologic disorders that impact motor activity This novel approach was validated using, a neurologically intact cohort, a cohort with unilateral Parkinsonian motor deficits due to midbrain lesioning, and a cohort with complete hind limb paralysis due to T8 spinal cord transection. In the SCI cohort, lumbosacral epidural electrical stimulation (EES) was applied, with and without administration of the serotonergic agonist Quipazine, to enable hind limb motor functions following paralysis. The results presented herein demonstrate the MfBA is capable of integrating multiple metrics of motor activity in order to characterize relationships between EES inputs that modulate mono- and polysynaptic outputs from spinal circuitry which in turn, can be used to elucidate underlying electrophysiologic mechanisms of motor behavior by synchronizing these datasets to metrics of movement and behavior. These results also demonstrate that proposed MfBA is an effective tool to integrate biomechanical and electrophysiology metrics, synchronized to therapeutic inputs such as EES or pharmacology, during body weight supported treadmill or open field motor activities, to target a high range of variations in motor behavior as a result of neurological deficit at the different levels of CNS.

Transcutaneous (TSS) and epidural spinal stimulation (ESS) are electrophysiological techniques that have been used to investigate the interactions between exogenous electrical stimuli and spinal sensorimotor networks that integrate descending motor signals with afferent inputs from the periphery during motor tasks such as standing and stepping. Recently, pilot-phase clinical trials using ESS and TSS have demonstrated restoration of motor functions that were previously lost due to spinal cord injury (SCI). However, the spinal network interactions that occur in response to TSS or ESS pulses with spared descending connections across the site of SCI have yet to be characterized. Therefore, we examined the effects of delivering TSS or ESS pulses to the lumbosacral spinal cord in nine individuals with chronic SCI. During low-frequency stimulation, participants were instructed to relax or attempt maximum voluntary contraction to perform full leg flexion while supine. We observed similar lower-extremity neuromusculature activation during TSS and ESS when performed in the same participants while instructed to relax. Interestingly, when participants were instructed to attempt lower-extremity muscle contractions, both TSS- and ESS-evoked motor responses were significantly inhibited across all muscles. Participants with clinically complete SCI tested with ESS and participants with clinically incomplete SCI tested with TSS demonstrated greater ability to modulate evoked responses than participants with motor complete SCI tested with TSS, although this was not statistically significant due to a low number of subjects in each subgroup. These results suggest that descending commands combined with spinal stimulation may increase activity of inhibitory interneuronal circuitry within spinal sensorimotor networks in individuals with SCI, which may be relevant in the context of regaining functional motor outcomes.

We appreciate the feedback from the authors of the Letter to the Editor regarding our case report.1 The overarching goal of our case report was to inform others of potential benefits and consequenc...

Evidence from preclinical and clinical research suggest that neuromodulation technologies can facilitate the sublesional spinal networks, isolated from supraspinal commands after spinal cord injury (SCI), by reestablishing the levels of excitability and enabling descending motor signals via residual connections. Herein, we evaluate available evidence that sublesional and supralesional spinal circuits could form a translesional spinal network after SCI. We further discuss evidence of translesional network reorganization after SCI in the presence of sensory inputs during motor training. In this review, we evaluate potential mechanisms that underlie translesional circuitry reorganization during neuromodulation and rehabilitation in order to enable motor functions after SCI. We discuss the potential of neuromodulation technologies to engage various components that comprise the translesional network, their functional recovery after SCI, and the implications of the concept of translesional network in development of future neuromodulation, rehabilitation, and neuroprosthetics technologies.

We report the effect of newly regenerated neural fibers via bioengineered scaffold on reorganization of spinal circuitry and restoration of motor functions with electrical epidural stimulation (EES) after spinal transection (ST). Restoration across multiple modalities was evaluated for 7 weeks after ST with implanted scaffold seeded with Schwann cells, producing neurotrophic factors and with rapamycin microspheres. Gradual improvement in EES-facilitated stepping was observed in animals with scaffolds, although, no significant difference in stepping ability was found between groups without EES. Similar number of regenerated axons through the scaffolds was found in rats with and without EES-enabled training. Re-transection through the scaffold at week 6, reduced EES-enabled motor function, remaining higher compared to rats without scaffolds. The combination of scaffolds and EES-enabled training demonstrated synaptic changes below the injury. These findings indicate that sub-functional connectivity with regenerated across injury fibers can reorganize of sub-lesional circuitry, facilitating motor functions recovery with EES.

Introduction: Spinal cord injury (SCI) often results in chronic secondary health conditions related to autonomic and metabolic dysfunction. Epidural electrical stimulation (EES) combined with task-specific training has been shown to enable motor function in individuals with chronic paralysis. The reported effects of EES on secondary health conditions, such as bladder function and body composition, are limited. We report the impact of EES on SCI-related secondary health changes in bladder function and body composition. Methods: Two participants with motor and sensory complete SCI performed 6 months of rehabilitation without EES followed by 12 months of task-specific training with EES after implantation of a 16-electrode array on the surface of the lumbosacral spinal cord. Participants performed three days of training per week in the laboratory, and additionally performed task-specific activities with EES at home during this time frame. Changes in bladder and body composition were recorded via clinically-available testing of neurogenic bladder functionality and dual-energy X-ray absorptiometry, respectively. Results: In one participant, we observed an increase in episodes of urinary incontinence with worsening bladder compliance and pressures at the end of the study. Bone mineral density changes were insignificant in both participants; however, one participant showed a substantial increase in lean mass (+9.1 kg; 6 months of training) via redistribution of body fat through an android/gynoid ratio reduction (−0.15; 6 months of training). Conclusion: EES optimized for standing and stepping may negatively impact neurogenic bladder functionality. Close monitoring of bladder health is imperative to prevent undesirable bladder compliance, which can lead to upper urinary tract deteriorations. Conversely, EES may serve as an adjunct tool with regular exercise modalities to improve body composition through activation of musculature innervated by spinal segments that are below the SCI.

An understanding of spinal cord functional neuroanatomy is essential for diagnosis and treatment of multiple disorders including, chronic pain, movement disorders, and spinal cord injury. Till now, no information is available on segment-specific spinal roots orientation in humans. In this study we collected neuroanatomical measurements of the dorsal and ventral roots from C2-L5, as well as spinal cord and vertebral bone measurements from adult cadavers. Spatial orientation of dorsal and ventral roots were measured and correlated to the anatomical landmarks of the spinal cord and vertebral column. The results show less variability in rostral root angles compared to the caudal angles across all segments. Dorsal and ventral rootlets were oriented mostly perpendicular to the spinal cord at the cervical level and demonstrate more parallel orientation at the thoracic and lumbar segments. The number of rootlets was the highest in dorsal cervical and lumbar segments. Spinal cord transverse diameter and size of the dorsal columns were largest at cervical and lumbar segments. The strongest correlation was found between the length of intervertebral foramen to rostral rootlet and vertebral bone length. These results could be used to locate spinal roots and spinal cord landmarks based on bone marks on CT or X-rays. These results also provide background for future correlations between anatomy of spinal cord and spinal column structures that could improve stereotactic surgical procedures and electrode positioning for spinal cord neuromodulation.One Sentence SummaryThis is the first detailed analysis of the segment-specific dorsal and ventral spinal roots spatial orientation measured and correlated to the anatomical landmarks of the spinal cord and vertebral column for human.

Spinal sensorimotor networks that are functionally disconnected from the brain because of spinal cord injury (SCI) can be facilitated via epidural electrical stimulation (EES) to restore robust, coordinated motor activity in humans with paralysis1–3. Previously, we reported a clinical case of complete sensorimotor paralysis of the lower extremities in which EES restored the ability to stand and the ability to control step-like activity while side-lying or suspended vertically in a body-weight support system (BWS)4. Since then, dynamic task-specific training in the presence of EES, termed multimodal rehabilitation (MMR), was performed for 43 weeks and resulted in bilateral stepping on a treadmill, independent from trainer assistance or BWS. Additionally, MMR enabled independent stepping over ground while using a front-wheeled walker with trainer assistance at the hips to maintain balance. Furthermore, MMR engaged sensorimotor networks to achieve dynamic performance of standing and stepping. To our knowledge, this is the first report of independent stepping enabled by task-specific training in the presence of EES by a human with complete loss of lower extremity sensorimotor function due to SCI.

Transcutaneous spinal stimulation (TSS), a noninvasive technique to modulate sensorimotor circuitry within the spinal cord, has been shown to enable a wide range of functions that were thought to be permanently impaired in humans with spinal cord injury. However, the extent to which TSS can be used to target specific mediolateral spinal cord circuitry remains undefined. We tested the hypothesis that TSS applied unilaterally to the skin ~2 cm lateral to the midline of the lumbosacral spine selectively activates ipsilateral spinal sensorimotor circuitry, resulting in ipsilateral activation of downstream lower extremity neuromusculature. TSS cathodes and anodes were positioned lateral from the midline of the spine in 15 healthy subjects while supine, and the timing of TSS pulses was synchronized to recordings of lower extremity muscle activity and force. At motor threshold, left and right TSS-evoked muscle activity was significantly higher in the ipsilateral leg compared with contralateral recordings from the same muscles. Similarly, we observed a significant increase in force production in the ipsilateral leg compared with the contralateral leg. Delivery of paired TSS pulses, during which an initial stimulus was applied to one side of the spinal cord and 50 ms later a second stimulus was applied to the contralateral side, revealed that ipsilateral leg muscle responses decreased following the initial stimulus, whereas contralateral muscle responses did not decrease, indicating side-specific activation of lateral spinal sensorimotor circuitry. Our results indicate TSS can selectively engage ipsilateral neuromusculature via lumbosacral sensorimotor networks responsible for lower extremity function in healthy humans. NEW & NOTEWORTHY We demonstrate the selectivity of transcutaneous spinal stimulation (TSS), which has been shown to enable function in humans with chronic paralysis. Specifically, we demonstrate that TSS applied to locations lateral to the spinal cord can selectively activate ipsilateral spinal sensorimotor networks. We quantified lumbosacral spinal network activity by recording lower extremity muscle electromyography and force. Our results suggest lumbosacral TSS engages side-specific spinal sensorimotor networks associated with ipsilateral lower extremity function in humans.

Epidural electrical stimulation (EES) of the spinal cord has been shown to restore function after spinal cord injury (SCI). Characterization of EES-evoked motor responses has provided a basic understanding of spinal sensorimotor network activity related to EES-enabled motor activity of the lower extremities. However, the use of EES-evoked motor responses to guide EES system implantation over the spinal cord and their relation to post-operative EES-enabled function in humans with chronic paralysis attributed to SCI has yet to be described. Herein, we describe the surgical and intraoperative electrophysiological approach used, followed by initial EES-enabled results observed in 2 human subjects with motor complete paralysis who were enrolled in a clinical trial investigating the use of EES to enable motor functions after SCI. The 16-contact electrode array was initially positioned under fluoroscopic guidance. Then, EES-evoked motor responses were recorded from select leg muscles and displayed in real time to determine electrode array proximity to spinal cord regions associated with motor activity of the lower extremities. Acceptable array positioning was determined based on achievement of selective proximal or distal leg muscle activity, as well as bilateral muscle activation. Motor response latencies were not significantly different between intraoperative recordings and post-operative recordings, indicating that array positioning remained stable. Additionally, EES enabled intentional control of step-like activity in both subjects within the first 5 days of testing. These results suggest that the use of EES-evoked motor responses may guide intraoperative positioning of epidural electrodes to target spinal cord circuitry to enable motor functions after SCI.

Background Traumatic spinal cord injury (SCI) disrupts signaling pathways between the brain and spinal networks below the level of injury. In cases of severe SCI, permanent loss of sensorimotor and autonomic function can occur. The standard of care for severe SCI uses compensation strategies to maximize independence during activities of daily living while living with chronic SCI-related dysfunctions. Over the past several years, the research field of spinal neuromodulation has generated promising results that hold potential to enable recovery of functions via epidural electrical stimulation (EES). Methods This review provides a historical account of the translational research efforts that led to the emergence of EES of the spinal cord to enable intentional control of motor functions that were lost after SCI. We also highlight the major limitations associated with EES after SCI and propose future directions of spinal neuromodulation research. Results Multiple, independent studies have demonstrated return of motor function via EES in individuals with chronic SCI. These enabled motor functions include intentional, controlled movement of previously paralyzed extremities, independent standing and stepping, and increased grip strength. In addition, improvements in cardiovascular health, respiratory function, body composition, and urologic function have been reported. Conclusions EES holds promise to enable functions thought to be permanently lost due to SCI. However, EES is currently restricted to scientific investigation in humans with SCI and requires further validation of factors such as safety and efficacy before clinical translation.

Positively charged oligo[poly(ethylene glycol) fumarate] (OPF+) scaffolds loaded with Schwann cells bridge spinal cord injury (SCI) lesions and support axonal regeneration in rat. The regeneration achieved is not sufficient for inducing functional recovery. Attempts to increase regeneration would benefit from understanding the effects of the scaffold and transplanted cells on lesion environment. We conducted morphometric and stereological analysis of lesions in rats implanted with OPF+ scaffolds with or without loaded Schwann cells 1, 2, 3, 4, and 8 weeks after thoracic spinal cord transection. No differences were found in collagen scarring, cyst formation, astrocyte reactivity, myelin debris, or chondroitin sulfate proteoglycan (CSPG) accumulation. However, when scaffold-implanted animals were compared with animals with transection injuries only, these barriers to regeneration were significantly reduced, accompanied by increased activated macrophages/microglia. This distinctive and regeneration permissive tissue reaction to scaffold implantation was independent of Schwann cell transplantation. Although the tissue reaction was beneficial in the short term, we observed a chronic fibrotic host response, resulting in scaffolds surrounded by collagen at 8 weeks. This study demonstrates that an appropriate biomaterial scaffold improves the environment for regeneration. Future targeting of the host fibrotic response may allow increased axonal regeneration and functional recovery.

We report a case of chronic traumatic paraplegia in which epidural electrical stimulation (EES) of the lumbosacral spinal cord enabled (1) volitional control of task-specific muscle activity, (2) volitional control of rhythmic muscle activity to produce steplike movements while side-lying, (3) independent standing, and (4) while in a vertical position with body weight partially supported, voluntary control of steplike movements and rhythmic muscle activity. This is the first time that the application of EES enabled all of these tasks in the same patient within the first 2 weeks (8 stimulation sessions total) of EES therapy.

Spinal cord injury (SCI) is a complex and devastating condition characterized by disruption of descending, ascending, and intrinsic spinal circuitry resulting in chronic neurologic deficits. In addition to limb and trunk sensorimotor deficits, SCI can impair autonomic neurocircuitry such as the motor networks that support respiration and cough. High cervical SCI can cause complete respiratory paralysis, and even lower cervical or thoracic lesions commonly result in partial respiratory impairment. Although electrophrenic respiration can restore ventilator-independent breathing in select candidates, only a small subset of affected individuals can benefit from this technology at this moment. Over the past decades, spinal cord stimulation has shown promise for augmentation and recovery of neurologic function including motor control, cough, and breathing. The present review discusses the challenges and potentials of spinal cord stimulation for restoring respiratory function by overcoming some of the limitations of conventional respiratory functional electrical stimulation systems.

Spinal cord injury (SCI) remains a debilitating condition for which there is no cure. In addition to loss of somatic sensorimotor functions, SCI is also commonly associated with impairment of autonomic function. Importantly, cough dysfunction due to paralysis of expiratory muscles in combination with respiratory insufficiency can render affected individuals vulnerable to respiratory morbidity. Failure to clear sputum can aggravate both risk for and severity of respiratory infections, accounting for frequent hospitalizations and even mortality. Recently, epidural stimulation of the lower thoracic spinal cord has been investigated as novel means for restoring cough by evoking expiratory muscle contraction to generate large positive airway pressures and expulsive air flow. This review article discusses available preclinical and clinical evidence, current challenges and clinical potential of lower thoracic spinal cord stimulation (SCS) for restoring cough in individuals with SCI.

Laboratory/animal-based proof of principle study.To validate the accuracy of a magnetic resonance imaging (MRI)-guided stereotactic system for intraspinal electrode targeting and demonstrate the feasibility of such a system for controlling implantation of intraspinal electrodes.Intraspinal microstimulation (ISMS) is an emerging preclinical therapy, which has shown promise for the restoration of motor function following spinal cord injury. However, targeting inaccuracy associated with existing electrode implantation techniques remains a major barrier preventing clinical translation of ISMS.System accuracy was evaluated using a test phantom comprised of nine target locations. Targeting accuracy was determined by calculating the root mean square error between MRI-generated coordinates and actual frame coordinates required to reach the target positions. System performance was further validated in an anesthetized pig model by performing MRI-guided intraspinal electrode implantation and stimulation followed by computed tomography of electrode location. Finally, system compatibility with a commercially available microelectrode array was demonstrated by implanting the array and applying a selection of stimulation amplitudes that evoked hind limb responses.The root mean square error between actual frame coordinates and software coordinates, both acquired using the test phantom, was 1.09 ± 0.20 mm. Postoperative computed tomography in the anesthetized pig confirmed spatially accurate electrode placement relative to preoperative MRI. Additionally, MRI-guided delivery of a microwire electrode followed by ISMS evoked repeatable electromyography responses in the biceps femoris muscle. Finally, delivery of a microelectrode array produced repeatable and graded hind limb evoked movements.We present a novel frame-based stereotactic system for targeting and delivery of intraspinal instrumentation. This system utilizes MRI guidance to account for variations in anatomy between subjects, thereby improving upon existing ISMS electrode implantation techniques.N/A.

In the version of this article originally published, Dimitry G. Sayenko's affiliations were not correct. The following affiliation for this author was missing: Department of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX, USA. This affiliation has been added for the author, and the rest of the affiliations have been renumbered accordingly. The error has been corrected in the HTML and PDF versions of this article.

OBJECT Despite a promising outlook, existing intraspinal microstimulation (ISMS) techniques for restoring functional motor control after spinal cord injury are not yet suitable for use outside a controlled laboratory environment. Thus, successful application of ISMS therapy in humans will require the use of versatile chronic neurostimulation systems. The objective of this study was to establish proof of principle for wireless control of ISMS to evoke controlled motor function in a rodent model of complete spinal cord injury. METHODS The lumbar spinal cord in each of 17 fully anesthetized Sprague-Dawley rats was stimulated via ISMS electrodes to evoke hindlimb function. Nine subjects underwent complete surgical transection of the spinal cord at the T-4 level 7 days before stimulation. Targeting for both groups (spinalized and control) was performed under visual inspection via dorsal spinal cord landmarks such as the dorsal root entry zone and the dorsal median fissure. Teflon-insulated stimulating platinum-iridium microwire electrodes (50 μm in diameter, with a 30- to 60-μm exposed tip) were implanted within the ventral gray matter to an approximate depth of 1.8 mm. Electrode implantation was performed using a free-hand delivery technique (n = 12) or a Kopf spinal frame system (n = 5) to compare the efficacy of these 2 commonly used targeting techniques. Stimulation was controlled remotely using a wireless neurostimulation control system. Hindlimb movements evoked by stimulation were tracked via kinematic markers placed on the hips, knees, ankles, and paws. Postmortem fixation and staining of the spinal cord tissue were conducted to determine the final positions of the stimulating electrodes within the spinal cord tissue. RESULTS The results show that wireless ISMS was capable of evoking controlled and sustained activation of ankle, knee, and hip muscles in 90% of the spinalized rats (n = 9) and 100% of the healthy control rats (n = 8). No functional differences between movements evoked by either of the 2 targeting techniques were revealed. However, frame-based targeting required fewer electrode penetrations to evoke target movements. CONCLUSIONS Clinical restoration of functional movement via ISMS remains a distant goal. However, the technology presented herein represents the first step toward restoring functional independence for individuals with chronic spinal cord injury.

Spinal cord injury can be defined as a loss of communication between the brain and the body due to disrupted pathways within the spinal cord. Although many promising molecular strategies have emerged to reduce secondary injury and promote axonal regrowth, there is still no effective cure, and recovery of function remains limited. Functional electrical stimulation (FES) represents a strategy developed to restore motor function without the need for regenerating severed spinal pathways. Despite its technological success, however, FES has not been widely integrated into the lives of spinal cord injury survivors. In this review, we briefly discuss the limitations of existing FES technologies. Additionally, we discuss how optogenetics, a rapidly evolving technique used primarily to investigate select neuronal populations within the brain, may eventually be used to replace FES as a form of therapy for functional restoration after spinal cord injury.

Background context Traumatic injuries occurring at the conus medullaris of the spinal cord cause permanent damage both to the central nervous system and to the cauda equina nerve roots. Purpose This proof-of-concept study was to determine whether implanting the nerve roots into a biodegradable scaffold would improve regeneration after injury. Methods All experimental works involving rats were performed according to the approved guidelines by the Mayo Clinic Institutional Animal Care and Use Committee. Surgical procedures were performed on 32 Sprague-Dawley rats. Four ventral cauda equina nerve roots were reimplanted either directly into the ventral cord stump or through a poly(lactic -co -glycolic acid) (PLGA) scaffold. These experimental groups were compared with a control group in which the nerves were inserted into a muscle fascia barrier that was placed between the spinal cord and the nerve roots. Animals were sacrificed at 4 weeks. Results There was no difference in motor neuron counts in the spinal cord rostral to the injury in all treatment groups, implying equal potential for the regeneration into implanted nerve roots. One-way analysis of variance testing, with Tukey post hoc test, showed a statistically significant improvement in axon regeneration through the injury in the PLGA scaffold treatment group compared with the control (p Conclusions This pilot study demonstrated that a PLGA scaffold improved regeneration of axons into peripheral nerve roots. However, the number of regenerating axons observed was limited and did not lead to functional recovery. Future experiments will employ a different scaffold material and possible growth factors or enzymes to increase axon populations.

Restoration of movement following spinal cord injury (SCI) has been achieved using electrical stimulation of peripheral nerves and skeletal muscles. However, practical limitations such as the rapid onset of muscle fatigue hinder clinical application of these technologies. Recently, direct stimulation of alpha motor neurons has shown promise for evoking graded, controlled, and sustained muscle contractions in rodent and feline animal models while overcoming some of these limitations. However, small animal models are not optimal for the development of clinical spinal stimulation techniques for functional restoration of movement. Furthermore, variance in surgical procedure, targeting, and electrode implantation techniques can compromise therapeutic outcomes and impede comparison of results across studies. Herein, we present a protocol and large animal model that allow standardized development, testing, and optimization of novel clinical strategies for restoring motor function following spinal cord injury. We tested this protocol using both epidural and intraspinal stimulation in a porcine model of spinal cord injury, but the protocol is suitable for the development of other novel therapeutic strategies. This protocol will help characterize spinal circuits vital for selective activation of motor neuron pools. In turn, this will expedite the development and validation of high-precision therapeutic targeting strategies and stimulation technologies for optimal restoration of motor function in humans.