Autonomous control of ventilation through closed-loop adaptive respiratory pacing.

Mechanical ventilation is the standard treatment when volitional breathing is insufficient, but drawbacks include muscle atrophy, alveolar damage, and reduced mobility. Respiratory pacing is an alternative approach using electrical stimulation-induced diaphragm contraction to ventilate the lung. Oxygenation and acid-base homeostasis are maintained by matching ventilation to metabolic needs; however, current pacing technology requires manual tuning and does not respond to dynamic user-specific metabolic demand, thus requiring re-tuning of stimulation parameters as physiological changes occur. Here, we describe respiratory pacing using a closed-loop adaptive controller that can self-adjust in real-time to meet metabolic needs. The controller uses an adaptive Pattern Generator Pattern Shaper (PG/PS) architecture that autonomously generates a desired ventilatory pattern in response to dynamic changes in arterial CO2 levels and, based on a learning algorithm, modulates stimulation intensity and respiratory cycle duration to evoke this ventilatory pattern. In vivo experiments in rats with respiratory depression and in those with a paralyzed hemidiaphragm confirmed that the controller can adapt and control ventilation to ameliorate hypoventilation and restore normocapnia regardless of the cause of respiratory dysfunction. This novel closed-loop bioelectronic controller advances the state-of-art in respiratory pacing by demonstrating the ability to automatically personalize stimulation patterns and adapt to achieve adequate ventilation.

A Wearable Sensor System to Measure Step-Based Gait Parameters for Parkinson's Disease Rehabilitation.

Spatiotemporal parameters of gait serve as an important biomarker to monitor gait impairments as well as to develop rehabilitation systems. In this work, we developed a computationally-efficient algorithm (SDI-Step) that uses segmented double integration to calculate step length and step time from wearable inertial measurement units (IMUs) and assessed its ability to reliably and accurately measure spatiotemporal gait parameters. Two data sets that included simultaneous measurements from wearable sensors and from a laboratory-based system were used in the assessment. The first data set utilized IMU sensors and a GAITRite mat in our laboratory to monitor gait in fifteen participants: 9 young adults (YA1) (5 females, 4 males, age 23.6 ± 1 years), and 6 people with Parkinson's disease (PD) (3 females, 3 males, age 72.3 ± 6.6 years). The second data set, which was accessed from a publicly-available repository, utilized IMU sensors and an optoelectronic system to monitor gait in five young adults (YA2) (2 females, 3 males, age 30.5 ± 3.5 years). In order to provide a complete representation of validity, we used multiple statistical analyses with overlapping metrics. Gait parameters such as step time and step length were calculated and the agreement between the two measurement systems for each gait parameter was assessed using Passing-Bablok (PB) regression analysis and calculation of the Intra-class Correlation Coefficient (ICC (2,1)) with 95% confidence intervals for a single measure, absolute-agreement, 2-way mixed-effects model. In addition, Bland-Altman (BA) plots were used to visually inspect the measurement agreement. The values of the PB regression slope were close to 1 and intercept close to 0 for both step time and step length measures. The results obtained using ICC (2,1) for step length showed a moderate to excellent agreement for YA (between 0.81 and 0.95) and excellent agreement for PD (between 0.93 and 0.98), while both YA and PD had an excellent agreement in step time ICCs (>0.9). Finally, examining the BA plots showed that the measurement difference was within the limits of agreement (LoA) with a 95% probability. Results from this preliminary study indicate that using the SDI-Step algorithm to process signals from wearable IMUs provides measurements that are in close agreement with widely-used laboratory-based systems and can be considered as a valid tool for measuring spatiotemporal gait parameters.

ReadySteady intervention to promote physical activity in older adults with Parkinson's disease: Study design and methods.

The main motor impairments of gait and balance experienced by people with Parkinson's disease (PD) contribute to a sedentary lifestyle, resulting in poor physical conditioning, loss of functional independence, and reduced quality of life. Despite the known benefits of physical activity in PD, the majority of older adults with PD are insufficiently active. Few studies incorporate behavioral change approaches to promoting physical activity in PD. The main goal of this research is to foster community mobility in older adults with PD by promoting physical activity and improving gait patterns using a theory-based behavioral change intervention. The ReadySteady intervention combines wellness motivation theory with polestriding physical activity, which has been shown to be beneficial for people with PD. The intervention will be tested using a randomized controlled design, including inactive older adults diagnosed with PD. Participants will be randomly assigned the 12-week ReadySteady intervention, 12-week polestriding, and education intervention, or 12-week education intervention. Thirty-six older adults with PD will participate in each of the interventions. Level of physical activity, clinical scores, quantitative measures of gait and balance control, and motivational variables for each intervention will be measured at three time points: pre-intervention, post-intervention (12 weeks), and follow-up (24 weeks). If the intervention is beneficial, it may serve as a sustainable addition to current practice in health promotion efforts serving the PD population.

Cueing Paradigms to Improve Gait and Posture in Parkinson's Disease: A Narrative Review.

Progressive gait dysfunction is one of the primary motor symptoms in people with Parkinson's disease (PD). It is generally expressed as reduced step length and gait speed and as increased variability in step time and step length. People with PD also exhibit stooped posture which disrupts gait and impedes social interaction. The gait and posture impairments are usually resistant to the pharmacological treatment, worsen as the disease progresses, increase the likelihood of falls, and result in higher rates of hospitalization and mortality. These impairments may be caused by perceptual deficiencies (poor spatial awareness and loss of temporal rhythmicity) due to the disruptions in processing intrinsic information related to movement initiation and execution which can result in misperceptions of the actual effort required to perform a desired movement and maintain a stable posture. Consequently, people with PD often depend on external cues during execution of motor tasks. Numerous studies involving open-loop cues have shown improvements in gait and freezing of gait (FoG) in people with PD. However, the benefits of cueing may be limited, since cues are provided in a consistent/rhythmic manner irrespective of how well a person follows them. This limitation can be addressed by providing feedback in real-time to the user about performance (closed-loop cueing) which may help to improve movement patterns. Some studies that used closed-loop cueing observed improvements in gait and posture in PD, but the treadmill-based setup in a laboratory would not be accessible outside of a research setting, and the skills learned may not readily and completely transfer to overground locomotion in the community. Technologies suitable for cueing outside of laboratory environments could facilitate movement practice during daily activities at home or in the community and could strongly reinforce movement patterns and improve clinical outcomes. This narrative review presents an overview of cueing paradigms that have been utilized to improve gait and posture in people with PD and recommends development of closed-loop wearable systems that can be used at home or in the community to improve gait and posture in PD.

Restoring Ventilatory Control Using an Adaptive Bioelectronic System.

Ventilatory pacing by electrical stimulation of the phrenic nerve or of the diaphragm has been shown to enhance quality of life compared to mechanical ventilation. However, commercially available ventilatory pacing devices require initial manual specification of stimulation parameters and frequent adjustment to achieve and maintain suitable ventilation over long periods of time. Here, we have developed an adaptive, closed-loop, neuromorphic, pattern-shaping controller capable of automatically determining a suitable stimulation pattern and adapting it to maintain a desired breath-volume profile on a breath-by-breath basis. The system adapts the pattern of stimulation parameters based on the error between the measured volume sampled every 40 ms and a desired breath volume profile. In vivo studies in anesthetized male Sprague-Dawley rats without and with spinal cord injury by spinal hemisection at C2 indicated that the controller was capable of automatically adapting stimulation parameters to attain a desired volume profile. Despite diaphragm hemiparesis, the controller was able to achieve a desired volume in the injured animals that did not differ from the tidal volume observed before injury (p = 0.39). Closed-loop adaptive pacing partially mitigated hypoventilation as indicated by reduction of end-tidal CO2 values during pacing. The closed-loop controller was developed and parametrized in a computational testbed before in vivo assessment. This bioelectronic technology could serve as an individualized and autonomous respiratory pacing approach for support or recovery from ventilatory deficiency.

Effects of vibrotactile feedback and grasp interface compliance on perception and control of a sensorized myoelectric hand.

Current myoelectric prosthetic limbs are limited in their ability to provide direct sensory feedback to users, which increases attentional demands and reliance on visual cues. Vibrotactile sensory substitution (VSS), which can be used to provide sensory feedback in a non-invasive manner has demonstrated some improvement in myoelectric hand control. In this work, we developed and tested two VSS configurations: one with a single burst-rate modulated actuator and another with a spatially distributed array of five coin tactors. We performed a direct comparative assessment of these two VSS configurations with able-bodied subjects to investigate sensory perception, myoelectric control of grasp force and hand aperture with a prosthesis, and the effects of interface compliance. Six subjects completed a sensory perception experiment under a stimulation only paradigm; sixteen subjects completed experiments to compare VSS performance on perception and graded myoelectric control during grasp force and hand aperture tasks; and ten subjects completed experiments to investigate the effect of mechanical compliance of the myoelectric hand on the ability to control grasp force. Results indicated that sensory perception of vibrotactile feedback was not different for the two VSS configurations in the absence of active myoelectric control, but it was better with feedback from the coin tactor array than with the single actuator during myoelectric control of grasp force. Graded myoelectric control of grasp force and hand aperture was better with feedback from the coin tactor array than with the single actuator, and myoelectric control of grasp force was improved with a compliant grasp interface. Further investigations with VSS should focus on the use of coin tactor arrays by subjects with amputation in real-world settings and on improving control of grasp force by increasing the mechanical compliance of the hand.

Bionic intrafascicular interfaces for recording and stimulating peripheral nerve fibers.

The network of peripheral nerves presents extraordinary potential for modulating and/or monitoring the functioning of internal organs or the brain. The degree to which these pathways can be used to influence or observe neural activity patterns will depend greatly on the quality and specificity of the bionic interface. The anatomical organization, which consists of multiple nerve fibers clustered into fascicles within a nerve bundle, presents opportunities and challenges that may necessitate insertion of electrodes into individual fascicles to achieve the specificity that may be required for many clinical applications. This manuscript reviews the current state-of-the-art in bionic intrafascicular interfaces, presents specific concerns for stimulation and recording, describes key implementation considerations and discusses challenges for future designs of bionic intrafascicular interfaces.

An IC-based controllable stimulator for respiratory muscle stimulation investigations.

Functional Electrical Stimulation can be used to restore motor functions loss consecutive to spinal cord injury, such as respiratory deficiency due to paralysis of ventilatory muscles. This paper presents a fully configurable IC-centered stimulator designed to investigate muscle stimulation paradigms. It provides 8 current stimulation channels with high-voltage compliance and real-time operation capabilities, to enable a wide range of FES applications. The stimulator can be used in a standalone mode, or within a closed-loop setup. Primary in vivo results show successful drive of respiratory muscles stimulation using a computer-based dedicated controller.

A model for differential leg joint function during human running.

Locomotion requires coordination of leg joints to maintain stability and to maneuver. We studied leg joint function during constant-average-velocity running and the sagittal-plane maneuvers of step ascent and descent. We tested two hypotheses: (1) that leg joints perform distinct functions during locomotion; and (2) that humans select functional parameters to maximize intrinsic dynamic stability. We recorded whole-body kinematics and forces when participants stepped up or down a single vertical step, and found that leg joints show functional differences during both constant-average-velocity locomotion and maneuvers. The hip, knee and ankle function as a motor, damper, and spring, respectively. We therefore constructed a simplified computational model of a human leg with a motor, damper, and spring in series (MDS). The intrinsic dynamics of the model resulted in sustained locomotion on level ground within narrow parameter ranges. However, using parameters experimentally derived from humans, the model showed only short-term stability. Humans may not optimize intrinsic dynamic stability alone, but may instead choose mechanical and behavioral parameters appropriate for both constant-average-velocity locomotion and maneuvers. Understanding joint-level mechanical function during unsteady locomotion helps to understand how differential joint function contributes to whole-body performance, and could lead to improvements in rehabilitation, prosthetic and robotic design.

Improving health-care delivery in low-resource settings with nanotechnology: Challenges in multiple dimensions.

In the two decades after 1990, the rates of child and maternal mortality dropped by over 40% and 47%, respectively. Despite these improvements, which are in part due to increased access to medical technologies, profound health disparities exist. In 2015, a child born in a developing region is nearly eight times as likely to die before the age of 5 than one born in a developed region and developing regions accounted for nearly 99% of the maternal deaths. Recent developments in nanotechnology, however, have great potential to ameliorate these and other health disparities by providing new cost-effective solutions for diagnosis or treatment of a variety of medical conditions. Affordability is only one of the several challenges that will need to be met to translate new ideas into a medical product that addresses a global health need. This article aims to describe some of the other challenges that will be faced by nanotechnologists who seek to make an impact in low-resource settings across the globe.

A System for Real-Time Feedback to Improve Gait and Posture in Parkinson's Disease.

For people with Parkinson's disease (PD), gait and postural impairments can significantly affect their ability to perform activities of daily living. Presentation of appropriate cues has been shown to improve gait in PD. Based on this, a treadmill-based system and experimental paradigm were developed to determine if people with PD can utilize real-time feedback (RTFB) of step length or back angle (uprightness) to improve gait and posture. Eleven subjects (mean age 67 ± 8 years) with mild-to-moderate PD (Hoehn and Yahr stage I-III) were evaluated regarding their ability to successfully utilize RTFB of back angle or step length during quiet standing and treadmill walking tasks during a single session in their medication-on state. Changes in back angle and step length due to feedback were compared using Friedman nonparametric tests with Wilcoxon Signed-Rank tests for post-hoc comparisons. Improvements in uprightness were observed as an increase in back angle during quiet standing (p = 0.005) and during treadmill walking (p = 0.005) with back angle feedback when compared to corresponding tasks without feedback. Improvements in gait were also observed as an increase in step length (p = 0.005) during step length feedback compared to tasks without feedback. These results indicate that people with mild-to-moderate PD can utilize RTFB to improve upright posture and gait. Future work will investigate the long-term effects of this RTFB paradigm and the development of systems for clinical or home-based use.

Effects of spinal cord injury-induced changes in muscle activation on foot drag in a computational rat ankle model.

Spinal cord injury (SCI) can lead to changes in muscle activation patterns and atrophy of affected muscles. Moderate levels of SCI are typically associated with foot drag during the swing phase of locomotion. Foot drag is often used to assess locomotor recovery, but the causes remain unclear. We hypothesized that foot drag results from inappropriate muscle coordination preventing flexion at the stance-to-swing transition. To test this hypothesis and to assess the relative contributions of neural and muscular changes on foot drag, we developed a two-dimensional, one degree of freedom ankle musculoskeletal model with gastrocnemius and tibialis anterior muscles. Anatomical data collected from sham-injured and incomplete SCI (iSCI) female Long-Evans rats as well as physiological data from the literature were used to implement an open-loop muscle dynamics model. Muscle insertion point motion was calculated with imposed ankle trajectories from kinematic analysis of treadmill walking in sham-injured and iSCI animals. Relative gastrocnemius deactivation and tibialis anterior activation onset times were varied within physiologically relevant ranges based on simplified locomotor electromyogram profiles. No-atrophy and moderate muscle atrophy as well as normal and injured muscle activation profiles were also simulated. Positive moments coinciding with the transition from stance to swing phase were defined as foot swing and negative moments as foot drag. Whereas decreases in activation delay caused by delayed gastrocnemius deactivation promote foot drag, all other changes associated with iSCI facilitate foot swing. Our results suggest that even small changes in the ability to precisely deactivate the gastrocnemius could result in foot drag after iSCI.

A system and method to interface with multiple groups of axons in several fascicles of peripheral nerves.

BACKGROUND: Several neural interface technologies that stimulate and/or record from groups of axons have been developed. The longitudinal intrafascicular electrode (LIFE) is a fine wire that can provide access to a discrete population of axons within a peripheral nerve fascicle. Some applications require, or would benefit greatly from, technology that could provide access to multiple discrete sites in several fascicles. NEW METHOD: The distributed intrafascicular multi-electrode (DIME) lead was developed to deploy multiple LIFEs to several fascicles. It consists of several (e.g. six) LIFEs that are coiled and placed in a sheath for strength and durability, with a portion left uncoiled to allow insertion at distinct sites. We have also developed a multi-lead multi-electrode (MLME) management system that includes a set of sheaths and procedures for fabrication and deployment. RESULTS: A prototype with 3 DIME leads was fabricated and tested in a procedure in a cadaver arm. The leads were successfully routed through skin and connective tissue and the deployment procedures were utilized to insert the LIFEs into fascicles of two nerves. COMPARISON WITH EXISTING METHOD(S): Most multi-electrode systems use a single-lead, multi-electrode design. For some applications, this design may be limited by the bulk of the multi-contact array and/or by the spatial distribution of the electrodes. CONCLUSION: We have designed a system that can be used to access multiple sets of discrete groups of fibers that are spatially distributed in one or more fascicles of peripheral nerves. This system may be useful for neural-enabled prostheses or other applications.

A functional model and simulation of spinal motor pools and intrafascicular recordings of motoneuron activity in peripheral nerve.

Decoding motor intent from recorded neural signals is essential for the development of effective neural-controlled prostheses. To facilitate the development of online decoding algorithms we have developed a software platform to simulate neural motor signals recorded with peripheral nerve electrodes, such as longitudinal intrafascicular electrodes (LIFEs). The simulator uses stored motor intent signals to drive a pool of simulated motoneurons with various spike shapes, recruitment characteristics, and firing frequencies. Each electrode records a weighted sum of a subset of simulated motoneuron activity patterns. As designed, the simulator facilitates development of a suite of test scenarios that would not be possible with actual data sets because, unlike with actual recordings, in the simulator the individual contributions to the simulated composite recordings are known and can be methodically varied across a set of simulation runs. In this manner, the simulation tool is suitable for iterative development of real-time decoding algorithms prior to definitive evaluation in amputee subjects with implanted electrodes. The simulation tool was used to produce data sets that demonstrate its ability to capture some features of neural recordings that pose challenges for decoding algorithms.

Joint-specific changes in locomotor complexity in the absence of muscle atrophy following incomplete spinal cord injury.

BACKGROUND: Following incomplete spinal cord injury (iSCI), descending drive is impaired, possibly leading to a decrease in the complexity of gait. To test the hypothesis that iSCI impairs gait coordination and decreases locomotor complexity, we collected 3D joint angle kinematics and muscle parameters of rats with a sham or an incomplete spinal cord injury. METHODS: 12 adult, female, Long-Evans rats, 6 sham and 6 mild-moderate T8 iSCI, were tested 4 weeks following injury. The Basso Beattie Bresnahan locomotor score was used to verify injury severity. Animals had reflective markers placed on the bony prominences of their limb joints and were filmed in 3D while walking on a treadmill. Joint angles and segment motion were analyzed quantitatively, and complexity of joint angle trajectory and overall gait were calculated using permutation entropy and principal component analysis, respectively. Following treadmill testing, the animals were euthanized and hindlimb muscles removed. Excised muscles were tested for mass, density, fiber length, pennation angle, and relaxed sarcomere length. RESULTS: Muscle parameters were similar between groups with no evidence of muscle atrophy. The animals showed overextension of the ankle, which was compensated for by a decreased range of motion at the knee. Left-right coordination was altered, leading to left and right knee movements that are entirely out of phase, with one joint moving while the other is stationary. Movement patterns remained symmetric. Permutation entropy measures indicated changes in complexity on a joint specific basis, with the largest changes at the ankle. No significant difference was seen using principal component analysis. Rats were able to achieve stable weight bearing locomotion at reasonable speeds on the treadmill despite these deficiencies. CONCLUSIONS: Decrease in supraspinal control following iSCI causes a loss of complexity of ankle kinematics. This loss can be entirely due to loss of supraspinal control in the absence of muscle atrophy and may be quantified using permutation entropy. Joint-specific differences in kinematic complexity may be attributed to different sources of motor control. This work indicates the importance of the ankle for rehabilitation interventions following spinal cord injury.

Accelerating locomotor recovery after incomplete spinal injury.

A traumatic spinal injury can destroy cells, irreparably damage axons, and trigger a cascade of biochemical responses that increase the extent of injury. Although damaged central nervous system axons do not regrow well naturally, the distributed nature of the nervous system and its capacity to adapt provide opportunities for recovery of function. It is apparent that activity-dependent plasticity plays a role in this recovery and that the endogenous response to injury heightens the capacity for recovery for at least several weeks postinjury. To restore locomotor function, researchers have investigated the use of treadmill-based training, robots, and electrical stimulation to tap into adaptive activity-dependent processes. The current challenge is to maximize the degree of functional recovery. This manuscript reviews the endogenous neural system response to injury, and reviews data and presents novel analyses of these from a rat model of contusion injury that demonstrates how a targeted intervention can accelerate recovery, presumably by engaging processes that underlie activity-dependent plasticity.

Longitudinal performance of a surgically implanted neuroprosthesis for lower-extremity exercise, standing, and transfers after spinal cord injury.

OBJECTIVE: To investigate the longitudinal performance of a surgically implanted neuroprosthesis for lower-extremity exercise, standing, and transfers after spinal cord injury. DESIGN: Case series. SETTING: Research or outpatient physical therapy departments of 4 academic hospitals. PARTICIPANTS: Subjects (N=15) with thoracic or low cervical level spinal cord injuries who had received the 8-channel neuroprosthesis for exercise and standing. INTERVENTION: After completing rehabilitation with the device, the subjects were discharged to unrestricted home use of the system. A series of assessments were performed before discharge and at a follow-up appointment approximately 1 year later. MAIN OUTCOME MEASURES: Neuroprosthesis usage, maximum standing time, body weight support, knee strength, knee fatigue index, electrode stability, and component survivability. RESULTS: Levels of maximum standing time, body weight support, knee strength, and knee fatigue index were not statistically different from discharge to follow-up (P>.05). Additionally, neuroprosthesis usage was consistent with subjects choosing to use the system on approximately half of the days during each monitoring period. Although the number of hours using the neuroprosthesis remained constant, subjects shifted their usage to more functional standing versus more maintenance exercise, suggesting that the subjects incorporated the neuroprosthesis into their lives. Safety and reliability of the system were demonstrated by electrode stability and a high component survivability rate (>90%). CONCLUSIONS: This group of 15 subjects is the largest cohort of implanted lower-extremity neuroprosthetic exercise and standing system users. The safety and efficiency data from this group, and acceptance of the neuroprosthesis as demonstrated by continued usage, indicate that future efforts toward commercialization of a similar device may be warranted.

Deep brain stimulation amplitude alters posture shift velocity in Parkinson's disease.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is now widely used to alleviate symptoms of Parkinson's disease (PD). The specific aim of this study was to identify posture control measures that may be used to improve selection of DBS parameters in the clinic and this was carried out by changing the DBS stimulation amplitude. A dynamic posture shift paradigm was used to assess posture control in 4 PD STN-DBS subjects. Each subject was tested at 4 stimulation amplitude settings. Movements of the center of pressure and the position of the pelvis were monitored and several quantitative indices were calculated. The presence of any statistically significant changes in several normalized indices due to reduced/no stimulation was tested using the one-sample t test. The peak velocity and the average movement velocity during the initial and mid phases of movement towards the target posture were substantially reduced. These results may be explained in terms of increased akinesia and bradykinesia due to altered stimulation conditions. Thus, the dynamic posture shift paradigm may be an effective tool to quantitatively characterize the effects of DBS on posture control and should be further investigated as a tool for selection of DBS parameters in the clinic.

Repetetive hindlimb movement using intermittent adaptive neuromuscular electrical stimulation in an incomplete spinal cord injury rodent model.

The long-term objective of this work is to understand the mechanisms by which electrical stimulation based movement therapies may harness neural plasticity to accelerate and enhance sensorimotor recovery after incomplete spinal cord injury (iSCI). An adaptive neuromuscular electrical stimulation (aNMES) paradigm was implemented in adult Long Evans rats with thoracic contusion injury (T8 vertebral level, 155+/-2 Kdyne). In lengthy sessions with lightly anesthetized animals, hip flexor and extensor muscles were stimulated using an aNMES control system in order to generate desired hip movements. The aNMES control system, which used a pattern generator/pattern shaper structure, adjusted pulse amplitude to modulate muscle force in order to control hip movement. An intermittent stimulation paradigm was used (5-cycles/set; 20-second rest between sets; 100 sets). In each cycle, hip rotation caused the foot plantar surface to contact a stationary brush for appropriately timed cutaneous input. Sessions were repeated over several days while the animals recovered from injury. Results indicated that aNMES automatically and reliably tracked the desired hip trajectory with low error and maintained range of motion with only gradual increase in stimulation during the long sessions. Intermittent aNMES thus accounted for the numerous factors that can influence the response to NMES: electrode stability, excitability of spinal neural circuitry, non-linear muscle recruitment, fatigue, spinal reflexes due to cutaneous input, and the endogenous recovery of the animals. This novel aNMES application in the iSCI rodent model can thus be used in chronic stimulation studies to investigate the mechanisms of neuroplasticity targeted by NMES-based repetitive movement therapy.