Andy J. Fong

Implications of Assist-As-Needed Robotic Step Training after a Complete Spinal Cord Injury on Intrinsic Strategies of Motor Learning

Robotic training paradigms that enforce a fixed kinematic control might be suboptimal for rehabilitative training because they abolish variability, an intrinsic property of neuromuscular control (Jezernik et al., 2003). In the present study we introduce “assist-as-needed” (AAN) robotic training paradigms for rehabilitation of spinal cord injury subjects. To test the efficacy of these robotic control strategies to teach spinal mice to step, we divided 27 adult female Swiss–Webster mice randomly into three groups. Each group was trained robotically by using one of three control strategies: a fixed training trajectory (Fixed group), an AAN training paradigm without interlimb coordination (Band group), and an AAN training paradigm with bilateral hindlimb coordination (Window group). Beginning at 14 d after a complete midthoracic spinal cord transection, the mice were trained daily (10 min/d, 5 d/week) to step on a treadmill 10 min after the administration of quipazine (0.5 mg/kg), a serotonin agonist, for a period of 6 weeks. During weekly performance evaluations, the mice trained with the AAN window paradigm generally showed the highest level of recovery as measured by the number, consistency, and periodicity of steps during the testing sessions. In all three measurements there were no significant differences between the Band and the Fixed training groups. These results indicate that the window training approach, which includes loose alternating interlimb coordination, is more effective than a fixed trajectory paradigm with rigid alternating interlimb coordination or an AAN paradigm without any interlimb constraints in promoting robust postinjury stepping behavior.

Spinal Cord-Transected Mice Learn to Step in Response to Quipazine Treatment and Robotic Training

In the present study, concurrent treatment with robotic step training and a serotonin agonist, quipazine, generated significant recovery of locomotor function in complete spinal cord-transected mice (T7–T9) that otherwise could not step. The extent of recovery achieved when these treatments were combined exceeded that obtained when either treatment was applied independently. We quantitatively analyzed the stepping characteristics of spinal mice after alternatively administering no training, manual training, robotic training, quipazine treatment, or a combination of robotic training with quipazine treatment, to examine the mechanisms by which training and quipazine treatment promote functional recovery. Using fast Fourier transform and principal components analysis, significant improvements in the step rhythm, step shape consistency, and number of weight-bearing steps were observed in robotically trained compared with manually trained or nontrained mice. In contrast, manual training had no effect on stepping performance, yielding no improvement compared with nontrained mice. Daily bolus quipazine treatment acutely improved the step shape consistency and number of steps executed by both robotically trained and nontrained mice, but these improvements did not persist after quipazine was withdrawn. At the dosage used (0.5 mg/kg body weight), quipazine appeared to facilitate, rather than directly generate, stepping, by enabling the spinal cord neural circuitry to process specific patterns of sensory information associated with weight-bearing stepping. Via this mechanism, quipazine treatment enhanced kinematically appropriate robotic training. When administered intermittently during an extended period of robotic training, quipazine revealed training-induced stepping improvements that were masked in the absence of the pharmacological treatment.

Epidural stimulation induced modulation of spinal locomotor networks in adult spinal rats

The importance of the in vivo dynamic nature of the circuitries within the spinal cord that generate locomotion is becoming increasingly evident. We examined the characteristics of hindlimb EMG activity evoked in response to epidural stimulation at the S1 spinal cord segment in complete midthoracic spinal cord-transected rats at different stages of postlesion recovery. A progressive and phase-dependent modulation of monosynaptic (middle) and long-latency (late) stimulation-evoked EMG responses was observed throughout the step cycle. During the first 3 weeks after injury, the amplitude of the middle response was potentiated during the EMG bursts, whereas after 4 weeks, both the middle and late responses were phase-dependently modulated. The middle- and late-response magnitudes were closely linked to the amplitude and duration of the EMG bursts during locomotion facilitated by epidural stimulation. The optimum stimulation frequency that maintained consistent activity of the long-latency responses ranged from 40 to 60 Hz, whereas the short-latency responses were consistent from 5 to 130 Hz. These data demonstrate that both middle and late evoked potentials within a motor pool are strictly gated during in vivo bipedal stepping as a function of the general excitability of the motor pool and, thus, as a function of the phase of the step cycle. These data demonstrate that spinal cord epidural stimulation can facilitate locomotion in a time-dependent manner after lesion. The long-latency responses to epidural stimulation are correlated with the recovery of weight-bearing bipedal locomotion and may reflect activation of interneuronal central pattern-generating circuits.

Facilitation of Stepping with Epidural Stimulation in Spinal Rats: Role of Sensory Input

We investigated the role of afferent information during recovery of coordinated rhythmic activity of the hindlimbs in rats with a complete spinal cord section (approximately T8) and unilateral deafferentation (T12–S2) to answer the following questions: (1) Can bilateral stepping be generated with only afferent projections intact on one side? (2) Can the sensory input from the non-deafferented side compensate for the loss of the afferent input from the deafferented side through the crossed connections within the lumbosacral spinal cord? (3) Which afferent projections to the spinal cord from the non-deafferented side predominantly mediate the effect of epidural stimulation to facilitate stepping? Recovery of stepping ability was tested under the facilitating influence of epidural stimulation at the S1 spinal segment, or epidural stimulation plus quipazine, a 5-HT agonist. All chronic spinal rats were able to generate stepping-like patterns on a moving treadmill on the non-deafferented, but not deafferented, side from 3 to 7 weeks after surgery when facilitated by epidural stimulation. Adaptation to the loss of unilateral afferent input was evident at 7 weeks after surgery, when some movements occurred on the deafferented side. Spinal-cord-evoked potentials were observed on both sides, although middle (monosynaptic) and late (long latency) responses were more prominent on the non-deafferented side. The afferent information arising from the non-deafferented side, however, eventually could mediate limited restoration of hindlimb movements on the deafferented side. These data suggest that facilitation of stepping with epidural stimulation is mediated primarily through ipsilateral afferents that project to the locomotor networks.

Plasticity of functional connectivity in the adult spinal cord

This paper emphasizes several characteristics of the neural control of locomotion that provide opportunities for developing strategies to maximize the recovery of postural and locomotor functions after a spinal cord injury (SCI). The major points of this paper are: (i) the circuitry that controls standing and stepping is extremely malleable and reflects a continuously varying combination of neurons that are activated when executing stereotypical movements; (ii) the connectivity between neurons is more accurately perceived as a functional rather than as an anatomical phenomenon; (iii) the functional connectivity that controls standing and stepping reflects the physiological state of a given assembly of synapses, where the probability of these synaptic events is not deterministic; (iv) rather, this probability can be modulated by other factors such as pharmacological agents, epidural stimulation and/or motor training; (v) the variability observed in the kinematics of consecutive steps reflects a fundamental feature of the neural control system and (vi) machine-learning theories elucidate the need to accommodate variability in developing strategies designed to enhance motor performance by motor training using robotic devices after an SCI.

Recovery of control of posture and locomotion after a spinal cord injury: solutions staring us in the face

Over the past 20 years, tremendous advances have been made in the field of spinal cord injury research. Yet, consumed with individual pieces of the puzzle, we have failed as a community to grasp the magnitude of the sum of our findings. Our current knowledge should allow us to improve the lives of patients suffering from spinal cord injury. Advances in multiple areas have provided tools for pursuing effective combination of strategies for recovering stepping and standing after a severe spinal cord injury. Muscle physiology research has provided insight into how to maintain functional muscle properties after a spinal cord injury. Understanding the role of the spinal networks in processing sensory information that is important for the generation of motor functions has focused research on developing treatments that sharpen the sensitivity of the locomotor circuitry and that carefully manage the presentation of proprioceptive and cutaneous stimuli to favor recovery. Pharmacological facilitation or inhibition of neurotransmitter systems, spinal cord stimulation, and rehabilitative motor training, which all function by modulating the physiological state of the spinal circuitry, have emerged as promising approaches. Early technological developments, such as robotic training systems and high-density electrode arrays for stimulating the spinal cord, can significantly enhance the precision and minimize the invasiveness of treatment after an injury. Strategies that seek out the complementary effects of combination treatments and that efficiently integrate relevant technical advances in bioengineering represent an untapped potential and are likely to have an immediate impact. Herein, we review key findings in each of these areas of research and present a unified vision for moving forward. Much work remains, but we already have the capability, and more importantly, the responsibility, to help spinal cord injury patients now.

High-Density Flexible Parylene-Based Multielectrode Arrays for Retinal and Spinal Cord Stimulation

Novel flexible parylene-based high-density electrode arrays have been developed for functional electrical stimulation in retinal and spinal cord applications. These electrode arrays are microfabricated according to single-metal-layer and, most recently, dual-metal-layer processes. A new heat-molding process has been implemented to conform electrode arrays to approximate the curvature of canine retinas, and chronic implantation studies have been undertaken to study the mechanical effects of parylene-based prostheses on the retina, with excellent results to date. Electrode arrays have also been implanted and tested on the spinal cords of murine models, with the ultimate goal of facilitation of locomotion after spinal cord injury; these arrays provide a higher density and better spatial control of stimulation and recording than is typically possible using traditional fine-wire electrodes. Spinal cord stimulation typically elicited three muscle responses, an early (direct), a middle (monosynaptic), and a late (polysynaptic) response, classified based on latency after stimulation. Stimulation at different rostrocaudal levels of the cord yielded markedly different muscle responses, highlighting the need for such high-density arrays.

Effects of consistency vs. variability in robotically controlled training of stepping in adult spinal mice

This paper studies the possible benefit that can be obtained by introducing variability into the robotic control of trajectories used to train hindlimb locomotion in adult spinal mice. The spinal cords of adult female Swiss-Webster mice were completely transected at a mid-thoracic level. Fourteen days post-transection, the spinal mice were robotically trained to step in the presence of a 5-HT agonist, quipazine, for a period of six weeks. In this pilot study nine animals were divided into three groups, each receiving a different control strategy: a fixed training trajectory (Group A), a variable training trajectory without interlimb coordination imposed (Group B) and a variable training trajectory with hindlimb bilateral coordination imposed (Group C). Preliminary results indicate that Group A recovers more slowly than the two groups receiving variable modes of robotic training. Groups B and C show higher levels of recovery than Group A in terms of the number of steps performed during testing sessions, as well as in their step periodicity and shape consistency. Group C displays a higher incidence of alternating stepping than Group B. These results indicate that variable trajectory robotic training paradigms may be more effective than fixed trajectory paradigms in promoting robust post-injury stepping behavior. Furthermore, it appears that the inclusion of interlimb coordination is an important contribution to successful training.