Simon M. Danner

Can the Human Lumbar Posterior Columns Be Stimulated by Transcutaneous Spinal Cord Stimulation? A Modeling Study

Stimulation of different spinal cord segments in humans is a widely developed clinical practice for modification of pain, altered sensation, and movement. The human lumbar cord has become a target for modification of motor control by epidural and, more recently, by transcutaneous spinal cord stimulation. Posterior columns of the lumbar spinal cord represent a vertical system of axons and when activated can add other inputs to the motor control of the spinal cord than stimulated posterior roots. We used a detailed three-dimensional volume conductor model of the torso and the McIntyre-Richard-Grill axon model to calculate the thresholds of axons within the posterior columns in response to transcutaneous lumbar spinal cord stimulation. Superficially located large-diameter posterior column fibers with multiple collaterals have a threshold of 45.4 V, three times higher than posterior root fibers (14.1 V). With the stimulation strength needed to activate posterior column axons, posterior root fibers of large and small diameters as well as anterior root fibers are coactivated. The reported results inform on these threshold differences, when stimulation is applied to the posterior structures of the lumbar cord at intensities above the threshold of large-diameter posterior root fibers.

Human spinal locomotor control is based on flexibly organized burst generators

Constant drive provided to the human lumbar spinal cord by epidural electrical stimulation can cause local neural circuits to generate rhythmic motor outputs to lower limb muscles in people paralysed by spinal cord injury. Epidural spinal cord stimulation thus allows the study of spinal rhythm and pattern generating circuits without their configuration by volitional motor tasks or task-specific peripheral feedback. To reveal spinal locomotor control principles, we studied the repertoire of rhythmic patterns that can be generated by the functionally isolated human lumbar spinal cord, detected as electromyographic activity from the legs, and investigated basic temporal components shared across these patterns. Ten subjects with chronic, motor-complete spinal cord injury were studied. Surface electromyographic responses to lumbar spinal cord stimulation were collected from quadriceps, hamstrings, tibialis anterior, and triceps surae in the supine position. From these data, 10-s segments of rhythmic activity present in the four muscle groups of one limb were extracted. Such samples were found in seven subjects. Physiologically adequate cycle durations and relative extension- and flexion-phase durations similar to those needed for locomotion were generated. The multi-muscle activation patterns exhibited a variety of coactivation, mixed-synergy and locomotor-like configurations. Statistical decomposition of the electromyographic data across subjects, muscles and samples of rhythmic patterns identified three common temporal components, i.e. basic or shared activation patterns. Two of these basic patterns controlled muscles to contract either synchronously or alternatingly during extension- and flexion-like phases. The third basic pattern contributed to the observed muscle activities independently from these extensor- and flexor-related basic patterns. Each bifunctional muscle group was able to express both extensor- and flexor-patterns, with variable ratios across the samples of rhythmic patterns. The basic activation patterns can be interpreted as central drives implemented by spinal burst generators that impose specific spatiotemporally organized activation on the lumbosacral motor neuron pools. Our data thus imply that the human lumbar spinal cord circuits can form burst-generating elements that flexibly combine to obtain a wide range of locomotor outputs from a constant, repetitive input. It may be possible to use this flexibility to incorporate specific adaptations to gait and stance to improve locomotor control, even after severe central nervous system damage.

Spinal Rhythm Generation by Step-Induced Feedback and Transcutaneous Posterior Root Stimulation in Complete Spinal Cord–Injured Individuals

Background. The human lumbosacral spinal circuitry can generate rhythmic motor output in response to different types of inputs after motor-complete spinal cord injury. Objective. To explore spinal rhythm generating mechanisms recruited by phasic step-related sensory feedback and tonic posterior root stimulation when provided alone or in combination. Methods. We studied stepping in 4 individuals with chronic, clinically complete spinal cord injury using a robotic-driven gait orthosis with body weight support over a treadmill. Electromyographic data were collected from thigh and lower leg muscles during stepping with 2 hip-movement conditions and 2 step frequencies, first without and then with tonic 30-Hz transcutaneous spinal cord stimulation (tSCS) over the lumbar posterior roots. Results. Robotic-driven stepping alone generated rhythmic activity in a small number of muscles, mostly in hamstrings, coinciding with the stretch applied to the muscle, and in tibialis anterior as stance-phase synchronized clonus. Adding tonic 30-Hz tSCS increased the number of rhythmically responding muscles, augmented thigh muscle activity, and suppressed clonus. tSCS could also produce rhythmic activity without or independent of step-specific peripheral feedback. Changing stepping parameters could change the amount of activity generated but not the multimuscle activation patterns. Conclusions. The data suggest that the rhythmic motor patterns generated by the imposed stepping were responses of spinal reflex circuits to the cyclic sensory feedback. Tonic 30-Hz tSCS provided for additional excitation and engaged spinal rhythm-generating networks. The synergistic effects of these rhythm-generating mechanisms suggest that tSCS in combination with treadmill training might augment rehabilitation outcomes after severe spinal cord injury.

Effects of transcutaneous spinal cord stimulation on voluntary locomotor activity in an incomplete spinal cord injured individual.

Non-patterned electrical spinal cord stimulation (SCS) via epidural electrodes can activate neural circuits involved in lower-limb motor control in individuals with spinal cord injury (SCI), and generate automatic, rhythmic flexion-extension movements in the paralyzed lower limbs. Here, we studied whether SCS can increase the excitability of locomotor circuits in a motor-incomplete SCI individual capable of voluntary treadmill stepping without support and whether this augmentation can be integrated into the residu- al voluntary motor control. SCS was applied through skin electrodes during active treadmill stepping. Sub-motor stim- ulation enhanced the voluntary lower limb EMG activities in a step-phase appropriate manner as well as reproducibly modified the coordination of hip and knee movements during stepping. Further study in a larger population is warranted.

Periodic modulation of repetitively elicited monosynaptic reflexes of the human lumbosacral spinal cord

In individuals with motor-complete spinal cord injury, epidural stimulation of the lumbosacral spinal cord at 2 Hz evokes unmodulated reflexes in the lower limbs, while stimulation at 22-60 Hz can generate rhythmic burstlike activity. Here we elaborated on an output pattern emerging at transitional stimulation frequencies with consecutively elicited reflexes alternating between large and small. We analyzed responses concomitantly elicited in thigh and leg muscle groups bilaterally by epidural stimulation in eight motor-complete spinal cord-injured individuals. Periodic amplitude modulation of at least 20 successive responses occurred in 31.4% of all available data sets with stimulation frequency set at 5-26 Hz, with highest prevalence at 16 Hz. It could be evoked in a single muscle group only but was more strongly expressed and consistent when occurring in pairs of antagonists or in the same muscle group bilaterally. Latencies and waveforms of the modulated reflexes corresponded to those of the unmodulated, monosynaptic responses to 2-Hz stimulation. We suggest that the cyclical changes of reflex excitability resulted from the interaction of facilitatory and inhibitory mechanisms emerging after specific delays and with distinct durations, including postactivation depression, recurrent inhibition and facilitation, as well as reafferent feedback activation. The emergence of large responses within the patterns at a rate of 5.5/s or 8/s may further suggest the entrainment of spinal mechanisms as involved in clonus. The study demonstrates that the human lumbosacral spinal cord can organize a simple form of rhythmicity through the repetitive activation of spinal reflex circuits.

Central control of interlimb coordination and speed‐dependent gait expression in quadrupeds

Quadrupeds express different gaits depending on speed of locomotion. Central pattern generators (one per limb) within the spinal cord generate locomotor oscillations and control limb movements. Neural interactions between these generators define interlimb coordination and gait. We present a computational model of spinal circuits representing four rhythm generators with left–right excitatory and inhibitory commissural and fore–hind inhibitory interactions within the cord. Increasing brainstem drive to all rhythm generators and excitatory commissural interneurons induces an increasing frequency of locomotor oscillations accompanied by speed‐dependent gait changes from walk to trot and to gallop and bound. The model closely reproduces and suggests explanations for multiple experimental data, including speed‐dependent gait transitions in intact mice and changes in gait expression in mutants lacking certain types of commissural interneurons. The model suggests the possible circuit organization in the spinal cord and proposes predictions that can be tested experimentally.

Augmentation of Voluntary Locomotor Activity by Transcutaneous Spinal Cord Stimulation in Motor-Incomplete Spinal Cord-Injured Individuals

The level of sustainable excitability within lumbar spinal cord circuitries is one of the factors determining the functional outcome of locomotor therapy after motor-incomplete spinal cord injury. Here, we present initial data using noninvasive transcutaneous lumbar spinal cord stimulation (tSCS) to modulate this central state of excitability during voluntary treadmill stepping in three motor-incomplete spinal cord-injured individuals. Stimulation was applied at 30 Hz with an intensity that generated tingling sensations in the lower limb dermatomes, yet without producing muscle reflex activity. This stimulation changed muscle activation, gait kinematics, and the amount of manual assistance required from the therapists to maintain stepping with some interindividual differences. The effect on motor outputs during treadmill-stepping was essentially augmentative and step-phase dependent despite the invariant tonic stimulation. The most consistent modification was found in the gait kinematics, with the hip flexion during swing increased by 11.3° ± 5.6° across all subjects. This preliminary work suggests that tSCS provides for a background increase in activation of the lumbar spinal locomotor circuitry that has partially lost its descending drive. Voluntary inputs and step-related feedback build upon the stimulation-induced increased state of excitability in the generation of locomotor activity. Thus, tSCS essentially works as an electrical neuroprosthesis augmenting remaining motor control.

Energy-Optimal Electrical-Stimulation Pulses Shaped by the Least-Action Principle

Electrical stimulation (ES) devices interact with excitable neural tissue toward eliciting action potentials (AP’s) by specific current patterns. Low-energy ES prevents tissue damage and loss of specificity. Hence to identify optimal stimulation-current waveforms is a relevant problem, whose solution may have significant impact on the related medical (e.g. minimized side-effects) and engineering (e.g. maximized battery-life) efficiency. This has typically been addressed by simulation (of a given excitable-tissue model) and iterative numerical optimization with hard discontinuous constraints - e.g. AP’s are all-or-none phenomena. Such approach is computationally expensive, while the solution is uncertain - e.g. may converge to local-only energy-minima and be model-specific. We exploit the Least-Action Principle (LAP). First, we derive in closed form the general template of the membrane-potential’s temporal trajectory, which minimizes the ES energy integral over time and over any space-clamp ionic current model. From the given model we then obtain the specific energy-efficient current waveform, which is demonstrated to be globally optimal. The solution is model-independent by construction. We illustrate the approach by a broad set of example situations with some of the most popular ionic current models from the literature. The proposed approach may result in the significant improvement of solution efficiency: cumbersome and uncertain iteration is replaced by a single quadrature of a system of ordinary differential equations. The approach is further validated by enabling a general comparison to the conventional simulation and optimization results from the literature, including one of our own, based on finite-horizon optimal control. Applying the LAP also resulted in a number of general ES optimality principles. One such succinct observation is that ES with long pulse durations is much more sensitive to the pulse’s shape whereas a rectangular pulse is most frequently optimal for short pulse durations.

Selectivity of transcutaneous stimulation of lumbar posterior roots at different spinal levels in humans

Posterior root-muscle (PRM) reflexes can be elic- ited by epidural as well as recently also transcutaneous elec- trical stimulation of the lumbar spinal cord. We tested the se- lectivity of transcutaneous spinal cord stimulation by eliciting PRM reflexes and recording the compound muscle action po- tentials of the thigh and shank. The stimulation set-up con- sisted of an electrode array with 7 levels centered at the spinal level of T12. With the variation of the stimulation level a defi- nite change in the recruitment of PRM reflexes was observed. Even though the distribution of the generated electrical field with transcutaneous electrodes is unfocused in relation to the target structures, a selective stimulation is possible.

Multi-Electrode Array for Transcutaneous Lumbar Posterior Root Stimulation

Interest in transcutaneous electrical stimulation of the lumbosacral spinal cord is increasing in human electrophysiological and clinical studies. The stimulation effects on lower limb muscles depend on the depolarization of segmentally organized posterior root afferents and, thus, the rostro-caudal stimulation site. In previous studies, selective stimulation was achieved by varying the positions of single self-adhesive electrodes over the thoracolumbar spine. Here, we developed a multi-electrode surface array consisting of 3 × 8 electrode pads and tested its stimulation-site specificity. The array was placed longitudinally over the spine covering the T10-L2 vertebrae. Two different hydrogel layer configurations were utilized: a single layer adhered to all electrode pads of the array and a configuration comprised of eight separate strips attached to the three transverse electrode pads of each level. Voltage measurements demonstrated that an effectively focused field distribution along the longitudinal extent of the array was not accomplished when using the single continuous hydrogel layer, and segmental selective stimulation of the posterior root afferents was not possible. The separate strips produced a focused electric field distribution at the rostro-caudal level of the electrode pads selected for stimulation. This configuration allowed for the preferential elicitation of posterior root-muscle reflexes in either the L2-L4 innervated quadriceps or the L5-S2 innervated triceps surae muscle groups. Such multi-electrode array for transcutaneous spinal cord stimulation shall allow for improved control of stimulation conditions in electrophysiological studies and time-dependent and site-specific stimulation patterns for neuromodulation applications.