Neuromodulation of the Spinal Cord for Movement Restoration

Spinal Cord Epidural Stimulation Facilitates Stepping and Standing in Mammals

Epidural stimulation in mammalian complete transection models showed the transformation of nonfunctional spinal circuits into functional locomotor states and also enabled processing of sensory information related to loading and position during stepping without descending influence ( ). Spinal epidural stimulation in decerebrate cats generated locomotor patterns modulation by peripheral feedback ( ). A series of studies on animal models with complete spinal cord injury suggested that the spinal cord contains the neural networks that control balance, and that these networks are normally activated by a tonic supraspinal drive ( ). Spinal cord epidural stimulation (scES) facilitated postural responses in these animal models. Furthermore, the fact that postural control was recovered to some extent after the suppression of vestibular, visual, and head–neck–trunk sensory input implies that somatosensory information from the lower limbs plays a crucial role in generating appropriate postural responses ( ). Interestingly, postural training and pharmacological interventions enhanced the positive effects of scES on postural control; however, even the combination of these three interventions was not sufficient to regain normal postural functions ( ).

Evidence of Sophisticated Neural Networks in the Human Spinal Cord Circuitry

Patterned locomotor activity was shown to be driven by constant epidural stimulation in humans when in lying positions, indicating the intrinsic capacity of the human spinal cord interneuronal systems to generate oscillatory and extensor patterns in the absence of observable descending drive and those sensory cues associate with weight-bearing loading ( ). Numerous human experiments also demonstrated that individuals who by clinical and functional assessments could not move voluntarily below their injury did show complex motor patterns when carefully assessed by clinical ( ) and neurophysiological measures ( ), and in some cases these were modulated with sensory cues ( ) and intentional efforts ( ). These indirect human experiments were the closest results to those reflecting the most definitive experiments in mammals of fictive locomotion, detailing the capacity of these circuits to control locomotion by integration of complex sensory signals ( ).

The human spinal cord was also shown to generate locomotor patterns and weight-bearing steps successfully in the absence of input from the brain when provided with specific and appropriate sensory information related to locomotion ( ), as shown in other mammals. This experimental approach was translated into an activity-based therapy, locomotor training, with significant success for postural and walking recovery in those with incomplete spinal cord injury ( ). Individuals with very low levels of neuromuscular activity, including those with limited or no detectable voluntary activity below the injury, recovered significant postural stability and nonweight-bearing mobility, but were not able to generate independent steps over ground. These experiments indicated sensory information was modulated during stepping even in individuals with motor-complete spinal cord injury, and raised the realistic possibility that epidural stimulation would enable the circuitry to generate locomotor patterns.

Spinal Cord Epidural Stimulation Facilitates Standing and Stepping Patterns in Humans

A series of studies performed on individuals with motor-complete spinal cord injury who were implanted with an epidural stimulation unit with the intent to reduce spasticity showed that lower-limb extensor motor patterns could be elicited in the supine position by scES ( ). In particular, two active electrodes of a quadripolar array, implanted at a vertebral level ranging from T12 to L1, were used to stimulate the spinal cord by applying stimulation amplitudes well above motor threshold at frequencies ranging from 5 to 15 Hz. These stimulation parameters initiated and retained lower-limb extension that resulted from the greater activation of hamstring and triceps surae muscles compared to the quadriceps and tibialis anterior, respectively. The same authors reported that the motor pattern became rhythmic when the stimulation frequency was increased to 21–31 Hz, without any change in stimulation site and amplitude. These interesting results were interpreted to mean that different stimulation frequencies at the same site of stimulation would access different inhibitory and/or excitatory pathways within spinal networks to elicit different motor patterns (i.e., tonic or rhythmic). Thus at frequencies between 5 and 15 Hz the spinal network was conceivably configured via presynaptic and synaptic mechanisms to favor the electromyographic (EMG) “extensor pattern,” and at higher frequencies to favor a rhythmic locomotor-like pattern. However, no recovery of stepping or standing ability was reported using these relatively higher- and lower-frequency stimulation paradigms.

The concept of implanting specifically for standing and stepping and integrating the ability of the spinal cord circuitry to interpret sensory cues for standing and stepping was tested in a motor-complete but sensory-incomplete individual with chronic spinal cord injury by implanting an epidural stimulator over the L1–S1 spinal cord. This individual achieved full weight-bearing standing with only assistance for balance when using scES parameters specific for standing (Stand-scES) and bilateral load-bearing proprioceptive input. Locomotor patterns that were not observed in 170 sessions of locomotor training emerged only with scES using parameters specific for stepping (Step-scES) and proprioceptive input related to alternating bilateral loading and kinematic extension and flexion. Tonic epidural stimulation modulated the human spinal circuitry into a physiological state that enabled sensory input, derived from standing and stepping movements, to serve as a source of neural control to perform these critical motor tasks lost after severe spinal cord injury.

Spinal Cord Epidural Stimulation Evoked Unforeseen Voluntary Movement Responses and Independent Standing in Humans With Motor-Complete Spinal Cord Injury

Voluntary initiated movement generated by this individual with a motor-complete spinal cord injury observed after 4 months of continuous scES revealed unexpected potential for even more recovery for motor control than thought possible by the original theory of the mammalian spinal cord containing intrinsic circuits only for repetitive locomotor-like patterns ( ). There may be the ability to target specific movements more precisely, generate multiple repetitions of movement, increase force, and sustain longer contractions evolved over time with task-specific training ( ). An initial interpretation of these unexpected observations was that the presence of ascending sensory fibers, albeit impaired, and significant neural plasticity driven by intense stimulation over several months had reconfigured sensory pathways into novel functional motor pathways allowing voluntary movement. In combination with scES configurations specific for voluntary movements (Vol-scES) and task-specific training, these pathways strengthened with further supraspinal and spinal plasticity. This hypothesis was addressed by testing an individual with a motor- and sensory-complete spinal cord injury. Most surprisingly, during his first attempts with Vol-scES (and with less than a week of any scES and no training) he was able to generate voluntary movements. Voluntary movements were also successful in the next two individuals, one with a motor-complete and sensory-incomplete spinal cord injury and the other with a motor- and sensory-complete spinal cord injury. The possibility of subliminal pathways still available for neural activation even in the most severe injuries now needs to be considered. Also, the theory of human control of voluntary movements attributed mostly or entirely to corticospinal mechanisms ( ), with the spinal cord as simply a conduit of these commands, may not be plausible in the context of these most recent findings in these four individuals with the most severe motor spinal cord injury.

Standing with full weight bearing and without physical assistance also improved with specific configurations for Stand-scES and repetitive daily training ( ). The human spinal circuitry generated motor patterns effective for standing without clinical or neurophysiological evidence of functional supraspinal connections. Sensory- and motor-complete spinal cord injury individuals achieved full weight-bearing standing without any external assistance and with minimal self-balance assistance only when the lumbosacral spinal cord was electrically stimulated. Stand-scES enabled independent standing and modulated lumbosacral spinal networks to a functional state that optimized the integration of task-specific afferent input to generate effective motor patterns with overall continuous EMG patterns in the lower-limb muscles and a constant level of ground reaction forces.