The Role of Functional Neuroanatomy of the Lumbar Spinal Cord in Effect of Epidural Stimulation

Epidural electrical stimulation (EES) of lumbosacral segments can restore a range of movements after spinal cord injury. However, the mechanisms and neural structures through which EES facilitates movement execution remain unclear. Here, we designed a computational model and performed in vivo experiments to investigate the type of fibers, neurons, and circuits recruited in response to EES. We first developed a realistic finite element computer model of rat lumbosacral segments to identify the currents generated by EES. To evaluate the impact of these currents on sensorimotor circuits, we coupled this model with an anatomically realistic axon-cable model of motoneurons, interneurons, and myelinated afferent fibers for antagonistic ankle muscles. Comparisons between computer simulations and experiments revealed the ability of the model to predict EES-evoked motor responses over multiple intensities and locations. Analysis of the recruited neural structures revealed the lack of direct influence of EES on motoneurons and interneurons. Simulations and pharmacological experiments demonstrated that EES engages spinal circuits trans-synaptically through the recruitment of myelinated afferent fibers. The model also predicted the capacity of spatially distinct EES to modulate side-specific limb movements and, to a lesser extent, extension versus flexion. These predictions were confirmed during standing and walking enabled by EES in spinal rats. These combined results provide a mechanistic framework for the design of spinal neuroprosthetic systems to improve standing and walking after neurological disorders.

It has been previously demonstrated that sustained nonpatterned electric stimulation of the posterior lumbar spinal cord from the epidural space can induce stepping-like movements in subjects with chronic, complete spinal cord injury. In the present paper, we explore physiologically related components of electromyographic (EMG) recordings during the induced stepping-like activity. To examine mechanisms underlying the stepping-like movements activated by electrical epidural stimulation of posterior lumbar cord structures. The study is based on the assessment of epidural stimulation to control spasticity by simultaneous recordings of the electromyographic activity of quadriceps, hamstrings, tibialis anterior, and triceps surae. We examined induced muscle responses to stimulation frequencies of 2.2-50 Hz in 10 subjects classified as having a motor complete spinal cord injury (ASIA A and B). We evaluated stimulus-triggered time windows 50 ms in length from the original EMG traces. Stimulus-evoked compound muscle action potentials (CMAPs) were analyzed with reference to latency, amplitude, and shape. Epidural stimulation of the posterior lumbosacral cord recruited lower limb muscles in a segmental-selective way, which was characteristic for posterior root stimulation. A 2.2 Hz stimulation elicited stimulus-coupled CMAPs of short latency which were approximately half that of phasic stretch reflex latencies for the respective muscle groups. EMG amplitudes were stimulus-strength dependent. Stimulation at 5-15 and 25-50 Hz elicited sustained tonic and rhythmic activity, respectively, and initiated lower limb extension or stepping-like movements representing different levels of muscle synergies. All EMG responses, even during burst-style phases were composed of separate stimulus-triggered CMAPs with characteristic amplitude modulations. During burst-style phases, a significant increase of CMAP latencies by about 10 ms was observed. The muscle activity evoked by epidural lumbar cord stimulation as described in the present study was initiated within the posterior roots. These posterior roots muscle reflex responses (PRMRRs) to 2.2 Hz stimulation were routed through monosynaptic pathways. Sustained stimulation at 5-50 Hz engaged central spinal PRMRR components. We propose that repeated volleys delivered to the lumbar cord via the posterior roots can effectively modify the central state of spinal circuits by temporarily combining them into functional units generating integrated motor behavior of sustained extension and rhythmic flexion/extension movements. This study opens the possibility for developing neuroprostheses for activation of inherent spinal networks involved in generating functional synergistic movements using a single electrode implanted in a localized and stable region.

Analysis of the computed recruitment order of an ensemble of ventral and dorsal root fibers should enlighten the relation between the position of a bipolar electrode and the observed order of muscle twitches. Thresholds of selected spinal root fibers are investigated in a two step procedure. First the electric field generated by the electrodes is computed with the Finite Element Method. In the second step the calculated voltage profile along each target neuron is used as input data for a cable model. For every electrode position the electrical excitability is analyzed for 12 large diameter ventral and dorsal root fibers of the second and fourth lumbar and first sacral segment. The predictions of the neural responses of any target fiber are based on the activating function concept and on the more accurate computer simulations of the electrical behavior of all nodes and internodes in the vicinity of the electrode. For epidural dorsal lumbosacral spinal cord stimulation we found the following rules. (i) The recruitment order of the spinal roots is highly related to the cathode level. (ii) Dorsal root fibers have the lowest threshold values, ventral root fibers are more difficult to excite and dorsal columns are not excitable within the clinical range of 10 V. (iii) For a cathode close to the level of the spinal cord entry of a target fiber thresholds are lowest and spike initiation is expected at the border between cerebrospinal fluid and white matter; excitation of L4 roots is not possible with 210 micros/10 V pulses when cathode is more than 2.2 cm cranial to their entry level (1.5 cm for S1 roots; standard data). (iv) Cathodes positioned (essentially) below the entry level cause spike initiation close to the cathode, in a region where the fibers follow the descending course within the cerebospinal fluid. (v) At rather low stimulation voltage twitches are expected in all investigated lower limb muscles for cathodes below L5 spinal cord level. Our simulations demonstrate a strong relation between electrode position and the order of muscle twitches which is based on the segmental arrangement of innervation of lower limb muscles. The proposed strategy allows the identification of the position of the electrode relative to spinal cord segments.