Epidural stimulation: comparison of the spinal circuits that generate and control locomotion in rats, cats and humans

Abstract

Although epidural stimulation is a technique that has been used for a number of years to treat individuals with a spinal cord injury, the intended outcome has been to suppress plasticity and pain. Over the last decade considerable progress has been made in realizing the potential of epidural stimulation to facilitate posture and locomotion in subjects with severe spinal cord injury who lack the ability to stand or to step. This progress has resulted primarily from experiments with mice, rats and cats having a complete spinal cord transection at a mid-thoracic level and in humans with a complete spinal cord injury. This review describes some of these experiments performed after the complete elimination of supraspinal input that demonstrates that the circuitry necessary to control remarkably normal locomotion appears to reside within the lumbosacral region of the spinal cord. These experiments, however, also demonstrate the essential role of processing proprioceptive information associated with weight-bearing stepping or standing by the spinal circuitry. For example, relatively simple tonic signals provided to the dorsum of the spinal cord epidurally can result in complex and highly adaptive locomotor patterns. Experiments emphasizing a significant complementary effect of epidural stimulation when combined with pharmacological facilitation, e.g., serotonergic agonists, and/or chronic step training also are described. Finally, a major point emphasized in this review is the striking similarity of the lumbosacral circuitry controlling locomotion in the rat and in the human.

Figure 1

Locomotor-like EMG patterns induced by epidural stimulation (ES) in an adult complete spinal cord transected (ST) rat stepping at a treadmill speed of 9 cm/sec (A) and in a complete spinal cord injured (SCI) patient (ASIA A) in a supine position (B) are shown. Rhythmic alternating EMG activity induced by ES (40 Hz) at L2 is observed in selected hindlimb muscles in the ST rat six weeks after the injury (A). Rhythmic activity is shown in one leg of the human subject in response to ES (30 Hz) at L2 (B). Abbreviations: RVL, right vastus lateralis; RSt, right semitendinosus; RTA, right tibialis anterior; RMG, right medial gastrocnemius; LMG, left medial gastrocnemius; LEDL, left extensor digitorum longus; Q, quadriceps; A, adductors; TA, tibialis anterior; TS, triceps surae.

Figure 2

EMG patterns in selected hindlimb muscles induced by ES (4 V) in a ST rat at 30 Hz (A) and 110 Hz (C) and by ES (7 V) in a SCI patient at 30 Hz (B) and 120 Hz (D) are shown. In the ST rat locomotor-like EMG patterns are observed at both stimulation frequencies (A and C). During ES at 110 Hz the locomotor-like rhythm is not changed dramatically, whereas the amplitude and/or duration of the EMG bursts of the LTA and LEDL were decreased. In the SCI patient locomotor-like EMG activity was observed in all muscles with ES (7 V) at L2 at a frequency of 30 Hz (B), but only tonic EMG activity was induced with ES at 120 Hz (D). Abbreviations: K.M., knee movements; all others same as in Fig. 1.

Figure 3

Differences in the initiation of locomotor-like activity in a ST rat in response to ES (4 V at 40 Hz) at S1 (A) and to ES in the presence of quipazine (0.3 mg/kg) (B) are shown. Vertical arrows indicate the initiation of ES. Note that the locomotor-like rhythm evoked by ES in the presence of quipazine was significantly slower than during ES alone in spite of the fact that the treadmill speed is the same (9 cm/sec) for both conditions. Abbreviations, same as in Fig. 1.

Figure 4

The effects of hip ischemia on locomotor-like EMG activity induced by ES in an individual with a complete SCI (ASIA A) are shown. EMG recordings from the leg muscles while gradually increasing the intensity of ES from 3.5 V to 5.5 V (in increments of 0.5 V) at L2 are shown in (A). Vertical arrows show the time points at which the stimulus intensity was increased. The transformation from tonic EMG activity into bursting EMG activity occurred at an ES intensity of 5.5 V. After 20 min of ischemia induced by a cuff over the hip, the emergence of the EMG activity while progressively increasing the intensity of ES (shown by arrows) is demonstrated in (B).

Figure 5

The spectral characteristics of a flexor (TA) and an extensor (MG) muscle in a ST rat (A) and a flexor (TA) and extensor (Sol) muscle in the leg of an individual with a complete SCI (B) during locomotor-like activity induced by ES (S1 at 40 Hz for the rat and L2 at 25 Hz for the human) are shown. The spectral analyses (power-frequency plots) are derived using Fast Fourier Transformation (FFT) procedures and are based on analysis of the burst enclosed in the shaded boxes in each muscle EMG trace. Similar analyses for the left semitendinosus (LSt), a biarticular muscle having both a flexor (knee flexion) and an extensor (hip extension) function, are shown from a ST rat in (C). Note the dominant spectral peaks that represent the periodicity of the stimulation frequency in those EMG bursts associated with extension, reflecting a predominance of monosynaptic-evoked potentials. Also note that there are no consistent dominant peaks during the flexor bursts in response to the same stimulation, suggesting that a predominance of polysynaptic-evoked potentials. Abbreviations, same as in Fig. 1.