Elsevier

Experimental Neurology

Volume 209, Issue 2, February 2008, Pages 417-425
Experimental Neurology

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

https://doi.org/10.1016/j.expneurol.2007.07.015Get rights and content

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.

Introduction

In mammals, networks of spinal neurons are able to generate a pattern of rhythmical, reciprocal activation of antagonistic muscles of the hindlimbs in the absence of supraspinal and/or afferent input. The networks that produce this rhythmical output are known as the spinal locomotor central pattern generators (CPG) (Grillner and Zangger, 1979). Recently it was shown that locomotor-like movements can be induced by epidural spinal cord stimulation (ES) in adult cats (Iwahara et al., 1991, Gerasimenko et al., 2002, Gerasimenko et al., 2003) and rats (Ichiyama et al., 2005, Lavrov et al., 2006) after a complete thoracic spinal cord transection (ST) as well as in individuals with a complete spinal cord injury (SCI) (Dimitrijevic et al., 1998a, Gerasimenko et al., 2001, Shapkova, 2004, Minassian et al., 2007). In each of these preparations, those intraspinal neurons that generate locomotor-like patterns remain intact, but unlike in CPG all sensory information from the hindlimbs can functionally project to this intraspinal network after the complete loss of supraspinal input. It is the combination of the potential of the intraspinal networks to generate locomotor-like rhythms and their ability to utilize the sensory information associated with movement that can result in rather remarkable weight-bearing stepping in spinal animals. The studies mentioned above clearly demonstrate that ES can activate the intraspinal neural networks that, in turn, can coordinate and recruit the motoneuronal pools with enough precision to generate oscillating movements of the lower limbs in a step-like fashion. What has not been clear from the results of these studies is the degree to which these step-like patterns generate effective weight-bearing stepping as opposed to simply producing a range of oscillating behaviors. Intricately linked to this question is the degree to which these motor patterns can be attributed to the neurons associated with the CPG as opposed to the sensory information provided to this circuitry in the presence of lumbosacral ES.

We will examine this issue in this review. The primary emphasis will be to provide a comparative perspective on the properties of these neural networks among different mammals, including humans. Are there distinctive differences in the localization of the locomotor networks in the lumbosacral spinal cord among mammals? Is there specificity in the parameters of ES that can be taken advantage of while facilitating effective locomotor activity among the different mammals? What is the significance of peripheral sensory feedback in the modulation, or even control, of locomotor behavior in these mammals during ES? Are there significant differences among mammals in the ability to generate locomotor patterns in response to ES? From a clinical perspective an assessment of the similarities and dissimilarities of the locomotor networks among different mammals may provide clues as to the potential of ES as an effective clinical tool in enhancing the potential for ambulation following a SCI. Based on studies to date, it also appears that there is a high level of relevance of these same issues to a range of other neuromotor disorders in which the locomotor potential has been compromised. Each of these questions and issues is addressed in the present review.

Section snippets

Quality of locomotion facilitated by ES in different mammals

In decerebrated cats, ES at the cervical enlargement induces quadrupedal step-like movements on a moving treadmill belt whereas ES at the lumbosacral enlargement induces locomotor activity only in the hindlimbs (Iwahara et al., 1991). In decerebrated cats consistent weight bearing and plantar foot placement on a moving treadmill belt is induced by ES of the lumbar cord (Gerasimenko et al., 2002). In acute ST (T9) cats, in contrast to decerebrated cats, ES induces only weak rhythmic hindlimb

Methodology of ES in facilitating locomotor-like activity

What are the specific parameters of ES that can facilitate locomotor-like activity in spinal animals? An important concept to emphasize at this point is that ES has the potential to facilitate, as well as induce, locomotor-like activity. The difference between facilitating and inducing locomotion has major clinical implications. For example, it will be inordinately more desirable clinically to modulate the properties of the spinal cord circuitry into a physiological state in which the

Site of stimulation

Iwahara et al. (1991) reported that ES at the L1 and L4 spinal segments was more effective than at the L5–S1 segments for inducing hindlimb stepping in the decerebrated cat. Subsequent studies have shown that ES at the L4–L5 segments elicits hindlimb stepping more effectively than stimulation at other spinal levels (Gerasimenko et al., 2002, Gerasimenko et al., 2003). In chronic spinal rats, ES at the lumbosacral level elicits some hindlimb rhythmic movements, with coordinated bilateral

Frequency of ES

In decerebrated cats the optimal frequency range of ES for inducing hindlimb stepping was 3–5 Hz (Iwahara et al., 1991, Gerasimenko et al., 2002). In decerebrated cats spinalized 5–7 days before an acute experiment the optimal frequencies for intraspinal microstimulation eliciting long-lasting locomotion was 2–6 Hz, although a few cycles of bilateral locomotion could be triggered during high-frequency (30–70 Hz) stimulation (Barthélemy et al., 2007).

In chronic ST rats ES in the range between 20

Strength of ES

The threshold intensity of ES for activation of the locomotor networks differs in animals and humans. In the decerebrated cat ES applied at L1–L4 with a current of ∼ 100 μA is most effective for inducing locomotion (Iwahara et al., 1991). In chronic ST rats the threshold to induce locomotor activity in response to ES at L2 is ∼ 7.5 V. Interestingly, the threshold for a hindlimb muscle response to a single epidural pulse was reported to be 3.4 V in rats (Ichiyama et al., 2005). To initiate

Role of afferent input to the spinal cord in controlling stepping facilitated by ES

Chronic spinal rats can generate some weight-bearing stepping in response to ES (Lavrov et al., 2006), but a key factor in defining the details of the stepping is the pattern of the afferent information being projected to the spinal cord. For example, if the speed of the treadmill belt is changed, then the details of the stepping pattern will adapt proportionately. If the level of weight bearing during stepping is increased, then the spinal cord will accommodate accordingly, i.e., increase the

Which axons and neurons are being activated by ES?

In animals and in humans with a chronic but incomplete SCI, ES will activate descending and ascending dorsal column axons as well as projections from the dorsal root, particularly as they project vertically and enter the spinal cord at the dorsal surface (Minassian et al., 2007). In humans and laboratory animals with a complete SCI above the lumbosacral segments, there will be no descending axons activated by ES, but the dorsal root afferents will be readily activated and, theoretically, the

What is the true potential of the spinal circuitry that remains in the lumbosacral spinal cord following a complete SCI at a thoracic or higher level?

Two experimental preparations provide strong evidence that the circuitry within the lumbosacral spinal cord, in the absence of any supraspinal input, is capable of generating remarkably normal locomotion, assuming the circuitry has access to the sensory input that is normally provided to the spinal circuitry during weight-bearing stepping. One preparation is the acute decerebrated cat when the dorsum of the spinal cord is stimulated at a frequency of 5 Hz at L4–L5 with a monopolar electrode.

How do we gain access to the lumbosacral circuits?

We must first reiterate the importance of the fact that the spinal circuitry has the capability to generate coordinated stepping and standing as well as to respond effectively to variations in the environment. To utilize this potential, it appears that the spinal circuitry remains in a dynamic state, but that it is possible to stabilize this circuitry at different physiological states. Given the appropriate sensory information, the circuitry may have a propensity for performing a given type of

Acknowledgments

The work presented in this paper was supported by NIH NS16333, NIH NS42291, RFBR-CRDF 07-04-91106, RFBR 07-04-00526, the Christopher and Dana Reeve Foundation, and the California Roman Reed Bill.

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