Getting the Spinal Cord to Think for Itself

NEUROLOGICAL REVIEW

SECTION EDITOR: DAVID E. PLEASURE, MD Getting the Spinal Cord to Think for Itself

Robert G. Kalb, MD

espite the interruption in communication between the brain and lower centers by spinal cord injury, many of the neurons engaged in generating locomotion survive. Sev- eral strategies have been used to activate spinal cord circuitry independent of the higher centers, including direct electrical stimulation, pharmacological agents, and training programsD that involve moving the legs through the motions of walking. Ambulatory leg movements are achieved by these interventions, leading to substantial functional improvements in the subset of patients with incomplete spinal cord injury. The neurobiological basis for these phenomena likely involves activity-dependent reconfiguration of synaptic connections within the spinal cord. Fostering this process may lead to further benefits for individuals with spinal cord injury. Arch Neurol. 2003;60:805-808

Within the realm of mindless activities, ing walking. The following 2 features bear only breathing rivals walking. Conscious highlighting: (1) even when discon- control can be superimposed, but munch- nected from supraspinal inputs, the iso- ing on a muffin and glancing at a news- lated spinal CPG can generate ambula- paper while walking is routine. Compen- tory alternating leg movements, and (2) satory minor adjustments for surface the isolated CPG circuitry can be trained irregularities, balance, speed, and rhythm to learn specific tasks. These 2 key prop- essentially proceed by autopilot. The neu- erties have captured the imagination of re- roanatomical system that subserves this re- searchers in the spinal cord injury (SCI) markable ability is widely distributed, in- field. If the neuronal ensemble within lum- volving neurons in the cerebral cortex, bar enlargement can be stimulated to gen- brainstem, cerebellum, and spinal cord. erate ambulatory leg movements, could Perhaps because of its presence in even the this form the basis for walking by indi- most primitive of chordates, the spinal cord viduals with SCI? Evidence now exists that is often thought to receive instructions pas- this approach can lead to important func- sively from higher centers. A consortium tional benefits for individuals with SCI. of neurons within the upper lumbar cord To begin to determine the utility of termed the central pattern generator (CPG) various methods for stimulating the spi- plays a fundamental role by interpreting nal CPG, it is important to identify and descending and segmental afferent sig- quantify the deficits that exist in individu- nals and patterning the firing of motor neu- als with clinically incomplete SCI.2 The rons.1 This network of neurons drives the characteristic abnormalities seen on gait rhythmic activation and relaxation of evaluation of individuals with SCI in- groups of leg muscles and coordinates the clude a reduction in walking speed, a movement of one leg with the other. longer swing-stance cycle duration, and a Studies of laboratory animals and, to shorter stride length. Angular displace- a lesser extent, human beings have pro- ments of leg joints during walking devi- vided insight into the structure and func- ate substantially from those seen in healthy tion of the spinal cord circuitry underly- individuals. Specific therapeutic interventions may lead to amelioration of particu- From the Department of Neurology, The Children’s Hospital of Philadelphia, lar walking deficits. It seems likely that if Philadelphia, Pa. a series of small improvements in these

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 proved to be more difficult, if not impossible, to achieve. Medications Used to Alleviate Spasticity Second, although visible leg movements were observed (and could be recorded by means of surface electromy- Central actions ography), they were feeble. It is questionable whether elec- Glycinergic Glycine trically stimulating the spinal cord engenders sufficient Threonine leg strength to permit weight bearing and walking. De- Noradrenergic spite these limitations, the demonstration of a human lum- Tizanidine hydrochloride bar spinal cord CPG is important. The generation of in- Clonidine hydrochloride choate walking movements in individuals with complete Chlorpromazine hydrochloride SCI has significant implications, as will be described Propranolol hydrochloride Serotonergic herein. Cyproheptidine hydrochloride An alternative electrical stimulation approach has GABAergic been used in individuals with incomplete SCI. Func- Diazepam tional electrical stimulation (FES) involves direct stimu- Progabide lation of peripheral nerves and/or muscles, in an at- Baclofen tempt to augment motor abilities that were curtailed by Other the initial injury.4-6 Some devices simply stimulate leg flex- Morphine sulfate Peripheral actions ors when a hand switch is pressed and stimulate leg ex- Dantrolene sodium tensors when released. More sophisticated multichan- Botulinum toxin nel devices with tilt sensors providing feedback are also Anesthetics available. Mastery of the FES-assisted ambulation re- Benzocaine quires a prolonged training period under the attentive Lidocaine hydrochloride (Xylocaine) guidance of a skilled therapist. In a multicenter Cana- dian study,4 application of FES to individuals with in- Abbreviation: GABAergic, secreting ␥-aminobutyric acid. complete SCI led to significant improvement of walking speed, stride length, and cycle duration. The effects on measures can be achieved, the aggregate benefit will walking could be attributed to the FES and training per lead to the most important outcome, an improvement se. Improvement in gait was seen in all individuals, re- in function. gardless of the severity of the initial deficit. The relative Several methods have been used to stimulate the iso- importance of FES vs training varied as a function of the lated human lumbar spinal cord and have met with vari- initial deficit. Individuals who began this program with able success in eliciting walking. Beyond the intrinsic ef- the smallest deficits experienced the most improve- ficacy of individual stimulation paradigms, a number of ment, and the increase in walking speed was entirely at- other factors have an impact on the utility of these ap- tributable to the training, not FES. proaches, including the age of the patient, the interval It has long been recognized that spasticity can be a between injury and stimulation, and the severity of the significant impediment to walking for individuals with SCI. The major approaches tried include (1) direct elec- SCI. The pharmacotherapeutic mainstays for individu- trical stimulation of the lumbar spinal cord, peripheral als with SCI include the antispasticity medications such nerves, or muscles; (2) pharmacological activation of spe- as ␥-aminobutyric acid, serotonin receptor antagonists, cific subtypes of neurotransmitter receptors; and (3) ac- and ␣-adrenergic receptor agonists (a complete list of tivation of segmental afferent nerve fibers in the leg by antispasticity medications is given in the Table).7,8 On moving paralyzed limbs through the trajectory of nor- the other hand, some degree of increased leg tone is help- mal walking. ful for these individuals by enabling upright posture and In the intact nervous system, descending inputs from promoting walking. Increasing antispasticity medica- brainstem neurons from the pedunculopontine nucleus tions past a threshold dose leads to worsening of gait in and the mesencephalic locomotor region provide a tonic ambulatory individuals with SCI. Titration of therapy with drive to the spinal CPG that is needed for locomotion. these drugs to achieve an optimal level of reflex tone in In an attempt to mimic this input, epidural stimulation legs must be tailored to meet individual needs. at the T10 through L1 vertebral levels was provided to More recent attention has turned to the idea that selected individuals with a complete SCI.3 One of the jus- some of the drugs used to control spasticity might be ca- tifications for this invasive approach is that epidural spi- pable of triggering or facilitating patterned leg move- nal cord stimulation is an accepted means of reducing ments. Studies of laboratory animals indicate this ap- spasticity. Epidural stimulation led to steplike move- proach could be very promising. For example, when the ␣ ments of the leg with organized flexion/extension of mul- 2-noradrenergic agonist clonidine hydrochloride is tiple groups of muscles. By changing stimulation vari- administered to cats with an acute spinal cord transec- ables, such as the strength of the electrical input and the tion, normal-appearing walking and hind-limb weight frequency and location along the dorsal spinal cord, in- support can be elicited.9 In addition, when animals vestigators were able to convert tonic leg extension into with chronic SCI are trained to walk, the administra- rhythmic and well-coordinated steplike movements. Al- tion of clonidine had significant additive effects that though this work is a remarkable achievement, there are increased the maximum speed of walking.10 Even un- some caveats. First, although steplike movements could trained cats with chronic SCI benefited from clonidine be elicited in a single leg, alternating leg movements administration.

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 In a placebo-controlled trial in individuals with clinically complete SCI, clonidine showed no beneficial effect on walking. In contrast, when administered to individuals with a partial SCI, clonidine led to improvements in walking.11 These clinical studies involved oral clonidine, and preliminary work has also been undertaken using intrathecal clonidine. The improvements in walking speed and the duration of the effects were more pro- nounced with intrathecal clonidine.12 Precisely how clonidine works to improve walking is not clear. However, it is likely not simply due to its antispasticity actions. Other drugs are equally effective in reducing spasticity yet do not trigger ambulatory leg movements. For example, the serotonergic antagonist cyproheptidine hydrochloride effectively reduces clonus and spontaneous spasms in individuals with SCI.13 Admin- istration of cyproheptidine to individuals with mark- edly increased tone derived important functional benefits. Cyproheptidine had no beneficial effects on Interactive locomotor training. A young woman with an incomplete spinal cord injury is suspended by means of a yellow parachute harness over a treadmill. individuals with partial SCI who did not have clonus or One physical therapist stabilizes the patient’s body over the moving treadmill spasticity. An important goal will be to understand the while 2 others move her weak legs through the motions of walking. Months of relationship between the circuitry underlying spasticity repeated training sessions lead to measurable improvement in gait. and that driving ambulation. If these two can be disso- ciated, the development of drugs that specifically stimu- herent plasticity of interneuronal communication within late the spinal cord CPG may occupy an important niche the spinal cord. in the therapy for individuals with SCI. Several centers that treat humans with SCI have ap- The above-described methods for engaging spinal plied these lessons to their patients and met with vary- cord CPGs involve the application of exogenous (elec- ing degrees of success.18,19 The basic approach involves trical or chemical) stimuli. Except in the case of com- supporting of body weight (unloading is accomplished plete anatomic spinal cord transection, the locus of ac- with a parachute harness), stationing the patient over a tion may involve activation of sites in addition to the treadmill, and having a physiotherapist assist leg move- lumbar spinal cord. An alternative method that enlists ments (Figure). Special attention is directed toward foot the participation of endogenous afferent systems within liftoff and subsequent planting of the companion ex- the segmental spinal cord is termed exercise therapy or tended leg. A common approach involves 15- to 30- interactive locomotor training. In humans and experi- minute sessions occurring 5 times per week for approxi- mental animals with SCI, a significant functional ben- mately 3 months. Individuals with partial injuries showed efit is derived from a training program of repeatedly mov- improvements in walking speed, endurance, and the need ing paralyzed limbs through the normal trajectory taken for support. Quantitative electromyographic analysis when walking. showed increased activity in leg muscles such as the gas- In the 1980s, several groups investigated the ben- trocnemius. In some individuals, the patterns of leg muscle eficial effects of locomotor training on cats with SCI.14-16 activation showed qualitative adjustments. Instead of the Spinalized animals were suspended over a treadmill, and coactivation of extensors and flexors evident before investigators lifted and placed the legs on the moving sur- therapy, a reciprocating pattern was achieved after therapy. face to replicate walking. These training sessions oc- Measurable improvements in leg movements could curred daily for several weeks. Over time, several mea- be achieved with the training of individuals with com- sures of functional improvement became evident. First, plete SCI, but the functional improvements were small. the amount of investigator intervention could be cut back; Stepping movements were only exhibited when body second, the amount of hind-limb unweighting by sus- weight was reduced, although the amount of unweight- pension could be reduced; and third, treadmill speed could ing diminished with training. Although locomotor- be increased. After 3 to 4 weeks of this training pro- patterned activation of leg muscles resulted from train- gram, spinalized animals were able to walk on a moving ing, these effects were quantitatively smaller in comparison treadmill unassisted. Furthermore, spinalized cats could with those in individuals with incomplete SCI. learn to step over and avoid a small obstruction on the In studies of spinalized cats, administration of cloni- moving treadmill. A distinct training program under- dine at the time of exercise therapy accelerated recov- taken with a second set of spinalized cats achieved full- ery.10 This has naturally led to the idea of combining in- weight support standing.17 The important conclusion to teractive locomotive training of humans with SCI with draw from this body of work is that the circuitry within pharmacological stimulation. Anecdotal reports use this the lumbar spinal cord is sufficient to evoke several im- approach, but whether this hastens and/or increases func- portant behaviors such as standing and walking. What tional improvement is difficult to know.20 In individu- is required is a specific pattern of segmental afferent in- als with SCI who have poor ambulatory leg movements put to stimulate and instruct the network. The capacity with body-weight support at the treadmill, initiation of to learn task-specific motor programs illustrates the in- ambulation pharmacologically or by means of electrical

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 stimulation might be particularly useful. Pharmacologi- REFERENCES cal supplementation to interactive gait training should be evaluated prospectively in clinical trials. 1. Grillner S, Matsushima T. The neural network underlying locomotion in lam- How long do the benefits of locomotive training last? prey: synaptic and cellular mechanisms. Neuron. 1991;7:1-15. A few studies have examined this issue, and in some in- 2. Barbeau H, Ladouceur M, Norman KE, Pepin A, Leroux A. Walking after spinal cord injury: evaluation, treatment, and functional recovery. Arch Phys Med Re- dividuals with incomplete SCI, the functional improve- habil. 1999;80:225-235. ments can be indefinite.21,22 A likely scenario is that once 3. Dimitrijevic MR, Gerasimenko Y, Pinter MM. Evidence for a spinal central pattern generator in humans. 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Noradrenergic agonists and locomotor training affect locomotor recovery after cord transection in adult cats. Brain Res Bull. ing of connectivity tailors each organism’s nervous sys- 1993;30:387-393. tem to the environment in which it was reared.24,25 It is plau- 11. Stewart JE, Barbeau H, Gauthier S. Modulation of locomotor patterns and spasticity with clonidine in spinal cord injured patients. Can J Neurol Sci. 1991;18: sible that this machinery can be engaged after SCI and, if 321-332. appropriately stimulated, can lead to useful restructuring 12. Remy-Neris O, Barbeau H, Daniel O, Boiteau F, Bussel B. Effects of intrathecal of synaptic organization. Insight into the molecular events clonidine injection on spinal reflexes and human locomotion in incomplete paraplegic subjects. Exp Brain Res. 1999;129:433-440. driving activity-dependent spinal cord development might 13. Wainberg M, Barbeau H, Gauthier S. The effects of cyproheptadine on locomo- be profitably applied to individuals with SCI to enhance tion and on spasticity in patients with spinal cord injuries. J Neurol Neurosurg interactive training therapy. Psychiatry. 1990;53:754-763. 14. Lovely RG, Gregor RJ, Roy RR, Edgerton VR. Effects of training on the recovery As advances in the acute care of individuals with SCI of full-weight-bearing stepping in the adult spinal cat. Exp Neurol. 1986;92:421- proceed, reductions in the severity of myelopathy will 435. 15. Forssberg H, Grillner S, Halbertsma J, Rossignol S. The locomotion of the low surely follow. In addition, progress is being made in coax- spinal cat, II: interlimb coordination. Acta Physiol Scand. 1980;108:283-295. ing axons to ignore inhibitory factors (largely derived from 16. Barbeau H, Rossignol S. Recovery of locomotion after chronic spinalization in myelin) and grow past a focal spinal cord lesion.26,27 These the adult cat. Brain Res. 1987;412:84-95. 17. 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The combined effects of clonidine and cyproheptadine with interactive training on the modulation of locomotion in spinal cord Accepted for publication February 4, 2003. injured subjects. J Neurol Sci. 1990;100:85-93. 21. Wernig A, Nanassy A, Muller S. Maintainance of locomotor ability following Lauf- This study was supported by the Spinal Cord Research band (treadmill) therapy in para- and tetraplegia persons: follow-up studies. Spi- Foundation/Paralyzed Veterans of America, Washington, DC, nal Cord. 1998;36:744-749. and the National Institutes of Health, Bethesda, Md. 22. Wirz M, Colombo G, Dietz V. Long term effects of locomotor training in spinal humans. J Neurol Neurosurg Psychiatry. 2001;71:93-96. Hughes Barbeau, PhD, kindly provided the image 23. Kalb RG. Regulation of motor neuron dendrite growth by NMDA receptor acti- exhibited in the Figure. vation. Development. 1994;120:3063-3071. 24. Shatz CJ. Impulse activity and the patterning of connections during CNS devel- Corresponding author and reprints: Robert G. Kalb, opment. Neuron. 1990;5:745-756. MD, Department of Neurology, The Children’s Hospital 25. Goodman CS, Shatz CJ. Developmental mechanisms that generate precise pat- of Philadelphia, Abramson Research Center, #814, 3615 terns of neuronal connectivity. Cell. 1993;72:77-98. 26. Qiu J, Cai D, Dai H, et al. Spinal axon regeneration induced by elevation of cyclic Civic Center Blvd, Philadelphia, PA 19104 (e-mail: Kalb AMP. Neuron. 2002;34:895-903. @email.chop.edu). 27. Schwab ME. Repairing the injured spinal cord. Science. 2002;295:1029-1031.

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