Spinal Cord Injury: Repair, Plasticity and Rehabilitation

Abstract

Devastating functional deficits following spinal cord injury (SCI) are no longer considered irreversible. Laboratory findings indicate that some improvements can be achieved with therapeutic approaches designed to promote tissue repair. It also has become widely recognised that the spinal cord is not a ‘hard‐wired’ structure; neural circuits can undergo spontaneous anatomical, neurophysiological, or molecular remodelling (i.e. endogenous neuroplasticity) after injury with accompanying behavioural changes. New rehabilitation regimens and spinal cord electrical stimulation have likewise been found to have great potential for enhancing neuroplasticity and activating synaptic networks below the spinal level of injury. While many challenges remain, promising therapeutic strategies are now emerging for promoting significant improvements in quality of life after SCI by integrating cellular and molecular treatments with neurorehabilitation and complementary neuroengineering approaches.

Key Concepts

  • Spinal cord injury is no longer viewed as an untreatable condition.
  • The spinal cord is not a rigidly wired structure; it can exhibit structural and functional remodelling.
  • Intrinsic ‘neuroplasticity’ can contribute to partial improvement in function post spinal cord injury.
  • Novel therapeutic approaches have emerged, which target cellular responses to spinal cord injury.
  • Spinal cord injuries are rarely anatomically complete, even when defined clinically as being functionally or neurologically complete.
  • Uninjured pathways and spinal interneurons can play important roles in subserving spontaneous functional improvements in lieu of original pathways that fail to show long‐distance regrowth.
  • Transplantation of neural progenitors that are destined to become spinal neurons may contribute to interneuronal relays capable of transmitting functional information between separated regions of the injured spinal cord.
  • Specialised rehabilitation regimens, exercise and electrical stimulation of muscles can promote and guide plasticity that improves motor function.
  • Electrical stimulation of the injured spinal cord can evoke some voluntary movement in people who otherwise exhibit complete loss of voluntary control of movement below the spinal level of injury.
  • Optimal therapeutic approaches for spinal cord injury are unlikely to result from a single type of treatment, but rather from strategies involving two or more complementary approaches.

Keywords: neuroplasticity; locomotor training; rehabilitation; spinal cord injury; spinal cord repair; intermittent hypoxia; operant conditioning; neural stimulation

Figure 1. (a) Depicts a unilateral interruption of the corticospinal tract (CST). As shown in the inset, the potential exists for functional recovery via axonal sprouts (arrow) emerging from CST axons on the intact side of the cord that project across the midline and thereby substitute for the loss of CST inputs to spinal circuits on the lesioned side. (b and c) Sprouting (red) above or below the site of injury also may result in formation of alternative or ‘by‐pass’ propriospinal pathways in lieu of the damaged original projections. See text for additional details.
Figure 2. A schematic illustration of a spinal central pattern generator (CPG) comprising a constellation of excitatory (green) and inhibitory (red) interneurons that receive inputs from supraspinal regions (not shown) and spinal sensory neurons (brown). These interneurons project onto alpha motoneurons that innervate antagonistic (i.e. flexor and extensor) muscles in the upper and lower extremities. Excitatory interneurons may project onto other excitatory neurons leading to ultimate excitation of motoneurons. Alternatively, excitatory interneurons may stimulate interneurons that inhibit motoneuron excitability. The sum of such activities results in alternating, rhythmic movements of the limbs. In this example of a stepping phase, one leg is raised whereas the other assumes weight bearing. This entails contraction of flexors and inhibition of extensors in the raised leg reflecting excitation and inhibition of corresponding motoneurons (noted by + and − and corresponding solid and dashed lines). The opposite is seen relative to the contralateral limb. Following spinal cord injury, the physiological state of the CPG can be modulated by training and segmental sensory activity such that locomotion can be reinstated independent of supraspinal input.
Figure 3. An illustration of treadmill training post‐SCI. Training entails a treadmill, partial body weight support, and trainers to assist with trunk and limb positions. The treadmill and manual movement of the legs by physical therapists or assistive devices enable an approximation of the normal stepping pattern which in turn provides segmental sensory feedback to the spinal central pattern generator. Spinal circuitry ultimately learns to generate fundamental elements of gait independent of descending inputs from the brain. See text for additional details.
Figure 4. An electrophysiological recording of phrenic nerve activity before and 15 and 60 min following three episodes of exposure to reduced oxygen. The dashed line indicates baseline activity before intermittent hypoxia. As illustrated, phrenic long‐term facilitation (pLTF) is indicated by a persistent increase in phrenic nerve burst amplitude following exposure to brief periods of intermittent hypoxia.
Figure 5. Operant conditioning of the human H‐reflex (a, b) and its therapeutic effects (c–e). (a) A person maintains a natural standing posture and a specific level of soleus electromyographic (EMG) activity with the aid of a visual feedback screen that shows the current absolute value of soleus EMG activity in relation to a specified range. Whenever the absolute value of soleus EMG activity stays in this range for several seconds, stimulation of the tibial nerve elicits an M‐wave (a direct muscle response) just above threshold and an H‐reflex. For the first 6 sessions (i.e. baseline sessions, 3/week), the person is exposed to the control mode, in which the H‐reflex is simply measured to determine its initial size. For the next 24 sessions (i.e. conditioning sessions, 3/week), the person is exposed to the up‐ or down‐conditioning mode, in which, after each conditioning trial, the screen provides immediate feedback as to whether the H‐reflex was above (up‐conditioning) or below [down‐conditioning (shown on screen)] a criterion value. The person completes 225 conditioning trials per session. The lower insert shows the monosynaptic pathway that is largely responsible for the H‐reflex. The upper insert shows the EMG activity for a representative trial. The first deflection indicates the nerve stimulus; the second is the M‐wave; and the third is the H‐reflex. (b, right) Average peri‐stimulus EMG activity from an up‐conditioned person (top) and a down‐conditioned person (bottom) for a baseline session (i.e. control mode) (solid) and for the last up‐ or down‐conditioning session (dashed). After conditioning, H‐reflex size has changed in the correct direction, whereas background EMG activity and M‐wave size have not changed. (b, left) Shown are average (±SEM) daily H‐reflex sizes for six successful up‐conditioned people (red upward triangles) and eight successful downconditioned people (blue downward triangles) over 24 conditioning sessions and 4 follow‐up sessions over the next 3 months. Over the conditioning sessions, H‐reflex size gradually changes in the correct direction, and the change is largely preserved months later. (c–e) In people with chronic incomplete spinal cord injury that has caused spasticity and impaired locomotion, successful down‐conditioning of the soleus H‐reflex reduces spasticity and improves locomotion. (c) H‐reflex down‐conditioning produces a >50% average increase in walking speed (N = 6; *p < 0.05 by paired t‐test). (d) H‐reflex down‐conditioning restores step symmetry (i.e. reduces limping). The figure shows successive step cycles before and after down‐conditioning from a representative person. Non‐conditioned‐leg foot contacts (nFCs; solid circles) and conditioned‐leg foot contact (cFCs; open circles) are shown. The short vertical dashed lines mark the midpoints between nFCs (i.e. the midpoints of the step cycle), which are when the cFCs should occur. Before H‐reflex down‐conditioning, the cFCs occur too late (i.e. the person is limping); after successful down‐conditioning, they occur on time. (e) H‐reflex down‐conditioning eliminates clonic (i.e. spastic) EMG activity during locomotion (Thompson et al., ; Thompson and Wolpaw, 2015).
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Further Reading

Barbeau H (2003) Locomotor training in neurorehabilitation: emerging rehabilitation concepts. Neurorehabilitation and Neural Repair 17 (1): 3–11.

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Reier PJ and Lane MA (2008) Degeneration, regeneration, and neuroplasticity in the nervous system. In: Conn PM (ed) Medical Neuroscience, 3rdchap 31 edn, pp. 691–727. New York, NY: Humana Press.

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Thompson AK and Wolpaw JR (2015) Targeted neuroplasticity for rehabilitation. Progress in Brain Research 218: 157–172.

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Reier, Paul J, Howland, Dena R, Mitchell, Gordon, Wolpaw, Jonathan R, Hoh, Daniel, and Lane, Michael A(Mar 2017) Spinal Cord Injury: Repair, Plasticity and Rehabilitation. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021403.pub2]