Retraining the injured spinal cord

Abstract

The present review presents a series of concepts that may be useful in developing rehabilitative strategies to enhance recovery of posture and locomotion following spinal cord injury. First, the loss of supraspinal input results in a marked change in the functional efficacy of the remaining synapses and neurons of intraspinal and peripheral afferent (dorsal root ganglion) origin. Second, following a complete transection the lumbrosacral spinal cord can recover greater levels of motor performance if it has been exposed to the afferent and intraspinal activation patterns that are associated with standing and stepping. Third, the spinal cord can more readily reacquire the ability to stand and step following spinal cord transection with repetitive exposure to standing and stepping. Fourth, robotic assistive devices can be used to guide the kinematics of the limbs and thus expose the spinal cord to the new normal activity patterns associated with a particular motor task following spinal cord injury. In addition, such robotic assistive devices can provide immediate quantification of the limb kinematics. Fifth, the behavioural and physiological effects of spinal cord transection are reflected in adaptations in most, if not all, neurotransmitter systems in the lumbosacral spinal cord. Evidence is presented that both the GABAergic and glycinergic inhibitory systems are up-regulated following complete spinal cord transection and that step training results in some aspects of these transmitter systems being down-regulated towards control levels. These concepts and observations demonstrate that (a) the spinal cord can interpret complex afferent information and generate the appropriate motor task; and (b) motor ability can be defined to a large degree by training.

Figure 1. Illustration of the concept of a ‘new spinal cord’ following SCI

In the upper portion of the figure synapses from all sources are illustrated as being supraspinal, intraspinal or peripheral (proprioceptive) afferents. The lower portion of the figure illustrates the fact that following SCI all synapses from supraspinal input will be eliminated (or partially eliminated in incomplete spinal injuries). As a result of the retraction of synapses of a supraspinal origin the remaining synapses would have a novel effect because of the differences in their relative efficacy, i.e. the remaining synapses no longer share their impact with synapses derived from supraspinal neurones. In addition, there is evidence for significant synaptic reorganization at the remaining synapses (Nacimiento et al. 1995) as illustrated by the enlarged synapses in the lower portion of the figure. This synaptic reorganization, however, could involve a proliferation of synapses to these neurones as well as an enlargement of the existing synapses.

Figure 2. Elevated GAD₆₇ after SCI

Photomicrographs of lumbar spinal cord transverse sections (30 μm thick) from control (A) and spinal transected (B, 6 months after a complete low-thoracic spinal cord transection) cats immunostained with K2 antibody (glutamic acid decarboxylase, GAD₆₇ specific). Compared to control cats, GAD₆₇ immunoreactivity is higher in the lumbar cords of transected than control cats. The largest increases after transection are in laminae II-III, lamina X, and the medial areas of laminae V, VI and VII (C). Scale bar in B is 200 μm and refers to all panels. (Adapted from Tillakaratne et al. 2000b.)

Figure 3. Normalization of swing phase kinematics in the presence of perturbations

A, application of vertical force fields on the hindlimb during one step cycle in a complete spinal rat. Robot arms were attached to the shank of the hindlimb during bipedal hindlimb stepping. The robot arms apply an upward force on the shank when the hindlimb moves forward during the swing phase of the step cycle. The magnitude of the force (arrows) is proportional to the horizontal velocity of the hindlimb. B, adaptations to the vertical force fields occur during stepping. In each trial (1-5), spinal rats were repeatedly exposed to the force field for 25 steps, followed by 25 steps without the force field. Swing duration (time from toe off (TO) to paw contact (PC)) and hindlimb coordination (interlimb TO-PC interval) were analysed and the data from 25 steps were averaged. Values are means ±s.e.m. for each trial (25 steps) from one spinal rat stepping at a treadmill speed of 11 cm s⁻¹. (Authors' unpublished observations.)

Figure 4. Loading effects on levels of activation of motor pools during stepping

Relationships between soleus EMG mean amplitude (μV) and limb peak load (N) from a non-disabled subject (A, ND-1) and a subject with a SCI classified on the ASIA scale as an A, i.e. having a complete injury (B, SCI-A1), over a range of loading conditions. Each data point represents one step and each symbol represents a series of consecutive steps at one level of body-weight support. (Adapted from Harkema et al. 1997.)

Figure 5. Unilateral stand training results in asymmetric GAD₆₇ staining patterns

A cross-section of the lumbar spinal cord stained at rostral L6 segment for GAD₆₇ taken from an adult spinal transected cat trained to stand unilaterally for 12 weeks starting 1 week after transection. There was a greater prominence of punctate staining for GAD₆₇ on the trained (B and D) compared to the untrained (A and C) side. This unilateral staining pattern was observed in sections followed caudally for about 3 mm. This was particularly evident around motoneurones in layer IX and in a rostrocaudal region corresponding to motor pools innervating knee flexors. Arrows indicate intense punctate staining on the cell body. Scale bars: A and B, 100 μm; C and D, 25 μm. (Authors' unpublished observations.)

Figure 6. Step training of spinal rats normalizes glycine receptor concentration

A, mean step lengths of control, spinal cord transected (Sp) and step trained Sp (Sp-Tr) rats. Sp and Sp-Tr rats were spinal cord transected at 7 days of age. Sp-Tr rats were trained to step on a motorized treadmill at 0.09 m s⁻¹ for 15 min per day, 5 days per week for 12 weeks. n = 4 per group. B, mean amounts of gephyrin and the α1 subunit of the glycine receptor in the lumbar spinal cord of Sp and Sp-Tr rats. These data are normalized to total spinal cord protein and expressed as a percentage of control based on densitometer units from Western blots using monoclonal antibody 7A (Roche Biochemicals). * Significantly different from control; † significantly different from Sp at P ≤ 0.05 according to a one-way analysis of variance and Fisher's least significant difference test. (Authors' unpublished observations.)

Figure 7. Relationship between glycine receptor concentration and step length

The relationship between the amount (expressed as a percentage of control) of the α1 subunit of the glycine receptor and step length in control, spinal (Sp) and Sp trained (Sp-Tr) rats is shown. Note that although the step training reduced the α1 subunit of the glycine receptor to control levels, the step length was significantly different from Control and Sp rats (see Fig. 6 for relevant statistics). (Authors' unpublished observations.)