Adult Long Evans rats received a photothrombotic stroke that destroyed >90% of the sensorimotor cortex unilaterally; they were subsequently treated intrathecally for 2 weeks with a function blocking antibody against the neurite growth inhibitory central nervous system protein Nogo-A. Fine motor control of skilled forelimb grasping improved to 65% of intact baseline performance in the anti-Nogo-A treated rats, whereas control antibody treated animals recovered to only 20% of baseline scores. Bilateral retrograde tract tracing with two different tracers from the intact and the denervated side of the cervical spinal cord, at different time points post-lesion, indicated that the intact corticospinal tract had extensively sprouted across the midline into the denervated spinal hemicord. The original axonal arbours of corticospinal tract fibres that had recrossed the midline were subsequently withdrawn, leading to a complete side-switch in the projection of a subpopulation of contralesional corticospinal tract axons. Anterograde tracing from the contralesional cortex showed a 2-3-fold increase of midline crossing fibres and additionally a massive sprouting of the pre-existing ipsilateral ventral corticospinal tract fibres throughout the entire cervical enlargement of the anti-Nogo-A antibody-treated rats compared to the control group. The laminar distribution pattern of the ipsilaterally projecting corticospinal tract fibres was similar to that in the intact spinal cord. These plastic changes were paralleled by a somatotopic reorganization of the contralesional motor cortex where the formation of an ipsilaterally projecting forelimb area was observed. Intracortical microstimulation of the contralesional motor cortex revealed that low threshold currents evoked ipsilateral movements and electromyography responses at frequent cortical sites in the anti-Nogo-A, but not in the control antibody-treated animals. Subsequent transection of the spared corticospinal tract in chronically recovered animals, treated with anti-Nogo-A, led to a reappearance of the initial lesion deficit observed after the stroke lesion. These results demonstrate a somatotopic side switch anatomically and functionally in the projection of adult corticospinal neurons, induced by the destruction of one sensorimotor cortex and the neutralization of the CNS growth inhibitory protein Nogo-A.
In severe spinal cord injuries, the tracts conveying motor commands to the spinal cord are disrupted, resulting in paralysis, but many patients still have small numbers of spared fibers. We have found that excitatory deep brain stimulation (DBS) of the mesencephalic locomotor region (MLR), an important control center for locomotion in the brain, markedly improved hindlimb function in rats with chronic, severe, but incomplete spinal cord injury. The medial medullary reticular formation was essential for this effect. Functional deficits of rats with 20 to 30% spared reticulospinal fibers were comparable to patients able to walk but with strong deficits in strength and speed [for example, individuals with American Spinal Injury Association Impairment Scale (AIS)-D scores]. MLR DBS enabled close to normal locomotion in these rats. In more extensively injured animals, with less than 10% spared reticulospinal fibers, hindlimbs were almost fully paralyzed, comparable to wheelchair-bound patients (for example, AIS-A, B, and C). With MLR DBS, hindlimb function reappeared under gravity-released conditions during swimming. We propose that therapeutic MLR DBS using the brain's own motor command circuits may offer a potential new approach to treat persistent gait disturbances in patients suffering from chronic incomplete spinal cord injury.
Whereas large injuries to the brain lead to considerable irreversible functional impairments, smaller strokes or traumatic lesions are often associated with good recovery. This recovery occurs spontaneously, and there is ample evidence from preclinical studies to suggest that adjacent undamaged areas (also known as peri-infarct regions) of the cortex 'take over' control of the disrupted functions. In rodents, sprouting of axons and dendrites has been observed in this region following stroke, while reduced inhibition from horizontal or callosal connections, or plastic changes in subcortical connections, could also occur. The exact mechanisms underlying functional recovery after small- to medium-sized strokes remain undetermined but are of utmost importance for understanding the human situation and for designing effective treatments and rehabilitation strategies. In the present study, we selectively destroyed large parts of the forelimb motor and premotor cortex of adult rats with an ischaemic injury. A behavioural test requiring highly skilled, cortically controlled forelimb movements showed that some animals recovered well from this lesion whereas others did not. To investigate the reasons behind these differences, we used anterograde and retrograde tracing techniques and intracortical microstimulation. Retrograde tracing from the cervical spinal cord showed a correlation between the number of cervically projecting corticospinal neurons present in the hindlimb sensory-motor cortex and good behavioural recovery. Anterograde tracing from the hindlimb sensory-motor cortex also showed a positive correlation between the degree of functional recovery and the sprouting of neurons from this region into the cervical spinal cord. Finally, intracortical microstimulation confirmed the positive correlation between rewiring of the hindlimb sensory-motor cortex and the degree of forelimb motor recovery. In conclusion, these experiments suggest that following stroke to the forelimb motor cortex, cells in the hindlimb sensory-motor area reorganize and become functionally connected to the cervical spinal cord. These new connections, probably in collaboration with surviving forelimb neurons and more complex indirect connections via the brainstem, play an important role for the recovery of cortically controlled behaviours like skilled forelimb reaching.
After a stroke to the motor cortex, sprouting of spared contralateral corticospinal fibers into the affected hemicord is one mechanism thought to mediate functional recovery. Little is known, however, about the role of the phylogenetically old, functionally very important brainstem-spinal systems. Adult mice were subjected to a unilateral photothrombotic stroke of the right motor cortex ablating 90% of the cross-projecting corticospinal cells. Unilateral retrograde tracing from the left cervical spinal hemicord devoid of its corticospinal input revealed widespread plastic responses in different brainstem nuclei 4 weeks after stroke. Whereas some nuclei showed no change or a decrease of their spinal projections, several parts of the medullary reticular formation as well as the spinally projecting raphe nuclei increased their projections to the cortically denervated cervical hemicord by 1.2-to 1.6-fold. The terminal density of corticobulbar fibers from the intact, contralesional cortex, which itself formed a fivefold expanded connection to the ipsilateral spinal cord, increased up to 1.6-fold specifically in these plastic, caudal medullary nuclei. A second stroke, ablating the originally spared motor cortex, resulted in the reappearance of the deficits that had partially recovered after the initial right-sided stroke, suggesting dependence of recovered function on the spared cortical hemisphere and its direct corticospinal and indirect corticobulbospinal connections.
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