Evidence for a role of the reticulospinal system in recovery of skilled reaching after cortical stroke: initial results from a model of ischemic cortical injury

Abstract

The purposes of this pilot study were to create a model of focal cortical ischemia in Macaca fascicularis and to explore contributions of the reticulospinal system in recovery of reaching. Endothelin-1 was used to create a focal lesion in the shoulder/elbow representation of left primary motor cortex (M1) of two adult female macaques. Repetitive microstimulation was used to map upper limb motor outputs from right and left cortical motor areas and from the pontomedullary reticular formation (PMRF). In subject 1 with a small lesion and spontaneous recovery, reaching was mildly impaired. Changes were evident in the shoulder/elbow representations of both the lesioned and contralesional M1, and there appeared to be fewer than expected upper limb responses from the left (ipsilesional) PMRF. In subject 2 with a substantial lesion, reaching was severely impaired immediately after the lesion. After 12 weeks of intensive rehabilitative training, reach performance recovered to near-baseline levels, but movement times remained about 50% slower. Surprisingly, the shoulder/elbow representation in the lesioned M1 remained completely absent after recovery, and there was a little change in the contralesional M1. There was a definite difference in motor output patterns for left versus right PMRF for this subject, with an increase in right arm responses from right PMRF and a paucity of left arm responses from left PMRF. The results are consistent with increased reliance on PMRF motor outputs for recovery of voluntary upper limb motor control after significant cortical ischemic injury.

Preclinical and Clinical Evidence on Ipsilateral Corticospinal Projections: Implication for Motor Recovery

“…First, HRP may bleed into un-intended spinal segments after injection resulting in false positive findings. Additionally, the use of WGA-HRP, a trans-synaptic tracer, does not eliminate the possibility that the origin of ipsilateral labeling is subcortical nuclei rather than an iCST or that ipsilateral projections are “re-crossed” branching collaterals of initially crossed fibers [2, 9]. Another major concern in animal studies is that the separation of sensory and cortical motor components is difficult to establish [32].…”

“…Supporting these findings, unilateral lesions proximal to the CST decussation failed to induce deficit at the ipsilateral limb, and iCST fibers failed to rescue limb function after contralateral pyramidal lesions [49]. Simultaneously, electrical stimulation of affected hemisphere after stroke in rodent model demonstrated improved recovery of skilled functions through promoting axonal sprouting at the subcortical (red nucleus) and spinal levels [9, 50]. However, controversial findings still suggest a role of iCST in recovery from injury.…”

“…Stimulation of intact motor cortex in children with CP resulted in bilateral contraction of hand muscles with high synchrony on cross-correlograms that sometimes manifested as mirror movements, suggesting that the two muscles may have received the same presynaptic inputs [72, 73]. Based on studies in cats and monkeys [8, 74], this could potentially be explained by the maintenance of dense bilateral CST projections that are otherwise retracted during development, or by bilateral cortical projections into brainstem nuclei [9, 12, 56, 75]. …”

“…In fact, unilateral lesions of the CST are associated with significant motor recovery which may suggest the existence or emergence of iCST projections in mammalian models [1–4] and human patients [6, 7]. However, this concept is challenged by evidence implicating subcortical brainstem descending pathways in the restoration of function after CST lesion especially in the event of bilateral pyramidotomy in monkeys [8, 9]. A potential role of iCST in recovery from injury would provide a rationale for targeting these fibers to modulate the recovery process.…”

Spasticity, Motor Recovery, and Neural Plasticity after Stroke

“…In particular, reticulospinal (RS) hyperexcitability resulted from loss of balanced inhibitory, and excitatory descending RS projections after stroke is the most plausible mechanism for poststroke spasticity (19). On the other hand, animal studies have strongly supported the possible role of RS pathways in motor recovery (20–36), while recent studies with stroke survivors have demonstrated that RS pathways may not always be beneficial (37, 38). The relation between spasticity and motor recovery and the role of plastic changes after stroke in this relation, particularly RS hyperexcitability, remain poorly understood among clinicians and researchers.…”