In rodents, after spinal lesion, neutralizing the neurite growth inhibitor Nogo-A promotes axonal sprouting and functional recovery. To evaluate this treatment in primates, 12 monkeys were subjected to cervical lesion. Recovery of manual dexterity and sprouting of corticospinal axons were enhanced in monkeys treated with Nogo-A-specific antibody as compared to monkeys treated with control antibody.
After injury, regrowth of axons in mammalian adult central nervous system is highly limited. However, in monkeys subjected to unilateral cervical lesion (C7-C8 level), neutralization of an important neurite outgrowth inhibitor, Nogo-A, stimulated axonal sprouting caudal to the lesion, accompanied by enhanced functional recovery of manual dexterity, compared with lesioned monkeys treated with a control antibody (Freund et al. [2006] Nat. Med. 12:790 -792). The present study aimed at comparing the same two groups of monkeys for axonal sprouting rostral to the cervical lesion. The corticospinal tract was labeled by injecting the anterograde tracer biotinylated dextran amine into the contralesional motor cortex. The corticospinal axons were interrupted at the level of the lesion, accompanied by retrograde axonal degeneration (axon dieback), reflected by the presence of terminal retraction bulbs. The number of terminal retraction bulbs was lower in anti-Nogo-A antibody treated monkeys, and, when present, they were found closer to the lesion than in controlantibody treated monkeys. Compared with control antibody treated monkeys, the antiNogo-A antibody treated monkeys exhibited an increased cumulated axon arbor length and a higher number of axon arbors going in the medial direction from the white to the gray matter. Higher in the cervical cord (at C5 level), the anti-Nogo-A treatment enhanced the number of corticospinal fibers crossing the midline, suggesting axonal sprouting. Thus, the anti-Nogo-A antibody treatment enhanced axonal sprouting rostral to the cervical lesion; some of these fibers grew around the lesion and into the caudal spinal segments. These processes paralleled the observed improved functional recovery.
In rodents and nonhuman primates subjected to spinal cord lesion, neutralizing the neurite growth inhibitor Nogo-A has been shown to promote regenerative axonal sprouting and functional recovery. The goal of the present report was to re-examine the data on the recovery of the primate manual dexterity using refined behavioral analyses and further statistical assessments, representing secondary outcome measures from the same manual dexterity test. Thirteen adult monkeys were studied; seven received an antiNogo-A antibody whereas a control antibody was infused into the other monkeys. Monkeys were trained to perform the modified Brinkman board task requiring opposition of index finger and thumb to grasp food pellets placed in vertically and horizontally oriented slots. Two parameters were quantified before and following spinal cord injury: (i) the standard 'score' as defined by the number of pellets retrieved within 30 s from the two types of slots; (ii) the newly introduced 'contact time' as defined by the duration of digit contact with the food pellet before successful retrieval. After lesion the hand was severely impaired in all monkeys; this was followed by progressive functional recovery. Remarkably, anti-Nogo-A antibody-treated monkeys recovered faster and significantly better than control antibody-treated monkeys, considering both the score for vertical and horizontal slots (Mann-Whitney test: P = 0.05 and 0.035, respectively) and the contact time (P = 0.008 and 0.005, respectively). Detailed analysis of the lesions excluded the possibility that this conclusion may have been caused by differences in lesion properties between the two groups of monkeys.
After a sub-total hemi-section of the cervical cord at level C7/C8 in monkeys, a paralysis of the homolateral hand is rapidly followed by an incomplete recovery of manual dexterity, reaching a plateau after about 40-50 days, whose extent appears related to the size of the lesion. During a few days after the lesion, the hand representation in the contralateral motor cortex disappeared, replaced by representations of either face or more proximal body parts. Later, however, following a time course (about 40 days) consistent with the functional recovery, progressive plastic changes in the contralateral motor cortex took place, as demonstrated by a progressive re-appearance of digit movements elicited by intracortical microstimulation. These progressive plastic changes, which parallel the functional recovery, correspond to a re-installation of a hand representation, though substantially diminished in size as compared to pre-lesion. Regarding the functional recovery, the motor cortex (including the re-established hand area) contralateral to the unilateral cervical cord lesion played a crucial role in re-establishing control on finger movements, as assessed by reversible inactivation experiments. In contrast, the motor cortex ipsilateral to the cervical cord lesion, with largely intact projections to the spinal cord, did not contribute significantly to the recovered movements by the affected hand. These observations indicate that the CS fibers spared by the lesion are not sufficient, at least in their pre-lesion condition, to control the motoneurones innervating the digit muscles and that the pathways conveying signals from the contralateral M1 underwent reorganization.Theme G: Motor system and sensorimotor integration Topic: Cortex
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