Pronounced species divergence in corticospinal tract reorganization and functional recovery after lateralized spinal cord injury favors primates

Abstract

Experimental and clinical studies suggest that primate species exhibit greater recovery after lateralized compared to symmetrical spinal cord injuries. Although this observation has major implications for designing clinical trials and translational therapies, advantages in recovery of nonhuman primates over other species has not been shown statistically to date, nor have the associated repair mechanisms been identified. We monitored recovery in more than 400 quadriplegic patients and found that that functional gains increased with the laterality of spinal cord damage. Electrophysiological analyses suggested that corticospinal tract reorganization contributes to the greater recovery after lateralized compared with symmetrical injuries. To investigate underlying mechanisms, we modeled lateralized injuries in rats and monkeys using a lateral hemisection, and compared anatomical and functional outcomes with patients who suffered similar lesions. Standardized assessments revealed that monkeys and humans showed greater recovery of locomotion and hand function than rats. Recovery correlated with the formation of corticospinal detour circuits below the injury, which were extensive in monkeys, but nearly absent in rats. Our results uncover pronounced inter-species differences in the nature and extent of spinal cord repair mechanisms, likely resulting from fundamental differences in the anatomical and functional characteristics of the motor systems in primates versus rodents. Although rodents remain essential for advancing regenerative therapies, the unique response of the primate corticospinal tract after injury re-emphasizes the importance of primate models for designing clinically relevant treatments.

Contribution of propriospinal neurons to recovery of hand dexterity after corticospinal tract lesions in monkeys

“…These studies suggested a relationship of PNs to recovery, but such lesion might affect other group of neurons besides PNs, and demonstration of causal contribution of PNs was still indirect. Furthermore, because there are considerable differences in neural structures and body apparatus related to hand movements between rodents and primates (12,36,37), studies in nonhuman primates are critical for translating therapeutic strategies to treat spinal cord injury in humans (38,39). Therefore, direct evidence to show the causal contribution of PNs to recovery in nonhuman primates was needed.…”

Rat models of spinal cord injury: from pathology to potential therapies

“…Spinal cord injury affects millions of people worldwide and typically has life-long consequences (Friedli et al, 2015). In the United States alone, ∼30 individuals sustain a spinal cord injury every day (Gomes-Osman et al, 2016), typically caused by motor vehicle accidents (38%), falls (>22%), violence (13.5%), and sports and recreational accidents (9%).…”

Intrinsic Axonal Growth and the Drive for Regeneration

“…Recent work (Friedli et al, 2015) highlights the utility and relevance of non-human primate clinical spinal cord injury models. Interestingly, these studies revealed significant interspecies differences in the mechanisms of corticospinal tract regeneration during motor recovery when comparing rodents to primates and humans.…”