A novel paraplegia model in awake behaving macaques

Abstract

Lower limb paralysis from spinal cord injury (SCI) or neurological disease carries a poor prognosis for recovery and remains a large societal burden. Neurophysiological and neuroprosthetic research have the potential to improve quality of life for these patients; however, the lack of an ethical and sustainable nonhuman primate model for paraplegia hinders their advancement. Therefore, our multidisciplinary team developed a way to induce temporary paralysis in awake behaving macaques by creating a fully implantable lumbar epidural catheter-subcutaneous port system that enables easy and reliable targeted drug delivery for sensorimotor blockade. During treadmill walking, aliquots of 1.5% lidocaine with 1:200,000 epinephrine were percutaneously injected into the ports of three rhesus macaques while surface electromyography (EMG) recorded muscle activity from their quadriceps and gastrocnemii. Diminution of EMG amplitude, loss of voluntary leg movement, and inability to bear weight were achieved for 60-90 min in each animal, followed by a complete recovery of function. The monkeys remained alert and cooperative during the paralysis trials and continued to take food rewards, and the ports remained functional after several months. This technique will enable recording from the cortex and/or spinal cord in awake behaving nonhuman primates during the onset, maintenance, and resolution of paraplegia for the first time, thus opening the door to answering basic neurophysiological questions about the acute neurological response to spinal cord injury and recovery. It will also negate the need to permanently injure otherwise high-value research animals for certain experimental paradigms aimed at developing and testing neural interface decoding algorithms for patients with lower extremity dysfunction. A novel implantable lumbar epidural catheter-subcutaneous port system enables targeted drug delivery and induction of temporary paraplegia in awake, behaving nonhuman primates. Three macaques displayed loss of voluntary leg movement for 60-90 min after injection of lidocaine with epinephrine, followed by a full recovery. This technique for the first time will enable ethical live recording from the proximal central nervous system during the acute onset, maintenance, and resolution of paraplegia.

Treadmill Training for Common Marmoset to Strengthen Corticospinal Connections After Thoracic Contusion Spinal Cord Injury

“…Furthermore, a few contusive SCI studies have been carried out in large primates because they are difficult to handle, labor-intensive, and require indispensable skilled daily care (Babu and Namasivayam, 2008). In addition, weight-supported treadmill rehabilitation requires an extremely hard step of putting a weight support jacket on monkeys and some other special rehabilitative setups (Krucoff et al, 2017). On the other hand, small marmosets are easy to handle, care for, and rehabilitate (Okano, 2021).…”

Neuromodulation in the restoration of function after spinal cord injury

“…For example, a comparison of epidural, subdural and intraspinal stimulation at dorsal and ventral locations on, or in, the cervical spinal cord of rhesus monkeys revealed that differences in selectivity and in the direct or indirect activation of motor neurons could be advantageous in different situations (eg, when facilitating endogenous movements versus directly activating muscle groups), and that this should be taken into account when designing neuroprostheses 32 . A newly developed primate model of paraplegia that can elicit temporary lower extremity paralysis may also be useful for neural interface development and optimisation of stimulating and recording parameters 33 . In rodent SCI models, kinematic feedback and multi-electrode epidural arrays have allowed real-time spatiotemporal neuromodulation of flexor and extensor activity during hindlimb stepping 23 , robotic interfaces have been combined with epidural and pharmacological stimulation of the spinal cord to restore hindlimb stepping 34 , and activity-based feedback has been used to trigger synchronised intraspinal microstimulation for improving forelimb function 35 .…”

Generating Artificial Sensations with Spinal Cord Stimulation in Primates and Rodents

“…A trocar was then introduced through the fascia just lateral to midline between the spinous processes and advanced so the tip just entered the epidural space. Epidural location was confirmed using a loss of resistance technique, fluoroscopic x-ray, and lack of cerebrospinal fluid (CSF) (34). Next, an 8-contact cylindrical percutaneous lead was introduced through the trocar and steered through dorsal epidural space to a target location in the mid-thoracic spine, or approximately across T8 (Supplementary Figure 1b).…”