Restoration of Direct Corticospinal Communication Across Sites of Spinal Injury

2019 ◽  
Author(s):  
Naveen Jayaprakash ◽  
David Nowak ◽  
Erik Eastwood ◽  
Nicholas Krueger ◽  
Zimei Wang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Motor Control ◽  
Neural Progenitor Cells ◽  
Corticospinal Tract ◽  
Spinal Injury ◽  
Combined Treatment ◽  
Fine Motor ◽  
Spinal Neurons ◽  
Injury Site ◽  
A Site

Injury to the spinal cord often disrupts long-distance axon tracts that link the brain and spinal cord, causing permanent disability. Axon regeneration is then prevented by a combination of inhibitory signals that emerge at the injury site and by a low capacity for regeneration within injured neurons. The corticospinal tract (CST) is essential for fine motor control but has proven refractory to many attempted pro-regenerative treatments. Although strategies are emerging to create relay or detour circuits that re-route cortical motor commands through spared circuits, these have only partially met the challenge of restoring motor control. Here, using a murine model of spinal injury, we elevated the intrinsic regenerative ability of CST neurons by supplying a pro-regenerative transcription factor, KLF6, while simultaneously supplying injured CST axons with a growth-permissive graft of neural progenitor cells (NPCs) transplanted into a site of spinal injury. The combined treatment produced robust CST regeneration directly through the grafts and into distal spinal cord. Moreover, selective optogenetic stimulation of regenerated CST axons and single-unit electrophysiology revealed extensive synaptic integration by CST axons with spinal neurons beyond the injury site. Finally, when KLF6 was delivered to injured neurons with a highly effective retrograde vector, combined KLF6/NPC treatment yielded significant improvements in forelimb function. These findings highlight the utility of retrograde gene therapy as a strategy to treat CNS injury and establish conditions that restore functional CST communication across a site of spinal injury.Significance StatementDamage to the spinal cord results in incurable paralysis because axons that carry descending motor commands are unable to regenerate. Here we deployed a two-pronged strategy in a rodent model of spinal injury to promote regeneration by the corticospinal tract, a critical mediator of fine motor control. Delivering pro-regenerative KLF6 to injured neurons while simultaneously transplanting neural progenitor cells to injury sites resulted in robust regeneration directly through sites of spinal injury, accompanied by extensive synapse formation with spinal neurons. In addition, when KLF6 was delivered with improved retrograde gene therapy vectors, the combined treatment significantly improved forelimb function in injured animals. This work represents important progress toward restoring regeneration and motor function after spinal injury.

scholarly journals Cervical Epidural Electrical Stimulation Restores Voluntary Arm Control In Paralyzed Monkeys

2020 ◽  
Author(s):  
Marco Capogrosso ◽  
Beatrice Barra ◽  
Sara Conti ◽  
Matthew Perich ◽  
Katie Zhuang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Electrical Stimulation ◽  
Motor Control ◽  
Spinal Injury ◽  
Cervical Spinal Cord ◽  
Three Dimensional ◽  
Sensory Afferents ◽  
Reach And Grasp ◽  
Cervical Spinal Injury ◽  
Stimulation Of

Abstract Regaining arm motor control is critical for people with paralysis. Despite promising results on grasping, no technology could restore effective arm control. Here, we show that electrical stimulation of the cervical spinal cord enabled three monkeys with cervical spinal injury to execute functional arm movements. We designed an epidural interface that engaged surviving spinal circuits via the recruitment of large sensory afferents to produce movement. Simple stimulation bursts produced sustained joint movements which, triggered by movement-related intracortical signals, enabled monkeys with arm paralysis to perform an unconstrained, three-dimensional reach and grasp task. This restoration of voluntary motor control was enabled by the synergistic integration of spared descending commands and electrical stimulation within the spinal cord. The simplicity of this technology promises realistic clinical translation.

scholarly journals Genetically identified spinal interneurons integrating tactile afferents for motor control

2015 ◽  
Vol 114 (6) ◽  
pp. 3050-3063 ◽  
Author(s):  
Tuan V. Bui ◽  
Nicolas Stifani ◽  
Izabela Panek ◽  
Carl Farah
Keyword(s):  
Spinal Cord ◽  
Motor Control ◽  
Sensory Information ◽  
Spinal Neuron ◽  
Spinal Neurons ◽  
Tactile Information ◽  
Spinal Interneurons ◽  
Motor Circuits ◽  
Neuron Populations ◽  
Genetic Techniques

Our movements are shaped by our perception of the world as communicated by our senses. Perception of sensory information has been largely attributed to cortical activity. However, a prior level of sensory processing occurs in the spinal cord. Indeed, sensory inputs directly project to many spinal circuits, some of which communicate with motor circuits within the spinal cord. Therefore, the processing of sensory information for the purpose of ensuring proper movements is distributed between spinal and supraspinal circuits. The mechanisms underlying the integration of sensory information for motor control at the level of the spinal cord have yet to be fully described. Recent research has led to the characterization of spinal neuron populations that share common molecular identities. Identification of molecular markers that define specific populations of spinal neurons is a prerequisite to the application of genetic techniques devised to both delineate the function of these spinal neurons and their connectivity. This strategy has been used in the study of spinal neurons that receive tactile inputs from sensory neurons innervating the skin. As a result, the circuits that include these spinal neurons have been revealed to play important roles in specific aspects of motor function. We describe these genetically identified spinal neurons that integrate tactile information and the contribution of these studies to our understanding of how tactile information shapes motor output. Furthermore, we describe future opportunities that these circuits present for shedding light on the neural mechanisms of tactile processing.

scholarly journals Combined treatment with enteric neural stem cells and chondroitinase ABC reduces spinal cord lesion pathology

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Benjamin Jevans ◽  
Nicholas D. James ◽  
Emily Burnside ◽  
Conor J. McCann ◽  
Nikhil Thapar ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Stem Cells ◽  
Gastrointestinal Tract ◽  
Neural Stem Cells ◽  
Combined Treatment ◽  
Axon Growth ◽  
Chondroitinase Abc ◽  
Simultaneous Application ◽  
Injury Site ◽  
Cord Injury

Abstract Background Spinal cord injury (SCI) presents a significant challenge for the field of neurotherapeutics. Stem cells have shown promise in replenishing the cells lost to the injury process, but the release of axon growth-inhibitory molecules such as chondroitin sulfate proteoglycans (CSPGs) by activated cells within the injury site hinders the integration of transplanted cells. We hypothesised that simultaneous application of enteric neural stem cells (ENSCs) isolated from the gastrointestinal tract, with a lentivirus (LV) containing the enzyme chondroitinase ABC (ChABC), would enhance the regenerative potential of ENSCs after transplantation into the injured spinal cord. Methods ENSCs were harvested from the GI tract of p7 rats, expanded in vitro and characterised. Adult rats bearing a contusion injury were randomly assigned to one of four groups: no treatment, LV-ChABC injection only, ENSC transplantation only or ENSC transplantation+LV-ChABC injection. After 16 weeks, rats were sacrificed and the harvested spinal cords examined for evidence of repair. Results ENSC cultures contained a variety of neuronal subtypes suitable for replenishing cells lost through SCI. Following injury, transplanted ENSC-derived cells survived and ChABC successfully degraded CSPGs. We observed significant reductions in the injured tissue and cavity area, with the greatest improvements seen in the combined treatment group. ENSC-derived cells extended projections across the injury site into both the rostral and caudal host spinal cord, and ENSC transplantation significantly increased the number of cells extending axons across the injury site. Furthermore, the combined treatment resulted in a modest, but significant functional improvement by week 16, and we found no evidence of the spread of transplanted cells to ectopic locations or formation of tumours. Conclusions Regenerative effects of a combined treatment with ENSCs and ChABC surpassed either treatment alone, highlighting the importance of further research into combinatorial therapies for SCI. Our work provides evidence that stem cells taken from the adult gastrointestinal tract, an easily accessible source for autologous transplantation, could be strongly considered for the repair of central nervous system disorders.

scholarly journals Comparison of Olfactory Bulbar and Mucosal Cultures in a Rat Rhizotomy Model

2014 ◽  
Vol 23 (11) ◽  
pp. 1465-1470 ◽  
Author(s):  
Ahmed Ibrahim ◽  
Daqing Li ◽  
Andrew Collins ◽  
Pawel Tabakow ◽  
Geoffrey Raisman ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Corticospinal Tract ◽  
Spinal Cord Injuries ◽  
Injured Patient ◽  
Laboratory Studies ◽  
Injury Site ◽  
Functional Benefit ◽  
Cell Transplants ◽  
Severed Axons ◽  
Cells Cultured

In an ongoing clinical trial, a spinal injured patient who received a transplant of autologous cells cultured from the olfactory bulb is showing greater functional benefit than three previous patients with transplants of mucosal origin. Previous laboratory studies of transplantation into rat spinal cord injuries show that the superior reparative benefits of bulbar over mucosal cultures are associated with regeneration of severed corticospinal tract fibers over a bridge of olfactory ensheathing cells (OECs) formed across the injury site. In a rat rhizotomy paradigm, we reported that transplantation of bulbar cell cultures also enables severed axons of the C6–T1 dorsal roots to regenerate across a bridge of OECs into the spinal cord and restore electrophysiological transmission and forepaw grasping during a climbing test. We now report a repeat of the same rhizotomy procedure in 25 rats receiving cells cultured from olfactory mucosal biopsies. In no case did the transplanted cells form a bridging pathway. No axons crossed from the severed roots to the spinal cord, and there was no restoration of forepaw grasping. This suggests that the superior clinical benefit in the patient receiving bulbar cell transplants is due to regeneration of severed fibers across the injury site, and this correlates with imaging and the pattern of functional recovery. Using present culture protocols, the yield of OECs from bulbar biopsies is around 50%, but that from mucosal biopsies is less than 5%. Improving the yield of OECs from mucosal biopsies might avoid the necessity for the intracranial approach to obtain bulbar cells.

UPAYA PENINGKATAN KEMAMPUAN MOTORIK KASAR ANAK DOWN SYNDROME DENGAN OLAHRAGA BOLA KAKI DI GOLDEN KIDS

2019 ◽  
Vol 1 (2) ◽  
pp. 139-151
Author(s):  
Sinto Robindo ◽  
Melda Rumia Rosmeri Simorangkir
Keyword(s):  
Spinal Cord ◽  
Down Syndrome ◽  
Cognitive Abilities ◽  
Body Movement ◽  
Movement Control ◽  
Fine Motor ◽  
Educational Goals ◽  
Motor Movement ◽  
Brain And Spinal Cord ◽  
Syndrome Child

ABSTRACT All aspects of development are very important in a person's life where the development of cognition, affection and psychomotor is well developed in accordance with its development, these three aspects can be said to be good and successful if the three aspects develop well. Like wise with the psychomotor aspect where between gross motor and fine motor are also balanced. Motoric is the development of coordinated body movement control between nerves, brain, and spinal cord (spinal cord or spinal cord). Child's gross motorization can be optimized by improving his motor movement coordination skills through physical activity in the form of coordination of body movements. Like throwing, catching, kicking, running, melopat, and maintaining balance. The condition of a Down Syndrome child who experiences weakness in the ability to think will affect in all aspects of his life. Down syndrome children have problems in cognitive abilities, effective and self-care abilities. This results in them needing special education. Basically, the educational goals that children with Down Syndrome want to achieve are not different from those of education in general. Because Down Syndrome children themselves are born in the midst of society. Keywords: football sports, gross motoric, down syndrome

Rehabilitation of the canine patient following spinal cord injury: a practical guide

2021 ◽  
Vol 26 (1) ◽  
pp. 1-6
Author(s):  
Cheryl Corral
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Spinal Injury ◽  
Neurological Deficits ◽  
Practical Guide ◽  
Cord Injury ◽  
Physical Therapies

This article forms part of a series exploring the rehabilitation of the canine shoulder, elbow, back, hip and stifle following injury or disease. Discussed here are different rehabilitation techniques used to address neurological deficits, pain and weakness following spinal injury, including physical therapies, electrotherapies and acupuncture.

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