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Objective. Spinal cord injury (SCI) leads to debilitating sensorimotor deficits that greatly limit quality of life. This work aims to develop a mechanistic understanding of how to best promote functional recovery following SCI. Electrical spinal stimulation is one promising approach that is effective in both animal models and humans with SCI. Optogenetic stimulation is an alternative method of stimulating the spinal cord that allows for cell-type-specific stimulation. The present work investigates the effects of preferentially stimulating neurons within the spinal cord and not glial cells, termed 'neuron-specific' optogenetic spinal stimulation. We examined forelimb recovery, axonal growth, and vasculature after optogenetic or sham stimulation in rats with cervical SCI. Approach. Adult female rats received a moderate cervical hemicontusion followed by the injection of a neuron-specific optogenetic viral vector ipsilateral and caudal to the lesion site. Animals then began rehabilitation on the skilled forelimb reaching task. At four weeks post-injury, rats received a micro-light emitting diode (µLED) implant to optogenetically stimulate the caudal spinal cord. Stimulation began at six weeks post-injury and occurred in conjunction with activities to promote use of the forelimbs. Following six weeks of stimulation, rats were perfused, and tissue stained for GAP-43, laminin, Nissl bodies and myelin. Location of viral transduction and transduced cell types were also assessed. Main Results. Our results demonstrate that neuron-specific optogenetic spinal stimulation significantly enhances recovery of skilled forelimb reaching. We also found significantly more GAP-43 and laminin labeling in the optogenetically stimulated groups indicating stimulation promotes axonal growth and angiogenesis. Significance. These findings indicate that optogenetic stimulation is a robust neuromodulator that could enable future therapies and investigations into the role of specific cell types, pathways, and neuronal populations in supporting recovery after SCI., (Creative Commons Attribution license.)

Spinal cord injuries lead to permanent physical impairment despite most often being anatomically incomplete disruptions of the spinal cord. Remaining connections between the brain and spinal cord create the potential for inducing neural plasticity to improve sensorimotor function, even many years after injury. This narrative review provides an overview of the current evidence for spontaneous motor recovery, activity-dependent plasticity, and interventions for restoring motor control to residual brain and spinal cord networks via spinal cord stimulation. In addition to open-loop spinal cord stimulation to promote long-term neuroplasticity, we also review a more targeted approach: closed-loop stimulation. Lastly, we review mechanisms of spinal cord neuromodulation to promote sensorimotor recovery, with the goal of advancing the field of rehabilitation for physical impairments following spinal cord injury., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Although there is currently no cure for paralysis due to spinal cord injury (SCI), the highest treatment priority is restoring arm and hand function for people with cervical SCI. Preclinical animal models provide an opportunity to test innovative treatments, but severe cervical injury models require significant time and effort to assess responses to novel interventions. Moreover, there is no behavioral task that can assess forelimb movement in rats with severe cervical SCI unable to perform antigravity movements., New Method: We developed a novel lever pressing task for rats with severe cervical SCI. We employed an automated adaptive algorithm to train animals using open-source software and commercially available hardware. We found that using the adaptive training required only 13.3 ± 2.5 training days to achieve behavioral proficiency. The lever press task could quantify immediate and long-term improvements in severely impaired forelimb function effectively. This behavior platform has potential to facilitate rehabilitative training and assess effects of therapeutic modalities following SCI., Comparison With Existing Methods: There is no existing assessment aiming to quantify forelimb extension movement in rodents without function against gravity. We found that the new lever press task in the antigravity position could assess the severity of cervical SCI as well as the compensatory movement in the proximal forelimb less affected by the injury., Conclusions: This study demonstrates that the new behavioral task is capable of tracking the functional changes with various therapies in rats with severe forelimb impairments in a cost- and time-efficient manner., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Transfer of information across a spinal lesion is required for many aspects of recovery across diverse motor systems. Our understanding of axonal plasticity and which subpopulations of neurons may contribute to bridging substrates following injury, however, remains relatively incomplete. Most recently, attention has been directed to propriospinal neurons (PSNs), with research suggesting that they are capable of bridging a spinal lesion in rodents. In the current study, subpopulations of both long (C5) and short (T6, T8) PSNs-as well as a supraspinal system, the rubrospinal tract (RST)-were assessed following low thoracic (T9) hemisection in the cat using the retrograde tracer Fluoro-Gold. Acutely, within 2 weeks post-hemisection, the numbers of short and long PSNs, as well as contralateral RST neurons, with axons crossing the lesion were significantly decreased relative to uninjured controls. This decrease persisted bilaterally and was permanent in the long PSNs and the contralateral red nucleus (RN). However, by 16 weeks post-hemisection, the numbers of ipsilesional and contralesional short PSNs bridging the lesion were significantly increased. Further, the number of contralesional contributing short PSNs was significantly greater in injured animals than in uninjured animals. A significant increase over uninjured numbers also was seen in the ipsilateral (non-axotomized) RN. These findings suggest that a novel substrate of undamaged axons, which normally terminates rostral to the lesion, grows past a thoracic lesion after injury. This rostral population represents a major component of the bridging substrate seen and may represent an important anatomical target for evolving rehabilitation approaches as a substrate capable of contributing to functional recovery.

Cervical spinal cord contusion is the most common human spinal cord injury, yet few rodent models replicate the pathophysiological and functional sequela of this injury. Here, we modified an electromechanical injury device and characterized the behavioral and histological changes occurring in response to a lateralized C4 contusion injury in rats. A key feature of the model includes a non-injurious touch phase where the spinal cord surface is dimpled with a consistent starting force. Animals were either left intact as a control, received a non-injury-producing touch on the surface of the cord ("sham"), or received a 0.6 mm or a 0.8 mm displacement injury. Rats were then tested on the forelimb asymmetry use test, CatWalk, and the Irvine, Beatties, and Bresnahan (IBB) cereal manipulation task to assess proximal and distal upper limb function for 12 weeks. Injuries of moderate (0.6 mm) and large (0.8 mm) displacement showed consistent differences in forelimb asymmetry, metrics of the CatWalk, and sub-scores of the IBB. Overall findings indicated long lasting proximal and distal upper limb deficits following 0.8 mm injury but transient proximal with prolonged distal limb deficits following 0.6 mm injury. Significant differences in loss of ipsilateral unmyelinated and myelinated white matter was detected between injury severities. Demyelination was primarily localized to the dorsolateral region of the hemicord and extended further rostral following 0.8 mm injury. These findings establish the C4 hemi-contusion injury as a consistent, graded model for testing novel treatments targeting forelimb functional recovery.

The effects of 2weeks of intralesional chondroitinase abc (ch'abc) treatment on anatomical plasticity and behavioral recovery are examined in adult cats and compared to results achieved with 4weeks of treatment following tightly controlled lateral hemisection injuries. Analyses also were completed using 35 cats with a range of hemisection magnitudes to assess relationships between treatment duration, lesion size and functional recovery. Results indicate that both 2 and 4weeks of treatment significantly increased the number of rubrospinal tract (RuST) neurons with axons below the lesion, but neither affected the number of corticospinal tract neurons. Similarly, both treatment periods also accelerated recovery of select motor tasks, which carries considerable importance with respect to human health care and rehabilitation. Four weeks of treatment promoted recovery beyond that seen with 2weeks in its significant impact on accuracy of movement critical for placement of the ipsilateral hindlimb onto small support surfaces during the most challenging locomotor tasks. Analyses, which extended to a larger group of cats with a range of lesion magnitudes, indicate that 4weeks of ch'abc treatment promoted earlier recovery as well as significantly greater targeting accuracy even in cats with larger lesions. Together, these results support the potential for ch'abc to promote anatomical and behavioral recovery and suggest that intraspinal treatment with ch'abc continues to enhance motor recovery and performance beyond the subacute injury period and diminishes the impact of lesion size., (Published by Elsevier Inc.)

Neural progenitor cells (NPCs) have shown modest potential and some side effects (e.g. allodynia) for treatment of spinal cord injury (SCI). In only a few cases, however, have NPCs shown promise at the chronic stage. Given the 1.275 million people living with chronic paralysis, there is a significant need to rigorously evaluate the cell types and methods for safe and efficacious treatment of this devastating condition. For the first time, we examined the pre-clinical potential of NPCs derived from human induced pluripotent stem cells (hiPSCs) to repair chronic SCI. hiPSCs were differentiated into region-specific (i.e. caudal) NPCs, then transplanted into a new, clinically relevant model of early chronic cervical SCI. We established the conditions for successful transplantation of caudalized hiPSC-NPCs and demonstrate their remarkable ability to integrate and produce multiple neural lineages in the early chronic injury environment. In contrast to prior reports in acute and sub-acute injury models, survival and integration of hiPSC-derived neural cells in the early chronic cervical model did not lead to significant improvement in forelimb function or induce allodynia. These data indicate that while hiPSCs show promise, future work needs to focus on the specific hiPSC-derivatives or co-therapies that will restore function in the early chronic injury setting., (© 2013.)