DATASET CITATION:
Richards J. H., Freeman D. D., Detloff M. R. (2024) Neuropathic Pain, Depressive-like Behaviors and Myeloid Cell Polarization in LysM-eGFP Mice of Both Sexes Following a Moderate Unilateral Cervical SCI. Open Data Commons for Spinal Cord Injury. ODC-SCI:940 http://dx.doi.org/10.34945/F5GC7C
ABSTRACT:
STUDY PURPOSE: Neuropathic pain is a multifaceted, chronically debilitating condition that has sensory descriminative, affective and cognitive components. Following spinal cord injury (SCI), approximately 60% of individuals are diagnosed with neuropathic pain and comorbid mood disorders, while only ~21% of the general population will experience a mood disorder in their lifetime. These experiments aim to characterize development of pain- and mood-related behaviors and correlate them with the innate immune response post-SCI. While humanizing the rodent is impossible, the results from this study inform clinical literature to closely examine sex-differences reported in humans to better understand the underlying shared etiologies of pain and depressive-like behaviors following CNS trauma. We hypothesize that nociceptive and depressive-like dysregulation occurs after SCI and is associated with aberrant macrophage infiltration in segmental pain centers.
DATA COLLECTED: We completed moderate (40kDyn, 2sec dwell time) unilateral C5 spinal cord contusion on male and female LysM-eGFP reporter mice (age >6weeks) to visualize infiltrating macrophages. von Frey, Hargreaves, open-field and sucrose preference tests were conducted weekly, while the forced swim test and the mechanical conflict avoidance paradigm were only conducted at the terminal timepoint. At 6-weeks post-SCI, mice exhibit nociceptive and depressive-like dysfunction compared to naïve and sham groups. There were no differences between sexes, indicating that sex is not a contributing factor driving nociceptive or depressive-like behaviors after SCI. Group averages based on experimental group revealed that SCI caused persistent mechanical allodynia and thermal hyperalgesia with indications of both learned-helplessness and anhedonia at the terminal timepoint of the experiment. SCI mice displayed increased myeloid cell presence (infiltrating macrophages: LysM+/CD68+, resident macrophages: LysM-/CD68+, microglia: IBA1+) in the lesion epicenter, ipsilateral C7-8 dorsal horn and C7-8 DRGs as evidenced by eGFP, CD68, and Iba1 immunostaining when compared to naïve and sham mice. This was further confirmed by SCI-induced alterations in the expression of genes indicative of myeloid cell activation states and their associated secretome in the dorsal horn and DRGs.
CONCLUSIONS: Utilizing hierarchical cluster analysis, we classified mice based on endpoint nociceptive and depressive-like behavior scores. Approximately 59.3% of SCI mice clustered based on increased paw withdrawal threshold to mechanical stimuli and immobility time in the forced swim test. In conclusion, moderate unilateral cervical SCI caused the development of pain-related and depressive-like behaviors in a subset of mice and these behavioral changes are consistent with immune system activation in the segmental pain pathway.
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DATASET CITATION:
Omondi C., Chou A., Fond K., Morioka K., Joseph N. R., Sacramento J. A., Iorio E. G., Torres-Espin A., Radabaugh H. L., Davis J. A., Gumbel J. H., Huie J. Russell., Ferguson A. R. (2024) Example AMPA Receptor and Housekeeping Protein Expression Data from Male Long-Evans Rats for the Purpose of Demonstrating the blotRig Western Blot Tool. Open Data Commons for Spinal Cord Injury. ODC-SCI:939 http://dx.doi.org/10.34945/F51C7B
ABSTRACT:
STUDY PURPOSE: The purpose of this study is to demonstrate best practices in analyzing western blot data. This study uses example western blot data from a spared peripheral nerve + spinal cord injury model to illustrate how technical replications and counterbalancing of experimental groups across western blot gels can improve rigor and reproducibility. The data are organized to be used easily in the blotRig tool, which we developed to aid in western blot experimental design and analysis.
DATA COLLECTED: The data collected are from 29 male Long-Evans rats that were grouped prior to western blot analysis into one of two groups, and spinal cord tissue was prepared for western blot analysis. Each sample was run on three technical replicate western blot gels, and densitometry values for the target protein (GluA2 AMPA receptor subunit) and beta actin loading controls were collected and analyzed.
CONCLUSIONS: These data were used to demonstrate the varying ways that western blot data can be analyzed. The data included here are organized so that an analyst can easily use these in the blotRig tool, where a linear mixed model is implemented to capture the random effect of replication and loading control as a covariate when assessing whether there are group differences in expression level for a target protein. These data will be forthcoming in an unblinded way, and this dataset will be cross-referenced
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DATASET CITATION:
Walker J. R., Espana R. A., Detloff M. Ryan. (2024) Effects of IB4+ nociceptor ablation on motor and pain-like behaviors in a female Sprague Dawley rat model with a unilateral C5 contusion injury. Open Data Commons for Spinal Cord Injury. ODC-SCI:786 http://dx.doi.org/10.34945/F5M599
ABSTRACT:
STUDY PURPOSE: The primary nociceptive C-fibers become hyperexcitable and sprout into the dorsal horn after cervical spinal cord injury. This study investigated whether this maladaptive nociceptor plasticity is causal to the stereotypical motor deficits seen in reaching and grasping.
DATA COLLECTED: An adult (~10weeks at start of experiment) female Sprague-Dawley rat (starting weight ~225g) unilateral C5 contusion model was used with unilateral C5 laminectomy controls. C7-8 DRGs received a single microinjection per DRG (2000nl/DRG at a rate of 200nl/min) of IB4 conjugated Saporin (1.2mg/ml) to ablate the IB4+ nociceptors or control, unconjugated saporin at the time of SCI. Rats were behaviorally tested for motor and pain like behaviors before and at 4 weeks post injury. Motor tests included the Vulintus Isometric Pull Task, Single Pellet Retrieval, Montoya Staircase, IBB Cereal Manipulation, and Cylinder test of Paw Preference. Pain-like behavior included Automated von Frey test for mechanical allodynia and Hargreaves' Test for thermal hyperalgesia. 10 sets of 25-micron sections of C7-8 cord and 10 sets of 20-micron sections of C7 and C8 DRGs underwent primary antibody and lectin stains nociceptor terminal arbors in the C7 and C8 dorsal horn and cell bodies in the dorsal root ganglia were identified via anti-CGRP and streptavidin conjugated-IB4 to quantify changes in sprouting and confirm cell ablation. Sprouting was quantified using ImageJ to determine the proportional area of immunofluorescent fibers. Cell ablation was confirmed by counting the number of IB4+ cells in the DRGs.
CONCLUSIONS: Ablation of IB4+ nociceptors at the time of spinal cord injury significantly improved the number of rats who were able to grasp a chocolate flavored food pellet compared to controls. Ablation did not yield significant improvements in other motor tests indicating a task specific mechanism of nociceptor involvement in forelimb motor control after SCI. Ablation of nociceptors in laminectomy controls did not have any adverse effects on motor control.
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DATASET CITATION:
Ryan C. B., Choi J. S., Kang B., Pereira C., Moraes C. T., Al-Ali H., Lee J. K. (2023) PI3K inhibition in foamy macrophages after T8 spinal cord contusion in female mice, and in cultured macrophages treated with spinal cord homogenate. Open Data Commons for Spinal Cord Injury. ODC-SCI:930 http://dx.doi.org/10.34945/F5JC70
ABSTRACT:
STUDY PURPOSE: Inflammation after spinal cord injury (SCI) creates a cellular environment adverse to neural regeneration. Macrophages are one of the major classes of inflammatory immune cells at the injury site, and a subset of these cells with pro-inflammatory function are “foamy” macrophages. These cells become lipid-laden due to excessive lipid uptake of myelin and cellular debris after injury and add to the harmful inflammatory milieu of the SCI wound. In this study, we investigated the cellular and molecular mechanisms by which foamy macrophages may drive the cellular pathology after subacute SCI (7 days post injury).
DATA COLLECTED: We developed a novel in vitro assay to model foamy macrophages formation after SCI using primary bone-marrow derived macrophages treated with wildtype spinal cord homogenate to represent virtually all the lipid sources present after SCI. In vitro analysis of foamy macrophages included protein blotting, RNA sequencing, Seahorse metabolic profiling, reactive oxygen species dye, qPCR analysis and immunocytochemistry. For in vivo experiments, 8-10-week-old female mice received mid-thoracic contusive SCI and were treated with Torin-2 filled liposomes at 1, 3, and 6 days post injury (dpi) and tissue analyzed at 7 dpi with immunohistochemistry.
CONCLUSIONS: Foamy macrophages phenotype is characterized by increased production of cytokines, reactive oxygen species and mitochondrial uncoupling. Bioinformatic pathway analysis of the foamy macrophage inflammatory signature revealed the importance of the PI3K/Akt/mTOR pathway in driving foamy macrophage formation. Inhibition of this pathway using Torin-2 reduced lipid content and reversed the pathological characteristics of the foamy macrophage phenotype such as inflammatory cytokine and reactive oxygen species (ROS) production in vitro. Dissection of the targets of Torin-2 demonstrated that PI3K, but not mTORC1, was necessary for reducing lipid droplet accumulation. Importantly, targeting macrophages in vivo using liposomes encapsulating Torin-2 significantly decreased lipid content in macrophages at the injury site after contusive SCI in mice. Using an in vitro autophagy flux assay, we demonstrated that while lipid accumulation in foamy macrophages leads to decreased autophagy, this is partly rescued by PI3K inhibition using Torin-2, but not by selective inhibition of mTORC1 using rapamycin. Lastly, an in vitro phagocytosis assay showed that Torin-2 also reduced phagocytosis in foamy macrophages. Together, these data identify PI3K as an important regulator of foamy macrophage formation after SCI, and that small molecules with Torin-2-like activity may be suitable for therapeutic development targeting this atypical pathological process in SCI.
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DATASET CITATION:
Cucarian J. Daniel., Raposo P., Nguyen A., Vavrek R., Torres-Espin A., Fouad K. (2023) Impact of Anti-Inflammatory Medication on Task-Specific Training Efficacy and Functional Recovery After Unilateral Dorsal Quadrant C4 Cervical Spinal Cord Injury in Female Lewis Rats. Open Data Commons for Spinal Cord Injury. ODC-SCI:955 http://dx.doi.org/10.34945/F57W2G
ABSTRACT:
STUDY PURPOSE: After spinal cord injury, inflammation is involved in secondary tissue damage. However, it may also promote neuroplasticity. We have shown earlier that promoting inflammation in a chronic setting in rats can promote the efficacy of rehabilitative training in a reaching task. Here we wanted to test whether the opposite is also true. Would common anti-inflammatory medications that could be given for any reason in later stages of a spinal lesion affect the efficacy of rehabilitative training in rats with unilateral incomplete cervical spinal cord injuries.
DATA COLLECTED: This experiment involved two experimental cohorts, with a total of fifty-three age-matched adult female Lewis rats (cohort 1: n=29, cohort 2: n=24). The rats underwent training in a single pellet grasping (SPG) task for 5 weeks before receiving a C4 dorsolateral quadrant transection. Afterwards, the rats were randomized into groups: In the first cohort, three groups were included, SCI only (n=10), SCI + Diphenhydramine (SCI+DPH; n=10), and SCI + Methylprednisolone (SCI + MP; n=9). In the second cohort, only the SCI and SCI+DPH groups were included, each with a n=12. One week after the spinal cord lesion, the rats received Diphenhydramine and Methylprednisolone at 20mg/kg and 30mg/kg, respectively in their drinking water for 4 weeks, in combination with eight weeks of SPG training (10min/day). Sensorimotor and behavioral assessments were carried out and video recorded, before the dorsolateral quadrant transection (baseline), as well as on a weekly basis following the lesion. These tests included the Horizontal Ladder, Open Field, Elevated Plus Maze, Light-dark box, Von Frey, and The Irvine, Beattie, and Bresnahan test. After the final day of testing, the rats were euthanized, perfused, and their spinal cord tissue was harvested. The cervical spinal cord tissue, including the lesion site, was cryosectioned at 25 microns and processed with Neurotrace staining. To quantify the extent of spinal cord injury, we measured the damaged and spared areas within the spinal cord using ImageJ-Fiji.
CONCLUSIONS: Despite the well-established anti-inflammatory properties of both Diphenhydramine and Methylprednisolone and their extended administration in this experiment, our findings indicate that they did not have significant effects on any of the outcome measures. These results indicate that although proinflammatory stimuli were reported to improve post spinal cord injury training efficacy, these commonly administered inflammatories (especially the anti histaminergic Diphenhydramine) do not affect forelimb grasping training efficacy.
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DATASET CITATION:
Lieu B., Everaert D. G., Ho C., Gorassini M. A. (2023) Effect of transcranial electrical stimulation (TES) on the First Flexion Angle and Abductor Hallucis H-reflex in a person with T4-motor-complete spinal cord injury. Open Data Commons for Spinal Cord Injury. ODC-SCI:980 http://dx.doi.org/10.34945/F50C71
ABSTRACT:
STUDY PURPOSE: Spasticity after a spinal cord injury (SCI) is common and can hinder completion of daily tasks. This case study examines the reduction in hypertonus in a person with T4-motor-complete-SCI using a commercial transcutaneous electrical stimulator (TES) at 150-Hz applied to the lower back and the possible mechanisms producing this reduction in leg tone.
DATA COLLECTED: Hypertonus of both lower legs before and during lumbosacral TES applied over the spinal column (MID) or 10-cm lateral (LAT) was measured with the pendulum test. To estimate how proprioceptive afferents and spinal neuronal networks were affected by lumbosacral TES, H-reflexes and cutaneomuscular reflexes, respectively, were also measured. Hypertonus disappeared in both legs but only during lumbosacral TES. During the pendulum test, MID TES increased the excursion of both lower legs after release from a horizontal position by an average of 63.3% that was similar to the increase produced by LATTES (47.8%). Both locations of lumbosacral TES increased H-reflexes but decreased the first
polysynaptic response of the cutaneomuscular reflex.
CONCLUSIONS: This case study demonstrates that a low cost, commercially available TES device applied to the lower back instantaneously “switches off” hypertonus but only during the applied high frequency (150 Hz) stimulation. Given that a relatively inexpensive, pocket-sized stimulator made it easier for this participant to carry out daily tasks, it is important to further explore the potential applicability of thoracolumbar TES to treat hypertonus in people with SCI, what types of TES parameters and injuries are most responsive and to investigate the mechanisms leading to the observed reduction in hypertonia.
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DATASET CITATION:
Raposo P., Nguyen A. T., Schmidt E. K.A., Torres Espin A., Fenrich K. K., Bennett D. J., Fouad K. (2023) Probiotic treatment in female Lewis rats following unilateral incomplete cervical (C5) contusion injury: Microbiome report. Open Data Commons for Spinal Cord Injury. ODC-SCI:688 http://dx.doi.org/10.34945/F5CP4D
ABSTRACT:
STUDY PURPOSE: The bidirectional communication between the gastrointestinal tract and the central nervous system appears to be linked to the intestinal microbiome. Research has shown that spinal cord injury (SCI) can disrupt the gut microbiome, leading to gut dysbiosis. These changes can have several negative impacts, such as exacerbated systemic inflammation and susceptibility to infection. Probiotics administered to mice with SCI have been shown to ameliorate gut dysbiosis, confer neuroprotection, and improve locomotor recovery. However, probiotics have also produced conflicting results, making potential claims regarding the application of probiotics as a therapeutic supplement ambiguous. This study aimed to investigate the effects of a commercially available probiotic on recovery in a rat model of cervical SCI.
DATA COLLECTED: Female Lewis rats (12 weeks and 180-220 g) received a C4-C5 laminectomy to expose the spinal cord. Using an Infinite Horizon impactor a 125 kdyn unilateral contusion was performed targeting the right side of the spinal C5 level (1.25 mm right of midline, 25 mm drop height at a 15-degree angle).
Probiotic treatment was initiated immediately after SCI using VSL#3 containing 450 billion colony-forming units (CFU) of lyophilized bacteria/g, including eight different strains (Bifidobacterium breve, Bifidobacterium infantis, Bifidobacterium longum, Lactobacillus acidophilus, Lactobacillus bulgaricus, Lactobacillus casei, Lactobacillus planatarum, and Streptococcus salivarus subspecies thermophilus). VSL#3 was administered daily via oral gavage for 7 days postinjury (DPI) at a dose of 5 billion CFU. Control group was gavaged with 0.5 ml of sterile filtered water. After 7 DPI, the 5 billion CFU of VSL#3 doses were adjusted to ensure equivalent consumption and administered ad libitum in drinking water for a total of 35 DPI.
The overall gut microbiome was assessed prior to injury (baseline) and at 3, 7, 14, and 35 DPI by collecting fresh fecal matter from the rats during their dark cycle and submitted for 16S rRNA analysis.
Dataset for Probiotic treatment for acute spinal cord injury: behavioural, histological and systemic cytokine profiles of female Lewis rats is in OSC-SCI#687
CONCLUSIONS: We could not detect any beneficial effects of the probiotic treatment. If anything it was detrimental as lesion size was slightly larger and the return of the gut microbiome to preinjury state was delayed by the treatment. Our results thus do not support the application of the utilized probiotic cocktail as a dietary supplement for the treatment of cervical SCI-induced gut dysbiosis and secondary complications.
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DATASET CITATION:
Raposo P. JF., Nguyen A. T., Schmidt E. KA., Torress Espin A., Fenrich K. K., Bennett D., Fouad K. (2023) Probiotic treatment in female Lewis rats following unilateral incomplete cervical (C5) contusion injury: behavior, histological and systemic cytokine data. Open Data Commons for Spinal Cord Injury. ODC-SCI:687 http://dx.doi.org/10.34945/F5HC7P
ABSTRACT:
STUDY PURPOSE: We tested whether a probiotic treatment immediately after a unilateral incomplete cervical spinal cord injury in female rats prevents gut dysbiosis, promotes motor recovery and dampens the related anxiety like behavior as we have previously reported for fecal matter transplants.
DATA COLLECTED: Female Lewis rats (12 weeks and 180-220 g) received a 125 kdyn unilateral contusion on the right side of the spinal C4-5 level (1.25 mm right of midline, 25 mm drop height at a 15-degree angle) using an Infinite Horizon impactor.
Probiotics were given immediately after SCI using VSL#3 containing eight different strains (Bifidobacterium breve, Bifidobacterium infantis, Bifidobacterium longum, Lactobacillus acidophilus, Lactobacillus bulgaricus, Lactobacillus casei, Lactobacillus planatarum, and Streptococcus salivarus subspecies thermophilus). VSL#3 was administered daily via oral gavage for 7 days at a dose of 5 billion CFU. Control group was gavaged with 0.5 ml of sterile water. After 7 DPI, the 5 billion CFU of VSL#3 doses were adjusted to ensure equivalent consumption and administered ad libitum in drinking water for a total of 35 days post injury (DPI). An open field test was used to assess motor function as well as depression/anxiety-like behavior. The elevated plus maze was carried out at baseline and 35 DPI by recording the rats for ten minutes and then analyze offline with customized software (https://github.com/cdoolin/rat-apps).
The rats were placed in a cylinder for 5 min to record the number of left and right forelimb paw placements on the cylinder wall during rearing and recorded weekly after injury. For the light-dark exploration test, the distance traveled in the light chamber, total number of transitions, time spent in each chamber and latency to enter the light chamber were recorded and analyzed offline. The test was carried out at baseline and 35 DPI.
The horizontal ladder served to examine skilled motor function, where a successful trial was concluded when rats walked across all rungs without rearing or stopping. Three successful trials were analyzed offline for the number of successful steps, missed steps, and forelimb slips.The von Frey test was used to assess mechanical allodynia.
The overall gut microbiome was assessed prior to injury (baseline) and at 3, 7, 14, and 35 DPI by collecting fresh fecal matter from rats at the beginning of their dark cycle and submitted for 16S rRNA analysis. The microbiome report for this study is in the associated odc-sci dataset #688.
Plasma samples were collected in the morning (animal's light cycle) and diluted 2-fold and run on the Rat Cytokine 27-Plex and Rat Stress Hormone 2-Plex discovery assays.
Images of lesion extension were taken from cryosectioned tissue slices with an epifluorescence microscope at 5× magnification and analyzed using ImageJ. Lesion size was calculated and represented as the percent of spared tissue. Images at 5× magnification were taken to visualize the entire spinal cord cross section 0.25 cm rostral to the lesion, at its epicenter, and 0.25 cm caudal. To analyze microglia in the spinal cord tissue, the area of Iba-1+ immunoreactivity was divided by the total area of each individual spinal cord cross section and expressed as a percentage of Iba1+ area using thresholding.
CONCLUSIONS: We could not detect any beneficial effects of the probiotic treatment. If anything it was detrimental as lesion size was slightly larger and the return of the gut microbiome to preinjury state was delayed by the treatment. Our results thus do not support the application of the utilized probiotic cocktail as a dietary supplement for the treatment of cervical SCI-induced gut dysbiosis and secondary complications.
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DATASET CITATION:
Aldrich J. C., Scheinfeld A. R., Lee S. E., Mahach K. M., Van de Veire B. C., Fonken L. K., Gaudet A. D. (2023) C57BL/6J mice exposed to dim light-at-night following a T9 contusion spinal cord injury exhibit modest improvements in locomotor recovery accompanied by increased behaviors related to depression and mechanical neuropathic pain. Open Data Commons for Spinal Cord Injury. ODC-SCI:956 http://dx.doi.org/10.34945/F5N30H
ABSTRACT:
STUDY PURPOSE: Nighttime disturbances are a common feature of extended hospital stays and likely lead to circadian disruption which, in turn, may exacerbate neuroinflammatory conditions. This study aimed to assess the effects of circadian disruption via exposure to dim light-at-night (dLAN) on locomotor recovery, tissue sparing, neuropathic pain sensitivity, and mood-related behaviors in mice following a T9 contusion spinal cord injury (SCI).
DATA COLLECTED: A more detailed methodology is available in the preprint: https://doi.org/10.1101/2023.09.15.557980. Briefly, male and female C57BL/6J mice were subjected to either moderate (65 kdyn) T9 contusion SCI or sham surgeries and subsequently housed under standard light-dark conditions (LD; 12 h light at 150 lux; 12 hr dark) or dLAN conditions (12 h light at 150 lux; 12 h dim light at 15 lux). The Basso mouse scale (BMS) was used to evaluate locomotor recovery at various timepoints from 1 to 35 days post-operation (dpo).
Heat hyperalgesia and mechanical allodynia were assessed using the Hargreaves test and the simplified up-down (SUDO) von Frey method, respectively, at 6 or 7 dpo and weekly thereafter. In both tests, left and right hindpaw scores are averaged together and for Hargreaves each hindpaw was tested three times.
Anxiety- and depressive-like behaviors were evaluated using the juvenile social exploration (JSE) test, sucrose preference test (SPT), and open-field test (OFT). JSE and OFT were performed prior to surgery and at 21 dpo while SPT was performed prior to surgery and at 14 and 29 dpo. For OFT and JSE, mouse behavior was tracked via Ethovision in an open area for 10 min followed by the introduction of a same-sex novel juvenile stimulus mouse (?4 weeks old) for 5 min. Distance traveled and percent time in the center 1/3rd of the arena for the first 5 min was recorded for OFT, while the amount of time spent interacting (e.g. sniffing, grooming, chasing, and fighting) with the juvenile was manually scored. For SPT, mice—housed alone or in sex-matched pairs, as noted in the dataset—were presented overnight with the choice of water or a 2% sucrose solution. Bottles containing water or sucrose were weighed before and after the test to determine the average amount consumed per mouse—i.e. in cases where two mice were housed together, the amount consumed was divided by two.
Finally, neuroprotection was assessed in 35 dpo spinal cord cryosections by measuring the lesion area and total cross-sectional area—based on anti-GFAP immunofluorescence staining of the astrocytic border—at 0.2 mm intervals surrounding the injury epicenter. Percent tissue sparing was calculated thusly: (total area – lesion area) / total area * 100%.
CONCLUSIONS: Subjecting C57BL/6J mice to SCI and housing them in dLAN had minimal effects on locomotor and pain-related outcomes. SCI mice exposed to dLAN displayed slightly improved locomotor function at 28 dpo—and no other timepoint—with an average BMS score of 6.25 vs. 5.05 for LD housed animals. Post-SCI dLAN exposure resulted in worsened mechanical hypersensitivity at 13 dpo—filament threshold 6.5 dLAN vs. 7.75 LD—and no difference in heat hypersensitivity. The impact of dLAN on mood-related behaviors in SCI mice was overall limited . No significant differences were observed in the sucrose preference and open-field tests between the two housing conditions—however, interestingly, SCI-dLAN mice exhibited a ~23% reduction in time spent on juvenile social exploration compared to SCI-LD mice, suggesting a potential increase in depressive-like behavior. Finally, consistent with the mild locomotor effect, we saw no difference in tissue sparing or lesion size in 35 dpo spinal cord sections. Overall, our findings indicate that C57BL/6J mice exposed to dim light-at-night following spinal cord injury displayed modest effects on locomotor recovery, pain-like responses, and mood-related behaviors. These results emphasize the need for future investigations to delve deeper into the impact of circadian disruption on post-injury outcomes, exploring a range of manipulations such as sleep fragmentation, stress, and varying lighting conditions, either individually or in combination, to better simulate more complex clinical scenarios.
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DATASET CITATION:
Pelisch N., Rosas Almanza J., Xiong S., Stehlik K. E., Aperi B. V., Kroner-Milsch A. (2023) Impact of Anti-CCL3 FANA Oligonucleotide in T10 contusion Spinal Cord Injury using female mice on locomotor function, and inflammation. Open Data Commons for Spinal Cord Injury. ODC-SCI:941 http://dx.doi.org/10.34945/F55305
ABSTRACT:
STUDY PURPOSE: Secondary damage after spinal cord injury (SCI) occurs because of a sequence of events after the initial injury, including exacerbated inflammation that contributes to increased lesion size and poor locomotor recovery. Thus, mitigating secondary damage is critical to preserve neural tissue and improve neurologic outcome. In this work, we examined the therapeutic potential of a novel antisense oligonucleotide (ASO) with special chemical modifications [2'-deoxy-2-fluoro-D-arabinonucleic acid (FANA) ASO] for specifically inhibiting an inflammatory molecule in the injured spinal cord. The chemokine CCL3 plays a complex role in the activation and attraction of immune cells and is upregulated in the injured tissue after SCI.
DATA COLLECTED: We used specific FANA ASO to inhibit CCL3 in a contusive mouse model of murine SCI (C57BL/6, female, Charles River). These chemically modified RNA inhibitors penetrate cell membranes without the need for transfection. Our results show that, after intrathecal injection, FANA ASO molecules targeting the chemokine CCL3 penetrate the spinal cord lesion site and suppress the expression of CCL3 transcripts (p-value < 0.001). Furthermore, they reduce other proinflammatory cytokines such as tumor necrosis factor (TNF, p-value < 0.001) and interleukin (IL)-1beta after SCI (p-value 0.0034).
CONCLUSIONS: In summary, we demonstrate for the first time the potential of FANA ASO molecules to penetrate the spinal cord lesion site to specifically inhibit CCL3, reducing proinflammatory cytokines and improve functional recovery after SCI. This novel approach may be used in new treatment strategies for SCI and other pathologic conditions of the CNS.
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DATASET CITATION:
Kuehn N., Schwarz A., Beretta C. A., Schwarte Y., Schmitt F., Motsch M., Weidner N., Puttagunta R. (2023) Lumbar (L2-L4) intermediate gray matter (laminae V-VIII) kainic acid-induced spinal cord injury in female Fisher 344 rats creates deficits in gross locomotion, coordination, balance and gait. Open Data Commons for Spinal Cord Injury. ODC-SCI:938 http://dx.doi.org/10.34945/F5DK52
ABSTRACT:
STUDY PURPOSE: Spinal cord injury (SCI) often occurs at spinal enlargements where the gray matter is the largest for input and output from and to the limbs. Much SCI research focuses on long-distance axonal regeneration, neglecting the importance of replacing lost gray matter for functional recovery. Here we show that the loss of the intermediate gray matter (laminae V-VIII) of L2-L4 leads to behavioral deficits that cannot be compensated for over time. Thereby establishing a lumbar intermediate gray matter spinal cord injury model for future cell transplantation work with detailed behavioral readouts.
DATA COLLECTED: Abbreviated Methods: (detailed information in the Methodology document) Female Fisher 344 rats (180-200g, ~10 weeks of age) were used for these studies. Group 1 was a study with thoracic T12 laminectomy with 1-2 bilateral kainic acid (KA) spinal cord injections (n=5, saline controls n=4) followed by behavioral testing (BBB score and subscore, uneven ladder slips) at 14 days post-injury. Group 2 was a study with thoracic T13 laminectomy with 3 bilateral kainic acid spinal cord injections (n=7, saline controls n=7) followed by behavioral testing (BBB score and subscore, Even Ladder Score, Even Ladder Slips, Uneven Ladder Score, Uneven Ladder Slips, Inclined Beam Time, Inclined Beam Score, Inclined Beam Steps, Inclined Beam Completions, Hargreaves, von Frey1.4g, von Frey 60g, pLDA CatWalk Score, CatWalk AB Seq, CatWalk Body Speed, CatWalk Duty Cycle, CatWalk Forepaw Stride Length, CatWalk Forepaw Swing Time, CatWalk Hindpaw Base of Support, CatWalk Hindpaw Stride Length, CatWalk Max Contact at, CatWalk Regularity Index, CatWalk CA Sequence, CatWalk Forelimb Stand Time, CatWalk Hindlimb Stand Time, CatWalk Forelimb Duty Cycle, CatWalk Hindlimb Duty Cycle, CatWalk Hindpaw Swing Time) at 14 days post-injury. Group 3 was a study with thoracic T13 laminectomy with 3 bilateral kainic acid spinal cord injections (KA n=3, saline controls n=3) followed by behavioral testing (BBB score and subscore) at 90 days post-injury.
CONCLUSIONS: Lesions in the mixed cohort (Group 1) which we found to be primarily in spinal levels T13/L1 and not overlapping into spinal L2 did not show significant gross hindlimb and coordination deficits two weeks after injury. The BBB score of the control group was 20.63 ± 0.38 (mean ± standard error of mean) and the KA group was 18.20 ± 0.92 and not significantly different (p = 0.0642, unpaired Welch’s t-test, n = 4 control and n = 5 KA animals). The BBB subscore for the controls was 12.75 ± 0.25 and for the KA animals was 10.8 ± 0.80 and was also not significantly different (p = 0.0750; unpaired Welch’s t-test, n = 4 control and n = 5 KA animals). Two weeks post-lesioning, the percent hindlimb slips for the controls was 1.19 ± 0.79% and for the KA group was 4.29 ± 2.24% (p = 0.2470, unpaired Welch’s t-test, n = 4 controls and n = 5 KA animals). In lesions targeting spinal levels L2-L4 with 3 bilateral kainic acid injections (Group 2), gross hindlimb function after 14 days was found (BBB scores: control = 17.57 ± 0.69, KA = 11.21 ± 2.25) as well significant deficits in hindlimb function dependent on coordination (BBB subscore control = 11.29 ± 0.18, KA = 4.57 ± 1.67). KA rats show a significantly higher number of hindlimb slips on both the even and uneven horizontal ladders indicating deficits in rhythmic walking (even ladder controls = 0.70 ± 0.34%, KA = 39.91 ± 15.81%) and coordination (uneven ladder controls = 1.71 ± 0.91%, KA = 48.68 ± 15.12%). Only 3 of the 7 KA rats were able to complete the inclined beam test (controls = 100 ± 0% completion, KA = 23.81 ± 14.02%). Those KA rats that did complete the beam had a lower performance score (Controls = 95.66 ± 1.25%, KA = 21.19 ± 13.32%) further indicating deficiencies in coordination and balance. From the CatWalk gait analysis, 9 SCI parameters were combined into a pLDA score which showed that KA rats have a significantly lower pLDA score two weeks after SCI (controls = 0.13 ± 0.01, KA = 0.076 ± 0.01). Similar lesion as Group 2, Group 3 was the 90-day study that examined if KA deficits showed sustained deficits (KA n=3, saline controls n=3), BBB score controls = 19.83 ± 0.60, KA = 10 ± 2.5; BBB subscore controls = 12 ± 0.58, KA = 2.33 ± 2.33). This work shows that intermediate gray matter (laminae V-VIII) lesions spanning L2-L4 specifically lead to a stable spinal cord injury with specific behavioral readouts for further examination of cell transplantation in restoring motor function.
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DATASET CITATION:
Dulin J. N., Baltazar A. (2023) Differences in anatomical outcomes between early chronic (8w) and far chronic (26w) time points after transplantation of mouse spinal cord neural progenitor cells into sites of cervical (C4) dorsal column lesion SCI in male and female mice. Open Data Commons for Spinal Cord Injury. ODC-SCI:887 http://dx.doi.org/10.34945/F5XK5Q
ABSTRACT:
STUDY PURPOSE: Spinal cord injury (SCI) affects millions of people worldwide. Neural progenitor cell (NPC) transplantation is a promising treatment for regenerating lost spinal cord tissue and restoring neurological function after SCI. However, relatively few studies have previously investigated anatomical outcomes at far chronic time points following NPC transplantation. This is a critical topic to investigate, given that stem and progenitor cell therapies would need to remain in place throughout the lifetime of an individual. We sought to determine how commonly assessed anatomical outcomes evolve between the early and far chronic time points post-NPC transplantation.
DATA COLLECTED: Abbreviated Methods: (More detailed information can be found in the Methodology document.)
Male and female C57BL/6 mice (17-33 g) were used for the study. Cervical (C4) dorsal column lesion SCI was performed, followed by immediate transplantation of GFP+ E12.5 mouse spinal cord neural progenitor cells. Three mice were excluded due to premature mortality. At either 8 weeks (n=13) or 26 weeks (n=14) following transplantation of NPCs into sites of cervical SCI, mice were perfused. We evaluated graft neuronal density, astroglial cell density, graft axon outgrowth, and regeneration of host axon populations into grafts.
CONCLUSIONS: We found that graft neuronal density does not change over time, but the numbers of graft-associated astrocytes and GFAP intensity is significantly increased in the far chronic phase compared to the early chronic time point. In addition, graft axon outgrowth was significantly decreased at 26w post-transplantation compared to 8w post-transplantation. In contrast, corticospinal axon regeneration into grafts was not diminished over time, but rather increased significantly from early to far chronic periods. Collectively, these results demonstrate that NPC transplants are dynamic and that commonly assessed outcome measures associated with graft efficacy evolve over the weeks to months post-transplantation into the spinal cord.
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DATASET CITATION:
Lee S. E., Greenough E. K., Oancea P., Scheinfeld A. R., Douglas A. M., Aldrich J. C., Gaudet A. D. (2023) Female C57BL6/J mice exhibit increased heat hyperalgesia and mechanical allodynia compared to males following a T9 contusion spinal cord injury as measured by Hargreaves and SUDO von Frey testing. Open Data Commons for Spinal Cord Injury. ODC-SCI:893 http://dx.doi.org/10.34945/F5SW2F
ABSTRACT:
STUDY PURPOSE: The purpose of this study was to test if contusion spinal cord injury (SCI) causes acute-to-chronic neuropathic pain-like symptoms in mice and to determine if there are sex differences in these SCI-induced pain-like behaviors. An in-depth analysis and discussion of these data was published in DOI: 10.1089/neu.2022.0482
DATA COLLECTED: The published study is the result of a comprehensive analysis of over 100 male and female 6-20 week old C57BL6/J mice pooled from several independent studies. All mice received either a sham (T9 laminectomy) or SCI surgery (T9 laminectomy followed by a 60-75 kdyn spinal cord contusion). Locomotor recovery was assessed via the Basso mouse scale (BMS), heat hyperalgesia in hindpaws was assessed via Hargreaves test (withdrawal latencies were measured for left and right hindpaws over three trials and averaged together into a single value), and mechanical allodynia in hindpaws (left and right averaged together) was assessed via the simplified up-down (SUDO) von Frey method. In general, BMS was performed at 1, 4, 7, 10, and 14 dpo (days post operation) and every 7 days thereafter, while SUDO and Hargreaves testing was performed weekly starting at 7 dpo. Initially, a range (60, 65, and 75 kdyn) of target forces was used to determine an appropriate contusion force to use in conjunction with Hargreaves and von Frey testing. 60 and 65 kdyn had comparable results and were pooled together while 75 kdyn resulted in confounding technical issues related to hindpaw placement (see CONCLUSIONS below)—consequently, 60 kdyn was ultimately chosen for the larger sex differences study. Overall, this data set includes pre-surgery testing data and at least 3 (usually 6+) post-surgery BMS, SUDO von Frey, and/or Hargreaves data points for 170 mice (48 SCI and 44 sham females; 38 SCI and 40 sham males).
CONCLUSIONS: In the preliminary study, mechanical and heat hypersensitivity was observed in female SCI mice relative to sham mice regardless of the contusion force used, with a significant decrease in Hargreaves latency being observed in 75 vs 60-65 kdyn suggesting enhanced heat hypersensitivity. However, 75 kdyn SCI caused excess motor deficits (e.g. impaired hindpaw plantar placement) that confounded pain sensitivity measurement at acute times (i.e. 7 and 14 dpo) leaving 60 kdyn as the better option for subsequent studies. In the larger sex differences study, we note that both males and females exhibit mechanical and heat hypersensitivity (measured by SUDO von Frey and Hargreaves test respectively) post-SCI relative to sham controls. For example, at 7 dpo SCI mice (males and females combined) have an average (± SEM) Hargreaves withdrawal latency of 11.2 ±0.6 sec compared to 15.0 ±0.4 sec for shams. Similarly, at 7 dpo SCI mice have an average SUDO von Frey threshold of 6.5 ±0.2 vs. 7.9 ±0.1 for shams. Although no sex differences were observed in locomotor recovery (measured via BMS), females display amplified SCI-induced mechanical hypersensitivity relative to males at 28 dpo (average SUDO score of 7.0 ±0.2 vs. 7.8 ±0.2) as well as a consistent ~3 sec decrease in thermal withdrawal latency from 7-28 dpo compared to males (e.g. males averaged across all dpo had a Hargreaves score of 12.2 ±0.5 sec vs. 9.2 ±0.3 sec for females).
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DATASET CITATION:
Pukos N., Marion C. M., Arnold W. David., Noble B. T., Popovich P. G., McTigue D. M. (2023) Chronic demyelination and myelin repair after T9 contusion spinal cord injuries in male and female mice as measured by new myelin formation, motor evoked potentials, nodal structure, and EM myelin analysis, and further determining the link to glutamatergic axon activity and OPC contacts using chemogenetics in a T3 crush model. Open Data Commons for Spinal Cord Injury. ODC-SCI:877 http://dx.doi.org/10.34945/F5K88N
ABSTRACT:
STUDY PURPOSE: This study builds off prior work from the McTigue lab showing spinal cord injury (SCI) in mice generates large numbers of oligodendrocytes. This generation was shown to peak between 4 and 7 weeks post-injury (wpi) but extend through at least 2 months post -njury (mpi). The purpose of this study was to significantly extend those findings to determine the long-term myelin changes that occur in response to SCI.
DATA COLLECTED: 70 male and female PDGFRalpha-CreERT2: Tau-mGFP mice were used to lineage trace new myelin forming in response to spinal cord injury at 4wpi, 10wpi, 2mpi, 3 mpi, and 6mpi. Mice were randomly assigned to either SCI or Naive groups. SCI mice received a 75kD midline contusion at T9 between approximately 2-4 months of age. An separate, additional cohort of 6 PDGFRalpha-CreERT2: Tau-mGFP mice received the same T9 contusion injuries, and their motor recovery and motor evoked potentials recorded through 2.5mpi. A final cohort of 6 PDGFRalpha-CreERT2: Tau-mGFP mice were sacrificed at 6mpi for TEM analysis to determine the proportion of myelinated, unmyelinated, and remyelinated axons in T9 contusion versus age-matched naive mice. Additionally, 67 female C57BL/6J mice, 2.5 months old, were randomly assigned to naive or T9 contusion groups as assigned above, and assessed at 1 wpi, 2.5wpi, 4 wpi, 10 wpi, or 26 wpi for changes in node structure and composition, Vglut2 expression and Vlgut1 contacts by OPCs. Finally, 13 male and female Vglut2-ires-Cre mice were injected with Gi (n=7) or Gq (n=6) DREADDs at 2-3 weeks of age, then received complete crush injuries at T3 at 2 months old. These mice received either saline or CNO to suppress (Gi) or enhance (Gq) Vglut2 neuron activity through 4wpi and were assessed for differences in oligodendrocyte progenitor cell interactions.
CONCLUSIONS: SCI drives new myelin formation for an extended period after injury, through at least 6mpi. Further, a peak in myelination occurs during the 3rd mpi. At this 3mpi peak remyelination point, motor evoked potentials significantly increased, suggesting enhanced axon potential conduction. Interestingly, two indices of demyelination were noted at chronic time points. Nav1.2 upregulation occurred through 10wpi, while nodal protein spreading and disorganization was detectable throughout 6mpi. This suggested chronic demyelination, which we then confirmed using EM. These findings indicate demyelination may continue chronically, potentially triggering the long-term remyelination response described above. Finally, this study sought a potential mechanism for initiating post-injury myelination. Indeed, oligodendrocyte progenitor cell processes contact glutamatergic axons in the injured spinal cord in an activity-dependent manner. When these axons were activated chemogenetically, OPC/axon contacts increased 2-fold, and when axon activity was inhibited, spontaneous OPC/axon contacts decreased by half revealing the necessity for axon activity to initiate OPC processes reaching out to axons. Encouragingly, this reveals a potential therapeutic target to enhance post-SCI myelin repair. As a whole, these results reveal the injured spinal cord is surprisingly dynamic over time, and suggests these tissues could be amenable to treatments targeted toward chronic demyelination.
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DATASET CITATION:
Dulin J. N., Aceves M., McCreedy D. A. (2023) Developmental stage of transplanted neural progenitor cells influences anatomical and functional outcomes after C5 dorsal column lesion and T12 contusion spinal cord injury in male and female C57BL/6 mice. Open Data Commons for Spinal Cord Injury. ODC-SCI:873 http://dx.doi.org/10.34945/F5TS33
ABSTRACT:
STUDY PURPOSE: Neural progenitor cell (NPC) transplantation is a promising therapeutic strategy for replacing lost neurons following spinal cord injury (SCI). However, how graft cellular composition influences regeneration and synaptogenesis of host axon populations, or recovery of motor and sensory functions after SCI, is poorly understood. We transplanted developmentally-restricted spinal cord NPCs, isolated from E11.5-E13.5 mouse embryos, into sites of adult mouse SCI and analyzed graft axon outgrowth, cellular composition, host axon regeneration, and locomotor and thermal sensory behavior.
DATA COLLECTED: Abbreviated Methods: (More detailed information can be found in the Methodology document.)
Male and female C57BL/6 mice (18-33 g) were used for this study. Either cervical (C5) dorsal column lesion SCI or thoracic (T12) contusion SCI (50 kdynes, Infinite Horizon impactor device) was performed. Either immediately after SCI (C5 dorsal column lesion groups) or 2 weeks after SCI (T12 contusion groups), mouse spinal cord neural progenitor cells of specific developmental stages or fibrin/thrombin matrix was injected into the lesion site. The specific developmental stages include: E11.5 NPCs, E12.5 NPCs, E13.5 NPCs, E12.5 dorsal NPCs, and E13.5 ventral NPCs.
For the animals receiving C5 dorsal column lesion, they were sacrificed at 4 weeks post-transplantation for histological analysis. No behavioral testing was performed on these animals. For the animals receiving T12 contusion, we conducted behavioral assessments both prior to SCI and until 70 days post-SCI, then performed histological assessments of graft survival. Behavioral assessments include open field locomotor (BMS) testing and Hargreaves (thermal sensitivity) testing of hindpaws. BMS was performed at 1, 3, 5, 7 days post-SCI and weekly until 70 DPI. Hargreaves testing was performed weekly at 14-70 DPI.
CONCLUSIONS: -Immunohistochemical analysis showed that the abundance of some subtypes of neurons are significantly different between graft types.
-Axon outgrowth is significantly greater in E11.5 grafts than all other groups.
-5-HT+ axon regeneration into E11.5 grafts is significantly greater than other graft types.
-CGRP+ axon regeneration into E13.5 grafts is significantly greater than other graft types.
-There was no effect of any graft type on hindlimb locomotor recovery compared to vehicle (fibrin/thrombin matrix).
-Animals with E13.5 grafts exhibited significantly lower thermal latency scores compared to all other treatment groups.
Together, these findings indicate that NPC graft cellular composition varies with the developmental stage of donor cells, and that anatomical and behavioral outcomes are influenced by graft type.
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DATASET CITATION:
Thorogood N., Waheed Z., Chernesky J., Burkhart I., Smith J., Sweeney S., Wudlick R., Douglas S., Wang D., Noonan V. (2023) An online survey about the top priorities for recovery and interest in Spinal Cord Stimulation for people living with SCI (Spinal Cord Injury). Open Data Commons for Spinal Cord Injury. ODC-SCI:853 http://dx.doi.org/10.34945/F53889
ABSTRACT:
STUDY PURPOSE: To obtain opinions from people living with SCI (Spinal Cord Injury) on the desired outcomes and perceived potential risks of SCS (Spinal Cord Stimulation).
DATA COLLECTED: 223 respondents living with SCI completed the survey. The majority of respondents were male (64%), were 10+ years post-SCI (63%), lived in the United States or Canada (90%) and had a mean age of 50.8 years. Most individuals had a traumatic SCI (81%) and 45% classified themselves as having tetraplegia. The top five desired outcomes of SCS include performing bowel and bladder care; less reliance on caregivers; maintaining physical health; mobility outside of the home and ability to travel. Perceived potential risks include further loss of function; increased neuropathic pain; requiring additional surgery from complications; skin breakdown over the implant; and infection requiring antibiotics. Barriers to participation in SCS clinical trials include inability to relocate, out-of-pocket expenses and awareness of therapy.
CONCLUSIONS: SCS clinical trial design, participant recruitment and translation of the technology can be improved by better understanding the desired outcomes and perceived potential risks for those living with SCI identified from this study.
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DATASET CITATION:
Amar Kumar P., Dulin J. N. (2023) hM4Di-mediated chemogenetic attenuation of acute nociceptive signaling enhances locomotor function and prevents the development of thermal hypersensitivity following moderate T10 spinal cord contusion injury in female Sprague-Dawley rats. Open Data Commons for Spinal Cord Injury. ODC-SCI:851 http://dx.doi.org/10.34945/F5730S
ABSTRACT:
STUDY PURPOSE: Identifying novel therapeutic approaches to promote recovery of neurological functions following spinal cord injury (SCI) remains a great unmet need. Nociceptive signaling in the acute phase of SCI has been shown to inhibit recovery of locomotor function and promote the development of chronic neuropathic pain. We therefore hypothesized that inhibition of nociceptive signaling in the acute phase of SCI might improve long-term functional outcomes in the chronic phase of injury. To test this hypothesis, we took advantage of a selective strategy utilizing AAV6 to deliver inhibitory (hM4Di) DREADDs to nociceptors of the L4-L6 dorsal root ganglia, in order to evaluate the effects of transient nociceptor silencing on long-term sensory and motor functional outcomes in a rat thoracic contusion SCI model.
DATA COLLECTED: Abbreviated Methods:
(More detailed information can be found in the Methodology document.)
Female Sprague-Dawley rats (200-250g) were used for this study. AAV6-hM4Di or AAV6-YFP (8x10^12 genome copies/mL) was injected into bilateral sciatic nerves 4 weeks prior to SCI/sham. Either thoracic (T10) contusion SCI (150 kydnes, 1 s dwell, Infinite Horizon Impactor device) or sham surgery was performed at Day 0. Immediately following SCI, either clozapine-N-oxide (CNO; hM4Di agonist) or vehicle (0.05% DMSO) was injected intraperitoneally. Beginning on the day of surgery, either CNO or vehicle + 5 mM saccharine was administered in drinking water for 14 days.
Following CNO or vehicle treatment from 0-14 days post-SCI, we conducted behavioral assessments until 70 days post-SCI, then performed histological assessments of lesion severity and axon plasticity. Behavioral assessments include open field locomotor (BBB) testing, CatWalk gait analysis, Hargreaves (thermal sensitivity) testing of hindpaws, von Frey (mechanical reactivity) testing of hindpaws, and acetone (cold allodynia) testing of hindpaws.
All behavioral testing except for BBB was performed weekly beginning at 2 weeks post-SCI and continuing until 10 weeks post-SCI. BBB data were collected at 1, 3, 7 days post-SCI then weekly until 10 weeks post-SCI. At the study endpoint, animals were transcardially perfused and spinal cord and DRG tissue was collected for histological analysis. The following histological measures were assessed: Lesion volume based on GFAP immunoreactivity, grey matter sparing based on NeuN labeling, white matter sparing based on beta-tubulin labeling, intensity of beta-tubulin immunoreactivity, density of CGRP+ fibers in the T10 and L4 spinal cord, density of IB4-binding fibers in the T10 and L4 spinal cord, density of synaptophysin+ punctae on ChAT+ motor neurons in the L4 spinal cord. Detailed histological analysis methods are described in the Methodology file.
Results:
-Immunohistochemistry results show highly selective expression of hM4Di within small diameter nociceptors including CGRP+ and IB4-binding neurons.
-A two-way repeated measures ANOVA identified a significant effect of time x treatment (P<0.0001) in the thermal hindlimb paw withdrawal scores between SCI-YFP and SCI-hM4Di animals. At the first time point tested following SCI (14 DPI), animals in the SCI-YFP group showed significantly reduced withdrawal latencies to a thermal stimulus relative to naïve controls, and this continued until 35 DPI (Tukey's multiple comparisons test, P<0.05 at each time point).
-No significant differences in von Frey mechanical reactivity scores, or acetone cold allodynia scores, were observed between SCI-YFP and SCI-hM4Di treatment groups.
-A repeated measures ANOVA identified a significant effect of treatment on open field locomotor (BBB) scores (P=0.0489), indicating that acute nociceptor silencing improved long-term locomotor recovery.
-Based on a pLDA analysis of CatWalk data, we found that compared to the naïve and sham groups, both SCI groups exhibited significantly lower pLDA scores at all timepoints post-SCI (P < 0.0002 in all cases); however, the pLDA scores of SCI groups were not significantly different to each other.
-Lesion volume, calculated by drawing regions of interest around GFAP+ reactive glial cell layers immediately surrounding the lesion cavity, was not significantly different between SCI-YFP and SCI-hM4Di subjects.
-We found that density of both CGRP+ and IB4-binding axons did not differ significantly between SCI groups.
CONCLUSIONS: Together, these findings suggest that nociceptor silencing early after SCI may promote beneficial plasticity in the acute phase of injury that can impact long-term functional outcomes, and support previous work highlighting primary nociceptors as possible therapeutic targets for pain management after SCI.
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DATASET CITATION:
Metz K., Concha Matos I., Hari K., Bseis O., Afsharipour B., Shihao L., Singla R., Fenrich K., Li Y., Bennett D. J., Gorassini M. A. (2023) H-reflex modulation from sensory conditioning in non injured female and male human participants. Open Data Commons for Spinal Cord Injury. ODC-SCI:824 http://dx.doi.org/10.34945/F5M88Z
ABSTRACT:
STUDY PURPOSE: Sensory signals travelling into the spinal cord, and the control of those sensory signals, are essential for human movement. For many years it was believed that sensory signals, specifically action potentials travelling along Ia afferents, were suppressed by GABAA receptor mediated primary afferent depolarization (PAD). Recent findings in animals and humans show a faciliatory role for PAD in Ia afferent conduction, putting into question previous reports showing that conditioning inputs that putatively evoke PAD suppress subsequent H-reflex (Ia – motoneuron) activations. In this dataset, and the accompanying paper, we present data used to examine the control of sensory signals by GABAergic inputs along the Ia-motoneuron pathway in humans.
DATA COLLECTED: Our sample compromised of 28 adult (age 20-58 years) human participants (11 male). Thirteen of the participants also participated in the related study (dataset 811), subject IDs match for overlapping participants. The Ia – motoneuron pathway was measured by percutaneously stimulating the tibial nerve in the popliteal fossa to activate a soleus H-reflex. The peak-peak amplitude of the soleus H-reflex was measured before (test) and after (cond) a conditioning stimulation to putatively activate GABAergic networks in the spinal cord and primary afferent depolarization (PAD) in the test (soleus) Ia afferents. Specifically, mechanical vibration of the tibialis anterior tendon at the ankle (3 pulses, 10 Hz) or percutaneous stimulation of the common fibular nerve (CFN; 1.0 or 1.5 x motor threshold, 200 Hz, 10 ms; near the fibular head on the ipsilateral leg) was applied at an interstimulus interval (ISI) before evoking the soleus H-reflex. The ISI (ISI_Vib; ISI_CFN) and average percent change of the peak-peak amplitude of the conditioned soleus H-reflex at various interstimulus intervals for each participant is presented in the data set (Vib_Hreflex; CFN_1.0xMT_Hreflex; CFN_1.5xMT_Hreflex; CFN_facilitation_Hreflex).
Soleus single motor units and ongoing EMG were measured in response to the conditioning stimulation (vibration or CFN stimulation) applied alone to isolate the postsynaptic effects of the conditioning stimulation on the soleus motoneurons. Specifically, the average firing rate of the soleus single motor units (taken from the peristimulus frequencygram [PSF]; PSF_Vib; PSF_CFN_1.0xMT; PSF_CFN_1.5xMT) or amplitude of the ongoing EMG (EMG_Vib; EMG_CFN_1.0xMT; EMG_CFN_1.5xMT) over many trials was averaged into 10 ms bins (Time_of_bin_Vib; Time_of_bin_CFN) for each participant. The average early (100-300 ms after the CFN stimulation) soleus motor unit firing rate was also measured for each participant (Early_MU_area). The number of units fired per 10 ms bin from the PSF were also measured using a peristimulus time histogram (PSTH; PSTH_Vib; PSTH_CFN_1.0xMT; PSTH_CFN_1.5xMT).
As a measure of post-activation depression, rate dependent depression (RDD) of the soleus H-reflex was compared to the longer CFN conditioning trials by repetitively activating (stimulating the tibial nerve in the popliteal fossa) the same soleus H-reflex at the same interstimulus intervals (500-2500ms). The average percent change of the soleus H-reflex in response to repetitive activation (by comparing the first H-reflex in a trial to the average of the next 7 H-reflexes) is presented in the data set (RDD_percent_change) for each ISI (ISI_CFN). This data is also presented showing the percent change of the soleus H-reflex in response to repetitive activations (RDD_2500_change_Hreflex; RDD_2000_change_Hreflex; RDD_1500_change_Hreflex; RDD_1000_change_Hreflex; RDD_500_change_Hreflex) and CFN conditioning stimulation (CFN_2500_change_Hreflex; CFN_2000_change_Hreflex; CFN_1500_change_Hreflex; CFN_1000_change_Hreflex; CFN_500_change_Hreflex) at each ISI (500-2500 ms) and for each H-reflex number in a trial (Hreflex_number).
CONCLUSIONS: The CFN conditioning stimulation often produced an early excitatory response in the soleus motor units and EMG, consistent with PAD-evoked spikes being activated in the soleus afferents that travel orthodromically to the afferent terminals and activating the soleus motoneurons. When this excitatory response from the CFN stimulation was present in the soleus motor units and EMG, subsequent activations of the soleus H-reflex pathway were suppressed out to 2500 ms. The profile of soleus H-reflex suppression from the CFN conditioning stimulation closely resembled the profile of rate dependent depression (RDD) from repeated activations of the soleus H-reflex at the same intervals (500-2500 ms) suggesting both may be mediated by post-activation depression. Suppression of extensor H-reflexes from flexor afferent conditioning appears to be mediated, at least in part, by post-activation depression from PAD-evoked spikes.
A more detailed description of the data can be found in the accompanying paper. Animal data from the paper is available upon request.
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DATASET CITATION:
Liu S., Xing C., Wei H., Guo J., Wang L., Li B., Ma H., Zhong H., Zhou M., Zhu S., Zhu R., Ning G. (2022) CatWalk Gait parameters at 8 weeks after T10 thoracic contusion using the MASCIS impactor model III in male and female 8- to 10-week old rats. Open Data Commons for Spinal Cord Injury. ODC-SCI:822 http://dx.doi.org/10.34945/F5VS3D
ABSTRACT:
STUDY PURPOSE: In preclinical studies of spinal cord injury (SCI), behavioral assessment is crucial in determining the effectiveness of interventions. As an automated gait analysis system, catwalk provides a large number of objective gait parameters through the acquisition and calculation of rodent footprints and videos. However, the gait parameters may not all be suitable for assessing hindlimb locomotor function in animals with thoracic contusion SCI. The purpose of this study was to discover CatWalk gait parameters applicable to different severity ranges (sham, mild, moderate, severe) of T10 spinal cord contusion injury in rats.
DATA COLLECTED: A total of 48 adult male and female Wistar rats, weighing 190-210 g and aged 8-10 weeks old, were used in this study. The thoracic spinal cord of rats was contused by MASCIS impactor model III (W. M. Keck Center, Rutgers University, United States) according to the modified Allen's method. The animals subsequently underwent T10 spinal cord contusions caused by a 10 g impactor dropped at varying heights of 12.5 mm (mild), 25.0 mm (moderate), and 50.0 mm (severe). Animals in the sham group only received laminectomy without contusion.N=12/group. Catwalk gait analysis were performed at 8 weeks post-injury. The performance of moving in one direction without stopping or turning around was recorded.The specific detection settings used in the experiment were as follows: camera gain = 17.75 dB, green intensity threshold = 0.12, red ceiling light= 17.1 V, and green walkway light = 15.4 V. Multiple groups were compared using Kruskal-Wallis test with Dunn's post-hoc test.
CONCLUSIONS: Among the CatWalk gait parameters, regularity index could reflect differences between the Sham, SCI-mil, and SCI-mod groups, but not between the SCI-mod and SCI-sev groups . Our work provides a comprehensively CatWalk gait parameters for SCI studies, which could be applicable to objectively reflect locomotor recovery of T10 spinal cord contusion injury in rats.
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DATASET CITATION:
Sydney-Smith J. D., Koltchev A. M., Moon L. D F., Warren P. M. (2022) Delayed viral vector mediated delivery of neurotrophin-3 improves skilled hindlimb placement on the horizontal ladder, hindlimb coordination during swimming, and stability walking in the open field after T9 thoracic contusion in female rats. Open Data Commons for Spinal Cord Injury. ODC-SCI:800 http://dx.doi.org/10.34945/F51G60
ABSTRACT:
STUDY PURPOSE: Restoration of skilled function is a key objective for spinal cord injury (SCI) patients. Intramuscular injections of viral (adeno-associated viral vector 1; AAV1) Neurotrophin-3 (NT-3) into the rat hindlimb 24 hours following thoracic T9 contusion has been shown to restore some functional locomotor activity, aid spinal neuroplasticity, and reduce spasms. Here, we test the hypothesis that injection of AAV1-CMV-NT3 to the rat abdominal and hindlimb muscles 48-hours following severe T9 contusion will enable functional recovery of skilled locomotive activity and reduced hyper reflexivity in female rats.
DATA COLLECTED: The dataset includes n=29 female Sprague Dawley rats, injured at 8 weeks of age. Animals received either: 1) a 250 kDyne thoracic level 9 (T9) contusion via the Infinite Horizon impactor; or 2) a Sham injury (all surgical procedures including the laminectomy, apart from the injury itself). 48-hours following injury contused animals received bilateral injections of either PBS vehicle or AAV1-CMV-NT3 into their tibialis anterior, gastrocnemius and rectus abdominus muscles. Experimental groups were thus defined as: 1) NT3 (contusion and AAV1-CMV-NT3 injection); 2) PBS (contusion and PBS injection; and 3) Sham (Sham injured). Animals were assessed for recovery over 10 weeks. Functional recovery was assessed prior to injury and then weekly using the Basso, Beattie and Bresnahan (BBB) locomotor rating scale, and horizontal ladder. At prior to injury and then at 4 and 9 weeks post injury the animals were assessed for coordination, spasm, and the number of hindlimb strokes in the swimming task. Spasm activity was assessed at 10 weeks post injury through H-reflex recordings. At 11 weeks post injury, CtB injections were made into the lateral head of the gastrocnemius in the left hindlimb to retrogradely trace innervating motor neurons. At the experimental (end-point 11 weeks following injury), blood samples were taken from which levels of NT3 protein in serum could be assessed. Following an overdose of anesthetic (sodium pentobarbital), animals were transcardially perfused. Magnetic resonance imaging (MRI) was used on intact cord following animal perfusion to determine the lesion volumetrics. Following ex vivo MRI, spinal cords were washed, sectioned and stained to histologically assess levels of vGlut1+ and NeuN.
CONCLUSIONS: NT3 levels: Analysis of blood serum showed that AAV1-CMV-NT3 injected animals alone had a 75-fold increase in NT3 11 weeks post injury.
Lesion volume: The treatment did not cause any alteration in lesion volumetrics. Injury caused a 68% reduction in total transverse cross-sectional area and a 36% reduction in presumptive spared white matter at the lesion epicenter as determined through ex vivo magnetic resonance imaging. However, no difference was shown between NT3 and PBS treated groups.
Behavior: Animals in the NT3 treatment group alone showed sustained and improvements in skilled functional behaviors including reduced right hindlimb slips and greater number of corrected missteps than PBS treated animals normalizing to Sham levels from six weeks post injury. NT3 treatment also caused an ~15% increase in hindlimb coordination during swimming as compared to PBS treated animals, and trunk stability within the open field (at nine- and ten-weeks post injury).
Histology: Histological analysis showed a near two-fold increase in vGlut1+ boutons on innervating proprioceptive fibers caused by injury (average number of puncta: Sham=2.6±0.17, PBS=4.9±0.45). However, NT3 treatment a reduction in puncta number to a level comparable with Sham injured animals (3.4±0.23 puncta). This may suggest behavioral alterations are attributable to a normalization of vGlut1+ boutons on innervating proprioceptive fibers.
Hyperreflexia: The injury did not cause spasticity or hyperreflexia in the animals as determined through visual and electrophysiological assessment via the H-reflex of the hindlimb (values consistent between groups for normalize H wave amplitude, maximum M wave amplitude, maximum H wave amplitude, Hmax:Mmax).
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DATASET CITATION:
Metz K., Concha-Matos I., Li Y., Afsharipour B., Thompson C. K., Negro F., Bennett D., Gorassini M. A. (2022) Facilitation of sensory axon conduction to motoneurons during cortical or sensory evoked primary afferent depolarization (PAD) in humans. Open Data Commons for Spinal Cord Injury. ODC-SCI:811 http://dx.doi.org/10.34945/F5WS3Q
ABSTRACT:
STUDY PURPOSE: Sensory feedback to the spinal cord is essential for motor control. After injury to the central nervous system, such as spinal cord injury, the mechanisms that regulate sensory feedback become unbalanced leading to poor motor control, spasticity and pain. Unfortunately, our understanding of sensory feedback is relatively limited, even in the uninjured nervous system, making the treatment of motor control issues related to sensory feedback challenging. It was previously believed that sensory feedback was regulated by specialized GABAergic neurons that inhibited sensory inputs in the spinal cord, termed presynaptic inhibition. Recent findings in rodents shows that these GABAergic pathways actually facilitate conduction along afferents in the spinal cord by depolarizing the afferent at vulnerable branch points and reducing branch point failure. Based on these recent findings, we evaluated similar pathways in uninjured humans, with future hopes of evaluating these pathways in participants with spinal cord injury.
DATA COLLECTED: The Ia - motoneuron pathway was measured using an H-reflex, evoked below half the maximum amplitude in either the soleus muscle (stimulation of the tibial nerve at the popliteal fossa) or the abductor hallucis (AbHal) muscle (stimulation of the tibial nerve at the popliteal fossa or at the medial malleolus). The peak-peak amplitude of the H-reflex was measured before (test) and after (cond) a conditioning stimulation to putative active GABAergic networks in the spinal cord and primary afferent depolarization (PAD) in the test (soleus or AbHal) afferents. Presynaptic effects of the conditioning stimulation on the test Ia afferents were discerned from postsynaptic effects on the test motoneurons using single motor unit and EMG analysis with the conditioning stimulation applied alone, thus giving information about the isolated postsynaptic effects of the conditioning stimulation. The probability of discharge of a tonically firing soleus single motor unit at the latency of the H-reflex (after tibial nerve stimulation) was also compared before and after a conditioning stimulation to putative evoked PAD.
Specifically, the cutaneous branch of the superficial fibular nerve (SFN) was electrically stimulated on the top of the foot at an intensity just above perception threshold at various interstimulus intervals (ISIs) between 0 and 300 ms to assess short-lasting phasic PAD (200 Hz, 10 ms) and at longer intervals (out to 130 seconds) to assess long-lasting tonic PAD (0.2 and 2 Hz for 10s, 200 Hz for 500 ms) using the soleus H-reflex. Similarly, the common fibular nerve (CFN) was electrically stimulated (near the fibular head on the ipsilateral leg) at motor threshold (1.0 x MT) 0-300 ms before activation of the soleus H-reflex. A heteronymous H-reflex in the Biceps Hetero (stimulation of the tibial nerve supplying the medial gastrocnemius) was also conditioned by SFN and CFN stimulation. Activation of the corticospinal tract (CST) using transcranial magnetic stimulation (TMS; 0.9 x active motor threshold) of the contralateral motor cortex was used to condition the soleus and AbHal H-reflex and assess short-lasting phasic PAD.
A peristimulus frequencygram (PSF) of the firing rate of a tonically discharging single motor unit in response to the putative PAD-evoking conditioning stimulation over many trials was created, with the time of the conditioning stimulation time-locked to 0 ms. The PSF was binned into 20 ms averages and the average firing rate at each bin was compared to the time when an H-reflex would have occurred at the various ISIs. A similar analysis was done for the EMG recorded during a small contraction.
Self-facilitation of the soleus H-reflex was also measured by comparing H-reflexes evoked every 5 seconds. The average peak-peak amplitude of the first 7 H-reflexes were compared to the peak-peak amplitude of the next 7 H-reflexes.
A more detailed description of the data collected can be found in the accompanying paper.
CONCLUSIONS: We find new evidence that sensory and corticospinal pathways known to activate GABAergic networks in the spinal cord can facilitate H-reflexes without any accompanying faciliatory postsynaptic effects.
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DATASET CITATION:
Stewart A. N., Glaser E. P., Mott C. A., Bailey W. M., Sullivan P. G., Patel S. P., Gensel J. C. (2022) Assessment of spinal cord glutathione levels and regulatory pathways at 1- and 3-days post-injury after 60 kDyn T9 spinal-contusion using the Infinite Horizons impactor in male and female 4- and 14-month old mice and evaluating n-acetylcysteine amide as a therapy in female 4- and 14-month old mice to restore spinal cord levels of glutathione and to protect against oxidative stress and affect locomotor outcomes and thermal sensitivity by 28-days after spinal cord injury.. Open Data Commons for Spinal Cord Injury. ODC-SCI:731 http://dx.doi.org/10.34945/F5XS31
ABSTRACT:
STUDY PURPOSE: The purpose of this study was to evaluate the role of advanced age at the time of spinal cord injury (SCI) on antioxidant defense, with an emphasis on glutathione synthesis and metabolism. Further, this study aimed to determine if enhancing spinal levels of glutathione using the cysteine supplement, n-acetylcysteine amide (NACA), would confer age-dependent effects on functional and histological outcomes.
DATA COLLECTED: Levels of spinal glutathione were deterred in sham and injured mice at 1- and 3-days post-injury (dpi). Further, the relative protein abundance of glutathione synthetase, peroxidase, reductase, and glutamyl-cysteine ligase were determined on western blot. Activity assays were used to determine the function of glutathione peroxidase and reductase at 1- and 3-dpi. Accumulation of oxidative stress using dot blots against 3-nitrotyrosine or 4-hydroxynonenol were obtained. Mice were treated with n-acetylcysteine amide and spinal cord levels of glutathione were determined both in naive 4-month-old mice and after SCI in 4- and 14-month-old mice and 1-dpi. Next, mice were treated with NACA for 3-dpi and were allowed to recover for 28-days. Locomotor functions were assessed on the BMS and horizontal ladder, and the Hargreaves test of thermal hypersensitivity was used to determine effects on SCI-induced pain. Lesion outcomes and neuron survival were assessed in tissue sections.
CONCLUSIONS: Older spinal cords have less glutathione prior to SCI compared to younger counterparts, and do not exhibit a strong decline in glutathione after injury. In contrast, younger spinal cords exhibit an injury-induced depletion by 3-dpi. Younger, but not older, spinal cords respond by up-regulating antioxidant activity of glutathione peroxidase which is independent of protein abundance. Treating SCI with NACA did not affect outcomes in younger mice, but trended towards a toxic effect on all outcomes in older mice. We conclude that being older at time of SCI does decrease antioxidant capacity but treatment using NACA to restore glutathione levels exerts unanticipated toxic trends that may, or may not, be associated with NACAs effects on glutathione.
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DATASET CITATION:
Fraussen J., Beckers L., van Laake-Geelen C. C.M.., Depreitere B., Deckers J., Cornips E. M.J.., Peuskens D., Somers V. (2022) Immune phenotyping SCI patients versus healthy controls. Open Data Commons for Spinal Cord Injury. ODC-SCI:774 http://dx.doi.org/10.34945/F5588X
ABSTRACT:
STUDY PURPOSE: Following a spinal cord injury (SCI), an inflammatory immune reaction is triggered which results in advanced secondary tissue damage. The systemic post-SCI immune response is poorly understood. This study aimed to extensively analyse the circulating immune cell composition in traumatic SCI patients in relation to clinical parameters.
DATA COLLECTED: High-dimensional flow cytometry was performed on peripheral blood mononuclear cells of 18 traumatic SCI patients and 18 healthy controls to determine immune cell subsets. SCI blood samples were collected at multiple time points in the (sub)acute (0 days to 3 weeks post-SCI, (s)aSCI) and chronic (6 to >18 weeks post-SCI, cSCI) disease phase. Not all time points were available for every included SCI patient due to organizational issues (late inclusion) or withdrawal of subjects from the study. Twelve SCI patients presented with a cervical injury, 5 with a thoracic injury and 1 with a lumbar injury. We first analyzed the major immune cell subsets in PBMC of HC, (s)aSCI patients and cSCI patients. These included CD14+ monocytes, natural killer (NK) cells, which are classically divided into cytotoxic CD56loCD16+ and highly cytokine producing CD56hiCD16+/- subsets, CD19+ B cells and CD3+ T cells, divided into CD4+ helper and CD8+ cytotoxic subsets. Next, the following subsets were studied in both CD4+ and CD8+ T cells: naive (Tnaive, CD45RA+CD45RO-), memory (Tm, CD45RA-CD45RO+), effector memory (Tem, CD45RA-CCR7-), central memory (Tcm, CD45RA-CCR7+), effector memory re-expressing CD45RA (Temra, CD45RA+CCR7-) and regulatory (Treg, CD25+CD127low). CD19+ B cells were studied in more detail by analysis of CD24hiCD38hi transitional, IgD+CD27- naive, IgD+CD27+ non class-switched memory (NCSM), IgD-CD27+ class-switched memory (CSM), IgM+IgD-CD27+ IgM only and IgD-CD27- double negative (DN) subsets. IgM, IgG and IgA were included to further define memory responses.
CONCLUSIONS: T cell frequencies were increased in cSCI patients. Both CD4+ T cells and B cells were shifted towards memory phenotypes in (s)aSCI patients and cSCI patients, respectively. Most profound changes were observed in the B cell compartment. Decreased immunoglobulin (Ig)G+ and increased IgM+ B cell frequencies reflected disease severity, as these correlated with American Spinal Injury Association (ASIA) impairment scale (AIS) scores. Post-SCI B cell responses consisted of an increased frequency of CD74+ cells and CD74 expression level within total B cells and B cell subsets. Findings from this study suggest that post-SCI inflammation is driven by memory immune cell subsets. The increased CD74 expression on post-SCI B cells could suggest the involvement of CD74-related pathways in neuroinflammation following SCI. In addition, the clinical and prognostic value of monitoring circulating IgM+ and IgG+ B cell levels in SCI patients should be further evaluated.
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This dataset has been removed from public view at the request of the authors, as the underlying records have been found to be insufficient. The authors regret any inconvenience caused.
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This dataset has been removed from public view at the request of the authors, as the underlying records have been found to be insufficient. The authors regret any inconvenience caused.
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DATASET CITATION:
Fouad K., Lucas Osma A. M., Vavrek R., Fenrich K. K., Bennett, D. (2022) Comparing the effect of skilled forelimb rehabilitative training after unilateral cervical contusion and dorsal quadrant spinal cord injury in female Lewis rats. Open Data Commons for Spinal Cord Injury. ODC-SCI:747 http://dx.doi.org/10.34945/F5DS3C
ABSTRACT:
STUDY PURPOSE: Moderate cervical spinal cord injury (SCI) models target spinal tracts involved in skilled reaching and grasping. Contusion SCIs are often considered the most clinically relevant injuries. They involve lateral gray matter damage and it is unknown whether rats with a cervical contusion can be trained in skilled reaching and grasping task (single pellet reaching, grasping and retrieval; SPRGR). Here we compare the impact of injury size on recovery in a SPRGR task, in rats with cervical unilateral contusion injuries (UCs) with a dorsolateral quadrant transection (DLQ).
DATA COLLECTED: Age matched adult female Lewis rats (n = 26 UC and n = 13 DLQ; 200–230 g; Charles River, Canada), were trained to retrieve food pellets. Untrained controls were placed in the training enclosures and received pellets on the floor of the enclosure where they could be licked rather than grasped. Following pre-training 5 days/week, for 6 weeks and baseline testing of the preferred paw all rats received a cervical SCI between C4-5 on the side of the preferred paw For DLQ injuries a dorsolateral quadrant SCI was performed using custom made blades. UC animals received a C5 unilateral contusion, with the tip of the impactor device (2.5 mm diameter, IH-0400 Impactor, Precision Systems and Instrumentation) over the spinal cord at 1.25 mm lateral of the midline. Impact force was set to 125 Kdyn with no dwell-time.
Starting 1 week post-injury, rats were divided into untrained and trained groups based on day 4 forelimb injury severity score. A blinded researcher evaluated performance in the trained task at 1, 3, and 5 weeks of training from 10 min videos. After the final day of testing, rats were euthanized, perfused, and spinal cord tissue was harvested.
Cervical spinal cords including the lesion site were cut at 25 microns and processed with Cresyl violet and Neurotrace staining.
Cresyl violet-stained spinal cord sections were assessed for lesion size using light and fluorescence microscopy. Tissues sections (25 µm) were imaged and quantified, every 200 µm from 2.4 mm rostral to 2.4 mm caudal of injury epicenter, to assess tissue damage. Using ImageJ the corticospinal tract (CST) and the rubrospinal tract (RST) damage was quantified based on the reported projection sites.
CONCLUSIONS: Both UCs and DLQs cause considerable damage to spinal tracts that are important for skilled forelimb movements. UCs lead to significantly more ventral and dorsal grey matter damage, as well as more ventral white matter damage than DLQs. UCs result in severe motor impairments in the reaching task soon after injury, yet there is some spontaneous recovery over time and training is effective in promoting additional recovery in the task. We conclude that the unilateral C5 contusion model is a suitableto evaluate the efficacy of training and other plasticity promoting treatments in rats.
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DATASET CITATION:
Mifflin K. A., Brennan F. H., Guan Z., Kigerl K. A., Filous A. R., Mo X., Schwab J. M., Popovich P. G. (2022) Lung immunity after complete thoracic spinal cord transection in female mice. Open Data Commons for Spinal Cord Injury. ODC-SCI:735 http://dx.doi.org/10.34945/F52G69
ABSTRACT:
STUDY PURPOSE: Pulmonary infection is a leading cause of morbidity and mortality after spinal cord injury (SCI). Although SCI causes atrophy and dysfunction in primary and secondary lymphoid tissues with a corresponding decrease in the number and function of circulating leukocytes, it is unknown if this SCI-dependent systemic immune suppression also affects the unique tissue-specific antimicrobial defense mechanisms that protect the lung. Here, we test the hypothesis that SCI directly impairs pulmonary immunity and subsequently increases the risk for developing pneumonia.
DATA COLLECTED: The dataset includes n=242 C57/Bl6 female mice aged 9-13 weeks. Mice received a complete transection SCI at either the thoracic level 1 (T1Tx) or 3 (T3Tx). Sham mice underwent a laminectomy only at the appropriate thoracic level. Flow cytometry was used to assess lung immune cells (neutrophils, T- and B-lymphocytes, alveolar macrophages, CD45+ immune cells) at 12h ((n=8-12 T3Tx, n=8-12 T3 sham), 3d (n=12 T3Tx, n=12 T3 sham, n=7 T1Tx, n=7 T1 sham), and 28d (n=12 T3Tx, n=12 T3 sham) post- injury. Corresponding cultures of lung homogenate on blood agar (n=7 12h & 3dpi T3Tx and 3dpi T3 Sham, n=12-14 28dpi T3 Sham mice, n=12-14 28dpi T3Tx, n=18 T1Tx, n=13 T1 Sham) and CHROMagar ™ plates (n=18 T1Tx, n=13 T1 Sham) at these timepoints were also used to assess pulmonary bacterial burden after injury. The drug AMD3100, a CXCR4 antagonist (1mg/mouse given subcutaneously 1h post-injury then daily for either 3d or 7d), was also tested in T1Tx mice to see if the drug improved pulmonary immune function as measured by flow cytometry (n=10 T1Tx vehicle and n= 13 T1Tx AMD3100 mice), altered blood immune cell counts (n=8 T1 sham, n=9 T1Tx vehicle and n=10 T1Tx AMD3100) or reduced bacteria load (n=21 T1Tx vehicle and n=23 T1Tx AMD3100 for 3dpi studies, n=9 T1Tx vehicle and n=10 T1Tx AMD3100 for 7dpi studies). A subset of AMD3100 treated mice also underwent an induced pneumonia procedure (n=11 T3Tx vehicle + pneumonia and n=11 T3TxAMD3100 + pneumonia). Finally, n=4 mice were pooled from T3 Sham or T3Tx groups to perform a PCR array for lung immunity genes and RT-qPCR on 10 identified hub genes at 12h and 3d post-injury.
CONCLUSIONS: Using mouse models of severe high thoracic level 1 or 3 SCI, we find that recruitment of circulating leukocytes and transcriptional control of immune signaling in the lung is impaired after SCI, creating an environment that is permissive for infection. Specifically, we see a sustained loss of pulmonary leukocytes (up to ~60% loss), a loss of alveolar macrophages (30% loss) at chronic timepoints post-injury, and a decrease in immune modulatory genes, especially cytokines (e.g. Tnf, Il6, Infg), needed to eliminate pulmonary infections. Importantly, this injury-dependent impairment of pulmonary antimicrobial defense is only partially overcome by boosting the recruitment of immune cells to the lung with the drug AMD3100, an FDA-approved drug that mobilizes leukocytes and hematopoietic stem cells from bone marrow. Collectively, these data indicate that the immune suppressive effects of SCI extend to the lung, a unique site of mucosal immunity. Furthermore, preventing lung infection after SCI will likely require novel strategies, beyond the use of orthodox antibiotics, to reverse or block tissue-specific cellular and molecular determinants of pulmonary immune surveillance.
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DATASET CITATION:
Brennan F. H., Li Y., Wang C., Ma A., Li Y., Pukos N., Campbell W. A., Witcher K. G., Guan Z., Kigerl K. A., Hall J. CE., Godbout J. P., Fischer A. J., McTigue D. M., He Z., Ma Q., Popovich P. G. (2022) Microglia coordinate cellular interactions during spinal cord repair after contusion or crush spinal cord injury in female mice. Open Data Commons for Spinal Cord Injury. ODC-SCI:695 http://dx.doi.org/10.34945/F5B012
ABSTRACT:
STUDY PURPOSE: Traumatic spinal cord injury (SCI) triggers a neuro-inflammatory response dominated by tissue-resident microglia and monocyte derived macrophages (MDMs). To better understand the specific role of microglia in SCI, we pharmacologically depleted microglia using the CSF1R antagonist PLX5622 (1200 ppm). We used behavioral, anatomical, histopathological, tract tracing, bulk RNA sequencing and single cell RNA sequencing techniques to reveal the cellular and molecular responses to SCI that are controlled by microglia. We also reconstituted mice with or without microglia, with recombinant CCL2 (rCCL2, 50 ng intraspinally at 2 dpi) and/or a TLR2 agonist (500 ng intraspinally at 2 dpi and/or 50 ug/kg i.p. at 3 dpi). We also collected baseline behavior and challenged mice with lipopolysaccharide (LPS, 1 mg/kg daily for four consecutive days) to determine whether PLX5622 has any off-target effects.
DATA COLLECTED: The dataset includes n=230 female mice aged 10-12-weeks on a C57BL/6J background. Mice received a 75 kdyne T9 IH contusion SCI, sham surgery, or a L1 or T9 complete forceps crush SCI. Mice were fed PLX5622 (1200 ppm) or Vehicle chow from 2 weeks before surgery/ intervention until the experimental end point of 3d, 4d, 7d, 14d, 21d, 28d or 35d after surgery/intervention. The Basso Mouse Scale (BMS) main score and sub-score were used to assess motor function at baseline and 1, 3, 7, 10, 14, 21, 28, and 35 days post-injury. The horizontal ladder task was performed at baseline and day 20, 27 and 34 post-injury. Lesion volume, lesion length, spared myelin, spared axons, astrogliosis, NG2 cell presence, microglia and macrophage presence were analyzed in histological sections using standard immunohistochemical techniques. Dividing cells were identified based on Bromodeoxyuridine (BrdU) labeling (50 mg/kg i.p BrdU administered daily in a subset of mice from 1-7 dpi). Biotinylated dextran amine (BDA, 1 ul, 10% solution) was injected into the motor cortex at 14 dpi to assess the distance of corticospinal tract retraction from a T9 crush SCI at 28 dpi. Injury parameters for all mice, including those used for bulk RNA sequencing or single cell RNA sequencing experiments, are provided. Gene expression datasets are available on Gene Expression Omnibus (GSE196928) and code is available on GitHub at https://github.com/OSU-BMBL/Spinal-cord-scRNAseq. Additional uninjured mice were used to establish baseline behavior and immune responses to LPS challenge in mice on PLX5622 diet. We used the BMS scale, hot plate and Von Frey tasks to assess motor and sensory function in uninjured mice.
CONCLUSIONS: Microglia have a beneficial role in SCI recovery. Depletion of microglia worsens motor recovery, and tissue pathology, impairs glial proliferation in contusion SCI and L1 crush SCI, and increases axon dieback after T9 crush SCI. Administration of rCCL2 and TLR2 prevents secondary damage and improves functional recovery in microglia depleted mice. PLX5622 has no effect on motor or sensory function in uninjured mice and minimal off-target effects on circulating myeloid lineage cells. Optimal repair after SCI and likely other forms of neurological disease, might be achieved by co-opting key ligand-receptor interactions between microglia, astrocytes and monocyte-derived macrophages.
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DATASET CITATION:
Madalena K. M., Brennan F. H., Popovich P. G. (2022) Genetic deletion of the glucocorticoid receptor in Cx3cr1+ myeloid cells is neuroprotective and improves motor recovery in female mice after 75 kdyne T9 contusion spinal cord injury. Open Data Commons for Spinal Cord Injury. ODC-SCI:734 http://dx.doi.org/10.34945/F56887
ABSTRACT:
STUDY PURPOSE: Glucocorticoid receptors (GRs), part of the nuclear receptor superfamily of transcription factors (TFs), are ubiquitously expressed in all cell types and regulate cellular responses to glucocorticoids (e.g., cortisol in humans; corticosterone in rodents). In myeloid cells, glucocorticoids binding to GRs can enhance or repress gene transcription, thereby imparting distinct and context-dependent functions in macrophages at sites of inflammation. In experimental models and in humans, glucocorticoids are widely used as anti-inflammatory treatments to promote recovery of function after SCI. Thus, we predicted that deleting GR in mouse myeloid lineage cells (i.e., microglia and monocyte-derived macrophages) would enhance inflammation at the site of injury and worsen functional recovery after traumatic spinal cord injury (SCI).
DATA COLLECTED: The dataset includes n=29 female mice with genotype of GRf/f (Macrophage GR intact) or Cx3cr1-Cre;GRf/f (Macrophage GR deleted). Mice received a 75 kdyne T9 IH contusion SCI or sham (laminectomy only) surgery. The Basso Mouse Scale (BMS) main score and sub-score were used to assess motor function. At 35 dpi, animals were perfused with 0.1M PBS followed by 4% PFA, and spinal tissues were cryopreserved in OCT at -80oC. Tissues were cut in serial sections on a cryostat, 12 um thick along the coronal axis. Spared myelin (EC), spared axons (NFH), and vessel sparing (CD31) were assessed using immunohistochemical staining. GFAP, Iba1, MBP, CD68, and Oil Red O staining was performed in coronal spinal histological sections at 35 days post-injury (dpi). Injury parameters are included for all injured mice. For validation of GR knockout in myeloid cells, we used additional male and female uninjured Cx3cr1-Cre;TdT mice (n=6) and uninjured TdTomato controls (n=4).
CONCLUSIONS: Contrary to our prediction, the intraspinal macrophage response to a moderate (75 kdyne) spinal contusion SCI was reduced in Cx3cr1-Cre;GRf/f conditional knockout mice (with GR specifically deleted in myeloid cells). This phenotype was associated with improvements in hindlimb motor recovery (increased BMS motor scores and subscores; 57% some-most coordination in macrophage GR deleted vs. 0% in macrophage GR intact, 71% paws parallel in macrophage GR deleted vs. 13% in macrophage GRintact, and 43% severe trunk in macrophage GR deleted vs. 62% in macrophage GR intact). GR depletion in myeloid cells also improved myelin sparing (47% more erichrome cyanine staining in lesion epicenter), axon preservation/regeneration (34% more neurofilament staining in lesion epicenter), and microvascular protection/plasticity (33% more CD31 staining) relative to SCI mice with normal myeloid cell GR expression. Further analysis of phagocytic macrophage morphology and myelin basic protein engulfment using CD68 and MBP staining revealed that macrophage GR deletion impairs lipid and myelin phagocytosis and presence of macrophages with a 'foamy' morphology. Together, these data reveal endogenous GR signaling as a key pathway that normally inhibits mechanisms of macrophage-mediated repair after SCI.
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DATASET CITATION:
Chou A., Beattie M. S., Bresnahan J. C., Burke J. F., Almeida C. A., Dhall S. S., DiGiorgio A. M., Duong-Fernandez X., Haefeli J., Hemmerle D. D., Huie J., Kyritsis N., Manley G. T., Moncivais S., Omondi C., Pascual L. U., Singh V., Talbott J. F., Thomas L. H., Torres-Espin A., Weinstein P. R., Whetstone W. D., Pan J. Z., Ferguson A. R. (2022) AIS impairment scale, injury characteristics, intraoperative data after spinal cord injury in patients from a TRACK-SCI cohort. Open Data Commons for Spinal Cord Injury. ODC-SCI:727 http://dx.doi.org/10.34945/F5KG6Z
ABSTRACT:
STUDY PURPOSE: The aim of the data collection was to identify predictors of whether a patient would improve on the ASIA Impairment Scale (AIS) grade between time of hospital admission and hospital discharge. Predictors investigated include injury characteristics, anesthetics and vasopressors used during surgery, MRI BASIC score, length of surgery and hospital stay, and intraoperative hemodynamics. The data were collected at a level I trauma center (Zuckerberg San Francisco General Hospital) and span both a retrospective and prospective study for the purpose of predictive modeling and external validation respectively.
DATA COLLECTED: The dataset include: (1) various injury characteristics such as the level of injury, presence of polytrauma, type of injury (e.g. penetrating, hemorrhagic, central cord, cervical, fracture, vertebral artery), and whether the patient had previous history of SCI or TBI; (2) vasopressor and anesthetic usage during surgery; (3) length of surgery and hospital stay; (4) intraoperative fraction of inspired oxygen; (5) the duration the patient was within and outside MAP goals in the ICU; (6) MRI BASIC Score; and (7) various intraoperative hemodynamics. In particular, the hemodynamics were derived from time series data of heart rate and systolic, diastolic, and mean arterial blood pressure during surgery. This includes summary statistics of mean, standard deviation, skew, and kurtosis. For mean arterial blood pressure specifically, the duration that a patient was outside a specific threshold (upper or lower) was also determined and recorded in the dataset.
CONCLUSIONS: Predictive models optimized from the data show that initial injury severity (either AIS at time of hospital admission or MRI BASIC score) were highly predictive variables for whether the patient improved in outcome by the time of hospital discharge. Additionally, intraoperative hyper- and hypotension (high and low MAP) were critical predictors; patients that spent more time in a hyper and/or hypotensive state were less likely to improve. Hypertension in particular was more predictive of worse outcome than hypotension. The lower MAP threshold predicting worse outcome was around 74-76 mmHg and the upper MAP threshold was around 103-104 mmHg.
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DATASET CITATION:
Cerqueira S. R., Benavides S., Lee H. E., Ayad N. G., Lee J. K. (2022) Neuroprotection and bromodomain and extra-terminal domain (BET) protein inhibition after T8 spinal cord contusion in female rats and mice. Open Data Commons for Spinal Cord Injury. ODC-SCI:696 http://dx.doi.org/10.34945/F5ZP4P
ABSTRACT:
STUDY PURPOSE: In this study, we tested the therapeutic potential of inhibiting bromodomain and extraterminal domain (BET) proteins after SCI, and investigated the role of the BET protein BRD4 in macrophages during progression of SCI pathology.
DATA COLLECTED: We investigated the anti-inflammatory and neuroprotective effects of BET inhibition in a rat moderate T8 contusion model (IH impactor; 200 kDyn). First, we performed a dose response study (7.5; 25; 75 mg/kg) of two compounds (IBET-151; IBET-762) administered intraperitoneally (IP) at 3 hours post-SCI. At 6 hours post-SCI, 4-mm long samples of spinal cord centered at the injury epicenter were collected to measure expression of proinflammatory cytokines using qPCR (n=6/group). We then performed IP administration of vehicle, IBET-151 or IBET-762 (50mg/kg) at 3 and 18 hours after SCI and verified transcription levels of proinflammatory cytokines at 24 hours post-SCI using RT-qPCR (n=6/group). Based on these data, we performed a long-term study using the same experimental SCI model, and treated animals with vehicle or IBET-762 (3h; 18h; 1, 2 and 3 days after SCI) (n=11-12/group). Rats were scored using the Basso, Beattie and Breshnahan (BBB) scale at day 1, and weekly thereafter. Eight weeks after SCI, animals were perfused, spinal cord injury sites removed and sectioned sagittally. Unbiased stereological quantifications of lesion size (GFAP negative area), fibrotic scar formation (PDGFRb positive area), and immune cell infiltration (CD11b positive area) in the lesion site were done in 3-5 sections per animal.
Next, we investigated the role of BRD4 in macrophages after SCI using LysM-Cre-TDT BRD4 KO mice. Female mice (8-10 weeks old) were subjected to a T8 contusion (IH impactor; 65 kDyn) (WT controls n=8; Brd4 KO n=8). Locomotor recovery was assessed at day 1 after SCI and weekly thereafter using the Basso Mouse Scale open field test for mice. Four weeks after SCI, mice were perfused and spinal cord injury sites collected and sectioned sagittally for histological evaluation. Unbiased stereological quantifications of lesion size (GFAP negative area), and macrophage infiltration (TDT positive area) in the lesion site were done in 3-5 sections per animal.
Finally, we evaluated the effect of macrophage-targeted BET inhibition using compound delivery via liposomes. Female mice (8-10 weeks old) were subjected to a T8 contusion (IH impactor; 65 kDyn) and liposomes were administered IP at days 1, 3, 6, 11, and 18 (vehicle liposomes n=5; IBET-762 liposomes n=5). Locomotor recovery was assessed at day 1 after SCI and weekly thereafter using the Basso Mouse Scale open field test for mice. Four weeks after SCI, mice were perfused and spinal cord injury sites collected and sectioned sagittally for histological evaluation. Unbiased stereological quantifications of lesion size (GFAP negative area), fibrotic scar (PDGFRb positive area), and macrophage infiltration (CD11b positive area) in the lesion site were done in 3-5 sections per animal.
CONCLUSIONS: Taken together, our data indicate that systemic I-BET762 treatment is neuroprotective, and the histopathological improvement observed is likely to be a result of effects on non-macrophage targets.
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DATASET CITATION:
Mirkiani S., Roszko D. A., O'Sullivan C. L., Faridi P., Hu D. S., Fang D., Everaert D. G., Toossi A., Konrad P. E., Robinson K., Mushahwar V. K. (2022) Gait kinematic parameters and onset/offset of EMG muscle activities during overground walking in healthy female Yucatan minipigs at different speed ranges from 0.4 m/s to 1.6 m/s. Open Data Commons for Spinal Cord Injury. ODC-SCI:713 http://dx.doi.org/10.34945/F5V01Q
ABSTRACT:
STUDY PURPOSE: The overall goal of this study was to provide a baseline for the overground walking in the healthy Yucatan mini pigs. Specifically, we assessed the effect of overground walking speed on various gait kinematic parameters and muscle activities.
DATA COLLECTED: Data were collected from nine neurologically-intact adult, female Yucatan mini pigs. The pigs were trained to traverse a straight 3.5 m walkway by following a human experimenter. A motion capture system was used for recording the biomechanics of walking. Wireless surface EMG electrodes were placed on the left and right gluteus medius (GM) muscles, the biceps femoris (BF) muscles, and the vastus lateralis (VL) muscles. For each pig, motion capture data (150 frames/sec) and EMG activity (3000 Hz) were recorded as the pigs traversed the walkway 20-120 times on a given testing day.
different parameters are averaged over many strides in a specific speed range. if less than 6 strides are in a speed range, the data is excluded from the analysis.
CONCLUSIONS: The data presented in this study show a significant decrease in stride duration (from 1.02±0.007 s to 0.50±0.001 s), stance (from 0.66±0.006 s to 0.23±0.002 s), and swing times (from 0.36±0.003 s to 0.27±0.001 s) as the result of increasing speed (from 0.4-0.59 m/s speed range to 1.4-1.6 m/s speed range). An increase in stride length (from 0.52±0.10 m to 0.74±0.008 m) was observed with increasing speed (from 0.4-0.59 m/s speed range to 1.4-1.6 m/s speed range). A transition in gait pattern occurred at the 1.0m/s walking speed can be observed. Significant increases in the range of motion of the knee (from 30.1±6.5 degrees to 49.1±0.7 degrees) and ankle (from 25.1±3.1 degrees to 44.5±2.5 degrees) joints were observed with increasing the speed of overground walking (from 0.4-0.59 m/s speed range to 1.4-1.6 m/s speed range). Also, the points of minimum and maximum joint angles occurred earlier in the gait cycle as the walking speed increased. The onset of EMG activity in the biceps femoris muscle occurred significantly earlier in the gait cycle with increasing speed.
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DATASET CITATION:
Stewart A. N., MacLean S. M., Stromberg A. J., Whelan J. P., Bailey W. M., Wilson M. E., Gensel J. C. (2021) Studying Sex as a Biological Variable: Considerations of weight, anemia and mortality following thoracic spinal cord contusion injury in male and female mice. Open Data Commons for Spinal Cord Injury. ODC-SCI:652 http://dx.doi.org/10.34945/F5D01P
ABSTRACT:
STUDY PURPOSE: The purpose of this study was to examine functional recovery, morbidity, mortality, etc. as a function of both sex and age in C57Bl/6J mice after thoracic contusion SCI (T9, 60kdyn, IH). Experimental groups consist of young and middle-aged mice (4 or 14 months old at the time of injury) of both sexes, male or female, that underwent contusion or sham injury. The data in this collection and a thorough interpretation of the data was published in manuscript form in Stewart et al., 2020 PMIDs: 32849242; 33193066: Considerations for Studying Sex as a Biological Variable in Spinal Cord Injury. Stewart AN, MacLean SM, Stromberg AJ, Whelan JP, Bailey WM, Gensel JC, Wilson ME. Front Neurol. 2020 Aug 5;11:802. doi:10.3389/fneur.2020.00802. eCollection 2020.
DATA COLLECTED: Collectively, data from 8 experimental groups: sex (2) x age (2) x injury (2). Sample sizes range from 5-10 depending upon the outcome measure and time of sacrifice. Data for this study include weights after injury, overall mortality, injury-induced anemia as determined by red blood cell ratios in plasma (28 days post injury), estrous cycle information for females (weekly for 4 weeks) along with endpoint (28 days) plasma estradiol levels, as well as, BMS scores at 1 and 28 days after injury. The data presented is a comprehensive collector of data collected over several years across different experiments utilizing both male and female mice. For this reason, not all outcomes were collected for all subjects (missing or NA is used to indicate data not collected). Not all studies used the same outcome measures (i.e. BMS) so not all outcomes were collected for each subject.
CONCLUSIONS: The data presented in this dataset show that sex contributes to a variety of factors after SCI including weight loss, anemia, and mortality. Further, age potentiates sex-dependent effects. Sex-specific accommodations, i.e. single housing, likely also impact SCI recovery. A corrigendum for the original manuscript was published to correct for some miscoded data, this data set reflects the corrected data as published in the corrigendum. Through our analyses, we identify several potential confounds that should be considered in a study design incorporating both sexes including differences in anatomy, behavior, housing, and drug metabolism. Ultimately, our ability to consider sex as a biological variable in the study of SCI will depend upon open and rigorous data reporting and interpretation.
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DATASET CITATION:
Torres-Espín A., Haefeli J., Ehsanian R., Torres D., Almeida C. A., Huie J., Chou A., Dirlikov B., Suen C. G., Nielson J. L., Kyritsis N., Duong-Fernandez X., Thomas L. H., Hemmerle D. D., Morozov D., Sanderson N., Talbott J. F., Manley G. T., Dhall S. S., Whetstone W. D., Bresnahan J. C., Beattie M. S., McKenna S. L., Pan J. Z., Ferguson A. R. (2021) ASIA Impairment Scale, level of injury, intraoperative time series mean arterial pressure and heart rate after spinal cord injury in patients in a multi-site retrospective TRACK-SCI cohort: site 2 of 2. Open Data Commons for Spinal Cord Injury. ODC-SCI:246 http://dx.doi.org/10.34945/F5MG68
ABSTRACT:
STUDY PURPOSE: The main goal for the collection of this data was to assess whether intraoperative hemodynamics (arterial pressure and heart rate) is associated to patient neurological improvement at hospital discharge in spinal cord injury (SCI). The data were collected in two level I trauma centers in Northern California (Santa Clara Valley Medical Center and Zuckerberg San Francisco General Hospital). This dataset represents the data from one of the centers, while the data collected in the other center is available elsewhere (see provenance). Both datasets have been harmonized, meaning variables and data dictionary align.
DATA COLLECTED: The dataset includes mean arterial pressure (MAP) and heart rate (HR) at 5 minute intervals during SCI associated surgery for n = 87 patients, as well as summaries across surgery time (average, standard deviation, kurtosis and skewness). The data also include demographics (age and gender), length metrics (surgery duration and days from injury to discharge), and injury characteristics and outcome metrics (AIS grade at admission, AIS grade at hospital discharge, dichotomized neurological level of injury: cervical vs. non-cervical).
CONCLUSIONS: Through joint analysis of both centers’ data and using machine learning methods we discovered a non-linear association of MAP during surgery and neurological improvement from hospital admission to hospital discharge. Moreover, we derived a MAP range [76-104/117mmHg] at which the longer the patient is outside that range (hypotension or hypertension) during surgery, the less likely is that the patient would have a robust neurological improvement (see the associated manuscript for further details).
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DATASET CITATION:
Torres-Espin A., Haefeli J., Ehsanian R., Torres D., Almeida C., Huie J., Chou A., Dirlikov B., Suen C. G., Nielson J. L., Kyritsis N., Duong-Fernandez X., Thomas L. H., Hemmerle D. D., Morozov D., Sanderson N., Talbott J., Manley G. T., Dhall S. S., Whetstone W. D., Bresnahan J. C., Beattie M. S., McKenna S. L., Pan J. Z., Ferguson A. R. (2021) ASIA Impairment Scale, level of injury, intraoperative time series mean arterial pressure and heart rate after spinal cord injury in patients in a multi-site retrospective TRACK-SCI cohort: site 1 of 2. Open Data Commons for Spinal Cord Injury. ODC-SCI:245 http://dx.doi.org/10.34945/F5R59J
ABSTRACT:
STUDY PURPOSE: The main goal for the collection of this data was to assess whether intraoperative hemodynamics (arterial pressure and heart rate) is associated to patient neurological improvement at hospital discharge in spinal cord injury (SCI). The data were collected in two level I trauma centers in Northern California (Santa Clara Valley Medical Center and Zuckerberg San Francisco General Hospital). This dataset represents the data from one of the centers, while the data collected in the other center is available elsewhere (see provenance). Both datasets have been harmonized, meaning variables and data dictionary align.
DATA COLLECTED: The dataset includes mean arterial pressure (MAP) and heart rate (HR) at 5 minute intervals during SCI associated surgery for n = 87 patients, as well as summaries across surgery time (average, standard deviation, kurtosis and skewness). The data also include demographics (age and gender), length metrics (surgery duration and days from injury to discharge), and injury characteristics and outcome metrics (AIS grade at admission, AIS grade at hospital discharge, dichotomized neurological level of injury: cervical vs. non-cervical).
CONCLUSIONS: Through joint analysis of both centers’ data and using machine learning methods we discovered a non-linear association of MAP during surgery and neurological improvement from hospital admission to hospital discharge. Moreover, we derived a MAP range [76-104/117mmHg] at which the longer the patient is outside that range (hypotension or hypertension) during surgery, the less likely is that the patient would have a robust neurological improvement (see the associated manuscript for further details).
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DATASET CITATION:
Keller A., Singh G., Joel S., Ugiliweneza B., D'Amico J., Gerasimenko Y., Behrman A. (2021) Trunk kinematic and center of pressure displacement time series data during transcutaneous lumbosacral spinal cord stimulation and passive pelvic tilt in human pediatric participants with trunk control impairments due to cervical or thoracic spinal cord injury (pilot clinical trial NCT03975634). Open Data Commons for Spinal Cord Injury. ODC-SCI:620 http://dx.doi.org/10.34945/F5NC7X
ABSTRACT:
STUDY PURPOSE: This was a pilot clinical trial that established the safety and feasibility of transcutaneous lumbosacral electrical spinal cord stimulation (scTS) to augment upright sitting posture and trunk control in children with spinal cord injury.
DATA COLLECTED: The feasibility of stimulation to potentiate upright sitting posture was assessed using trunk kinematics (degrees of flexion/extension in cervical, thoracic and lumbar trunk segments) and center of pressure displacement (the change in distance in mediolateral and anteroposterior directions as stimulation intensity was increased as well as during passive pelvic tilt without stimulation. 3D Kinematics (angular excursions) were measured using MVN BIOMECH Awinda MTW2-3A7G6 sensors (Xsens Technologies B.V. Enschede, Netherlands). The data was sampled at 60Hz and collected in MVN: 2019.2.1 software (XML format), mean flexion/extension angles (generated using a Kalman filter (Xsens Kalman Filter, XKF) from a 3D reconstruction of body segment position of trunk segments was calculated during at least 10 seconds of stable baseline sitting prior to stimluation and for when the participant was sitting with transcutaneous spinal stimulation on; center of pressure (COP) displacements were measured using force plate (Burtec, FP4060-NC-1000). Mean normalized COP was quantified as a change from COP values acquired during 10 seconds of baseline sitting to the COP values during sitting with individualized optimal transcutaneous stimulation intensity that induced upright posture.
CONCLUSIONS:
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DATASET CITATION:
Keller A. V., Singh G., Sommerfeld J., King M., Ugiliweneza B., D’Amico J., Gerasimenko Y., Behrman A. L. (2021) Hemodynamic stability, incidence of pain, skin redness, autonomic dysreflexia and other safety related outcome measures of transcutaneous electrical spinal cord stimulation in children with cervical and thoracic spinal cord injuries. Open Data Commons for Spinal Cord Injury. ODC-SCI:465 http://dx.doi.org/10.34945/F5HP4N
ABSTRACT:
STUDY PURPOSE: This was a pilot study to establish the safety and feasibility of transcutaneous electrical spinal cord stimulation (scTS) to augment upright sitting posture and trunk control in children with spinal cord injury.
DATA COLLECTED: The primary safety-related outcome measures were assessed over the 3 days for each participant and included: hemodynamic stability assessed using brachial arm blood pressure (mmHg) and heart rate (beats per minute) at baseline (no stimulation), during stimulation, at the end of experiments and if a child presents with symptoms of autonomic dysreflexia (e.g. facial flushing, reporting of headache, etc); incidence of autonomic dysreflexia (increase in blood pressure over 20 mmHg from a previous blood pressure measurement); incidence of pain in response to stimulation (assessed using FACES Pain Scale-Revised for children under 8 and Visual Analogue Scale for children 8 and older); incidence of skin redness under the stimulating electrodes. Trunk kinematics and center of pressure displacement data are published as a separate dataset on ODC-SCI titled:
"Trunk kinematic and center of pressure displacement time series data during transcutaneous lumbosacral spinal cord stimulation and passive pelvic tilt in human pediatric participants with trunk control impairments due to cervical or thoracic spinal cord injury (pilot clinical trial NCT03975634)"
CONCLUSIONS:
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DATASET CITATION:
Schmidt E. K. A.., Raposo P. J. F.., Madsen K. L., Fenrich K. K., Kabarchuk G., Fouad K. (2021) Effects of a fecal transplant from anxious donors on rehabilitative training, microbiota composition, systemic inflammation and behaviour following a unilateral cervical spinal contusion (C5, 125kdyn) in female Lewis rats. Open Data Commons for Spinal Cord Injury. ODC-SCI:578 http://dx.doi.org/10.34945/F5XW2P
ABSTRACT:
STUDY PURPOSE: The purpose of this study was to determine whether optimal donor selection would influence the outcome of a fecal microbiota transplant (FMT) and the efficacy of rehabilitative training after a unilateral C5 spinal contusion (infinite horizons impactor, 125 kdyns) in female Lewis rats. Uninjured, genetically identical FMT donors (n=10) were selected as rats who displayed naturally reduced baseline activity levels and increased anxiety-like behaviour. Experimental groups consisted of a group that was gavaged with the FMT solution for 3 days following SCI (SCI+FMT, n=15) and a group that received a vehicle control solution (SCI+Vehicle, n=15).
DATA COLLECTED: Data collected for this study include:
16s rRNA sequencing of fecal matter collected pre-injury, on the day of injury, then 3, 7, 14 and 56 days post injury. This data includes the bacteria bacteroidetes, firmicutes, proteobacteria, cyanobacteria, lactobacillus, as well as the alpha diversity.
Rehabilitation training on a single pellet reaching task. This includes the number of attempts and success rate at baseline (pre-injury) and throughout 8 weeks of rehab training after SCI (10 min per day, 5 days per week, analyzed once per week).
Von Frey test at 1 and 9 weeks post SCI (normalized to baseline values).
The percentage of ipsilesional paw placements in the cylinder test (9 weeks post SCI).
The total distance travelled in the open field (9 weeks post SCI).
The total distance travelled and the percentage of time spent in the open arms of an elevated plus maze (9 weeks post SCI).
The time spent in the light component of the light-dark box test (9 weeks post SCI).
The percentage of sucrose solution consumed over 2 hours (9 weeks post SCI).
The time spent interacting in the social interaction test (9 weeks post SCI).
Lesion analysis.
IBA1 density immediately caudal to the lesion, at and immediately rostral to the lesion.
Plasma analytes were measured at baseline, 3, 21 and 77 days post SCI.
FITC dextran assay for intestinal permeability (7 days post SCI displayed as a fold change from baseline, this was a separate experiment which also includes lesion analysis and plasma analytes at 7 days post SCI).
DATA USAGE NOTES: The data presented in this dataset show that a fecal transplant from anxious donors (with decreased levels of Lactobacillus in their stool) does not prevent SCI-induced dysbiosis. This fecal transplant had some long-term side effects on systemic and local inflammation and also increased anxiety-like behaviour in the recipient rats. Overall, this study shows that optimal donor selection is critical for successful FMT treatment following SCI.
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DATASET CITATION:
Stehlik K. E., Pelisch N., Kurpad S. N., Swartz K. R., Kroner A. (2021) Treatment with Gallium Maltolate after spinal cord thoracic contusion in female mice, functional outcome and inflammatory markers. Open Data Commons for Spinal Cord Injury. ODC-SCI:619 http://dx.doi.org/10.34945/F5S59V
ABSTRACT:
STUDY PURPOSE: Hemorrhage after SCI is associated with worse functional outcome, compared to non-hemorrhage SCI cases. Toxicity and pro-inflammatory effects of hemoglobin, its breakdown factors, and iron deposition may contribute to this problem. Gallium nitrate and Gallium maltolate are used in cancer therapy and in treatment of bacterial infections as iron competitors, resulting in iron starvation and cell death of bacteria or cancer cells, which have a high iron demand. While this mechanism is not necessarily relevant to control tissue hemorrhage after SCI, the additional anti-inflammatory role of gallium maltolate made it an interesting treatment consideration.
DATA COLLECTED: This experiment was performed in two cohorts of female, 8-week-old C57BL/6 mice (Charles River Laboratories). Under isoflurane anesthesia, mice were subjected to a 40 kdyne contusion (Infinite Horizon Impactor) injury at T11. In the first cohort, gallium maltolate versus a saline control (n=8-10) was injected subcutaneously immediately after injury, as well as at two and at four days later (200mg/KG). In contrast to earlier reports, this dose was not well tolerated: some mice died and the experiment was terminated at day 7. In the second cohort, mice received 25mg/KG gallium maltolate or saline s.c. on day 0 (immediately after injury), and every second day for the survival period (three or seven days). This dose was well tolerated. At day 3 or 7 after SCI, mice were euthanized with an overdose of Phenytoin/ Pentobarbital (120 mg/kg) and transcardially perfused with ice cold 1x PBS. A 5 mm piece of spinal cord centering on the lesion was dissected out, and immediately snap frozen. RNA was extracted using the RNeasy Lipid Tissue Mini Kit (Qiagen, Hilden, Germany) according to the manufacturer’s instructions, followed by RNA quantification and characterization of purity using Nanodrop (Thermo Scientific) and reverse transcription of 1 µg of RNA using QuantiTect Reverse Transcription Kit (Qiagen). Q-PCR was performed in duplicates using a PCR thermal cycler (LightCycler® 480 System, Roche) with specific primers using LightCycler® 480 Mastermix (Roche). Gene expression levels were analyzed using the ddct method normalized to peptidylprolyl isomerase A (PPIA) as a housekeeping gene and laminectomy as a baseline. The following primers were used for Q-PCR: PPIA: ATG TGC CAG GGT GGT GAC TTT A (forward primer 5'–3'); TGT GTT TGG TCC AGC ATT TGC C (reverse primer 5'–3'), TNF: TTG CTC TGT GAA GGG AAT GG (forward primer 5'–3'); GGC TCT GAG GAG TAG ACA ATA AAG (reverse primer 5'–3'), IL-1b: ATG GGC AAC CAC TTA CCT ATT T (forward primer 5'–3'); GTT CTA GAG AGT GCT GCC TAA TG (reverse primer 5'–3'), IL-6: CTT CCA TCC AGT TGC CTT CT (forward primer 5'–3'); CTC CGA CTT GTG AAG TGG TAT AG (reverse primer 5'–3'). iNOS: GAA CGG AGA ACG TTG GAT TTG (forward primer 5'–3'); TCA GGT CAC TTT GGT AGG ATT T (reverse primer 5'–3'), bax: CAT CTT CTT CCA GAT GGT GA (forward primer 5'–3'); GTT TCA TCC AGG ATC GAG CAG (reverse primer 5'–3').
DATA USAGE NOTES: Cohort 1: The average BMS score was significantly lower in gallium-treated mice at day 1 and 3. A lower number of gallium-treated mice were able to support their weight at day 1, 3 and 5 after SCI. Cohort 2: BMS scores and weight support at day 1 after injury were not different between groups. Q-PCR revealed no differences in expression levels of TNF, IL-6, IL-1ß, bax or iNOS between gallium maltolate and saline treated mice at day 3 and 7 after SCI. Bax, IL6 and iNOS showed a trend for higher expression levels in gallium-treated mice at day 3 after injury. Gallium treatment did not improve the functional outcome after SCI early after injury. However, the deterioration compared to controls could also have been caused by worse overall physiologic conditions of the mice. In the second cohort, no difference was seen between the groups at day 1. No anti-inflammatory effect was detected by Q-PCR at day 3 or 7. In summary, we did not detect any beneficial effect on functional outcome or Q-PCR level in gallium maltolate-treated mice.
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DATASET CITATION:
Batty N. J., Vavrek R., Raposo P., Fouad K. (2021) Behaviour and histopathology after simultaneous cortical infusion of PKA and EPAC agonists and rehabilitative forelimb motor training after incomplete cervical spinal cord injury in female rats. Open Data Commons for Spinal Cord Injury. ODC-SCI:556 http://dx.doi.org/10.34945/F56C7W
ABSTRACT:
STUDY PURPOSE: There is a profound lack of regenerative potential following injury to the adult central nervous system. This has been found to be due in part to the decline of cyclic AMP (cAMP) that has been demonstrated to occur as the nervous system develops, as well as the fact that cAMP levels drop further following injury. cAMP is a ubiquitous signalling molecule found throughout the body, and in many different cell types including neurons. It primarily acts through two downstream effectors: Protein Kinase A (PKA) and the Exchange Protein Activation by cAMP (EPAC). Studies investigating the role of these downstream effectors have found that manipulation of these effectors can lead to an increase in neurite extension and even functional recovery after SCI. Recent in vitro work from our lab has demonstrated that simultaneous activation of both PKA and EPAC results in a synergistic increase in neurite extension and neuronal development.
The aim of the current study was to investigate the application of agonists for EPAC or for both EPAC and PKA to the motor forelimb cortex innervating the injured corticospinal tract as a means to increase the beneficial effects of rehabilitative motor therapy after cervical SCI in rats.
DATA COLLECTED: Female adult Lewis rats from Charles River Laboratories, Canada, weighing 180-220 g were used for this dataset. All rats were pre-trained in the single pellet grasping (SPG) task and received a unilateral dorsal-lateral quadrant (DLQ) spinal cord transection injury at cervical vertebrae level 4 on the side of the dominant paw. Prior to exclusion criteria, n = 13 in the Dual Agonist group, n = 15 in the EPAC Agonist group, n = 23 in control. Lesion size analysis, SPG functional scores, High Speed grasp motion analysis score, Von Frey data, MEP Latency, Count of Significant bins in collateral CST fiber density heatmapping data. Pharmacological compounds used in this study were: - 8-CPT-2'-Me-cAMP (EPAC Agonist) - 6-BnZ-cAMP (PKA Agonist) Pharmacological compounds were dissolved in sterile phosphate buffered saline, loaded into Alzet osmotic mini-pumps (model 2002) to a final in pump concentration of 300 micromolar per compound, and left in an incubator overnight at 37 degrees celsius to prime the pumps to start drug flow. Pumps were installed in the animals immediately following SCI and connected to an Alzet brain infusion kit (No. 2) that was modified to shorten the cannula needle down to 1.5 millimeters. When placed over the skull of the animal, this would result in a cortical penetration depth of approximately 0.5 millimeters. The infusion kits were installed over the motor forelimb cortex innervating the injured side of the spinal cord. Pumps remained in place for two weeks to allow for the pumps to fully release their contents. Control animals received pumps filled with saline. Corticospinal tract tracing was performed using Biotin Dextran Amine (BDA). A 10% BDA solution is made using sterile phosphate buffer. Each animal received 3 injections of 1 microliter of this solution in the cortical area surrounding the motor forelimb cortex innervating the injured CST (approximately 1.5 mm rostral and 1.5 mm lateral to bregma)
DATA USAGE NOTES: Prolonged cortical injusion of agonists for EPAC or for both EPAC and PKA did not result in increases in functional motor recovery or CST plasticity using this methodology
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DATASET CITATION:
Parhizi B., Barss T. S., Mushahwar V. K. (2021) Alteration of H-reflex and MEP amplitude in the flexor carpi radialis muscle with transcutaneous spinal cord stimulation during static and leg cycling tasks in neurologically intact male and female humans. Open Data Commons for Spinal Cord Injury. ODC-SCI:602 http://dx.doi.org/10.34945/F5B59T
ABSTRACT:
STUDY PURPOSE: Transcutaneous spinal cord stimulation (tSCS) is a novel, non-invasive approach used to activate and modulate spinal networks. tSCS facilitates upper extremity function, generates locomotor-like responses, and may facilitate sensorimotor recovery after neural injury when paired with rehabilitation interventions. However, one drawback of tSCS is that its underlying mechanisms of action are not well understood. It has been suggested recently that tSCS modulates spinal circuitry in a manner similar to epidural spinal cord stimulation. In this study, we investigated the ability of tSCS applied to the lumbar and cervical spinal cord to modulate cervical circuitry. We raised two questions in this study: 1) To what extent can the cervical circuitry of the spinal cord be modulated by tSCS as measured in the flexor carpi radialis (FCR) by Hoffmann (H-)reflex and motor evoked potential (MEP) amplitude? 2) Does providing tSCS at multiple segments of the spinal cord (lumbar and cervical combined) converge to alter excitability of H-reflex or MEP amplitude to a greater extent compared to either site alone? The neuromodulatory effects of tSCS were assessed during both a static task and relative to a leg cycling paradigm to determine if tSCS alters cervico-lumbar coupling.
DATA COLLECTED:
To explore the changes in amplitude of FCR H-reflexes and MEPs, 14 neurologically-intact participants completed the H-reflex (3 female, 11 male) and MEP (4 female, 10 male) assessments, with 11 completing both protocols. Because 3 individuals were excluded from MEP assessment due to possible contraindications to transcranial magnetic stimulation (TMS), 3 additional participants were recruited to complete only the MEP portion of the protocol. For each measure, participants completed two tasks that include a static task and leg cycling at a constant speed (?60 rpm). During each task, participants completed 4 tSCS conditions: (1) No tSCS, 2) tSCS active over the cervical spinal cord (Cervical); 3) tSCS active over the lumbar spinal cord (Lumbar); 4) tSCS active simultaneously on cervical and lumbar spinal cord (Combined). Thus, for each participant in each group 8 experimental conditions are available.
Additionally, information about the level of background muscle activity, amplitude of evoked motor response (M-wave), maximum evoked motor response (Mmax), maximum MEP amplitude (MEPmax), peak muscle activation during a maximum voluntary contraction (MVC), and the amplitude of stimulation at the cervical and lumbar sites for each participant are included. The peak-to-peak amplitude of M-wave, H-reflex, and MEP, as well as baseline activity of the FCR muscle, were analyzed in a window of 400 ms (staring 100ms pre-stimulus, ending 300ms post-stimulus). A window of 100ms pre-stimulus (-100ms to 0ms relative to stimulus onset) was selected to calculate the baseline FCR and ECR EMG activity averaged over ten sweeps for each experimental condition. To obtain the value of pre-stimulus muscular contraction, the mean of the signal in this 100ms window was calculated and subtracted from the whole trace to remove any offset in the signal. The pre-stimulus background activity was then rectified and calculated as the mean activity in the 100ms window. The peak-to-peak amplitude of post-stimulus H-reflex, M-wave, and MEP were calculated by averaging ten sweeps per condition. The average values were then normalized to the value of Mmax for H-reflex measurements and to the value of MEPmax for MEP measurements, obtained in a separate trial immediately before the initiation of the testing conditions. The post-stimulus window of analysis for each evoked response was selected based on visual inspection.
The FCR H-reflex was evoked by stimulating the median nerve using bipolar electrodes with 1ms square wave pulses. Transcranial magnetic stimulation was applied to the contralateral motor cortex using a double cone coil to elicit MEPs with a single monophasic pulse. Transcutaneous stimulation of the spinal cord was delivered by a constant current stimulator through two 2.5 cm round cathodic electrodes placed midline at C3-4 and C6-7, and T11 and L1 spinous processes. Two 5 × 10 cm rectangular electrodes were placed bilaterally over the iliac crests as anodes for the cervical tSCS while two additional anode electrodes were placed laterally for the lumbar tSCS. Muscle activity of four muscles in the left arm was recorded via electromyography (EMG) during each trial: FCR, extensor carpi radialis (ECR), biceps brachii (BB) and triceps brachii (TB). Muscle activity was recorded from surface Ag-AgCl electrodes placed on the muscle belly and recorded at a sampling rate of 2000Hz. All EMG signals were amplified 1000x during data collection and band-pass filtered from 30 to 1000 Hz. The EMG signals were used to record H-reflexes and MEPs from the FCR muscle.
The amplitude of FCR H-reflexes, M-waves, and MEPs along with FCR/ECR pre-stimulus baseline activity were compared across different experimental conditions using repeated-measure ANOVA (rmANOVA). During the static task, the effects of condition (No tSCS, Cervical, Lumbar, and Combined) were compared for H-reflex, MEP, M-wave and baseline muscle activity with a 1 x 4 ANOVA. Similarly, during the cycling task, the effects of condition (Static No-tSCS, Cycle No-tSCS, Cycle Cervical, Cycle Lumbar, and Cycle Combined) were compared for H-reflex, MEP, M-wave, baseline muscle activity, and cycling cadence with a 1 x 5 ANOVA. Significant effects were followed by pairwise comparisons corrected by Tukey’s HSD adjustment for multiple comparisons. Differences with p ? 0.05 were accepted as statistically significant.
This dataset represents a stand-alone data.
DATA USAGE NOTES: This study demonstrates, for the first time, that tonic activation of spinal cord networks through multiple sites of tSCS provides a facilitation of both spinal reflex and corticospinal pathways.
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DATASET CITATION:
Nielson J. L., Liu A. W., Guandique C. F., Tovar C. A., Young W., Beattie M. S., Bresnahan J. C., Ferguson A. R. (2021) A comprehensive set of hemodynamic parameters, blood gases and hemoglobin levels during spinal cord injury procedure followed by weekly assessments of locomotor and bladder function recovery with survival histology data from 334 rats in the MASCIS trial. Open Data Commons for Spinal Cord Injury. ODC-SCI:567 http://dx.doi.org/10.34945/F5V884
ABSTRACT:
STUDY PURPOSE: To describe the application of topological data analysis (TDA) for data-driven discovery in preclinical spinal cord injury (SCI) data sets mined from the Visualized Syndromic Information and Outcomes for Neurotrauma-SCI (VISION-SCI) repository.
DATA COLLECTED: This dataset contains MASCIS OSU trial subjects (N=334) for all measures of survival, histology, perioperative vitals and blood gases, functional recovery, bladder health and weight over 1–6 weeks post SCI.
DATA USAGE NOTES:
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DATASET CITATION:
Almeida C. A., Torres-Espin A., Huie J. Russell., Sun D., Noble-Haeusslein L. J., Young W., Beattie M. S., Bresnahan J. C., Nielson J. L., Ferguson A. R. (2021) Hemodynamics, weight and overground locomotion from 1125 rats with different spinal cord injury thoracic contusion severities recovered from the Multicenter Spinal Cord Injury Study (MASCIS). Open Data Commons for Spinal Cord Injury. ODC-SCI:595 http://dx.doi.org/10.34945/F5QG66
ABSTRACT:
STUDY PURPOSE: Results of the process of archeological data recovery of spinal cord injury (SCI) data sets from the Multicenter Spinal Cord Injury Study (MASCIS). The goal for this subset of the MASCIS dataset was to externally validate previous fundings on the importance of peri-surgery blood pressure in long term recovery.
DATA COLLECTED: This data represents a derivative dataset that involved large scale data integration and analysis of different epochs of the MASCIS study. MASCIS is multi-site preclinical drug trial conducted in the 1990s with the primary goal of testing the efficacy of the anti-inflammatory glucocorticoid methylprednisolone, and other therapies administered acutely after an SCI in rats. The dataset contains diverse data from 1125 rats. Different groups of injury were conducted using a thoracic contusion injury model. The presented subset of the data contains summaries of blood pressure, weight and BBB scores in different injury severity groups.
DATA USAGE NOTES: This dataset constitutes a demonstration of the value of data archeology. The curation of the MASCIS study has generated this data resource that can be use for secondary analysis and further discovery.
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DATASET CITATION:
Schmidt E. K., Raposo P. J F., Vavrek R., Fouad K. (2021) Lipopolysaccharide treatment in the subacute stage of cervical spinal cord injury enhances motor recovery and increases anxiety-like behaviour in female rats. Open Data Commons for Spinal Cord Injury. ODC-SCI:459 http://dx.doi.org/10.34945/F5FW2B
ABSTRACT:
STUDY PURPOSE: Previous published work in our laboratory found that eliciting inflammation with lipopolysaccharide (LPS) in the chronic (8 weeks) stage of cervical level 4 dorsolateral quadrant spinal cord injury (SCI) enhances the efficacy of rehabilitative training (10.1093/brain/awy128). The purpose of the present study is to determine whether sub-acute LPS treatment has a similar effect, since the lesion environment is already in a more inflammatory state at this earlier time point. 2 cohorts of female Lewis rats (n=50) were included for the present data. Of those 50, 22 did not participate (lack of attempts) in rehabilitative training but were still included for their behavioural data in the elevated plus maze. Rats were pre-trained on a single pellet reaching task prior to SCI. 10 days after a unilateral dorsal quadrant cut lesion (Cervical level 4; ipsilateral to preferred paw) rats received a single intraperitoneal injection of either 0.5mg/kg LPS or saline followed by 6 weeks of rehabilitative training..
DATA COLLECTED: Data collected include: sickness behaviour, weight, and body temperature measured before, 4, 8, 24, 48, and 72 hours after LPS or saline injections; rat’s success rate and attempt rate in the single pellet reaching task; success rate in the gap test (where a physical gap was introduced to between the pellet dispenser and the rat so they could not scoop the pellet into their mouths); High speed analysis of the rat’s reaching and grasping movements before and after SCI; Horizontal ladder, cylinder, open field and Von Frey tests; lesion analysis and analysis of corticospinal tract sprouting into the grey matter; histological analysis of microglia and astrocytes rostral, caudal and at the injury site; elevated plus maze.
DATA USAGE NOTES: The present data shows that a single injection of LPS in the sub-acute stage of SCI has similar beneficial effects on motor recovery as chronic application. Compared to rats that did not receive LPS, LPS treated rats had a higher success rate in the trained single pellet reaching tasks, particularly in the gap test that did not allow for compensatory scooping movements. Lipopolysaccharide treated rats also displayed a chronic (tissue collected 8 weeks following injections) reduction of microglia and astrocyte expression around the lesion site. LPS treated rats also have improved motor recovery in the untrained cylinder test. However, this motor recovery came at a cost since inducing inflammation also had a long-term (i.e. 4 weeks after injections) negative effect on anxiety-like behaviour.
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DATASET CITATION:
Brennan F. H., Noble B. T., Wang Y., Guan Z., Davis H., Mo X., Harris C., Eroglu C., Ferguson A. R., Popovich P. G. (2021) Acute post-injury blockade of a2d-1 calcium channel subunits on pathological autonomic plasticity after T3 crush spinal cord injury in female mice. Open Data Commons for Spinal Cord Injury. ODC-SCI: 555 http://dx.doi.org/10.34945/F5V30C
ABSTRACT:
STUDY PURPOSE: After a spinal cord injury (SCI), normally innocuous visceral or somatic stimuli can trigger uncontrolled reflex activation of sympathetic circuitry, causing pathological dysautonomia. Here, we tested the hypothesis that SCI causes remarkable structural remodeling and synaptic plasticity, creating abnormal spinal sympathetic reflexes that promote dysautonomia. We also tested whether treating mice with prophylactic gabapentin (GBP), an FDA-approved drug that inhibits a2d-1-mediated synaptogenesis in the brain, can prevent these pathologies.
DATA COLLECTED: The dataset includes n = 183 adult female mice on a C57BL/6J background and n=16 adult female mice on a 129SVE background with a2d-1 overexpression or wild type littermates. Mice received a T3 crush SCI or sham control surgery. Mice were injected subcutaneously 3x/d with GBP (66.7 mg/kg) or Saline from 1 day post-injury (dpi) until 28 or 35 days post-injury, and were perfused at 28, 35, 42, or 56 dpi. Additional mice were used for pharmacokinetic studies and time-course studies of anatomical reorganization (sham, 7 dpi, 14 dpi, 21 dpi, 28 dpi). Anatomical reorganization was assessed using Vglut2+ pre-synaptic puncta, Vglut2+Homer1+ excitatory synapse count, quantification of spinal PRV+ neurons that control lymphoid tissue, lumbar CGRP fiber sprouting, and FosB+ neuron counts. Dysautonomia was assessed using spleen weight, spleen B and T cell quantification, and spontaneous and induced autonomic dysreflexia experiments. Additional outcome measures include a2d-1+ cell number, percent a2d-1+ area, thrombospondin mRNA and protein levels, and principal component analysis results (spinal sympathetic reflex index).
DATA USAGE NOTES: We show that remarkable structural remodeling and synaptic plasticity occur within spinal autonomic circuitry after SCI, creating abnormal spinal sympathetic reflexes that promote dysautonomia. If SCI mice are treated with human equivalent doses of GBP, beginning at one day post-injury, well before the onset of post-injury plasticity and dysautonomia, both structural plasticity and pathological dysautonomia can be prevented. This prophylactic GBP regimen blocks multi-segmental excitatory synaptogenesis, and abolishes sprouting of autonomic neurons that innervate immune organs and sensory afferents that trigger pain and autonomic dysreflexia (AD). Prophylactic GBP decreases the frequency and severity of AD and protects against SCI-induced immune suppression. These benefits persist even one month after stopping GBP treatment. GBP could be repurposed to prevent dysautonomia in at-risk individuals with a high-level SCI.
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DATASET CITATION:
Schmidt E. K A., Raposo P. J F., Torres-Espin A., Fenrich K. K., Fouad K. (2021) Minocycline treatment for acute cervical spinal cord injury in female rats: microbiota composition. Open Data Commons for Spinal Cord Injury. ODC-SCI: 454 http://dx.doi.org/10.34945/F5F30N
ABSTRACT:
STUDY PURPOSE: Minocycline has been widely studied for its local anti-inflammatory properties; however little is known about its antibiotic and systemic immune effects following spinal cord injury (SCI). The aim of the present study is to elucidate multiple system-wide changes involving the microbiota-immune axis induced by minocycline treatment in a rodent model of cervical contusion SCI (unilateral contusion 125 kdyns at an angle of 15 degrees to the right at C5). This study included 4 groups of adult female Lewis rats: uninjured n=10, uninjured + minocycline n=10, SCI n=8, SCI + minocycline n=9. Minocycline (or sterile water for untreated control groups) was administered at a dose of 50mg/kg via oral gavage for 7 days immediately following injury..
DATA COLLECTED: fecal microbiota data: 16s rRNA sequencing data (at the phylum, class, order, family, genus and species taxonomic levels) from fecal samples collected before injury, on the day of injury, 5, 14 and 28 days post injury
DATA USAGE NOTES: The present data shows that 7 days of minocycline treatment had a drastic acute effect on the microbiota composition regardless of whether the animal was uninjured or had a SCI. Later effects of SCI vs. uninjured rats emerged by 28 days post-SCI.
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DATASET CITATION:
Schmidt E. K A., Raposo P. J F., Torres-Espin A., Fenrich K. K., Fouad K. (2021) Minocycline treatment for acute cervical spinal cord injury in female rats: behavioural, histopathological and systemic immune effects. Open Data Commons for Spinal Cord Injury. ODC-SCI: 457 http://dx.doi.org/10.34945/F5JS3M
ABSTRACT:
STUDY PURPOSE: Minocycline has been widely studied for its local anti-inflammatory properties; however little is known about its antibiotic and systemic immune effects following spinal cord injury (SCI). The aim of the present study is to elucidate multiple system-wide changes involving the microbiota-immune axis induced my minocycline treatment in a rodent model of cervical contusion SCI (unilateral contusion 125 kdyns at an angle of 15 degrees to the right at C5). This study included 4 groups of adult female Lewis rats: uninjured n=10, uninjured + minocycline n=10, SCI n=8, SCI + minocycline n=9. Minocycline (or sterile water for untreated control groups) was administered at a dose of 50mg/kg via oral gavage for 7 days immediately following injury..
DATA COLLECTED: pICRUST bioinformatics software was used to predict the metagenomic functional content of the 16s rRNA data; behavioural data from the open field and cylinder tasks, anxiety- and depressive-like behaviour was analyzed in the elevated plus maze, light/dark box and sucrose preference tests; quantification of the lesion area and extension; 29 plasma analytes (cytokines, chemokines and hormones) were measured before injury, 5, 14, and 28 days post injury; quantification of microglia (iba1) immunoreactivity above, at and below the lesion site; body weight monitored weekly throughout the experiment. 16s rRNA sequencing data from fecal samples collected before injury, on the day of injury, 5, 14 and 28 days post injury is located in a separate dataset.
DATA USAGE NOTES: The present data shows that 7 days of minocycline treatment had a drastic acute effect on the microbiota composition regardless of whether the animal was uninjured or had a SCI. SCI resulted in a delayed (measured 28 days after injury) suppression of inflammatory cytokines/chemokines in the plasma, which was prevented with minocycline treatment. Minocycline treatment had a modest but insignificant anxiolytic effect in the light/dark box following SCI. Finally, we did not find minocycline treatment to attenuate lesion size or extension, however there was an increase in iba1 immunoreactivity above and below the lesion site in the minocycline + SCI group compared to untreated SCI rats.
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DATASET CITATION:
Ehsanian R., Haefeli J., Crew J. D., Dirlikov B., Bresnahan J. C., Beattie M. S., Ferguson A. R., McKenna S. L. (2021) Surgical Blood Pressure and Expected Motor Recovery in Individuals with Traumatic Spinal Cord Injury. Open Data Commons for Spinal Cord Injury. ODC-SCI: 536 http://dx.doi.org/10.34945/F58C7H
ABSTRACT:
STUDY PURPOSE: Mean arterial blood pressure (MAP) during surgical intervention for individuals with spinal cord injury (SCI) was used to assess associations with motor recovery during the acute phase (post-surgery to rehabilitation discharge)..
DATA COLLECTED: Retrospective data were abstracted for 25 patients with Spinal Cord injury admitted to SCVMC Trauma Service as well as SCVMC Physical Medicine & Rehabilitation Department. Abstracted data included: Sex, Cause of Injury, Number of unique Vasopressors, Level of Injury, American Spinal Injury Association Impairment Scale (AIS) Grade, AIS motor score, Age, Time to surgery, Days between American Spinal Injury Association (ASIA) exam, Rehabilitation Length of Stay, Acute Length of Stay, and Mean Arterial Blood Pressure. AIS motor score changes were assessed at the earliest postoperative assessment and at discharge from acute rehabilitation. MAP was measured by an arterial line blood pressure monitor during spinal stabilization surgery.
DATA USAGE NOTES: Recovery trajectories may be impacted by deviations from normotensive states (i.e., hypertension and hypotension) during surgery in individuals with SCI.
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DATASET CITATION:
Kyritsis N., Torres Espin A., Schupp P. G., Huie J. Russell., Chou A., Duong-Fernandez X., Thomas L. H., Tsolinas R. E., Hemmerle D. D., Pascual L. U., Singh V., Pan J. Z., Talbott J. F., Whetstone W. D., Burke J. F., DiGiorgio A. M., Weinstein P. R., Manley G. T., Dhall S. S., Ferguson A. R., Oldham M. C., Bresnahan J. C., Beattie M. S. (2021) Acute blood RNA sequencing from SCI human patients. Open Data Commons for Spinal Cord Injury. ODC-SCI: 405 http://dx.doi.org/10.34945/F5QC7J
ABSTRACT:
STUDY PURPOSE: The purpose of this study is to discover, through high throughput methods, blood RNA biomarkers with the ability to diagnose accurately the severity of the spinal cord injury at the acute stage.
DATA COLLECTED: Total RNA was collected from white blood cells of 38 spinal cord injury patients, 10 healthy subjects and 10 non-CNS trauma patients. The samples were collected on average within the first 24 hours after injury. Subsequently the RNA was used for RNAseq. These subjects were enrolled in the Transforming Research and Clinical Knowledge in Spinal Cord Injury (TRACK-SCI) clinical study, and we included clinical variables such as age, sex, race, prior CNS pathology, concurrent TBI, injury severity score, AIS grade, neurological level of injury, and motor and sensory scores. Both clinical and transcriptomic data were used to generate a predictive model for the initial severity of spinal cord injury.
DATA USAGE NOTES: Analysis of our gene expression data revealed 197 genes that they are expressed in an severity-dependent manner. Furthermore, unsupervised gene co-expression network analysis was used for the discovery of 16 gene modules that are induced upon spinal cord injury. A logistic regression model using these modules displayed high accuracy in diagnosing the initial injury severity.
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DATASET CITATION:
Fenrich K. K., Hallworth B. W., Vavrek R., Raposo P. JF., Misiaszek J. E., Bennett D. J., Fouad K., Torres-Espin A. (2021) Self-directed reaching and grasping rehabilitation using automatic pellet presentation system after cervical dorsolateral quadrant injury in female rats. Open Data Commons for Spinal Cord Injury. ODC-SCI: 553 http://dx.doi.org/10.34945/F5ZW20
ABSTRACT:
STUDY PURPOSE: This data was collected as part of a study on the advantages of self-directed rehabilitation reaching and grasping training by using an automatic pellet presentation (APP) system. The goal of the study was to understand the factors that determine better rehabilitation-induced recovery in forelimb motor function after cervical spinal cord injury in rats exposed to the APP training system.
DATA COLLECTED: The dataset contains data from 19 unique female Lewis rats with a unilateral dorsolateral quadrant section injury at cervical level C4. Animals were exposed to the APP system up to 2 months before injury and up to 2 months after rehabilitation onset one week after injury. Metrics in the data include the number of trials the animal performs in the APP system (number of attempts to reach a pellet) per day, the number of trials that are failed per day, the number of trials the animal reached but dropped per day, and the number of trials that the animals successfully reaches and grasps per day. Summary metrics includes cumulated values per day and averages at baseline (last 2 weeks of training before injury), rehabilitation onset (3 first days of rehabilitation) and rehabilitation final (last week of rehabilitation period). Summary measures of injury are included. Principal component scores for the first 3 components resulting from a non-linear principal component analysis on the summary metrics are also included, as well as the results of a k-mean clustering analysis.
DATA USAGE NOTES: The analysis of this data shown in the originating publication indicates that both intensity and amount of training is one of the major factors influencing recovery induced by performing the single pellet task with the APP system. However, the analysis also indicate that rehabilitation training becomes progressively less efficient as both the amount and intensity of rehabilitation training increases.
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DATASET CITATION:
Schmidt, E., Torres-Espin, A., Raposo, P., Madsen, K., Kigerl, K., Popovich., P., Fenrich, K.F., Fouad, K. (2020) Data for Fecal Transplant Prevents Gut Dysbiosis and Anxiety-like Behaviour After Spinal Cord Injury in Rats. Open Data Commons for Spinal Cord Injury. ODC-SCI:262 http://doi.org/10.7295/W97942VQ
ABSTRACT:
STUDY PURPOSE: To establish a model of anxiety following a cervical contusion spinal cord injury (SCI) in rats and to determine whether the microbiota play a role in the observed behavioural changes.
DATA COLLECTED: This dataset includes n=57 rats from 2 experiments. Experiment 1: sham (underwent surgery with no SCI) n=6; unilateral cervical contusion SCI n=6. Experiment 2: Healthy (no operation, no gavage) n=10; Sham n=11; SCI (gavaged with a control solution) n=10; SCI-FMT (gavaged with fecal microbiota transplant solution) n=14. A subset of subjects from experiment 2 were used for the fecal 16s rRNA analysis (healthy n = 10; SCI-FMT n = 10; sham n = 5; SCI n = 5). Fecal matter for the 16s rRNA analysis were collected before injury, 3 days after injury and 4 weeks after injury. A PICRUST analysis was performed to infer the functional pathways involved using the 16s rRNA gene data. Rats were assessed on a battery of behavioural tests: the light-dark box, the cylinder test, the sucrose preference test, the elevated plus maze and the open field. Lesion size was calculated as the percentage of damaged tissue area throughout the rostral-caudal extension of the injury site.
PRIMARY CONCLUSION: Treatment with a fecal microbiota transplant in the acute post-injury period prevents spinal cord injury-induced gut dysbiosis as well as the development of anxiety-like behaviour.
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DATASET CITATION:
Batty, N. J., Torres-Espín, A., Vavrek, R., Raposo, P., Fouad, K. (2020) Behavior and histopathology after single-session cortical electrical stimulation and rehabilitative forelimb motor training in cervical spinal cord injury in females rats. Open Data Commons for Spinal Cord Injury. ODC-SCI:458 http://doi.org/10.34945/F59885
DOI:10.34945/F59885
ABSTRACT:
STUDY PURPOSE: The aim of the study was to investigate the use of electrical cortical stimulation of injured corticospinal tract as a means to increase the beneficial effects of rehabilitative motor therapy after SCI in rats. The study showed that a single session of electrical stimulation of the injured fibers led to an increase in corticospinal tract (CST) plasticity, and functional recovery after training
DATA COLLECTED: Female adult Lewis rats from Charles River Laboratories, Canada, weighing 180-220 g were used for this dataset. All rats were pre-trained in the single pellet grasping (SPG) task and received a unilateral dorsal-lateral quadrant (DLQ) spinal cord transection injury at cervical vertebrae level 4 on the side of the dominant paw. n = 11 in the stimulated group, n = 9 in control. Lesion size analysis, SPG functional scores, High Speed grasp motion analysis score, CST fiber counts, Count of Significant bins in collateral CST fiber density heatmapping data
PRIMARY CONCLUSION: Electrical stimulation of injured corticospinal fibers prior to rehabilitative training can increase their plasticity and thus the effect of rehabilitative training
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DATASET CITATION:
Aceves, M., Dietz, V. A., Dulin, J. N., Jeffery, U., Jeffery, N. D. 2020. Repeated measurements of hindlimb CatWalk variables in normal rats. Open Data Commons for Spinal Cord Injury. ODC-SCI:432. doi: 10.34945/F54S3W
ABSTRACT:
STUDY PURPOSE: To provide a set of reference data for expected variability in hindlimb locomotor outcomes for normal young adult rats using the Catwalk.
DATA COLLECTED: Data that are automatically collected on hindlimb function in rats by the CatWalk. Recordings were made on 16 male 9-week-old (250-275 g) Sprague-Dawley rats after a training period and at 8 weekly intervals.
PRIMARY CONCLUSION: There is a large variation in within-rat variability between different CatWalk outcomes. Selection of the most appropriate variables can improve sensitivity of experiments that measure locomotor outcome.
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DATASET CITATION:
Puko, N., McTigue, D.M. (2020). Data for manuscript: Delayed short-term tamoxifen treatment does not promote remyelination or neuron sparing after spinal cord injury. Open Data Commons for Spinal Cord Injury. ODC-SCI:419 http://dx.doi.org/10.34945/F5QP4H
ABSTRACT:
STUDY PURPOSE: Tamoxifen is widely used to spatially and temporally control gene expression; however, whether tamoxifen has off-target effects remains elusive. Here, we tested whether delayed short-term tamoxifen treatment changed motor and/or anatomical recovery after spinal cord injury.
DATA COLLECTED: This dataset includes n = 40 adult C57BL/6J mice (n = 20 female, n = 20 male) that received a moderate (75 kDyne) spinal cord contusion injury. Tamoxifen or corn-oil was gavaged 19-22 days post-injury and mice were sacrificed 42 days post-injury. Motor recovery was assessed using the Basso Mouse Scale, automated horizontal ladder, and activity box. Anatomical recovery was analyzed via white matter sparing (Eriochrome Cyanine), neuron survival (NeuN), axon sparing (NF-H) and regeneration (GAP-43), astrocyte reactivity (GFAP), lesion size (GFAP), cell proliferation (EDU; NG2/EDU; CD68/NG2), and changes in myelination (nodes of Ranvier; Caspr/Kv1.2).
PRIMARY CONCLUSION: Delayed short-term tamoxifen gavage does not alter motor recovery, neuroprotection, or neurorestoration after spinal cord injury.
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DATASET CITATION:
Liu, Y., Wang, X., Li, W., Zhang, Q., Li, Y., Zhang, Z., Zhu, J., Chen, B., Williams, P.R., Zhang, Y., Yu, B., Gu, X., He, Z. (2019). T10 lateral hemisection spinal cord injury with multiple histological and behavioral outcomes. Open Data Commons for Spinal Cord Injury. ODC-SCI:212 http://doi.org/10.7295/W9HQ3X20
ABSTRACT:
STUDY PURPOSE: A major hurdle for functional recovery after spinal cord injury is the limited re- growth of the axons in the corticospinal tract (CST) that originate in the motor cortex and innervate the spinal cord. In this study, we tested whether post-lesional AAV-assisted co- expression of two soluble proteins, namely insulin-like growth factor 1 (IGF1) and osteopontin (OPN), in cortical neurons leads to CST regrowth and CST-dependent functional recovery.
DATA COLLECTED: With an incomplete spinal cord injury model (T10 lateral hemisection), we tested the sensitizing effect of OPN/IGF1 on corticospinal neurons, the extent of axon regrowth both in the injured side (axon regeneration) and the intact side (collateral axon sprouting). In addition, we assessed behavioral performance for both gross and skilled locomotion in mice treated with OPN/IGF1 post T10 lateral hemisection.
PRIMARY CONCLUSION: Our results demonstrate a potentially translatable strategy for restoring cortical dependent function after injury in the adult.
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DATASET CITATION:
Ferguson, A.R., Irvine,K.-A., Gensel, J.C., Nielson, J.L., Lin, A., Ly, J., Segal, M.R., Ratan, R.R., Bresnahan, J.C., Beattie, M.S. (2018) Cervical (C5), unilateral spinal cord injury with diverse injury modalities, multiple behavioral outcomes, and histopathology. Open Data Commons for Spinal Cord Injury. ODC-SCI:26 http://doi.org/10.7295/W9T72FMZ
ABSTRACT:
STUDY PURPOSE: This project was a multivariate validation study of unilateral cervical contusion (hemi-contusion) model-development efforts.
DATA COLLECTED: The dataset includes N=159 rats with hemisections (n=9), NYU MASCIS weight drop contusions: sham (n=10), 6.25 mm (n=10), 12.5 mm (n=32); Infinite Horizon Impactor: sham (n=6), 75 kdyn (n=58), 100 kdyn (n=34). Behavioral recovery was monitored over 6 weeks using mutiple assements taken from the same subjects: Grooming Score, Paw Placement in a Cylinder, BBB locomotor subscore, Forelimb Open Field Score, and numerous Catwalk footprint analysis metrics. Histopathology metrics included lesion epicenter gray matter sparing, white matter sparing, total tissue sparing, and motorneuron numbers.
PRIMARY CONCLUSION: Principal component analysis (PCA)-based multidimensional pattern detectors can resolve the ‘syndrome space’ across multiple models of SCI, allowing direct comparison of subjects with diverse injury types, outcome sets and therapeutics.
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