Effect-Size Discrepancies in Literature Versus Raw Datasets from Experimental Spinal Cord Injury Studies: A CLIMBER Meta-Analysis.

Translation of spinal cord injury (SCI) therapeutics from pre-clinical animal studies into human studies is challenged by effect size variability, irreproducibility, and misalignment of evidence used by pre-clinical versus clinical literature. Clinical literature values reproducibility, with the highest grade evidence (class 1) consisting of meta-analysis demonstrating large therapeutic efficacy replicating across multiple studies. Conversely, pre-clinical literature values novelty over replication and lacks rigorous meta-analyses to assess reproducibility of effect sizes across multiple articles. Here, we applied modified clinical meta-analysis methods to pre-clinical studies, comparing effect sizes extracted from published literature to raw data on individual animals from these same studies. Literature-extracted data (LED) from numerical and graphical outcomes reported in publications were compared with individual animal data (IAD) deposited in a federally supported repository of SCI data. The animal groups from the IAD were matched with the same cohorts in the LED for a direct comparison. We applied random-effects meta-analysis to evaluate predictors of neuroconversion in LED versus IAD. We included publications with common injury models (contusive injuries) and standardized end-points (open field assessments). The extraction of data from 25 published articles yielded n = 1841 subjects, whereas IAD from these same articles included n = 2441 subjects. We observed differences in the number of experimental groups and animals per group, insufficient reporting of dropout animals, and missing information on experimental details. Meta-analysis revealed differences in effect sizes across LED versus IAD stratifications, for instance, severe injuries had the largest effect size in LED (standardized mean difference [SMD = 4.92]), but mild injuries had the largest effect size in IAD (SMD = 6.06). Publications with smaller sample sizes yielded larger effect sizes, while studies with larger sample sizes had smaller effects. The results demonstrate the feasibility of combining IAD analysis with traditional LED meta-analysis to assess effect size reproducibility in SCI.

Unsupervised Machine Learning on Motion Capture Data Uncovers Movement Strategies in Low Back Pain.

Chronic low back pain (LBP) is a leading cause of disability and opioid prescriptions worldwide, representing a significant medical and socioeconomic problem. Clinical heterogeneity of LBP limits accurate diagnosis and precise treatment planning, culminating in poor patient outcomes. A current priority of LBP research is the development of objective, multidimensional assessment tools that subgroup LBP patients based on neurobiological pain mechanisms, to facilitate matching patients with the optimal therapies. Using unsupervised machine learning on full body biomechanics, including kinematics, dynamics, and muscle forces, captured with a marker-less depth camera, this study identified a forward-leaning sit-to-stand strategy (STS) as a discriminating movement biomarker for LBP subjects. A forward-leaning STS strategy, as opposed to a vertical rise strategy seen in the control participants, is less efficient and results in increased spinal loads. Inefficient STS with the subsequent higher spinal loading may be a biomarker of poor motor control in LBP patients as well as a potential source of the ongoing symptomology.

Nociceptor-dependent locomotor dysfunction after clinically-modeled hindlimb muscle stretching in adult rats with spinal cord injury.

In the course of investigating how common clinical treatments and adaptive technologies affect recovery after spinal cord injury (SCI), we discovered that a clinically-modeled hindlimb stretching protocol dramatically, but transiently, reduces locomotor function. Nociceptive sensory input is capable of altering motor output at the spinal level, and nociceptive neurons are sensitized after SCI. Here we tested the hypotheses that stretch-induced locomotor deficits are dependent on nociceptive afferents by depleting TRPV1+ sensory afferents using capsaicin injections in neonatal rats. Following maturation, animals received 25g-cm contusive SCI at T10. After plateau of locomotor recovery at 6 weeks, daily stretching was performed for 3 weeks, followed by 2 weeks without stretch, and again for two additional weeks. Animals were sacrificed 2 h after the last stretching session for histological assessments. Consistent with previous findings, stretch-induced drops in locomotor function were observed in nociceptor-intact animals but were nearly absent in nociceptor-depleted animals. These functional changes were accompanied by corresponding increases in the number of c-Fos+ nuclei throughout the lumbar enlargement. As expected, nociceptor-depleted animals had very little CGRP+ axonal innervation of the dorsal horn. Nociceptor-intact stretched animals had significantly higher levels of CGRP+ as compared to non-stretched SCI rats, suggesting that stretching promoted intraspinal CGRP+ sprouting. These results indicate that stretch-induced locomotor dysfunction in animals with incomplete SCI involves C-fibers, adding a negative post-SCI role to their adaptive roles (e.g., bladder control), and suggesting that the clinical use of muscle stretching to combat contractures and spasticity may be unintentionally detrimental to locomotor function.

Electromyographic patterns of the rat hindlimb in response to muscle stretch after spinal cord injury.

STUDY DESIGN: Experimental Study. OBJECTIVES: To characterize the specific hindlimb electromyographic (EMG) patterns in response to muscle stretch and to measure the applied forces during stretching in the rat model of moderate SCI. SETTING: Kentucky Spinal Cord Injury Research Center, Louisville, KY, USA. METHODS: Female Sprague Dawley rats (n = 4) were instrumented for telemetry-based EMG recording (right rectus femoris and biceps femoris) and received a moderate T10 spinal cord injury (SCI). The major hindlimb muscle groups were stretched using our clinically modeled protocol. The EMG responses were recorded biweekly for 8 weeks. The forces applied during stretching were measured using a custom-designed glove. Locomotor function was assessed using the BBB Open Field Locomotor Scale, 3D kinematics and gait analysis. RESULTS: Three main EMG patterns in response to stretch were identified: clonic-like, air-stepping, and spasms. Torques applied during stretching ranged from 0.4-8 N•cm, and with the exception of the quadriceps, did not change significantly over the weeks of stretching. Two stretching sessions a week did not result in a significant disruption to locomotor function. CONCLUSIONS: Stretching evokes EMG patterns in rats similar to those reported in humans including clonus and spasms. The torques used during stretching are comparable, based on the ratio of torque to body weight, to the few previously published studies that measured the forces and/or torques applied by physical therapists when stretching patients. Future studies are warranted to fully explore the impact of muscle stretch on spinal cord function after injury. SPONSORSHIP: DoD, KSCHIRT, NIH.

Disruption of Locomotion in Response to Hindlimb Muscle Stretch at Acute and Chronic Time Points after a Spinal Cord Injury in Rats.

After spinal cord injury (SCI) muscle contractures develop in the plegic limbs of many patients. Physical therapists commonly use stretching as an approach to avoid contractures and to maintain the extensibility of soft tissues. We found previously that a daily stretching protocol has a negative effect on locomotor recovery in rats with mild thoracic SCI. The purpose of the current study was to determine the effects of stretching on locomotor function at acute and chronic time points after moderately severe contusive SCI. Female Sprague-Dawley rats with 25 g-cm T10 contusion injuries received our standard 24-min stretching protocol starting 4 days (acutely) or 10 weeks (chronically) post-injury (5 days/week for 5 or 4 weeks, respectively). Locomotor function was assessed using the BBB (Basso, Beattie, and Bresnahan) Open Field Locomotor Scale, video-based kinematics, and gait analysis. Locomotor deficits were evident in the acute animals after only 5 days of stretching and increasing the perceived intensity of stretching at week 4 resulted in greater impairment. Stretching initiated chronically resulted in dramatic decrements in locomotor function because most animals had BBB scores of 0-3 for weeks 2, 3, and 4 of stretching. Locomotor function recovered to control levels for both groups within 2 weeks once daily stretching ceased. Histological analysis revealed no apparent signs of overt and persistent damage to muscles undergoing stretching. The current study extends our observations of the stretching phenomenon to a more clinically relevant moderately severe SCI animal model. The results are in agreement with our previous findings and further demonstrate that spinal cord locomotor circuitry is especially vulnerable to the negative effects of stretching at chronic time points. While the clinical relevance of this phenomenon remains unknown, we speculate that stretching may contribute to the lack of locomotor recovery in some patients.