Spinal cord lesion MRI and behavioral outcomes in a miniature pig model of spinal cord injury: exploring preclinical potential through an ad hoc comparison with human SCI.

STUDY DESIGN: prospective case series of Yucatan miniature pig spinal cord contusion injury model with comparison to human cases of spinal cord injury (SCI). OBJECTIVES: to describe magnetic resonance imaging (MRI) measures of spinal cord lesion severity along with estimates of lateral corticospinal tracts spared neural tissue in both a less severe and more severe contusion SCI model, as well as to describe their corresponding behavioral outcome changes. SETTING: University laboratory setting. METHODS: Following a more severe and less severe SCI, each pig underwent spinal cord MRI to measure lesion characteristics, along with locomotor and urodynamics outcomes testing. RESULTS: In the pig with more severe SCI, locomotor and urodynamic outcomes were poor, and both the spinal cord lesion volume and damage estimates to the lateral corticospinal tracts were large. Conversely, in the pig with less severe SCI, locomotor and urodynamic outcomes were favorable, with the spinal cord lesion volume and damage estimates to the lateral corticospinal tracts being less pronounced. For two human cases matched on estimates of damage to the lateral corticospinal tract regions, the clinical presentations were similar to the pig outcomes, with more limited mobility and more limited bladder functional independence in the more severe case. CONCLUSIONS: Our initial findings contribute valuable insights to the emergent field of MRI-based evaluation of spinal cord lesions in pig models, offering a promising avenue for understanding and potentially improving outcomes in spinal cord injuries.

Predictive values of spinal cord diffusion magnetic resonance imaging to characterize outcomes after contusion injury.

OBJECTIVES: To explore filtered diffusion-weighted imaging (fDWI), in comparison with conventional magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI), as a predictor for long-term locomotor and urodynamic (UD) outcomes in Yucatan minipig model of spinal cord injury (SCI). Additionally, electrical conductivity of neural tissue using D-waves above and below the injury was measured to assess correlations between fDWI and D-waves data. METHODS: Eleven minipigs with contusion SCI at T8-T10 level underwent MRI at 3T 4 h. post-SCI. Parameters extracted from region of interest analysis included Daxial from fDWI at injury site, fractional anisotropy and radial diffusivity from DTI above the injury site along with measures of edema length and cord width at injury site from T2 -weighted images. Locomotor recovery was assessed pre- and weekly post-SCI through porcine thoracic injury behavior scale (PTIBS) and UD were performed pre- and at 12 weeks of SCI. D-waves latency and amplitude differences were recorded before and immediately after SCI. RESULTS: Two groups of pigs were found based on the PTIBS at week 12 (p < 0.0001) post-SCI and were labeled "poor" and "good" recovery. D-waves amplitude decreased below injury and increased above injury. UD outcomes pre/post SCI changed significantly. Conventional MRI metrics from T2 -weighted images were significantly correlated with diffusion MRI metrics. Daxial at injury epicenter was diminished by over 50% shortly after SCI, and it differentiated between good and poor locomotor recovery and UD outcomes. INTERPRETATION: Similar to small animal studies, fDWI from acute imaging after SCI is a promising predictor for functional outcomes in large animals.

SmartPill™ Administration to Assess Gastrointestinal Function after Spinal Cord Injury in a Porcine Model-A Preliminary Study.

Gastrointestinal (GI) complications, including motility disorders, metabolic deficiencies, and changes in gut microbiota following spinal cord injury (SCI), are associated with poor outcomes. After SCI, the autonomic nervous system becomes unbalanced below the level of injury and can lead to severe GI dysfunction. The SmartPill™ is a non-invasive capsule that, when ingested, transmits pH, temperature, and pressure readings that can be used to assess effects in GI function post-injury. Our minipig model allows us to assess these post-injury changes to optimize interventions and ultimately improve GI function. The aim of this study was to compare pre-injury to post-injury transit times, pH, and pressures in sections of GI tract by utilizing the SmartPill™ in three pigs after SCI at 2 and 6 weeks. Tributyrin was administered to two pigs to assess the influences on their gut microenvironment. We observed prolonged GET (Gastric Emptying Time) and CTT (Colon Transit Time), decreases in contraction frequencies (Con freq) in the antrum of the stomach, colon, and decreases in duodenal pressures post-injury. We noted increases in Sum amp generated at 2 weeks post-injury in the colon, with corresponding decreases in Con freq. We found transient changes in pH in the colon and small intestine at 2 weeks post-injury, with minimal effect on stomach pH post-injury. Prolonged GETs and CTTs can influence the absorptive profile in the gut and contribute to pathology development. This is the first pilot study to administer the SmartPill™ in minipigs in the context of SCI. Further investigations will elucidate these trends and characterize post-SCI GI function.

Porcine spinal cord injury model for translational research across multiple functional systems.

Animal models are necessary to identify pathological changes and help assess therapeutic outcomes following spinal cord injury (SCI). Small animal models offer value in research in terms of their easily managed size, minimal maintenance requirements, lower cost, well-characterized genomes, and ability to power research studies. However, despite these benefits, small animal models have neurologic and anatomical differences that may influence translation of results to humans and thus limiting the success of their use in preclinical studies as a direct pipeline to clinical studies. Large animal models, offer an attractive intermediary translation model that may be more successful in translating to the clinic for SCI research. This is largely due to their greater neurologic and anatomical similarities to humans. The physical characteristics of pig spinal cord, gut microbiome, metabolism, proportions of white to grey matter, bowel anatomy and function, and urinary system are strikingly similar and provide great insight into human SCI conditions. In this review, we address the variety of existing porcine injury models and their translational relevance, benefits, and drawbacks in modeling human systems and functions for neurophysiology, cardiovascular, gastrointestinal and urodynamic functions.

Buspirone Dose-Response on Facilitating Forelimb Functional Recovery in Cervical Spinal Cord Injured Rats.

Buspirone, widely used as a neuropsychiatric drug, has also shown potentials for motor function recovery of injured spinal cord. However, the optimum dosages of such treatment remain unclear. In this study, we investigated the dose-response of Buspirone treatment on reaching and grasping function in cervical cord injured rats. Seventeen adult Sprague-Dawley rats were trained to reach and grasp sugar pellets before a C4 bilateral dorsal column crush injury. After 1 week post-injury, the rats were divided into 3 groups to receive 1 of 3 different dosages of Buspirone (i.p., 1 dose/day: 1.5, n = 5; 2.5, n = 6 and 3.5 mg/kg b.w., n = 6). Forelimb reaching and grip strength test were recorded once per week, within 1 hour of Buspirone administration for 11 weeks post-injury. Different dose groups began to exhibit differences in reaching scores from 4 weeks post-injury. From 4-11 weeks post-injury, the reaching scores were highest in the lowest-dose group rats compared to the other 2 dose groups rats. Average grip strength was also found higher in the lowest-dose rats. Our results demonstrate a significant dose-dependence of Buspirone on the recovery of forelimb motor functions after cervical cord injury with the best performance occurring at the lowest dose tested.

Ultrasound-driven piezoelectric current activates spinal cord neurocircuits and restores locomotion in rats with spinal cord injury.

BACKGROUND: Neuromodulation via electrical stimulation (ES) is a common technique to treat numerous brain and spinal cord related neurological conditions. In the present study, we examined the efficacy of piezoelectric stimulation (pES) by a custom miniature piezostimulator to activate the spinal cord neurocircuit in comparison with conventional epidural ES in rats. METHODS: Stimulation electrodes were implanted on L2 and S1 spinal cord and were connected to a head-plug for ES, and a piezostimulator for pES. EMG electrodes were implanted into hindlimb muscles. To generate piezoelectric current, an ultrasound beam was delivered by an external ultrasound probe. Motor evoked potentials (MEPs) were recorded during the piezoelectric stimulation and compared with the signals generated by the ES. RESULTS: Our results suggest that ultrasound intensity as low as 0.1 mW/cm2 could induce MEPs in the hindlimbs. No significant difference was found either in MEPs or in muscle recruitments for ES and pES. Similar to ES, pES induced by 22.5 mW/cm2 ultrasound restored locomotion in paralyzed rats with complete thoracic cord injury. Locomotion EMG signals indicated that pES works same as ES. CONCLUSION: We propose piezoelectric stimulation as a new avenue of neuromodulation with features overtaking conventional electrical stimulation to serve future bioelectronic medicine. Video abstract.

Development of a battery-free ultrasonically powered functional electrical stimulator for movement restoration after paralyzing spinal cord injury.

BACKGROUND: Functional electrical stimulation (FES) is used to restore movements in paretic limbs after severe paralyses resulting from neurological injuries such as spinal cord injury (SCI). Most chronic FES systems utilize an implantable electrical stimulator to deliver a small electric current to the targeted muscle or nerve to stimulate muscle contractions. These implanted stimulators are generally bulky, mainly due to the size of the batteries. Furthermore, these battery-powered stimulators are required to be explanted every few years for battery replacement which may result in surgical failures or infections. Hence, a wireless power transfer technique is desirable to power these implantable stimulators. METHODS: Conventional wireless power transduction faces significant challenges for safe and efficient energy transfer through the skin and deep into the body. Inductive and electromagnetic power transduction is generally used for very short distances and may also interfere with other medical measurements such as X-ray and MRI. To address these issues, we have developed a wireless, ultrasonically powered, implantable piezoelectric stimulator. The stimulator is encapsulated with biocompatible materials. RESULTS: The stimulator is capable of harvesting a maximum of 5.95 mW electric power at an 8-mm depth under the skin from an ultrasound beam with about 380 mW/cm2 of acoustic intensity. The stimulator was implanted in several paraplegic rats with SCI. Our implanted stimulator successfully induced several hindlimb muscle contractions and restored leg movement. CONCLUSIONS: A battery-free miniature (10 mm diameter × 4 mm thickness) implantable stimulator, developed in the current study is capable of directly stimulating paretic muscles through external ultrasound signals. The required cost to develop the stimulator is relatively low as all the components are off the shelf.

Experimental spinal cord injury and behavioral tests in laboratory rats.

Traumatic spinal cord injury (SCI) results in some serious neurophysiological consequences that alter healthy body functions and devastate the quality of living of individuals. To find a cure for SCI, researchers around the world are working on different neurorepair and neurorehabilitation modalities. To test a new treatment for SCI as well as to understand the mechanism of recovery, animal models are being widely used. Among them, SCI rat models are arguably the most prominent. Furthermore, it is important to select a suitable behavioral test to evaluate both the motor and sensory recovery following any therapeutic intervention. In this paper, we review the rat models of spinal injury and commonly used behavioral tests to serve as a useful guideline for neuroscientists in the field of SCI research.