The Neuroprotective Effect of Kefir on Spinal Cord Ischemia/Reperfusion Injury in Rats

Objective

The main causes of spinal cord ischemia are a variety of vascular pathologies causing acute arterial occlusions. We investigated neuroprotective effects of kefir on spinal cord ischemia injury in rats.

Methods

Rats were divided into three groups : 1) sham operated control rats; 2) spinal cord ischemia group fed on a standard diet without kefir pretreatment; and 3) spinal cord ischemia group fed on a standard diet plus kefir. Spinal cord ischemia was performed by the infrarenal aorta cross-clamping model. The spinal cord was removed after the procedure. The biochemical and histopathological changes were observed within the samples. Functional assessment was performed for neurological deficit scores.

Results

The kefir group was compared with the ischemia group, a significant decrease in malondialdehyde levels was observed (p<0.05). Catalase and superoxide dismutase levels of the kefir group were significantly higher than ischemia group (p<0.05). In histopathological samples, the kefir group is compared with ischemia group, there was a significant decrease in numbers of dead and degenerated neurons (p<0.05). In immunohistochemical staining, hipoxia-inducible factor-1α and caspase 3 immunopositive neurons were significantly decreased in kefir group compared with ischemia group (p<0.05). The neurological deficit scores of kefir group were significantly higher than ischemia group at 24 h (p<0.05).

Conclusion

Our study revealed that kefir pretreatment in spinal cord ischemia/reperfusion reduced oxidative stress and neuronal degeneration as a neuroprotective agent. Ultrastructural studies are required in order for kefir to be developed as a promising therapeutic agent to be utilized for human spinal cord ischemia in the future.     

Spinal Cord Stimulation Attenuates Below‐Level Mechanical Hypersensitivity in Rats After Thoracic Spinal Cord Injury

ObjectivesThe burden of pain after spinal cord injury (SCI), which may occur above, at, or below injury level, is high worldwide. Spinal cord stimulation (SCS) is an important neuromodulation pain therapy, but its efficacy in SCI pain remains unclear. In SCI rats, we tested whether conventional SCS (50 Hz, 80% motor threshold [MoT]) and 1200 Hz, low-intensity SCS (40% MoT) inhibit hind paw mechanical hypersensitivity, and whether conventional SCS attenuates evoked responses of wide-dynamic range (WDR) neurons in lumbar spinal cord.Materials and MethodsMale rats underwent a moderate contusive injury at the T9 vertebral level. Six to eight weeks later, SCS or sham stimulation (120 min, n = 10) was delivered through epidural miniature electrodes placed at upper-lumbar spinal cord, with using a crossover design. Mechanical hypersensitivity was examined in awake rats by measuring paw withdrawal threshold (PWT) to stimulation with von Frey filaments. WDR neurons were recorded with in vivo electrophysiologic methods in a separate study of anesthetized rats.ResultsBoth conventional SCS and 1200 Hz SCS increased PWTs from prestimulation level in SCI rats, but the effects were modest and short-lived. Sham SCS was not effective. Conventional SCS (10 min) at an intensity that evokes the peak Aα/β waveform of sciatic compound action potential did not inhibit WDR neuronal responses (n = 19) to graded or repeated electrical stimulation that induces windup.ConclusionsConventional SCS and 1200 Hz, low-intensity SCS modestly attenuated below-level mechanical hypersensitivity after SCI. Inhibition of WDR neurons was not associated with pain inhibition from conventional SCS.     

The Regenerative Effect of Trans-spinal Magnetic Stimulation After Spinal Cord Injury: Mechanisms and Pathways Underlying the Effect

Spinal cord injury (SCI) leads to a loss of sensitive and motor functions. Currently, there is no therapeutic intervention offering a complete recovery. Here, we report that repetitive trans-spinal magnetic stimulation (rTSMS) can be a noninvasive SCI treatment that enhances tissue repair and functional recovery. Several techniques including immunohistochemical, behavioral, cells cultures, and proteomics have been performed. Moreover, different lesion paradigms, such as acute and chronic phase following SCI in wild-type and transgenic animals at different ages (juvenile, adult, and aged), have been used. We demonstrate that rTSMS modulates the lesion scar by decreasing fibrosis and inflammation and increases proliferation of spinal cord stem cells. Our results demonstrate also that rTSMS decreases demyelination, which contributes to axonal regrowth, neuronal survival, and locomotor recovery after SCI. This research provides evidence that rTSMS induces therapeutic effects in a preclinical rodent model and suggests possible translation to clinical application in humans.Electronic supplementary materialThe online version of this article (10.1007/s13311-020-00915-5) contains supplementary material, which is available to authorized users.     

Neuroprotective Effect of Graded Postischemic Reoxygenation in Spinal Cord Ischemia in the Rabbit

Early ischemia/reperfusion-induced changes of four phospholipid compounds bound to the inner cell membrane leaflet, i.e., phosphatidic acid, inositol phospholipids, serine phospholipids, and ethanolamine plasmalogens, were studied in a model of spinal cord ischemia in the rabbit during normoxic and graded postischemic reoxygenation. Light and electron microscopic analysis after normoxic reoxygenation disclosed neuronal membrane argyrophilia of the interneuronal pool located in lamina VII of L4-L6 segments. The number of small neurons (10–25 in diameter) affected by somatodendritic argyrophilia was greatly reduced, and concomitantly the ultrastructure of the endoplasmic reticulum, mitochondria, and Golgi complexes remained almost undamaged when graded postischemic reoxygenation had been applied. A statistically significant increase of phosphatidylserine and ethanolamine plasmalogen levels, and a decrease of phosphatidic acid, were detected after a short-lasting graded postischemic reoxygenation. The formation of thiobarbituric acid-reactive substances was significantly reduced during 60 min of graded postischemic reoxygenation and remained close to control or ischemic levels. The present data indicate that graded postischemic reoxygenation, which is considered to be neuroprotective, can prevent neuronal argyrophilia and the development of reperfusion-induced alterations of organelles. Moreover, reoxygenation can positively modify ischemia-induced changes of some membrane-bound phospholipids.     

Clinical Trial Designs for Neuromodulation in Chronic Spinal Cord Injury Using Epidural Stimulation

Study DesignThis is a narrative review focused on specific challenges related to adequate controls that arise in neuromodulation clinical trials involving perceptible stimulation and physiological effects of stimulation activation.Objectives1) To present the strengths and limitations of available clinical trial research designs for the testing of epidural stimulation to improve recovery after spinal cord injury. 2) To describe how studies can control for the placebo effects that arise due to surgical implantation, the physical presence of the battery, generator, control interfaces, and rehabilitative activity aimed to promote use-dependent plasticity. 3) To mitigate Hawthorne effects that may occur in clinical trials with intensive supervised participation, including rehabilitation.Materials and MethodsFocused literature review of neuromodulation clinical trials with integration to the specific context of epidural stimulation for persons with chronic spinal cord injury.ConclusionsStandard of care control groups fail to control for the multiple effects of knowledge of having undergone surgical procedures, having implanted stimulation systems, and being observed in a clinical trial. The irreducible effects that have been identified as “placebo” require sham controls or comparison groups in which both are implanted with potentially active devices and undergo similar rehabilitative training.     

Spinal Cord Injury Induced by a Cervical Spinal Cord Stimulator

Objective: The use of cervical spinal cord stimulators for the treatment of refractory neck and upper extremity pain is widely accepted and growing in use as a treatment modality. This case highlights a previously unreported potential complication of spinal cord stimulators. Methods: Analysis of a patient with a cervical spinal cord stimulator presenting with a spinal cord injury. Patient was followed from presentation in the emergency room until 1‐year follow‐up in the office. Results: The patient in this case presented after a fall and sustained a cervical spinal cord injury induced by the electrodes of her spinal cord stimulator working as a space occupying mass. Conclusion: As more patients are undergoing implantation of spinal cord stimulators we must be aware of the long‐term risks that can be encountered.     

Effect of Electrical Stimulation of Hamstrings and L3/4 Dermatome on Gait in Spinal Cord Injury

Objective. To determine the effect of electrical stimulation of hamstrings and L3/4 dermatome on the swing phase of gait. Materials and Methods. Five subjects with incomplete spinal cord injury (SCI) with spasticity were included. Two electrical stimulation methods were investigated, i.e., hamstrings and L3/4 dermatome stimulation. Both interventions were applied during the swing phase of gait. The main outcome measures were step length, maximum hip, and knee flexion during the swing phase of gait. In three subjects changes of spinal inhibition during gait were evaluated using the Hoffman reflex/m (motor)–wave (H/M) ratio at mid swing. Results. The hip flexion decreased 4.6° (p < 0.05) when the hamstrings were stimulated during the swing phase, whereas the knee flexion was not changed. The step length did not change significantly. One subject showed a decrease of the H/M ratio to a nonpathologic level during hamstrings stimulation. Conclusion. It was concluded that hamstrings stimulation during the swing phase results in a reduction of the hip flexion in all five SCI subjects. The H/M ratio of the vastus lateralis was normalized using hamstrings stimulation in one of three subjects. Stimulation of the L3/4 dermatome provides no significant changes in gait performance, but in one subject the H/M ratio increased.     

Sacral Nerve and Spinal Cord Stimulation for Intractable Neuropathic Pain Caused by Spinal Cord Infarction

Central cord pain is very difficult to relieve, even with the many kinds of medical and surgical treatments available. Following spinal cord infarctions, central cord pain can develop. The problems that may arise could include limb pain, pelvic pain, difficulties voiding, and difficulties defecating. We are reporting a case of central cord pain caused by a spinal cord infarction of the conus medullaris. Limb pain was reduced by spinal cord stimulation. Voiding and defecation difficulties and pelvic pain were reduced by sacral nerve stimulation. Thus, in a case involving both intractable limb and pelvic pain, a combination therapy of these two stimulations might be an effective treatment modality.     

Biomarker Optimization of Spinal Cord Stimulation Therapies

ObjectivesWe are in the process of designing and testing an intradural stimulation device that will shorten the distance between the location of the electrode array and the targeted neural tissue, thus improving the efficacy of electrical current delivery. Identifying a biomarker that accurately reflects the response to this intervention is highly valued because of the potential to optimize interventional parameters or predict a response before it is clinically measurable. In this report, we summarize the findings pertaining to the study of biomarkers so that we and others will have an up-to-date reference that critically evaluates the current approaches and select one or several for testing during the development of our device.Materials and MethodsWe have conducted a broad survey of the existing literature to catalogue the biomarkers that could be coupled to intradural spinal cord stimulation. We describe in detail some of the most promising biomarkers, existing limitations, and suitability to managing chronic pain.ResultsChronic, intractable pain is an all-encompassing condition that is incurable. Many treatments for managing chronic pain are nonspecific in action and intermittently administered; therefore, patients are particularly susceptible to large fluctuations in pain control over the course of a day. The absence of a reliable biomarker challenges assessment of therapeutic efficacy and contributes to either incomplete and inconsistent pain relief or, alternatively, intolerable side effects. Fluctuations in metabolites or inflammatory markers, signals captured during dynamic imaging, and genomics will likely have a role in governing how a device is modulated.ConclusionsEfforts to identify one or more biomarkers are well underway with some preliminary evidence supporting their efficacy. This has far-reaching implications, including improved outcomes, fewer adverse events, harmonization of treatment and individuals, performance gains, and cost savings. We anticipate that novel biomarkers will be used widely to manage chronic pain.     

Model-Based Optimization of Spinal Cord Stimulation for Inspiratory Muscle Activation

ObjectiveHigh-frequency spinal cord stimulation (HF-SCS) is a potential method to provide natural and effective inspiratory muscle pacing in patients with ventilator-dependent spinal cord injuries. Experimental data have demonstrated that HF-SCS elicits physiological activation of the diaphragm and inspiratory intercostal muscles via spinal cord pathways. However, the activation thresholds, extent of activation, and optimal electrode configurations (i.e., lead separation, contact spacing, and contact length) to activate these neural elements remain unknown. Therefore, the goal of this study was to use a computational modeling approach to investigate the direct effects of HF-SCS on the spinal cord and to optimize electrode design and stimulation parameters.Materials and MethodsWe developed a computer model of HF-SCS that consisted of two main components: 1) finite element models of the electric field generated during HF-SCS, and 2) multicompartment cable models of axons and motoneurons within the spinal cord. We systematically evaluated the neural recruitment during HF-SCS for several unique electrode designs and stimulation configurations to optimize activation of these neural elements. We then evaluated our predictions by testing two of these lead designs with in vivo canine experiments.ResultsOur model results suggested that within physiological stimulation amplitudes, HF-SCS activates both axons in the ventrolateral funiculi (VLF) and inspiratory intercostal motoneurons. We used our model to predict a lead design to maximize HF-SCS activation of these neural targets. We evaluated this lead design via in vivo experiments, and our computational model predictions demonstrated excellent agreement with our experimental testing.ConclusionsOur computational modeling and experimental results support the potential advantages of a lead design with longer contacts and larger edge-to-edge contact spacing to maximize inspiratory muscle activation during HF-SCS at the T2 spinal level. While these results need to be further validated in future studies, we believe that the results of this study will help improve the efficacy of HF-SCS technologies for inspiratory muscle pacing.     

Spatiotemporal Distribution of Electrically Evoked Spinal Compound Action Potentials During Spinal Cord Stimulation

ObjectivesRecent studies using epidural spinal cord stimulation (SCS) have demonstrated restoration of motor function in individuals previously diagnosed with chronic spinal cord injury (SCI). In parallel, the spinal evoked compound action potentials (ECAPs) induced by SCS have been used to gain insight into the mechanisms of SCS-based chronic pain therapy and to titrate closed-loop delivery of stimulation. However, the previous characterization of ECAPs recorded during SCS was performed with one-dimensional, cylindrical electrode leads. Herein, we describe the unique spatiotemporal distribution of ECAPs induced by SCS across the medial-lateral and rostral-caudal axes of the spinal cord, and their relationship to polysynaptic lower-extremity motor activation.Materials and MethodsIn each of four sheep, two 24-contact epidural SCS arrays were placed on the lumbosacral spinal cord, spanning the L3 to L6 vertebrae. Spinal ECAPs were recorded during SCS from nonstimulating contacts of the epidural arrays, which were synchronized to bilateral electromyography (EMG) recordings from six back and lower-extremity muscles.ResultsWe observed a triphasic P1, N1, P2 peak morphology and propagation in the ECAPs during midline and lateral stimulation. Distinct regions of lateral stimulation resulted in simultaneously increased ECAP and EMG responses compared with stimulation at adjacent lateral contacts. Although EMG responses decreased during repetitive stimulation bursts, spinal ECAP amplitude did not significantly change. Both spinal ECAP responses and EMG responses demonstrated preferential ipsilateral recruitment during lateral stimulation compared with midline stimulation. Furthermore, EMG responses were correlated with stimulation that resulted in increased ECAP amplitude on the ipsilateral side of the electrode array.ConclusionsThese results suggest that ECAPs can be used to investigate the effects of SCS on spinal sensorimotor networks and to inform stimulation strategies that optimize the clinical benefit of SCS in the context of managing chronic pain and the restoration of sensorimotor function after SCI.