Electromagnetic Field Stimulation Attenuates Phasic Nociception after Complete Spinal Cord Injury in Rats.
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ABSTRACT:
SUBMITTER: Kumar S
PROVIDER: S-EPMC8615391 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.
| S-EPMC7855640 | biostudies-literature
Project description:Epidural electrical stimulation can restore limb motor function after spinal cord injury by reactivating the surviving neural circuits. In previous epidural electrical stimulation studies, single electrode sites and continuous tetanic stimulation have often been used. With this stimulation, the body is prone to declines in tolerance and locomotion coordination. In the present study, rat models of complete spinal cord injury were established by vertically cutting the spinal cord at the T8 level to eliminate disturbance from residual nerve fibers, and were then subjected to epidural electrical stimulation. The flexible extradural electrode had good anatomical topology and matched the shape of the spinal canal of the implanted segment. Simultaneously, the electrode stimulation site was able to be accurately applied to the L2-3 and S1 segments of the spinal cord. To evaluate the biocompatibility of the implanted epidural electrical stimulation electrodes, GFAP/Iba-1 double-labeled immunofluorescence staining was performed on the spinal cord below the electrodes at 7 days after the electrode implantation. Immunofluorescence results revealed no significant differences in the numbers or morphologies of microglia and astrocytes in the spinal cord after electrode implantation, and there was no activated Iba-1+ cell aggregation, indicating that the implant did not cause an inflammatory response in the spinal cord. Rat gait analysis showed that, at 3 days after surgery, gait became coordinated in rats with spinal cord injury under burst stimulation. The regained locomotion could clearly distinguish the support phase and the swing phase and dynamically adjust with the frequency of stimulus distribution. To evaluate the matching degree between the flexible epidural electrode (including three stimulation contacts), vertebral morphology, and the level of the epidural site of the stimulation electrode, micro-CT was used to scan the thoracolumbar vertebrae of rats before and after electrode implantation. Based on the experimental results of gait recovery using three-site stimulation electrodes at L2-3 and S1 combined with burst stimulation in a rat model of spinal cord injury, epidural electrical stimulation is a promising protocol that needs to be further explored. This study was approved by the Animal Ethics Committee of Chinese PLA General Hospital (approval No. 2019-X15-39) on April 19, 2019.
| S-EPMC7996032 | biostudies-literature
Project description:Neurotensin (NT) is an endogenous tridecapeptide in the central nervous system. NT-containing neurons and NT receptors are widely distributed in the spinal dorsal horn (SDH), indicating their possible modulatory roles in nociception processing. However, the exact distribution and function of NT, as well as NT receptors (NTRs) expression in the SDH, have not been well documented. Among the four NTR subtypes, NTR2 is predominantly involved in central analgesia according to previous reports. However, the expression and function of NTR2 in the SDH has not yet been directly elucidated. Specifically, it remains unclear how NT-NTR2 interactions contribute to NT-mediated analgesia. In the present study, by using immunofluorescent histochemical staining and immunohistochemical staining with in situ hybridization histochemical staining, we found that dense NT- immunoreactivity (NT-ir) and moderate NTR2-ir neuronal cell bodies and fibers were localized throughout the superficial laminae (laminae I-II) of the SDH at the light microscopic level. In addition, γ-aminobutyric acid (GABA) and NTR2 mRNA were colocalized in some neuronal cell bodies, predominantly in lamina II. Using confocal and electron microscopy, we also observed that NT-ir terminals made both close contacts and asymmetrical synapses with the local GABA-ir neurons. Second, electrophysiological recordings showed that NT facilitated inhibitory synaptic transmission but not glutamatergic excitatory synaptic transmission. Inactivation of NTR2 abolished the NT actions on both GABAergic and glycinergic synaptic release. Moreover, a behavioral study revealed that intrathecal injection of NT attenuated thermal pain, mechanical pain, and formalin induced acute inflammatory pain primarily by activating NTR2. Taken together, the present results provide direct evidence that NT-containing terminals and fibers, as well as NTR2-expressing neurons are widely distributed in the spinal dorsal horn, GABA-containing neurons express NTR2 mainly in lamina II, GABA coexists with NTR2 mainly in lamina II, and NT may directly increase the activity of local inhibitory neurons through NTR2 and induce analgesic effects.
| S-EPMC8740200 | biostudies-literature
Project description:Spinal cord stimulation has become an important modality in pain treatment especially for neuropathic pain conditions refractory to pharmacotherapy. However, the molecular control of inhibitory and excitatory mechanisms observed after spinal cord stimulation are poorly understood. Here, we used RNA-seq to identify differences in the expression of genes and gene networks in spinal cord tissue from nerve-injured rats with and without repetitive conventional spinal cord stimulation treatment. Five weeks after chronic constrictive injury to the left sciatic nerve, male and female rats were randomized to receive repetitive spinal cord stimulation or no treatment. Rats receiving spinal cord stimulation underwent epidural placement of a miniature stimulating electrode and received seven sessions of spinal cord stimulation (50 Hz, 80% motor threshold, 0.2 ms, constant current bipolar stimulation, 120 min/session) over four consecutive days. Within 2 h after the last spinal cord stimulation treatment, the L4-L6 spinal segments ipsilateral to the side of nerve injury were harvested and used to generate libraries for RNA-seq. Our RNA-seq data suggest further increases of many existing upregulated immune responses in chronic constrictive injury rats after repetitive spinal cord stimulation, including transcription of cell surface receptors and activation of non-neuronal cells. We also demonstrate that repetitive spinal cord stimulation represses transcription of several key synaptic signaling genes that encode scaffold proteins in the post-synaptic density. Our transcriptional studies suggest a potential relationship between specific genes and the therapeutic effects observed in patients undergoing conventional spinal cord stimulation after nerve injury. Furthermore, our results may help identify new therapeutic targets for improving the efficacy of conventional spinal cord stimulation and other chronic pain treatments.
| S-EPMC6293371 | biostudies-literature
Project description:Background: Chronic spinal cord injury (SCI) portends a low probability of recovery, especially in the most severe subset of motor-complete injuries. Active spinal cord stimulation with or without intensive locomotor training has been reported to restore movement after traumatic SCI. Only three cases have been reported where participants developed restored volitional movement with active stimulation turned off after a period of chronic stimulation and only after intensive rehabilitation with locomotor training. It is unknown whether restoration of movement without stimulation is possible after stimulation alone. Objective: We describe the development of spontaneous volitional movement (SVM) without active stimulation in a subset of participants in the Epidural Stimulation After Neurologic Damage (ESTAND) trial, in which locomotor training is not prescribed as part of the study protocol, and subject's rehabilitation therapies are not modified. Methods: Volitional movement was evaluated with the Brain Motor Control Assessment using sEMG recordings and visual examination at baseline and at follow-up visits with and without stimulation. Additional functional assessment with a motor-assisted bicycle exercise at follow-up with and without stimulation identified generated work with and without effort. Results: The first seven participants had ASIA Impairment Scale (AIS) A or B thoracic SCI, a mean age of 42 years, and 7.7 years post-injury on average. Four patients developed evidence of sustained volitional movement, even in the absence of active stimulation after undergoing chronic epidural spinal cord stimulation (eSCS). Significant increases in volitional power were found between those observed to spontaneously move without stimulation and those unable (p < 0.0005). The likelihood of recovery of spontaneous volitional control was correlated with spasticity scores prior to the start of eSCS therapy (p = 0.048). Volitional power progressively improved over time (p = 0.016). Additionally, cycling was possible without stimulation (p < 0.005). Conclusion: While some SVM after eSCS has been reported in the literature, this study demonstrates sustained restoration without active stimulation after long-term eSCS stimulation in chronic and complete SCI in a subset of participants. This finding supports previous studies suggesting that "complete" SCI is likely not as common as previously believed, if it exists at all in the absence of transection and that preserved pathways are substrates for eSCS-mediated recovery in clinically motor-complete SCI. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03026816.
| S-EPMC7340010 | biostudies-literature
Project description:BackgroundEpidural stimulation of the spinal cord can be used to enable stepping on a treadmill (electrical enabling motor control, eEmc) after a complete mid-thoracic spinal cord transection in adult rats. Herein we have studied the effects of eEmc using a sub-threshold intensity of stimulation combined with spontaneous load-bearing proprioception to facilitate hindlimb stepping and standing during daily cage activity in paralyzed rats.MethodsWe hypothesized that eEmc combined with spontaneous cage activity would greatly increase the frequency and level of activation of the locomotor circuits in paralyzed rats. Spontaneous cage activity was recorded using a specially designed swivel connector to record EMG signals and an IR based camcorder to record video.Results and conclusionThe spinal rats initially were very lethargic in their cages showing little movement. Without eEmc, the rats remained rather inactive with the torso rarely being elevated from the cage floor. When the rats used their forelimbs to move, the hindlimbs were extended and dragged behind with little or no flexion. In contrast, with eEmc the rats were highly active and the hindlimbs showed robust alternating flexion and extension resulting in step-like movements during forelimb-facilitated locomotion and often would stand using the sides of the cages as support. The mean and summed integrated EMG levels in both a hindlimb flexor and extensor muscle were higher with than without eEmc. These data suggest that eEmc, in combination with the associated proprioceptive input, can modulate the spinal networks to significantly amplify the amount and robustness of spontaneous motor activity in paralyzed rats.
| S-EPMC4016220 | biostudies-literature
Project description:We evaluated the mechanisms underlying the spinal cord stimulation (SCS)-induced analgesic effect on neuropathic pain following spared nerve injury (SNI). On day 3 after SNI, SCS was performed for 6 h by using electrodes paraspinally placed on the L4-S1 spinal cord. The effects of SCS and intraperitoneal minocycline administration on plantar mechanical sensitivity, microglial activation, and neuronal excitability in the L4 dorsal horn were assessed on day 3 after SNI. The somatosensory cortical responses to electrical stimulation of the hind paw on day 3 following SNI were examined by using in vivo optical imaging with a voltage-sensitive dye. On day 3 after SNI, plantar mechanical hypersensitivity and enhanced microglial activation were suppressed by minocycline or SCS, and L4 dorsal horn nociceptive neuronal hyperexcitability was suppressed by SCS. In vivo optical imaging also revealed that electrical stimulation of the hind paw-activated areas in the somatosensory cortex was decreased by SCS. The present findings suggest that SCS could suppress plantar SNI-induced neuropathic pain via inhibition of microglial activation in the L4 dorsal horn, which is involved in spinal neuronal hyperexcitability. SCS is likely to be a potential alternative and complementary medicine therapy to alleviate neuropathic pain following nerve injury.
| S-EPMC7177766 | biostudies-literature
Project description:BackgroundStimulation of the spinal cord has been shown to have great potential for improving function after motor deficits caused by injury or pathological conditions. Using a wide range of animal models, many studies have shown that stimulation applied to the neural networks intrinsic to the spinal cord can result in a dramatic improvement of motor ability, even allowing an animal to step and stand after a complete spinal cord transection. Clinical use of this technology, however, has been slow to develop due to the invasive nature of the implantation procedures, the lack of versatility in conventional stimulation technology, and the difficulty of ascertaining specific sites of stimulation that would provide optimal amelioration of the motor deficits. Moreover, the development of tools available to control precise stimulation chronically via biocompatible electrodes has been limited. In this paper, we outline the development of this technology and its use in the spinal rat model, demonstrating the ability to identify and stimulate specific sites of the spinal cord to produce discrete motor behaviors in spinal rats using this array.MethodsWe have designed a chronically implantable, rapidly switchable, high-density platinum based multi-electrode array that can be used to stimulate at 1-100 Hz and 1-10 V in both monopolar and bipolar configurations to examine the electrophysiological and behavioral effects of spinal cord epidural stimulation in complete spinal cord transected rats.ResultsIn this paper, we have demonstrated the effectiveness of using high-resolution stimulation parameters in the context of improving motor recovery after a spinal cord injury. We observed that rats whose hindlimbs were paralyzed can stand and step when specific sets of electrodes of the array are stimulated tonically (40 Hz). Distinct patterns of stepping and standing were produced by stimulation of different combinations of electrodes on the array located at specific spinal cord levels and by specific stimulation parameters, i.e., stimulation frequency and intensity, and cathode/anode orientation. The array also was used to assess functional connectivity between the cord dorsum to interneuronal circuits and specific motor pools via evoked potentials induced at 1 Hz stimulation in the absence of any anesthesia.ConclusionsTherefore the high density electrode array allows high spatial resolution and the ability to selectively activate different neural pathways within the lumbosacral region of the spinal cord to facilitate standing and stepping in adult spinal rats and provides the capability to evoke motor potentials and thus a means for assessing connectivity between sensory circuits and specific motor pools and muscles.
| S-EPMC3599040 | biostudies-literature
Project description:Previous studies have shown that epidural stimulation of the lumbosacral spinal cord (scES) can re-enable lower limb volitional motor control in individuals with chronic, clinically motor complete spinal cord injury (SCI). This observation entails that residual supraspinal connectivity to the lumbosacral spinal circuitry still persisted after SCI, although it was non-detectable when scES was not provided. In the present study, we aimed at exploring further the mechanisms underlying scES-promoted recovery of volitional lower limb motor control by investigating neuroimaging markers at the spinal cord lesion site via magnetic resonance imaging (MRI). Spinal cord MRI was collected prior to epidural stimulator implantation in 13 individuals with chronic, clinically motor complete SCI, and the spared tissue of specific regions of the spinal cord (anterior, posterior, right, left, and total cord) was assessed. After epidural stimulator implantation, and prior to any training, volitional motor control was evaluated during left and right lower limb flexion and ankle dorsiflexion attempts. The ability to generate force exertion and movement was not correlated to any neuroimaging marker. On the other hand, spared tissue of specific cord regions significantly and importantly correlated with some aspects of motor control that include activation amplitude of antagonist (negative correlation) muscles during left ankle dorsiflexion, and electromyographic coordination patterns during right lower limb flexion. The fact that amount and location of spared spinal cord tissue at the lesion site were not related to the ability to generate volitional lower limb movements may suggest that supraspinal inputs through spared spinal cord regions that differ across individuals can result in the generation of lower limb volitional motor output prior to any training when epidural stimulation is provided.
| S-EPMC7654217 | biostudies-literature
Project description:Although stem cell therapy holds promise for the treatment of spinal cord injury (SCI), its practical applications are limited by the low degree of neural differentiation. Electrical stimulation is one of the most effective ways to promote the differentiation of stem cells into neurons, but conventional wired electrical stimulation may cause secondary injuries, inflammation, pain, and infection. Here, based on the high conductivity of graphite and the electromagnetic induction effect, graphite nanosheets with neural stem cells (NSCs) are proposed as an electromagnetic cellularized patch to generate in situ wirelessly pulsed electric signals under a rotating magnetic field for regulating neuronal differentiation of NSCs to treat SCI. The strength and frequency of the induced voltage can be controlled by adjusting the rotation speed of the magnetic field. The generated pulsed electrical signals promote the differentiation of NSCs into functional mature neurons and increase the proportion of neurons from 12.5% to 33.7%. When implanted in the subarachnoid region of the injured spinal cord, the electromagnetic cellularized patch improves the behavioral performance of the hind limbs and the repair of spinal cord tissue in SCI mice. This work opens a new avenue for remote treatment of SCI and other nervous system diseases.
| S-EPMC11321663 | biostudies-literature