Divergent Findings in Brain Reorganization After Spinal Cord Injury: A Review

Spinal cord injury (SCI) leads to a general lack of sensory and motor functions below the level of injury and may promote deafferentation‐induced brain reorganization. Functional magnetic resonance imaging (fMRI) has been established as an essential tool in neuroscience research and can precisely map the spatiotemporal distribution of brain activity. Task‐based fMRI experiments associated with the tongue, upper limbs, or lower limbs have been used as the primary paradigms to study brain reorganization following SCI. A review of the current literature on the subject shows one common trait: while most articles agree that brain networks are usually preserved after SCI, and that is not the case as some articles describe possible alterations in brain activation after the lesion. There is no consensus if those alterations indeed occur. In articles that show alterations, there is no agreement if they are transient or permanent. Besides, there is no consensus on which areas are most prone to activation changes, or on the intensity and direction (increase vs. decrease) of those possible changes. In this article, we present a critical review of the literature and trace possible reasons for those contradictory findings on brain reorganization following SCI. fMRI studies based on the ankle dorsiflexion, upper‐limb, and tongue paradigms are used as case studies for the analyses.     

Spinal Cord Stimulation for Pain Treatment After Spinal Cord Injury

In addition to restoration of bladder, bowel, and motor functions, alleviating the accompanying debilitating pain is equally important for improving the quality of life of patients with spinal cord injury(SCI). Currently,however, the treatment of chronic pain after SCI remains a largely unmet need. Electrical spinal cord stimulation(SCS) has been used to manage a variety of chronic pain conditions that are refractory to pharmacotherapy. Yet, its efficacy, benefit profiles, and mechanisms of action in SCI pain remain elusive, due to limited research, methodological weaknesses in previous clinical studies, and a lack of mechanistic exploration of SCS for SCI pain control. We aim to review recent studies and outline the therapeutic potential of different SCS paradigms for traumatic SCI pain. We begin with an overview of its manifestations,classification, potential underlying etiology, and currentchallenges for its treatment. The clinical evidence for using SCS in SCI pain is then reviewed. Finally, future perspectives of pre-clinical research and clinical study of SCS for SCI pain treatment are discussed.     

Expression Profile of Flotillin-2 and Its Pathophysiological Role After Spinal Cord Injury

Some receptors that block axonal regeneration or promote cell death after spinal cord injury (SCI) are localized in membrane rafts. Flotillin-2 (Flot-2) is an essential protein associated with the formation of these domains and the clustering of membranal proteins, which may have signaling activities. Our hypothesis is that trauma will change Flot-2 expression and interference of this lipid raft marker will promote functional locomotor recovery after SCI. Analyses were conducted to determine the spatiotemporal profile of Flot-2 expression in adult rats after SCI, using the MASCIS impactor device. Immunoblots showed that SCI produced a significant decrease in the level of Flot-2 at 2 days post-injury (DPI) that increased until 28 DPI. Confocal microscopy revealed Flot-2 expression in neurons, reactive astrocytes and oligodendrocytes specifically associated to myelin structures near or close to the axons of the cord. In the open field test and grid walking assays, to monitor locomotor recovery of injured rats infused intrathecally with Flot-2 antisense oligonucleotides for 28 days showed significant behavioral improvement at 14, 21 and 28 DPI. These findings suggest that Flot-2 has a role in the nonpermissive environment that blocks locomotor recovery after SCI by clustering unfavorable proteins in membrane rafts.     

Foxj2 Expression in Rat Spinal Cord After Injury and Its Role in Inflammation

Foxj2 (forkhead box J2), a novel member of the forkhead/HNF3 family, binds DNA with a dual sequence specificity. It may play a role in maintenance and survival of developing and adult neurons. However, its expression and function in the central nervous system lesion are still unclear. In this study, we performed a spinal cord injury (SCI) model in adult Sprague–Dawley rats and investigated the dynamic changes of Foxj2 expression in the spinal cord. Western blot analysis revealed that Foxj2 was present in normal spinal cord. It gradually increased, reached a peak at day 5 after SCI, and then declined during the following days. Double immunofluorescence staining revealed wide expression of Foxj2, which is detected in neurons and astrocytes. After injury, Foxj2 expression was increased predominantly in astrocytes, which highly expressed proliferating cell nuclear antigen, a marker for proliferating cells. And knockdown of Foxj2 in cultured primary astrocytes by siRNA showed that Foxj2 played an important role in lipopolysaccharide-induced inflammatory responses. These results suggested that Foxj2 may be involved in the pathophysiology of SCI, and further research is needed to have a good understanding of its function and mechanism.     

Targeted-Plasticity in the Corticospinal Tract After Human Spinal Cord Injury

Spinal cord injury (SCI) often results in impaired or absent sensorimotor function below the level of the lesion. Recent electrophysiological studies in humans with chronic incomplete SCI demonstrate that voluntary motor output can be to some extent potentiated by noninvasive stimulation that targets the corticospinal tract. We discuss emerging approaches that use transcranial magnetic stimulation (TMS) over the primary motor cortex and electrical stimulation over a peripheral nerve as tools to induce plasticity in residual corticospinal projections. A single TMS pulse over the primary motor cortex has been paired with peripheral nerve electrical stimulation at precise interstimulus intervals to reinforce corticospinal synaptic transmission using principles of spike-timing dependent plasticity. Pairs of TMS pulses have also been used at interstimulus intervals that mimic the periodicity of descending indirect (I) waves volleys in the corticospinal tract. This data, along with information about the extent of the injury, provides a new framework for exploring the contribution of the corticospinal tract to recovery of function following SCI.     

Glial Cells Shape Pathology and Repair After Spinal Cord Injury

Glial cell types were classified less than 100 years ago by del Rio-Hortega. For instance, he correctly surmised that microglia in pathologic central nervous system (CNS) were “voracious monsters” that helped clean the tissue. Although these historical predictions were remarkably accurate, innovative technologies have revealed novel molecular, cellular, and dynamic physiologic aspects of CNS glia. In this review, we integrate recent findings regarding the roles of glia and glial interactions in healthy and injured spinal cord. The three major glial cell types are considered in healthy CNS and after spinal cord injury (SCI). Astrocytes, which in the healthy CNS regulate neurotransmitter and neurovascular dynamics, respond to SCI by becoming reactive and forming a glial scar that limits pathology and plasticity. Microglia, which in the healthy CNS scan for infection/damage, respond to SCI by promoting axon growth and remyelination—but also with hyperactivation and cytotoxic effects. Oligodendrocytes and their precursors, which in healthy tissue speed axon conduction and support axonal function, respond to SCI by differentiating and producing myelin, but are susceptible to death. Thus, post-SCI responses of each glial cell can simultaneously stimulate and stifle repair. Interestingly, potential therapies could also target interactions between these cells. Astrocyte–microglia cross-talk creates a feed-forward loop, so shifting the response of either cell could amplify repair. Astrocytes, microglia, and oligodendrocytes/precursors also influence post-SCI cell survival, differentiation, and remyelination, as well as axon sparing. Therefore, optimizing post-SCI responses of glial cells—and interactions between these CNS cells—could benefit neuroprotection, axon plasticity, and functional recovery.     

Noninvasive Neuroprosthesis Promotes Cardiovascular Recovery After Spinal Cord Injury

Spinal cord injury (SCI) leads to severe impairment in cardiovascular control, commonly manifested as a rapid, uncontrolled rise in blood pressure triggered by peripheral stimuli—a condition called autonomic dysreflexia. The objective was to demonstrate the translational potential of noninvasive transcutaneous stimulation (TCS) in mitigating autonomic dysreflexia following SCI, using pre-clinical evidence and a clinical case report. In rats with SCI, we show that TCS not only prevents the instigation of autonomic dysreflexia, but also mitigates its severity when delivered during an already-triggered episode. Furthermore, when TCS was delivered as a multisession therapy for 6 weeks post-SCI, the severity of autonomic dysreflexia was significantly reduced when tested in the absence of concurrent TCS. This treatment effect persisted for at least 1 week after the end of therapy. More importantly, we demonstrate the clinical applicability of TCS in treatment of autonomic dysreflexia in an individual with cervical, motor-complete, chronic SCI. We anticipate that TCS will offer significant therapeutic advantages, such as obviating the need for surgery resulting in reduced risk and medical expenses. Furthermore, this study provides a framework for testing the potential of TCS in improving recovery of other autonomic functions such lower urinary tract, bowel, and sexual dysfunction following SCI.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-021-01034-5.Key Words: Spinal cord injuries, Cardiovascular dysfunction, Blood pressure, Autonomic dysreflexia, Transcutaneous stimulation, Noninvasive neuromodulation     

Reorganization of Intact Descending Motor Circuits to Replace Lost Connections After Injury

Neurons have a limited capacity to regenerate in the adult central nervous system (CNS). The inability of damaged axons to re-establish original circuits results in permanent functional impairment after spinal cord injury (SCI). Despite abortive regeneration of axotomized CNS neurons, limited spontaneous recovery of motor function emerges after partial SCI in humans and experimental rodent models of SCI. It is hypothesized that this spontaneous functional recovery is the result of the reorganization of descending motor pathways spared by the injury, suggesting that plasticity of intact circuits is a potent alternative conduit to enhance functional recovery after SCI. In support of this hypothesis, several studies have shown that after unilateral corticospinal tract (CST) lesion (unilateral pyramidotomy), the intact CST functionally sprouts into the denervated side of the spinal cord. Furthermore, pharmacologic and genetic methods that enhance the intrinsic growth capacity of adult neurons or block extracellular growth inhibitors are effective at significantly enhancing intact CST reorganization and recovery of motor function. Owing to its importance in controlling fine motor behavior in primates, the CST is the most widely studied descending motor pathway; however, additional studies in rodents have shown that plasticity within other spared descending motor pathways, including the rubrospinal tract, raphespinal tract, and reticulospinal tract, can also result in restoration of function after incomplete SCI. Identifying the molecular mechanisms that drive plasticity within intact circuits is crucial in developing novel, potent, and specific therapeutics to restore function after SCI. In this review we discuss the evidence supporting a focus on exploring the capacity of intact motor circuits to functionally repair the damaged CNS after SCI.     

Neuropathic Pain After Spinal Cord Injury: Challenges and Research Perspectives

Neuropathic pain is a debilitating consequence of spinal cord injury (SCI) that remains difficult to treat because underlying mechanisms are not yet fully understood. In part, this is due to limitations of evaluating neuropathic pain in animal models in general, and SCI rodents in particular. Though pain in patients is primarily spontaneous, with relatively few patients experiencing evoked pains, animal models of SCI pain have primarily relied upon evoked withdrawals. Greater use of operant tasks for evaluation of the affective dimension of pain in rodents is needed, but these tests have their own limitations such that additional studies of the relationship between evoked withdrawals and operant outcomes are recommended. In preclinical SCI models, enhanced reflex withdrawal or pain responses can arise from pathological changes that occur at any point along the sensory neuraxis. Use of quantitative sensory testing for identification of optimal treatment approach may yield improved identification of treatment options and clinical trial design. Additionally, a better understanding of the differences between mechanisms contributing to at- versus below-level neuropathic pain and neuropathic pain versus spasticity may shed insights into novel treatment options. Finally, the role of patient characteristics such as age and sex in pathogenesis of neuropathic SCI pain remains to be addressed.     

Axon Guidance Molecules and Neural Circuit Remodeling After Spinal Cord Injury

…once the development was ended, the founts of growth and regeneration of the axons and dendrites dried up irrevocably. Santiago Ramón y Cajal

Cajal’s neurotropic theory postulates that the complexity of the nervous system arises from the collaboration of neurotropic signals from neuronal and non-neuronal cells and that once development has ended, a paucity of neurotropic signals means that the pathways of the central nervous system are “fixed, ended, immutable”. While the capacity for regeneration and plasticity of the central nervous system may not be quite as paltry as Cajal proposed, regeneration is severely limited in scope as there is no spontaneous regeneration of long-distance projections in mammals and therefore limited opportunity for functional recovery following spinal cord injury. It is not a far stretch from Cajal to hypothesize that reappropriation of the neurotropic programs of development may be an appropriate strategy for reconstitution of injured circuits. It has become clear, however, that a significant number of the molecular cues governing circuit development become re-active after injury and many assume roles that paradoxically obstruct the functional re-wiring of severed neural connections. Therefore, the problem to address is how individual neural circuits respond to specific molecular cues following injury, and what strategies will be necessary for instigating functional repair or remodeling of the injured spinal cord.     

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.     

Local Transcutaneous Cooling of the Spinal Cord in the Rat: Effects on Long-Term Outcomes After Compression Spinal Cord Injury

This study tested efficiency of a novel thermoelectric cooler for local transcutaneous spinal cord cooling. Spinal cord compression was made by epidural balloon inflation at T8-T9 level of the spinal cord. Experimental animals (n = 20) were divided into two groups. In the hypothermic group, local cooling started 25 min after spinal cord injury and lasted for 1 h with paravertebral temperature maintained at 28.5°C (±0.3). Normothermic group underwent identical procedures, but their temperature was maintained normothermic. The assessment of neurologic recovery was performed once a week during a 4 weeks survival period. After 4 weeks animals were sacrificed and the extent of the spinal cord lesion morphometrically evaluated. There were no statistically significant intergroup differences in BBB scores and preserved volumes of the spinal cord tissue. In consecutive cross-sectional areas, hypothermic animals had significantly more preserved white matter at the cranial periphery of the lesion. It was concluded that mild posttraumatic hypothermia (31.8°C) had some protective effect on tissue loss after spinal cord injury but this effect was not associated with functional improvement.     

Cannabidiol-treated Rats Exhibited Higher Motor Score After Cryogenic Spinal Cord Injury

Cannabidiol (CBD), a non-psychoactive constituent of cannabis, has been reported to induce neuroprotective effects in several experimental models of brain injury. We aimed at investigating whether this drug could also improve locomotor recovery of rats submitted to spinal cord cryoinjury. Rats were distributed into five experimental groups. Animals were submitted to laminectomy in vertebral segment T10 followed or not by application of liquid nitrogen for 5?s into the spinal cord at the same level to cause cryoinjury. The animals received injections of vehicle or CBD (20?mg/kg) immediately before, 3?h after and daily for 6?days after surgery. The Basso, Beattie, and Bresnahan motor evaluation test was used to assess motor function post-lesion one?day before surgery and on the first, third, and seventh postoperative days. The extent of injury was evaluated by hematoxylin-eosin histology and FosB expression. Cryogenic lesion of the spinal cord resulted in a significant motor deficit. Cannabidiol-treated rats exhibited a higher Basso, Beattie, and Bresnahan locomotor score at the end of the first week after spinal cord injury: lesion?+?vehicle, day 1: zero, day 7: four, and lesion?+?Cannabidiol 20?mg/kg, day 1: zero, day 7: seven. Moreover, at this moment there was a significant reduction in the extent of tissue injury and FosB expression in the ventral horn of the spinal cord. The present study confirmed that application of liquid nitrogen to the spinal cord induces reproducible and quantifiable spinal cord injury associated with locomotor function impairments. Cannabidiol improved locomotor functional recovery and reduced injury extent, suggesting that it could be useful in the treatment of spinal cord lesions.     

MCM7 Expression Is Altered in Rat After Spinal Cord Injury

Minichromosome maintenance protein 7 (MCM7), a member of the minichromosome maintenance protein family, is essential for eukaryotic DNA replication initiation and the early stage of the elongation process. MCM7 participates in the cell cycle control of genome duplication. While it is ubiquitously expressed in all tissues, the biological function of MCM7 in the central nervous system is still with limited acquaintance. In the present study, we performed a spinal cord injury (SCI) model in adult rats. Western blotting indicated a marked alteration of MCM7 after SCI. Immunohistochemistry analysis revealed a wide distribution of MCM7 in the spinal cord. Double immunofluorescence staining showed that MCM7 immunoreactivity was increased predominantly in neurons, astrocytes, and microglia after SCI. We also examined the expression profiles of active caspase-3, proliferating cell nuclear antigen (PCNA), and Ki67, whose changes were correlated with the expression profiles of MCM7. Moreover, colocalization of MCM7/active caspase-3 was detected in neuronal nuclei (NeuN), and colocalization of MCM7/PCNA was detected in NeuN, glial fibrillary acidic protein, and CD11b, respectively. Our results suggest that MCM7 might be implicated in the apoptosis of neuron and proliferation of astrocytes and microglia after SCI.     

Heterogeneous Cortical Effects of Spinal Cord Stimulation

ObjectivesThe understanding of the cortical effects of spinal cord stimulation (SCS) remains limited. Multiple studies have investigated the effects of SCS in resting-state electroencephalography. However, owing to the large variation in reported outcomes, we aimed to describe the differential cortical responses between two types of SCS and between responders and nonresponders using magnetoencephalography (MEG).Materials and MethodsWe conducted 5-minute resting-state MEG recordings in 25 patients with chronic pain with active SCS in three sessions, each after a one-week exposure to tonic, burst, or sham SCS. We extracted six spectral features from the measured neurophysiological signals: the alpha peak frequency; alpha power ratio (power 7–9 Hz/power 9–11 Hz); and average power in the theta (4–7.5 Hz), alpha (8–12.5 Hz), beta (13–30 Hz), and low-gamma (30.5–60 Hz) frequency bands. We compared these features (using nonparametric permutation t-tests) for MEG sensor and cortical map effects across stimulation paradigms, between participants who reported low (< 5, responders) vs high (≥ 5, nonresponders) pain scores, and in three representative participants.ResultsWe found statistically significant (p < 0.05, false discovery rate corrected) increased MEG sensor signal power below 3 Hz in response to burst SCS compared with tonic and sham SCS. We did not find statistically significant differences (all p > 0.05) between the power spectra of responders and nonresponders. Our data did not show statistically significant differences in the spectral features of interest among the three stimulation paradigms or between responders and nonresponders. These results were confirmed by the MEG cortical maps. However, we did identify certain trends in the MEG source maps for all comparisons and several features, with substantial variation across participants.ConclusionsThe considerable variation in cortical responses to the various SCS treatment options necessitates studies with sample sizes larger than commonly reported in the field and more personalized treatment plans. Studies with a finer stratification between responders and nonresponders are required to advance the knowledge on SCS treatment effects.