Spinal Cord Injury Group Research Articles

Gut Microbiota Disorders Promote Inflammation and Aggravate Spinal Cord Injury Through the TLR4/MyD88 Signaling Pathway.

Background: In spinal cord injury (SCI), systemic inflammation and the death of nerve cells in the spinal cord are life threatening. The connection between gut microbiota and signaling pathways has been a hot research topic in recent years. The Toll-like receptor 4/Myeloid differentiation factor 88 (TLR4/MyD88) signaling pathway is closely related to the inflammatory response. This study explored whether the gut microbiota imbalance could affect the TLR4/MyD88 signaling pathway to regulate SCI to provide a new basis for SCI research and treatment.Methods: An SCI model was constructed to study the influence on the injury of gut microbiota. 16S amplicon sequencing was used to identify the diversity and abundance of gut microbes. Fecal microbiota transplantation was performed in mice with SCI. ELISA was used to detect the serum levels of pro-inflammatory and anti-inflammatory factors in mice. Hematoxylin and eosin staining was used to observe SCI in mice. Immunofluorescence was used to detect the rates of loss glial fibrillary acidic protein (GFAP), neuronal nuclear protein (NeuN), and ionized calcium-binding adapter molecule 1 (IBA1) in the spinal cord as indicators of apoptosis. The expression of the TLR4/MyD88 signaling pathway was detected by qRT-PCR and western blotting.Results: Significant differences were observed in the gut microbiota of SCI mice and normal mice. The gut microbiota of SCI mice was imbalanced. The levels of pro-inflammatory cytokines tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 in SCI mice were increased, as was the level of the toxic induced nitric oxide synthase. The levels of anti-inflammatory factors IL-4, transforming growth factor-β, and IL-10 were decreased, as was the level of arginase-1. The apoptosis rates of GFAP, NeuN, and IBA1 were increased. The TLR4/MyD88 signaling pathway was activated. In the SCI group, inflammation increased after fecal transplantation, apoptosis of GFAP, NeuN, and IBA1 increased, and SCI was more serious.Conclusion: The TLR4/MyD88 signaling pathway promotes the death of nerve cells by inducing inflammation. Gut microbiota dysregulation can lead to aggravated SCI by activating the TLR4/MyD88 signaling pathway.

Prevalence of comorbidities and secondary health conditions among the Finnish population with spinal cord injury

Study designA cross-sectional study.ObjectivesTo explore the prevalence of comorbidities, secondary health conditions (SHCs), and multimorbidity in the Finnish population with spinal cord injury (SCI).SettingThe data were collected from the Finnish Spinal Cord Injury Study (FinSCI). Participants were identified from three SCI outpatient clinics responsible for the lifelong follow-up of persons with SCI in Finland, (n = 884 participants, response rate; 50%).MethodsThe FinSCI-questionnaire included a question from the National Study of Health, Well-being, and Service (FinSote) for screening 12 comorbidities. The reference data of the general population for that question were received from the Finnish Institute for Health and Welfare. The Spinal Cord Injury Secondary Condition Scale (SCI-SCS) was used to screen 16 SHCs. The data were analysed with univariate testing and multivariable negative binomial regression modelling.ResultsThe most common comorbidities were high blood pressure/hypertension (38%), back problems (28%), and high cholesterol (22%). The most common SHCs were joint and muscle pain (81%), muscle spasms (74%), chronic pain (71%), and bowel problems (71%). The prevalence of comorbidities was highest among persons aged ≥76 years (mean; 2.0; scale range; 0–12). The prevalence of SHCs was highest in the severity of SCI group C1–4 AIS A, B, and C (mean; 8.9; scale range; 0–16).ConclusionsFurther research on geriatrics in SCI, non-traumatic SCI, and knowledge of the needs of persons with cervical lesion AIS A, B, or C is required, due to the fact that the prevalence of multimorbidity is high in these groups.

Impact of fractional amplitude of low-frequency fluctuations in motor- and sensory-related brain networks on spinal cord injury severity.

Spinal cord injury (SCI) can cause motor, sensory, and autonomic dysfunctions and may affect the cerebral functions. However, the mechanisms of plastic changes in the brain according to SCI severity remain poorly understood. Therefore, in the current study, we compared the brain activity of the entire neural network according to severity of SCI using fractional amplitude of low-frequency fluctuations (fALFF) analysis in resting-state functional magnetic resonance imaging (rs-fMRI). A total of 59 participants were included, consisting of 19 patients with complete SCI, 20 patients with incomplete SCI, and 20 healthy individuals. Their motor and sensory functions were evaluated. The rs-fMRI data of low-frequency fluctuations were analyzed based on fALFF. Differences in fALFF values among complete-SCI patients, incomplete-SCI patients, and healthy controls were assessed using ANOVA. Then post hoc analysis and two-sample t-tests were conducted to assess the differences between the three groups. Pearson correlation analyses were used to determine correlations between clinical measures and the z-score of the fALFF in the SCI groups. Patients with SCI (complete and incomplete) showed lower fALFF values in the superior medial frontal gyrus than the healthy controls, and were associated with poor motor and sensory function (p < .05). Higher fALFF values were observed in the putamen and thalamus, and were negatively associated with motor and sensory function (p < .05). In conclusion, alterations in the neural activity of the motor- and sensory-related networks of the brain were observed in complete-SCI and incomplete-SCI patients. Moreover, plastic changes in these brain regions were associated with motor and sensory function.

Quantifying the Changes of Mechanical and Electrical Properties of Paralyzed Muscle in Survivors With Cervical Spinal Cord Injury.

Background: Survivors with spinal cord injury (SCI) have neuromuscular deficits such as muscle atrophy that lead to functional impairments. This study utilized myotonometry and electrical impedance myography (EIM) to quantitatively evaluate the changes in muscle mechanical properties and compositions after SCI.Methods: This study adopted a cross-sectional design. Eighteen SCI patients and 18 healthy individuals were recruited. The outcome measures were: (1) The myotonometer measured muscle mechanical parameters of oscillation frequency (freq), dynamic stiffness, logarithmic decrement (decr), mechanical stress relaxation time, and indication of creep. (2) The electrical impedance myography measured parameters of resistance (R), reactance (X), and phase angle (θ). (3) muscle strength (maxForce); (4) clinical scales of Manual Muscle Testing (MMT) and modified Ashworth scale (MAS). All outcome measures were compared between the bicep brachii muscle of the weaker side of the SCI group and the non-dominate side of the healthy group. Correlation analysis was performed at quantitative data and clinical scales.Results: Freq, stiffness, and maxForce of the SCI group were significantly lower (p < 0.01) than those of the healthy control. The relaxation time and creep were significantly higher in the SCI group than in the control group. Significant differences of R and Xc were observed between the two groups. Significant correlation was observed between freq, stiffness, and months past injury, and between Xc, creep, and relaxation time.Conclusions: Reduced muscle tone and stiffness might relate to muscle atrophy, and higher relax time and creep may be caused by poor contractile ability. The changes in EIM parameters could indirectly reflect the muscle cell size, and fatty and connective tissue alterations. These findings support the feasibility of myotonometer and EIM to quantify muscle mechanical and intrinsic properties in patients with SCI. The results could facilitate the understanding of neuromuscular changes that are related to functional impairments.

Insulin-like growth factor 1 promotes neurological functional recovery after spinal cord injury through inhibition of autophagy via the PI3K/Akt/mTOR signaling pathway.

Spinal cord injury (SCI) is a serious trauma; however, the mechanisms underlying the role of insulin-like growth factor 1 (IGF-1) in autophagy following SCI remain to be elucidated. The present study aimed to investigate the therapeutic effect of IGF-1 on SCI and to determine whether IGF-1 regulates autophagy via the PI3K/Akt/mTOR signaling pathway. SH-SY5Y neuroblastoma cells were assigned to the H2O2, IGF-1 and control groups to investigate subsequent neuron injury in vitro. An MTT assay was performed to evaluate cell survival. In addition, Sprague-Dawley rats were randomly assigned to SCI, SCI + IGF-1 and sham groups, and Basso-Beatlie-Bresnahan scores were assessed to determine rat neurological function. Western blotting was used to analyze the autophagy level and the activation of the PI3K/Akt/mTOR signaling pathway. Cell survival was increased significantly in the IGF-1 group compared with the control group in vitro (P<0.05). Furthermore, neurological function was improved in the SCI + IGF-1 group compared with the control group in vivo (P<0.05). The western blotting results further demonstrated that LC3II/LC3I expression was increased in the IGF-1 group compared with the sham group in vivo and compared with the control group in vitro (both P<0.05). In the SCI + IGF-1 group, the expression levels of PI3K, phosphorylated (p)-Akt and p-mTOR were higher compared with those in the sham and SCI groups in vivo (P<0.05). Moreover, in the IGF-1 group, the expression levels of p-Akt and p-mTOR were higher compared with the control and the H2O2 groups in vitro (P<0.05). Collectively, the results of the present study suggested that IGF-1 promoted functional recovery in rats following SCI through neuroprotective effects. Furthermore, the underlying mechanism may involve activation of the PI3K/Akt/mTOR signaling pathway, followed by inhibition of autophagy. However, further investigation into the association between IGF-1-regulated autophagy and the activation of different subtypes of PI3K is required.

Increased Ipsilateral M1 Activation after Incomplete Spinal Cord Injury Facilitates Motor Performance.

Incomplete spinal cord injury (SCI) may result in muscle weakness and difficulties with force gradation. Although these impairments arise from the injury and subsequent changes at spinal levels, changes have also been demonstrated in the brain. Blood-oxygen-level dependent (BOLD) imaging was used to investigate these changes in brain activation in the context of unimanual contractions with the first dorsal interosseous muscle. BOLD- and force data were obtained in 19 individuals with SCI (AISA Impairment Scale [AIS] C/D, level C4-C8) and 24 able-bodied controls during maximal voluntary contractions (MVCs). To assess force modulation, participants performed 12 submaximal contractions with each hand (at 10, 30, 50, and 70% MVC) by matching their force level to a visual target. MVCs were weaker in the SCI group (both hands p < 0.001), but BOLD activation did not differ between SCI and control groups. For the submaximal contractions, force (as %MVC) was similar across groups. However, SCI participants showed increased activity of the ipsilateral motor cortex and contralateral cerebellum across all contractions, with no differential effect of force level. Activity of ipsilateral M1 was best explained by force of the target hand (vs. the non-target hand). In conclusion, the data suggest that after incomplete cervical SCI, individuals remain capable of producing maximal supraspinal drive and are able to modulate this drive adequately. Activity of the ipsilateral motor network appears to be task related, although it remains uncertain how this activity contributes to task performance and whether this effect could potentially be harnessed to improve motor functioning.

Inhibit inflammation and apoptosis of pyrroloquinoline on spinal cord injury in rat.

BackgroundPyrroloquinoline quinone (PQQ) is a redox cofactor that can participate in a variety of physiological and biochemical processes, such as anti-inflammatory, cytoprotection, anti-aging, and anti-apoptosis. PQQ plays an important protective role in the central nervous system (CNS). However, the effects of PQQ on astrocytes of the CNS and spinal cord injury (SCI) of rats is still unclear. The present study investigates the role of PQQ in inflammation, apoptosis, and autophagy after SCI in rats. And the effect of PQQ on lipopolysaccharide (LPS)-induced apoptosis and inflammation of astrocytes in vitro, to explore the neuroprotective mechanism of PQQ.MethodsSixty specific pathogen free (SPF) SD male rats (200–250 g) were randomly divided into Normal group, Sham group, SCI group, and SCI + PQQ group, with 15 rats in each group. BBB score, HE staining, Nissl staining, Western blot, immunofluorescence, and other methods were used for detection.ResultsOur results showed that PQQ could upregulate BBB score in SCI rats. In the second place, PQQ can increase the number and improve the morphology of neurons after SCI. The expression of IL-1β, TNF-α, IL-6 was significantly decreased after PQQ treatment. And then, the ratio of B-cell lymphoma-2 (Bcl-2)/Bcl-2 associated X protein (Bax) increased significantly, and the positive signal of NeuN increased obviously after PQQ treatment. There are a large number of co-localizations between Bcl-2 and NeuN. Meanwhile, PQQ could down-regulate the expression of Active-Caspase3, and PQQ treatment could reverse the transfer of Active-Caspase3/Caspase3 from the cytoplasm to the nucleus in neurons and astrocytes after SCI. At the same time, PQQ had no significant effect on the LC3b/a ratio. PQQ could decrease the LAMP2 expression in spinal cord after injury. The expression level of phospho-Akt (p-AKT) increased after SCI and decreased after PQQ treatment. In primary astrocytes, LPS could induce the expression levels of IL-1β, TNF-α, and IL-6, and which were inhibited by PQQ treatment at 12 hours. After treatment with LPS, the expression level of Active-Caspase3 increased, which could be reversed by PQQ treatment for 24 h.ConclusionsThese results suggest that PQQ can ameliorate the motor function of hind limbs and the pathological changes of neurons and injured spinal cord after SCI, down-regulate the expressions of IL-1β, TNF-α, and IL-6, inhibit apoptosis after SCI, and inhibit LPS-induced apoptosis and inflammation of astrocytes.

Recovery of motor function in rats with complete spinal cord injury following implantation of collagen/silk fibroin scaffold combined with human umbilical cord-mesenchymal stem cells

This study aimed to assess the effect of the collagen/silk fibroin scaffolds seeded with human umbilical cord-mesenchymal stem cells on functional recovery after acute complete spinal cord injury.The fibroin and collagen were mixed (mass ratio, 3:7), and the composite scaffolds were produced. Forty rats were randomly divided into the Sham group (without spinal cord injury), spinal cord injury group (spinal cord transection without any implantation), collagen/silk fibroin scaffolds group (spinal cord transection with implantation of the collagen/silk fibroin scaffolds), and collagen/silk fibroin scaffolds + human umbilical cord-mesenchymal stem cells group (spinal cord transection with the implantation of the collagen/silk fibroin scaffolds co-cultured with human umbilical cord-mesenchymal stem cells). Motor evoked potential, Basso-Beattie-Bresnahan scale, modified Bielschowsky's silver staining, and immunofluorescence staining were performed.The BBB scores in the collagen/silk fibroin scaffolds + human umbilical cord-mesenchymal stem cells group were significantly higher than those in the spinal cord injury and collagen/silk fibroin scaffolds groups (p<0.05 or p<0.01). The amplitude and latency were markedly improved in the collagen/silk fibroin scaffolds + human umbilical cord-mesenchymal stem cells group compared with the spinal cord injury and collagen/silk fibroin scaffolds groups (p<0.05 or p<0.01). Meanwhile, compared to the spinal cord injury and collagen/silk fibroin scaffolds groups, more neurofilament positive nerve fiber ensheathed by myelin basic protein positive structure at the injury site were observed in the collagen/silk fibroin scaffolds + human umbilical cord-mesenchymal stem cells group (p<0.01, p<0.05). The results of Bielschowsky's silver staining indicated more nerve fibers was observed at the lesion site in the collagen/silk fibroin scaffolds + human umbilical cord-mesenchymal stem cells group compared with the spinal cord injury and collagen/silk fibroin scaffolds groups (p<0.01, p< 0.05).The results demonstrated that the transplantation of human umbilical cord-mesenchymal stem cells on a collagen/silk fibroin scaffolds could promote nerve regeneration, and recovery of neurological function after acute spinal cord injury.

Peak oxygen uptake in sportsmen with spinal cord injury: importance of body composition.

Although peak oxygen uptake (VO<inf>2peak</inf>) is considered the most useful index of functional capacity, it's difficult to interpret the results of cardiopulmonary exercise testing (CPET) in individuals with spinal cord injury (SCI). In fact, VO<inf>2peak</inf> is usually normalized for total body weight, but body composition in persons with SCI largely varies depending on physical activity and time since injury, with a progressive loss of fat-free mass (FFM). This can lead to a misinterpretation of the cardiopulmonary fitness in this population. Our study proposes a methodology of evaluation, based on bioelectrical impedance analysis (BIA), which could provide more individualized and accurate data in sportsmen with SCI. Case-control study. Ambulatory patients at the Sports Medicine Unit of the IRCCS A. Gemelli University Polyclinic Foundation, Rome, Italy. Comparison of data derived from BIA, echocardiography and CPET between 10 male sportsmen with complete, high SCI (group T) and 10 able-bodied controls (group C). Mean VO<inf>2peak</inf>, weight-normalized VO<inf>2peak</inf>, fat-free mass (FFM)-normalized VO<inf>2peak</inf> and body cellular mass (BCM)-normalized values were significantly lower in group T. At the same heart rate (on average the 55% of the maximal theoretical for age), mean of absolute VO<inf>2</inf>, weight-normalized VO<inf>2</inf> and FFM-normalized VO<inf>2</inf> were still significantly lower in group T. Considering the BCM-normalized VO<inf>2</inf>, the group T showed greater values than controls, 39.4±7.8 vs. 31.1±8.5 mL/kg/min. Body composition is a crucial factor for properly interpreting a CPET in individuals with SCI. In particular, normalization of VO<inf>2peak</inf> values for the BCM seems the most reliable tool to assess the real functional capacity in this population. A more accurate definition of the aerobic power and functional capacity of people with SCI can improve the monitoring of rehabilitations protocols and physical exercise in this population.

Active and Passive Immunization with Myelin Basic Protein as a Method for Early Treatment of Traumatic Spinal Cord Injury; a Meta-Analysis.

Introduction:Traumatic spinal cord injury (SCI), as a dangerous central nervous system damage, continues to threaten communities by imposing various disabilities and costs. Early adjustment of the immune system response using Myelin Basic Protein (MBP) immunization may prevent the SCI-related secondary damages. As a result, the current study is designed to review and analyse the evidence on active and passive immunization with MBP for treatment of traumatic SCI.Methods:Medline, Embase, Scopus, and Web of Science databases were systematically searched until the end of 2020. Criteria for inclusion in the current study included pre-clinical studies, which performed passive (injection of MBP-activated T cells) or active (administration of MBP or MBP-modified peptides) immunization with MBP after traumatic SCI. Exclusion criteria was defined as lack of a non-treated SCI group, lack of evaluation of locomotion, review studies, and combination therapy. Finally, analyses were conducted using STATA software, and a standardized mean difference (SMD) with a 95% confidence interval (CI) were reported.Results:Data from 17 papers were included in the present study. Finally, analysis of these data showed that passive immunization (SMD=0.87; 95%CI: 0.19-1.55; p=0.012) and active immunization (SMD=2.08, 95%CI: 1.42-2.73; p<0.001) for/with MBP both have good efficacy in improving locomotion following traumatic SCI. However, significant heterogeneity was observed in both of them. The most important sources of heterogeneity in active immunization were differences in SCI models, route of administration, time interval between SCI and transplantation, and type of vaccine used. In passive immunization, however, these sources were the model of SCI and the time interval between SCI and transplantation. Although, there was substantial heterogeneity among studies, subgroup analysis showed that active immunization improved locomotion after traumatic SCI in all tested conditions (with differences in injury model, severity of injury, method of administration, different time interval between SCI to vaccination, etc.). Conclusion:The results of the present study demonstrated that immunization with MBP, especially in its active form, could significantly improve motor function following SCI in rats and mice. Therefore, it could be considered as a potential treatment in acute settings such as emergency departments. However, the safety of this method is still under debate. Therefore, it is recommended for future research to focus on the investigation of safety of MBP immunization in animal studies, before conducting human clinical trials.

Increased risk of sensorineural hearing loss in patients with spinal cord injury: a nationwide longitudinal follow-up study.

Retrospective cohort study with 10 years follow-up. To compare the risks of sensorineural hearing loss in patients with and without spinal cord injury, based on a nationally representative sample. Taiwan's Longitudinal Health Insurance Database 2005. A total of 2006 participants who had been aged between 20 and 69 and who had spinal cord injury as of 2002-06 were enrolled in the spinal cord injury group. The non-spinal cord injury group consisted of 8024 sex- and age-matched, randomly sampled participants without spinal cord injury. Then, their sensorineural hearing loss -cumulative incidence curves were generated using the Kaplan-Meier method. Stratified Cox proportional-hazard regression was employed to estimate the effect of having spinal cord injury on patients' subsequent risk of sensorineural hearing loss. During the follow-up, 30 patients in the spinal cord injury group and 87 in the non-spinal cord injury group developed sensorineural hearing loss. As such, the cumulative incidence of sensorineural hearing loss was significantly higher in the spinal cord injury group than the non-spinal cord injury group (2.16 vs. 1.21 per 1000 person-years, p = 0.008). The adjusted hazard ratio of sensorineural hearing loss for the spinal cord injury group was 1.75 times that of the non-spinal cord injury group (95% CI, 1.14-2.68, p = 0.01). The patients with non-cervical SCI appeared to have a higher magnitude of SNHL risk than their cervical SCI counterparts. Our study showed that patients with spinal cord injury have an increased risk of developing sensorineural hearing loss.

Increased Risk of Carpal Tunnel Syndrome in People With Spinal Cord Injury: A Nationwide Longitudinal Follow-Up Study

ObjectiveTo investigate the long-term risk of carpal tunnel syndrome (CTS) in people with spinal cord injury (SCI). DesignRetrospective cohort study. SettingTaiwan's Longitudinal Health Insurance Database 2005, containing data about 1 million people randomly sampled from among those registered in the National Health Insurance Program as of 2005. ParticipantsThe SCI group consisted of 1681 subjects with SCI, and the comparison group comprised 6724 propensity score-matched subjects without SCI (N=8405). The variables included in propensity-score matching were age, sex, comorbid conditions, and socioeconomic status. InterventionsNot applicable. Main Outcome MeasuresThe occurrence of newly diagnosed CTS, defined by at least 1 hospital discharge or 2 outpatient visits with a diagnosis of CTS. ResultsThe incidence density of CTS in the SCI group was 7.55 per 1000 person-years (95% confidence interval [CI], 6.03-9.33), and in the comparison group, 4.61 per 1000 person-years (95% CI, 4.08-5.19). The hazard ratio (HR) of CTS for the SCI group was therefore 1.59 (95% CI, 1.24-2.03). Additionally, the HR of CTS for the cervical-SCI subgroup, 1.90 (95% CI, 1.21-2.97) was considerably higher than that of its noncervical counterpart, 1.47 (95% CI, 1.09-1.98). ConclusionsPeople with both cervical and noncervical SCI have an increased risk of developing CTS, as compared with those without SCI. Moreover, the CTS risk appears to be higher for individuals with cervical SCI than their noncervical SCI counterparts.

Accentuated early postprandial satiety in people with spinal cord injury versus able-bodied controls

In persons with spinal cord injury (SCI), reduced fat-free mass and movement-related energy expenditure increase obesity risk. Although plausible mechanisms exist, it remains unknown whether impaired appetite regulation potentiates obesity risk in SCI. This study compared postprandial responses of appetite-related hormones, appetite perceptions and the sensitivity of appetite to covert preload energy manipulation in persons with SCI and able-bodied (AB) controls. In a counterbalanced order, 12 men with high-level SCI (≥T6 vertebrae) and 12 AB controls completed two trials, consuming covert high-energy (HE; 2513 kJ) and low-energy (LE; 1008 kJ) preloads on separate occasions. Subjective appetite perceptions were assessed at 30 min intervals following preload consumption (up to 150 min) and energy intake was determined from ad libitum test meals. Appetite-related hormone (total PYY, GLP-1 and acylated ghrelin) responses were measured in the HE trial only. Within the early postprandial phase (0–60 min), subjective ratings of fullness (d = 0.83) and satisfaction (d = 0.87) were higher (P ≤ 0.028) in the group with SCI. No group differences in PYY, GLP-1 or acylated ghrelin were detected in a fasted state or postprandially (d ≤ 0.64; p ≥ 0.053). Ad libitum energy intake was lower in the SCI group (1086 vs. 1713 kJ, respectively, d = 1.00; P = 0.020) but no effect of trial (preload) was found. These findings suggest that, following isocaloric preloads, postprandial satiety may be augmented, rather than attenuated, in people with SCI.

Treadmill training based on the overload principle promotes locomotor recovery in a mouse model of chronic spinal cord injury

Rehabilitative treatment, including treadmill training, is considered an important strategy for restoring motor function after spinal cord injury (SCI). However, many unexplained problems persist regarding the appropriate rehabilitative method and the mechanism underlying the beneficial effects of rehabilitation. Moreover, only a few preclinical studies have been performed on rehabilitative interventions for chronic SCI, although most patients have chronic injuries. In fact, several preclinical studies reported that rehabilitative training was less effective when applied during the chronic phase than when applied sooner. While numerous studies have examined the effects of treadmill training during the subacute phase, the training conditions vary considerably among preclinical reports. Therefore, establishing a standard training protocol is essential for achieving beneficial rehabilitation effects at the chronic stage. Since the difficulty of applying an appropriate training load hinders training at constant speeds, it is important to adjust the training intensity in accordance with the exercise tolerance of an individual animal to provide further functional recovery benefits. Here, we created a novel quadrupedal treadmill training protocol based on the overload principle for mice with incomplete thoracic SCI. We subjected SCI model mice to rehabilitative training according to the protocol for two consecutive weeks starting at 42 days after injury. We examined the treadmill speeds at which the mice were able to run based on the severity of paresis and investigated the impact of the protocol on functional recovery. Assessment of running speed changes during the treadmill training period revealed faster treadmill speeds for mice with mild paresis than for those with severe paresis. The training parameters, including the speed and distance traveled, were positively correlated with the changes in motor function. These results suggest that the most suitable running speed during treadmill training differs according to the level of motor dysfunction and that running longer distances has a positive impact on motor functional recovery. Based on this established protocol, we compared functional and histological results between the chronic SCI groups with and without rehabilitation. The gait analyses showed significantly better functional improvement in the rehabilitation group than in the nonrehabilitation group. Histological analyses revealed that the BDNF- and VGLUT1-positive areas of lumbar enlargement were significantly increased in the rehabilitation group. These findings implied that rehabilitation promoted not only motor performance but also motor control, including forelimb-hindlimb coordination, even in chronic SCI, resulting in functional improvement by treadmill training alone. Therefore, rehabilitative training based on the overload principle appears to be one of the appropriate treatment options for incomplete thoracic SCI, and evidence of its efficacy exists in actual clinical settings.

Reconstruction of the cervical spinal cord based on motor function restoration and mitigation of oxidative stress and inflammation through eNOS/Nrf2 signaling pathway using ibuprofen-loaded nanomicelles

Motor disfunction and oxidative and inflammatory stress after spinal cord injuries (SCIs) occur as a result of primary mechanical damage and secondary degeneration process. In the present study, we aimed to examine the protective effect of fabricated ibuprofen- polyethylene glycol (PEG)/polylactide acid (PLA) diblock copolymer nanomicelles on reconstruction of motor-evoked potential (MEP) of cervical spinal cord, the posterior limb function, ROS and RNS levels, expression of inflammation cytokines, and enzymatic and non-enzymatic antioxidant systems after an experimental SCI. Also, qPCR assay was employed to assess eNOS and Nrf2 at the mRNA level. It was shown that that the drug loading and entrapment efficiency of fabricated nanomicelles were around 9.3% and 72.09%, respectively. Also, the average size and zeta potential of blank PEG-PLA diblock copolymer nanomicelles and drug-loaded nanomicelles were 32.4 ± 2.18 nm, 36.2 ± 2.01 nm and −21.73 ± 4.21 mV, −34.48 ± 3.38 M, respectively. Moreover, ibuprofen-PEG/PLA diblock copolymer nanomicelles revealed a slight burst release within the first 20 h, followed by a continuous release phase over 12 h. It was seen that in control group, MEP amplitude decreased to 17.41 ± 3.75 mV at 1 h after surgery, whereas MEP amplitudes in ibuprofen- and ibuprofen-PEG/PLA -nanomicelles- treated animals were remarkably increased in comparison with the control group, and this enhancement was more pronounced for ibuprofen-PEG/PLA -treated animals. Finally, it was determined that compared with those in the SCI group, the spinal cord function score, SOD, CAT and GSH levels in the ibuprofen-PEG/PLA -nanomicelles- treated group were significantly increased, whereas ROS, RNS, TNF-α, IL-Iβ and IL-6 levels and eNOS and Nrf2 mRNA levels were significantly reduced. In conclusion, this study indicates that the ibuprofen-PEG/PLA -nanomicelles provide significant improvement in the motor function restoration and mitigation of inflammation and oxidative stress stimulated by SCI through eNOS/Nrf2 signaling pathway.

Intrathecal Administration of Melatonin Ameliorates the Neuroinflammation- Mediated Sensory and Motor Dysfunction in A Rat Model of Compression Spinal Cord Injury.

Spinal cord injury (SCI), often characterized by sensory-motor dysfunction, is a major debilitating disorder of the central nervous system. As no useful treatment for post- SCI complications has been approved thus far, finding novel treatments is of great importance. Considering the promising effects of melatonin (MEL) against destructive mechanisms in other models of brain damage, in the current study, we evaluated its ameliorative effects on sensory- motor outcomes, inflammatory mediators, histological changes and other post-SCI complications. Rats in SCI and MEL groups underwent laminectomy followed by a severe compression injury by an aneurysm clip. Then, intrathecal treatment with vehicle (5% dimethyl sulfoxide) or MEL was carried out post-injury. Acetone drop, von Frey, inclined plane, and BBB tests as well as weight changes and auricle temperature, were used to evaluate the neuropathic pain, motor function, and other post-SCI complications. The effects of MEL on the activity of MMP-2 and MMP-9 were assessed using the gelatin zymography method every week till day 28 post-SCI. Histopathological assessments were performed on days 14, 21, and 28. MEL treatment resulted in decreased motor dysfunction, mechanical and cold allodynia, auricle temperature, and also ameliorated weight loss. Moreover, MEL suppressed MMP-9 activity while increasing that of MMP-2 post-SCI, indicating its anti-neuroinflammatory effects. Also, MEL significantly preserved white matter myelinated areas and the number of sensory neurons post-SCI. The results suggest MEL as a promising candidate for medical therapies with advantageous effects on improving functional recovery through suppressing inflammatory mediators, and attenuating spinal tissue damages.

Identifying glial scar tissue using infrared thermography: a spinal cord injury pilot study

Introduction: Glial scarring after a spinal cord injury (SCI) can represent both a physical and a molecular barrier for axonal regeneration and thus its removal has been found to be helpful in the recovery process. For this removal to be feasible in humans, an efficient method is needed to clearly identify glial tissue without inflicting more damage. Objective: To evaluate infrared thermography as a tool for identifying glial scar tissue in chronic SCI. Material and methods: An exploratory experimental pilot study was performed on Sprague-Dawley rats divided into sham and SCI (T9). All animals were subjected to a baseline thermography performed after a laminectomy that was either followed by closure of the surgical planes (sham group) or injury infliction (SCI group). Five weeks later, a second thermography was performed. Afterward, the spinal cord (T8-T10) was removed and processed for glial fibrillary acidic protein (GFAP) immunohistochemistry, which was used as a gold standard for identifying reactive astrocytes and glial scar. All animals received the same care throughout the study. Results: The thermography did not reveal a statistical difference for the baseline values (p = 0.24); however, a significant difference in thermography values was found 5 weeks later (p = 0.01). This difference significantly correlated with astrocyte counts at the site of injury (r = –0.57; p = 0.03, Spearman’s correlation). Conclusions: Infrared thermography could be useful to evaluate the extent of glial scar after SCI.

Graph theoretical structural connectome analysis of the brain in patients with chronic spinal cord injury: preliminary investigation.

Retrospective study. We aimed to characterize the convergent disruptions of the structural connectivity based on network modeling technique (i.e., graph theory) to identify significant changes in network organization/reorganization between uninjured and chronic spinal cord injury (SCI) participants. USA. Ten adult participants including 4 with chronic SCI and 6 uninjured were scanned using a multi-shell diffusion imaging on a 3.0 T MR scanner. Whole brain structural connectivity matrix was estimated by performing the quantification of the number of white matter fibers (called edges) connecting each possible pair of brain region (called nodes). Brain regions were defined according to Desikan-Killiany cortical atlas. Using connectivity matrix, connectivity strength as well as six different graph theoretical measurements were computed for each participant. They include: (1) global efficiency; (2) local efficiency; (3) degree; (4) betweenness centrality; (5) average shortest length and (6) clustering coefficient. Finally network based statistics was applied to extract nodes/connections with significant differences between groups (uninjured vs SCI). The SCI group showed significant decreases in betweenness centrality in the left precentral gyrus (T-score=2.98, p value=0.02), and the right caudal middle frontal gyrus (score = 2.35, p value=0.047). It also showed significant decrease in left transverse temporal gyrus (T-score=2.36, p value=0.046) in clustering coefficient. In addition, altered regions in the occipital and parietal lobe were also identified. These results suggest that not only local but also global alterations of the white matter occur after SCI. The proposed modeling technique has the potential to serve as a screening tool to identify any areas of the brain affected after SCI.

Rapid GFAP and Iba1 expression changes in the female rat brain following spinal cord injury.

Evidence suggests that rapid changes to supporting glia may predispose individuals with spinal cord injury (SCI) to such comorbidities. Here, we interrogated the expression of astrocyte- and microglial-specific markers glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule 1 (Iba1) in the rat brain in the first 24 hours following SCI. Female Sprague-Dawley rats underwent thoracic laminectomy; half of the rats received a mild contusion injury at the level of the T10 vertebral body (SCI group), the other half did not (Sham group). Twenty-four hours post-surgery the amygdala, periaqueductal grey, prefrontal cortex, hypothalamus, lateral thalamus, hippocampus (dorsal and ventral) in rats were collected. GFAP and Iba1 mRNA and protein levels were measured by real-time quantitative polymerase chain reaction and Western blot. In SCI rats, GFAP mRNA and protein expression increased in the amygdala and hypothalamus. In contrast, gene and protein expression decreased in the thalamus and dorsal hippocampus. Interestingly, Iba1 transcripts and proteins were significantly diminished only in the dorsal and ventral hippocampus, where gene expression diminished. These findings demonstrate that as early as 24 hours post-SCI there are region-specific disruptions of GFAP and Iba1 transcript and protein levels in higher brain regions. All procedures were approved by the University of Technology Sydney Institutional Animal Care and Ethics Committee (UTS ACEC13-0069).

Beyond the lesion site: minocycline augments inflammation and anxiety-like behavior following SCI in rats through action on the gut microbiota

BackgroundMinocycline is a clinically available synthetic tetracycline derivative with anti-inflammatory and antibiotic properties. The majority of studies show that minocycline can reduce tissue damage and improve functional recovery following central nervous system injuries, mainly attributed to the drug’s direct anti-inflammatory, anti-oxidative, and neuroprotective properties. Surprisingly the consequences of minocycline’s antibiotic (i.e., antibacterial) effects on the gut microbiota and systemic immune response after spinal cord injury have largely been ignored despite their links to changes in mental health and immune suppression.MethodsHere, we sought to determine minocycline’s effect on spinal cord injury-induced changes in the microbiota-immune axis using a cervical contusion injury in female Lewis rats. We investigated a group that received minocycline following spinal cord injury (immediately after injury for 7 days), an untreated spinal cord injury group, an untreated uninjured group, and an uninjured group that received minocycline. Plasma levels of cytokines/chemokines and fecal microbiota composition (using 16s rRNA sequencing) were monitored for 4 weeks following spinal cord injury as measures of the microbiota-immune axis. Additionally, motor recovery and anxiety-like behavior were assessed throughout the study, and microglial activation was analyzed immediately rostral to, caudal to, and at the lesion epicenter.ResultsWe found that minocycline had a profound acute effect on the microbiota diversity and composition, which was paralleled by the subsequent normalization of spinal cord injury-induced suppression of cytokines/chemokines. Importantly, gut dysbiosis following spinal cord injury has been linked to the development of anxiety-like behavior, which was also decreased by minocycline. Furthermore, although minocycline attenuated spinal cord injury-induced microglial activation, it did not affect the lesion size or promote measurable motor recovery.ConclusionWe show that minocycline’s microbiota effects precede its long-term effects on systemic cytokines and chemokines following spinal cord injury. These results provide an exciting new target of minocycline as a therapeutic for central nervous system diseases and injuries.