Effects Of Spinal Cord Injury Research Articles

Effect of spinal cord injury at C6–C7 on global upper-limb coordination during grasping: Manipulability approach

This study describes an analysis of the upper-limb coordination through the calculation of manipulability indices borrowed from robotics. From the current arm posture as input data, this original approach allows the quantification of the hand capacities to generate linear velocities represented with a 3D ellipsoid from which two indices were derived. Its volume that represents the global velocity generation capacities and its isotropy that characterizes preferential direction for velocity generation were assessed during multi-directional reach-to-grasp task performed by subjects suffering from spinal cord injury (SCI) at C6–C7 and control subjects. Results showed that subjects with a SCI presented higher values for the ellipsoid volume independently of the movement direction suggesting a modification of their motor coordination. Secondly, some similarities of the ellipsoid isotropy were found between the two groups suggesting that despite the injury, some aspects of the coordination remained or were recovered.

Spinal Cord Injury and Osteoporosis: Causes, Mechanisms, and Rehabilitation Strategies

Spinal cord injury (SCI) has a huge impact on the individual, society and the economy. Though advances in acute care resulted in greatly reduced co-morbidities, there has been much less progress preventing long-term sequelae of SCI. Among the long-term consequences of SCI is bone loss (osteoporosis) due to the mechanical unloading of the paralyzed limbs and vascular dysfunction below the level of injury. Though osteoporosis may be partially prevented via pharmacologic interventions during the acute post-injury phase, there are no clinical guidelines to treat osteoporosis during the chronic phase. Thus there is need for scientific advances to improve the rehabilitative approaches to SCI-related osteoporosis. Recent advances in application of a new technology, functional electrical stimulation, provide a new and exciting opportunity to improve bone metabolism and to provide mechanical strain to the paralyzed lower limbs sufficient to stimulate new bone formation in individuals with SCI. The purpose of this minireview is to delineate our current understanding of SCI-related osteoporosis and to highlight recent literature towards its prevention and treatment.

Role of Neuregulin-1/ErbB Signaling in Stem Cell Therapy for Spinal Cord Injury-Induced Chronic Neuropathic Pain

Chronic neuropathic pain is a common and debilitating consequence of spinal cord injury (SCI). In a rat contusion injury model, we observed that chronic neuropathic pain is present on day 7 after SCI and persists for the entire 56-day observation period. However, currently available pain therapies are inadequate for SCI-induced neuropathic pain. In this study, we show that spinal transplantation of mouse embryonic stem cell-derived oligodendrocyte progenitor cells (OPCs) enhances remyelination in the injured spinal cord and reduces SCI-induced chronic neuropathic pain. Moreover, we found that SCI reduces the protein level of neuregulin-1 and ErbB4 in the injured spinal cord and that OPC transplantation enhances the spinal expression of both proteins after SCI. Finally, intrathecal injection of neuregulin-1 small interfering RNA, but not the control nontarget RNA, diminishes OPC transplantation-produced remyelination and reverses the antinociceptive effect of OPC transplantation. Our findings suggest that the transplantation of embryonic stem cell-derived OPCs is an appropriate therapeutic intervention for treatment of SCI-induced chronic neuropathic pain, and that neuregulin-1/ErbB signaling plays an important role in central remyelination under pathological conditions and contributes to the alleviation of such pain.

Asiaticoside attenuates the effects of spinal cord injury through antioxidant and anti-inflammatory effects, and inhibition of the p38-MAPK mechanism

Asiaticoside has potent pharmacological activity and broader pharmacological effects, including anti‑oxidant, antidepressant and hepatic protection effects, and the inhibition of tumor cell proliferation. However, the mechanism underlying the effects of asiaticoside on neurological pain in spinal cord injury (SCI) remain to be fully elucidated. Therefore, the present study investigated the specific mechanism underlying the beneficial action of asiaticoside in a SCI rat model. In the present study, Basso, Beattie and Bresnahan scores was determined to analyze the therapeutic effects of asiaticoside on the neurological function of the SCI rat model. The water content of the spinal cord was also determined to measure its effects on the SCI rats. Oxidative stress, levels of nitric oxide and inflammation were detected using commercial kits. Western blot analysis was used to measure the protein expression levels of p38‑mitogen‑activated protein kinase (MAPK) in the SCI rat. Asiaticoside effectively augmented the Basso, Beattie and Bresnahan scores of the SCI rats. Significant reductions in the water content of the spinal cord, the levels of inducible nitric oxide synthase (iNOS), and the activities of the nuclear factor‑κB p65 unit, tumor necrosis factor‑α, interleukin(IL)‑1β and IL‑6 were observed in the experimental animals. Furthermore, on examination of the oxidative stress‑associated parameters, increased production of malondialdehyde and decreased levels of superoxide dismutase, glutathione and glutathione peroxidase were detected in the SCI rat model. Asiaticoside also significantly suppressed the expression of p38‑MAPK, which indicated that the therapeutic effects of asiaticoside may be associated with the p38‑MAPK pathway. These data confirmed that asiaticoside attenuates SCI through antioxidant and anti‑inflammatory effects, and through inhibition of the p38‑MAPK mechanism.

31st g. Heiner sell lectureship: secondary medical consequences of spinal cord injury.

Persons with spinal cord injury (SCI) have secondary medical consequences of paralysis and/or the consequences of extreme inactivity. The metabolic changes that result from reduced activity include insulin resistance with carbohydrate disorders and dyslipidemia. A higher prevalence of coronary artery calcification was found in persons with SCI than that in matched able-bodied controls. A depression in anabolic hormones, circulating testosterone and growth hormone, has been described. Adverse soft tissue body composition changes of increased adiposity and reduced skeletal muscle are appreciated. Immobilization is the cause for sublesional disuse osteoporosis with an associated increased risk of fragility fracture. Bowel dysmotility affects all segments of the gastrointestinal tract, with an interest in better defining and addressing gastroesophageal reflux disease and difficulty with evacuation. Developing and testing more effective approaches to cleanse the bowel for elective colonoscopy are being evaluated. The extent of respiratory dysfunction depends on the level and completeness of SCI. Individuals with higher spinal lesions have both restrictive and obstructive airway disease. Pharmacological approaches and expiratory muscle training are being studied as interventions to improve pulmonary function and cough strength with the objective of reducing pulmonary complications. Persons with spinal lesions above the 6th thoracic level lack both cardiac and peripheral vascular mechanisms to maintain blood pressure, and they are frequently hypotensive, with even worse hypotension with upright posture. Persistent and/or orthostatic hypotension may predispose those with SCI to cognitive impairments. The safety and efficacy of anti-hypotensive agents to normalize blood pressure in persons with higher level cord lesions is being investigated.

Bog Bilberry Anthocyanin Extract Improves Motor Functional Recovery by Multifaceted Effects in Spinal Cord Injury

The aim of this study was to determine the therapeutic efficiency of bog bilberry anthocyanin extract (BBAE) treatment starting 1 d after spinal cord injury (SCI) in rats and to investigate the underlying mechanism. The BBAE contained cyanidin-3-glucoside, malvidin-3-galactoside and malvidin-3-glucoside. SCI models were induced using the weight-drop method in Sprague-Dawley rats and additionally with sham group (laminectomy only). The animals were divided into four groups: vehicle-treated group; 10 mg/kg BBAE-treated group; 20 mg/kg BBAE-treated group; sham group. BBAE-treated or vehicle-treated group was administered orally at one day after SCI and then daily for 8 weeks. Locomotor functional recovery was assessed during the 8 weeks post operation period by performing a Basso, Beattie, and Bresnahan (BBB) locomotor score test. At the end of study, the animals were killed, and 1.5 cm segments of spinal cord encompassing the injury site were removed for immunohistochemistry, histopathological and western blotting analysis. Immunohistochemistry for GFAP, aggrecan, neurocan and NeuN was used to assess the degree of astrocytic glial scar formation and neuron survival. Immunohistochemistry and western blotting analysis for TNF-α, IL-6, IL-1β was used to evaluate the anti-inflammation effect of BBAE. To evaluate its inhibition effect on the astrocytes, we performed the MTT assay and immunohistochemistry for Ki67 in vitro. Results show that the BBAE-treated animals showed significantly better locomotor functional recovery, neuron death and smaller glial scar formation after spinal cord injury in vivo. In addition, BBAE administration could inhibit astrocyte proliferation in vivo and vitro. Therefore, BBAE may be useful as a promising therapeutic agent for SCI.

Astrocytic CX43 hemichannels and gap junctions play a crucial role in development of chronic neuropathic pain following spinal cord injury

Chronic neuropathic pain is a frequent consequence of spinal cord injury (SCI). Yet despite recent advances, upstream releasing mechanisms and effective therapeutic options remain elusive. Previous studies have demonstrated that SCI results in excessive ATP release to the peritraumatic regions and that purinergic signaling, among glial cells, likely plays an essential role in facilitating inflammatory responses and nociceptive sensitization. We sought to assess the role of connexin 43 (Cx43) as a mediator of CNS inflammation and chronic pain. To determine the extent of Cx43 involvement in chronic pain, a weight-drop SCI was performed on transgenic mice with Cx43/Cx30 deletions. SCI induced robust and persistent neuropathic pain including heat hyperalgesia and mechanical allodynia in wild-type control mice, which developed after 4 weeks and was maintained after 8 weeks. Notably, SCI-induced heat hyperalgesia and mechanical allodynia were prevented in transgenic mice with Cx43/Cx30 deletions, but fully developed in transgenic mice with only Cx30 deletion. SCI-induced gliosis, detected as upregulation of glial fibrillary acidic protein in the spinal cord astrocytes at different stages of the injury, was also reduced in the knockout mice with Cx43/Cx30 deletions, when compared with littermate controls. In comparison, a standard regimen of post-SCI treatment of minocycline attenuated neuropathic pain to a significantly lesser degree than Cx43 deletion. These findings suggest Cx43 is critically linked to the development of central neuropathic pain following acute SCI. Since Cx43/Cx30 is expressed by astrocytes, these findings also support an important role of astrocytes in the development of chronic pain.

Role of Microglia and Astrocyte in Central Pain Syndrome Following Electrolytic Lesion at the Spinothalamic Tract in Rats

Central pain syndrome (CPS) is a debilitating state and one of the consequences of spinal cord injury in patients. Many pathophysiological aspects of CPS are not well documented. Spinal glia activation has been identified as a key factor in the sensory component of chronic pain. In this study, the role of glial subtypes in the process of CPS induced by unilateral electrolytic lesion of spinothalamic tract (STT) is investigated. Male rats received a laminectomy at T8-T9 and then unilateral electrolytic lesion centered on the STT. Thermal and mechanical thresholds as well as locomotor function were measured on days 0, 3, 7, 14, 21, and 28 post-injuries by tail flick, von Frey filament, and open field tests, respectively. To investigate the spinal glial activation following denervation in STT-lesioned groups, Iba1 and GFAP were detected by immunohistochemistry and Western blotting at the same time points. Data showed that STT lesion significantly decreased thermal pain at day 3 in comparison with sham groups. Significant bilateral allodynia appeared in hind paws at day 14 after spinal cord injury and continued to day 28 (P < 0.05). Additionally, electrolytic spinal lesion attenuated locomotor function of injured animals after 7 days (P < 0.05). In both histological assessments and Western blotting, Iba1 increased at days 3 and 7 while increased GFAP occurred from day 14 to 28 after lesion. It appears that microglial activation is important in the early stages of pain development and astrocytic activation occurs later. These events may lead to behavioral outcomes especially central neuropathic pain.

Air Gun Impactor—A Novel Model of Graded White Matter Spinal Cord Injury in Rodents

Understanding mechanisms of spinal cord injury and repair requires a reliable experimental model. We have developed a new device that produces a partial damage of spinal cord white matter by means of a precisely adjusted stream of air applied under high pressure. This procedure is less invasive than standard contusion or compression models and does not require surgical removal of vertebral bones. We investigated the effects of spinal cord injury made with our device in 29 adult rats, applying different experimental parameters. The rats were divided into three groups in respect to the applied force of the blast wave. Functional outcome and histopathological effects of the injury were analyzed during 12-week follow-up. The lesions were also examined by means of magnetic resonance imaging (MRI) scans. The weakest stimulus produced transient hindlimb paresis with no cyst visible in spinal cord MRI scans, whereas the strongest was associated with permanent neurological deficit accompanied by pathological changes resembling posttraumatic syringomyelia. Obtained data revealed that our apparatus provided a spinal cord injury animal model with structural changes very similar to that present in patients after moderate spinal cord trauma.

A Hebbian Approach to Retraining Spared Circuits after Spinal Cord Injury (P02.005)

Objective: 1) Characterize spared neural circuitry after spinal cord injury; 2) Determine efficacy of Hebbian exercises targeting neural circuits above the injury level. Background Spinal cord injury (SCI) only rarely causes complete cord transection. Even patients without volitional movement below a lesion often retain some intact circuitry. The fibers most likely to withstand SCI originate in the brainstem, which generally does not mediate conscious movement. To reestablish conscious control over spared circuits, treatments must strengthen connections between brainstem circuits and volitional corticospinal pathways ABOVE the injury. Using a Hebbian approach of 9Fire Together, Wire Together9, we plan to strengthen these connections with exercises that stimulate both cortical and brainstem pathways simultaneously. We have demonstrated the efficacy of this approach in a rodent SCI model (Harel et al., 2010). We now show further preclinical evidence for efficacy, and introduce a clinical study translating this strategy toward human SCI patients. Design/Methods: PRECLINICAL EXPERIMENTS: To extend our previous results, we compared efficacy of dual-mode (brainstem+corticospinal) to single-mode training in a unilateral pyramidotomy model. Multiple behavioral and histological outcomes were assessed. PLANNED CLINICAL STUDY: Chronic thoracic SCI patients are evaluated with a clinical-neurophysiological testing battery including computerized posturography, motor and sensory evoked potentials, and poly-electromyography. Motor-incomplete subjects are randomized into three groups: 1)treadmill training (spinal); 2)balance training (brainstem); or 3)dual-mode training (balance plus corticospinal hand exercises). Primary outcomes: Gait disability; MEP amplitudes at L4 and S1. Results: PRECLINICAL EXPERIMENTS: In mice with unilateral pyramidotomy, dual-mode but not single-mode exercise significantly improved skilled ladder climbing and several principal components of gait kinematics. Histological assessments of CST fiber sprouting will be presented. BASELINE CLINICAL MEASUREMENTS: Initial results of seated computerized posturography, evoked potentials, and poly-electromyography will be presented. Conclusions: Dual-mode exercise rehabilitation targeting cortical and brainstem pathways ABOVE spinal lesions improves outcomes in animal models of SCI. This rehabilitation approach is feasible for application toward human SCI patients. Supported by: NINDS K08NS056212. NINDS R01NS33020. Falk Medical Research Trust. Department of Veterans Affairs RR&D National Center of Excellence for the Medical Consequences of Spinal Cord Injury (#B4162-C). Disclosure: Dr. Harel has received personal compensation for activities with AlphaDetail and Beebe & O9Neil as a consultant. Dr. Song has nothing to disclose. Dr. Tang has nothing to disclose. Dr. Spungen has nothing to disclose. Dr. Strittmatter has received personal compensation for activities with Biogen Idec. Dr. Strittmatter has received royalty payments from Axerion Therapeutics. Dr. Strittmatter holds stock and/or stock options in Axerion Therapeutics. Dr. Strittmatter has received research support from Axerion Therapeutics.

Application of epidural electrostimulation to treat bladder dysfunction in patients with consequences of traumatic injury of lumbar and sacral segments of the spinal cord

Background. Bladder dysfunction is one of the most frequent and severe clinical manifestations of traumatic disease of the spinal cord, which causes chronic inflammatory processes in the urinary tract and impairs the quality of life of a patient.Methods. The results of correction of bladder dysfunction after epidural electrostimulation in 69 patients with consequences of spinal cord injury of lumbar and sacral segments of the spinal cord are presented. The degree of urination control was evaluated (none, partial, complete) before and after applied treatment.Results: in group A partial urination control was achieved in 45% of patients, in group B — in 61.5%, in 1 (7.7%) patient bladder control function restored completely. In group C a positive result in restoration of bladder function was achieved in 89.6% of patients, in group D — in all patients. It was incontinentia vera, at which we achieved best results of correction, 90.5% of patients showed positive results.Conclusions. Epidural electrostimulation is an effective method of correction of bladder dysfunction in patients with consequences of traumatic injury of spinal cord lumbar and sacral segments.

Vibration Elicits Involuntary, Step-Like Behavior in Individuals With Spinal Cord Injury

Background. Impaired walking is a debilitating consequence of spinal cord injury (SCI). This impairment arises, to some degree, from disruption of supraspinal pathways that activate the spinal locomotor central pattern generator (CPG). Evidence in nondisabled (ND) individuals suggests that vibration activates locomotor CPGs, eliciting involuntary step-like behavior. Objective. To compare vibration-elicited step-like behavior in individuals with chronic SCIs with the responses of ND individuals and to assess the influence of locomotor training on these responses. Methods. Participants included 7 individuals with motor-incomplete SCIs (MISCIs) and 6 with motor-complete SCIs (MCSCIs) who were untrained, 6 individuals with MISCIs who underwent locomotor training, and 8 ND individuals. Kinematic and EMG data were collected while vibration was applied to the quadriceps, hamstrings, or tensor fascia latae (TFL) muscles. Consistency and robustness of vibration-elicited responses was determined from hip and knee angle data. Results. Consistent and reliable step-like behaviors were elicited in individuals with MISCIs and MCSCIs, although responses were not as robust as those in ND individuals. Vibration to the TFL elicited the most robust responses. Consistency and robustness were not influenced by SCI severity or locomotor training but appeared to increase with repeated testing. Conclusion. These results confirm that vibration elicits step-like behaviors in individuals with SCIs, even those with no voluntary motor function in the legs. Further research is warranted to investigate the use of vibration as an approach to activating the spinal CPGs associated with stepping, perhaps as an adjunct to locomotor training for individuals with SCIs.

Alteration of Forebrain Neurogenesis after Cervical Spinal Cord Injury in the Adult Rat

Spinal cord injury (SCI) triggers a complex cellular response at the injury site, leading to the formation of a dense scar tissue. Despite this local tissue remodeling, the consequences of SCI at the cellular level in distant rostral sites (i.e., brain), remain unknown. In this study, we asked whether cervical SCI could alter cell dynamics in neurogenic areas of the adult rat forebrain. To this aim, we quantified BrdU incorporation and determined the phenotypes of newly generated cells (neurons, astrocytes, or microglia) during the subchronic and chronic phases of injury. We find that subchronic SCI leads to a reduction of BrdU incorporation and neurogenesis in the olfactory bulb and in the hippocampal dentate gyrus. By contrast, subchronic SCI triggers an increased BrdU incorporation in the dorsal vagal complex of the hindbrain, where most of the newly generated cells are identified as microglia. In chronic condition 90 days after SCI, BrdU incorporation returns to control levels in all regions examined, except in the hippocampus, where SCI produces a long-term reduction of neurogenesis, indicating that this structure is particularly sensitive to SCI. Finally, we observe that SCI triggers an acute inflammatory response in all brain regions examined, as well as a hippocampal-specific decline in BDNF levels. This study provides the first demonstration that forebrain neurogenesis is vulnerable to a distal SCI.

Pain in Spinal Cord Injury

SUMMARYAn important and detrimental effect of spinal cord injury (SCI) is pain, which develops in approximately two-thirds of all SCI patients, while approximately half of SCI patients develop chronic neuropathic pain (NP). Thus far, there is no cure for SCI NP, and oral pharmacological intervention is often inadequate, commonly resulting in a pain reduction of only 20-30%. In this short review, we will present an overview of the important features of SCI pain including taxonomy, epidemiology and classification, as well as a suggested oral pharmacological treatment strategy for SCI NP and the current evidence available from randomized placebo-controlled trials. Considerations and evidence for the nonpharmacological treatment of SCI will be discussed briefly.

The effects of spinal cord injury and exercise on bone mass: A literature review

Bone loss is a common and often debilitating condition that accompanies spinal cord injury. Because bone loss after spinal cord injury is multifactorial, it can be difficult to assess and treat. This process becomes even more complex as secondary conditions associated with aging are introduced. There are two purposes of this literature review. The first is to summarize information concerning the mechanisms of bone loss and osteoporosis after spinal cord injury. The second is to summarize existing data concerning the effects of exercise on bone loss after spinal cord injury. Literature was reviewed concerning the bone loss process and the non-pharmacological treatment options for ameliorating bone loss after spinal cord injury. (Part One) Osteoporosis is universal in persons with chronic complete spinal cord injury, which increases the risk of bone fracture. Bone loss after spinal cord injury is both sublesional and regional with the greatest areas of bone demineralization being in the sublesional trabecular laden areas of the distal and proximal epiphyses of the femur and tibia. (Part Two) While passive weight bearing of paralyzed lower extremities appears to be ineffective, stressing the bones through muscular contractions initiated by electrical stimulation (FES) have yielded positive results in some cases. The intensity, frequency, and duration of stress to the bones appear to be important determinants of improved bone parameters. Although further quantification of these components is needed, some generalized guidelines can be deduced from completed research. Intensities showing positive results have been loads of one to one and a half times body weight for FES exercise or having participants FES cycle at their highest power output. Safety precautions must be used to decrease risk of bone fracture. Generally, the frequency is effective with three or more weekly exercise sessions. Studies of duration suggest that several months to one or more years of FES are necessary. In order to promote healthy and independent aging in patients with spinal cord injury, it is important to understand the processes, consequences and effective treatments involved with bone loss.

The Effects of Spinal Cord Injury Induced by Shortening on Motor Evoked Potentials and Spinal Cord Blood Flow

Spinal cord injury due to spinal shortening is disastrous, but the amount that the spine can be shortened without injury is unknown. We assessed spinal cord injury and changes in spinal cord blood flow after spinal shortening in swine. Ten pigs underwent pedicle screw instrumentation between T10 and T13 followed by a T11 and T12 vertebrectomy resulting in spinal shortening. Spinal cord function and spinal cord blood flow were monitored simultaneously with use of transcranial motor evoked potentials and laser Doppler flowmetry, respectively. A staged shortening procedure was performed: phase 1 resulted in no morphological change in the spinal cord, phase 2 resulted in buckling of the spinal cord, and phase 3 resulted in kinking of the spinal cord. After loss of motor evoked potential signals, which was considered to indicate spinal cord injury, the spinal instrumentation was tightened. The motor evoked potentials and spinal cord blood flow were monitored for an additional thirty minutes, and a wake-up test was then performed. Finally, a spinal cord specimen was obtained and evaluated histologically. The motor evoked potential data demonstrated no evidence of spinal cord injury during phases 1 and 2. However, the signals were lost during phase 3, indicating spinal cord injury. The mean shortening was 35 ± 2.7 mm, which was similar to the mean vertebral body height at the thoracolumbar level (33.6 ± 1.9 mm), indicating that spinal cord injury resulted from shortening equivalent to the height of one vertebra. Spinal shortening did not cause injury if the amount of shortening was less than the mean segmental height of the entire spinal column (27.7 ± 1.6 mm for T1-L6). The spinal cord blood flow increased slightly (by 11.6% ± 20.6%) during phase 2, but decreased by 43.1% ± 11.4% during phase 3. The wake-up test performed after thirty minutes revealed no movement in the lower limbs. Spinal shortening of =104.2% of one vertebral body height at the thoracolumbar level caused spinal cord injury, but shortening of =73.8% did not result in injury. swine.

Spinal Cord Injury Causes More Damage to Fracture Healing of Later Phase than Ovariectomy in Young Mice

The purpose of this study was to compare the effects of spinal cord injury (SCI) and ovariectomy (OVX) on femoral fracture healing of later phase in young mice. Sixty young female C57 mice were randomized into three groups: SCI, OVX, and age-matched intact control. The femoral fracture was generated at 3 weeks after SCI or OVX. At 1 month after fracture, the femoral fracture area was evaluated through the healing status using radiograph; bone mineral density using dual X-ray absorptometry; callus formation and mineralization and neovascularization in callus using micro-computed tomography; biomechanical analysis using testing machine; and histology analysis by staining with hematoxylin-eosin stain. SCI mice showed lower bone mineral density in the femoral callus as compared with OVX mice. Callus geometric microstructural parameters of the femora in SCI mice were significantly lower than OVX mice. SCI induced significant changes of biomechanical parameters in the femoral fracture healing area. The callus formation and callus neovascularization in SCI mice were significantly lower than in OVX mice. SCI induces more deterioration of fracture healing in the femoral diaphysis than OVX.

Anatomical study of serotonergic innervation and 5-HT1A receptor in the human spinal cord

Serotonergic innervation of the spinal cord in mammals has multiple roles in the control of motor, sensory and visceral functions. In rats, functional consequences of spinal cord injury at thoracic level can be improved by a substitutive transplantation of serotonin (5-HT) neurons or regeneration under the trophic influence of grafted stem cells. Translation to either pharmacological and/or cellular therapies in humans requires the mapping of the spinal cord 5-HT innervation and its receptors to determine their involvement in specific functions. Here, we have performed a preliminary mapping of serotonergic processes and serotonin-lA (5-HT1A) receptors in thoracic and lumbar segments of the human spinal cord. As in rodents and non-human primates, 5-HT profiles in human spinal cord are present in the ventral horn, surrounding motoneurons, and also contact their presumptive dendrites at lumbar level. 5-HT1A receptors are present in the same area, but are more densely expressed at lumbar level. 5-HT profiles are also present in the intermediolateral region, where 5-HT1A receptors are absent. Finally, we observed numerous serotonergic profiles in the superficial part (equivalent of Rexed lamina II) of the dorsal horn, which also displayed high levels of 5-HT1A receptors. These findings pave the way for local specific therapies involving cellular and/or pharmacological tools targeting the serotonergic system.

Respiratory function following bilateral mid-cervical contusion injury in the adult rat

The consequences of spinal cord injury (SCI) are often viewed as the result of white matter damage. However, injuries occurring at any spinal level, especially in cervical and lumbar enlargement regions, also entail segmental neuronal loss. Yet, the contributions of gray matter injury and plasticity to functional outcomes are poorly understood. The present study addressed this issue by investigating changes in respiratory function following bilateral C3/C4 contusion injuries at the level of the phrenic motoneuron (PhMN) pool which in the adult rat extends from C3 to C5/6 and provides innervation to the diaphragm. Despite extensive white and gray matter pathology associated with two magnitudes of injury severity, ventilation was relatively unaffected during both quiet breathing and respiratory challenge (hypercapnia). On the other hand, bilateral diaphragm EMG recordings revealed that the ability to increase diaphragm activity during respiratory challenge was substantially, and chronically, impaired. This deficit has not been seen following predominantly white matter lesions at higher cervical levels. Thus, the impact of gray matter damage relative to PhMNs and/or interneurons becomes evident during conditions associated with increased respiratory drive. Unaltered ventilatory behavior, despite significant deficits in diaphragm function, suggests compensatory neuroplasticity involving recruitment of other spinal respiratory networks which may entail remodeling of connections. Transynaptic tracing, using pseudorabies virus (PRV), revealed changes in PhMN-related interneuronal labeling rostral to the site of injury, thus offering insight into the potential anatomical reorganization and spinal plasticity following cervical contusion.

Evidence for greater burden of peripheral arterial disease in lower extremity arteries of spinal cord-injured individuals

Spinal cord injury leads to increased risk for cardiovascular disease and results in greater risk of death. Subclinical markers of atherosclerosis have been reported in carotid arteries of spinal cord-injured individuals (SCI), but the development of lower extremity peripheral arterial disease (PAD) has not been investigated in this population. The purpose of this study was to determine the effect of spinal cord injury on ankle-brachial index (ABI) and intima-media thickness (IMT) of upper-body and lower-extremity arteries. We hypothesized that the aforementioned measures of lower-extremity PAD would be worsened in SCI compared with controls and that regular participation in endurance exercise would improve these in both groups. To test these hypotheses, ABI and IMT were determined in 105 SCI and compared with 156 able-bodied controls with groups further subdivided into physically active and sedentary. ABIs were significantly lower in SCI versus controls (0.96 ± 0.12 vs. 1.06 ± 0.07, P < 0.001), indicating a greater burden of lower-extremity PAD. Upper-body IMTs were similar for brachial and carotid arteries in controls versus SCI. Lower extremity IMTs revealed similar thicknesses for both superficial femoral and popliteal arteries, but when normalized for artery diameter, individuals with SCI had greater IMT than controls in the superficial femoral (0.094 ± 0.03 vs. 0.073 ± 0.02 mm/mm lumen diameter, P < 0.01) and popliteal (0.117 ± 0.04 vs. 0.091 ± 0.02 mm/mm lumen diameter, P < 0.01) arteries. The ABI and normalized IMT of SCI compared with controls indicate that subclinical measures of lower-extremity PAD are worsened in individuals with SCI. These findings should prompt physicians to consider using the ABI as a screening method to detect lower-extremity PAD in SCI.