Operant Conditioning of Spinal Stretch Reflexes in Patients with Spinal Cord Injuries

Hyperactive spinal stretch reflexes (SSRs) often occur with spinal cord injuries (SCI). These altered SSRs may impair movement. Recent studies in monkeys and human subjects have indicated that the magnitude of SSRs can be modulated using operant conditioning. The purpose of this study was to determine whether hyperactive biceps brachii SSRs could be operantly conditioned downward. Seventeen chronic (>1 year postlesion) spinal cord-injured patients participated. Subjects were trained to keep biceps background prestretch) electromyographic (EMG) activity and elbow angle at predetermined levels prior to having the elbow rapidly extended by a torque motor to elicit the biceps SSR. All subjects participated in six baseline sessions over a 2-week period. Then, subjects were randomly assigned to either control or training groups for the next 24 sessions over an 8-week period. By the end of the study, training subjects had significantly reduced biceps SSRs (t test, P < 0.001), while control subjects SSRs were not significantly reduced (t test, P > 0.05). The reduced SSRs persisted for up to 4 months following cessation of training. The results of this study support the hypothesis that hyperactive SSRs can be operantly conditioned downward in SCI patients.     

蛛网膜下腔移植自体激活许旺细胞治疗大鼠脊髓损伤***

背景：许旺细胞能够分泌多种神经营养因子,促进脊髓损伤功能的恢复。但异体许旺细胞移植可引发自身免疫反应,且在移植方式上,局部移植无法避免二次损伤,静脉移植虽可以透过血脊髓屏障到达损伤局部,但不能达到有效的治疗浓度。 目的：探讨经蛛网膜下腔移植自体激活许旺细胞对脊髓损伤大鼠功能恢复的影响。 方法：66只大鼠均建立脊髓损伤模型,造模后随机分为3组,自体激活许旺细胞组通过结扎单侧隐神经从而激活许旺细胞,自体未激活许旺细胞组、模型对照组仅在相同部位手术但不结扎神经。切除各组手术远端1 cm神经,采用组织块法进行许旺细胞的体外分离培养及纯化。1周后,自体激活许旺细胞组、自体未激活许旺细胞组分别通过蛛网膜下腔注入经Hoechst33342标记的对应许旺细胞悬液,模型对照组仅注入等量DMEM。对脊髓损伤后肢体功能的恢复进行BBB运动功能评分及脚印分析,通过苏木精-伊红染色和GFAP染色从组织学角度评价脊髓损伤恢复情况。 结果与结论：从术后第4周开始,自体激活许旺细胞组BBB后肢功能评分明显优于另两组(P < 0.05)。移植后2周,可见迁移至大鼠脊髓损伤局部的许旺细胞。与自体未激活许旺细胞组比较,移植后5周自体激活许旺细胞组的前后足中心距离、后肢第3足趾外旋角度均显著减小(P < 0.05),移植后13周损伤区胶质瘢痕面积明显减小(P < 0.05),损伤区空洞面积明显减小(P < 0.05)。证实经蛛网膜下腔移植自体激活许旺细胞可以促进脊髓损伤的恢复。     

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

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

Relative Adrenal Insufficiency in Patients with Acute Spinal Cord Injury

Introduction  Relative adrenal insufficiency has been shown to occur in the settings of critical illness and septic shock, impairing the body’s ability to respond to stress. Studies have demonstrated that the treatment of adrenal insufficiency (AI) results in shock reversal, hemodynamic stability, and a subsequent decrease in mortality. Endocrine changes and AI have been reported in patients with spinal cord injuries during their extended courses of rehabilitation. Discussion  We describe two cases of patients with cervical spine injuries who presented with acute adrenal insufficiency following their injuries. With the addition of low-dose corticosteroids, each patient had symptom resolution and demonstrated clinical improvement. Conclusion   Patients with spinal cord injuries are at risk for AI, both in the acute and chronic settings following injury prompting the need for an increased awareness of this condition. Although variability exists in the exact criteria for the diagnosis of AI, the combination of clinical symptoms, depressed serum cortisol concentrations, and responsiveness to exogenous steroid therapy should all contribute to the diagnosis of this condition.     

The Ability of Human Schwann Cell Grafts to Promote Regeneration in the Transected Nude Rat Spinal Cord

Advances in the purification and expansion of Schwann cells (SCs) from adult human peripheral nerve, together with biomaterials development, have made the construction of unique grafts with defined properties possible. We have utilized PAN/PVC guidance channels to form solid human SC grafts which can be transplanted either with or without the channel. We studied the ability of grafts placed with and without channels to support regeneration and to influence functional recovery; characteristics of the graft and host/graft interface were also compared. The T9–T10 spinal cord of nude rats was resected and a graft was placed across the gap; methylprednisolone was delivered acutely to decrease secondary injury. Channels minimized the immigration of connective tissue into grafts but contributed to some necrotic tissue loss, especially in the distal spinal cord. Grafts without channels contained more myelinated axons (x= 2129 ± 785) vs (x = 1442 ± 514) and were larger in cross-sectional area (x = 1.53 ± 0.24 mm²) vs (x= 0.95 ± 0.86 mm²). The interfaces formed between the host spinal cord and the grafts placed without channels were highly interdigitated and resembled CNS–PNS transition zones; chondroitin sulfate proteoglycans was deposited there. Whereas several neuronal populations including propriospinal, sensory, motoneuronal, and brainstem neurons regenerated into human SC grafts, only propriospinal and sensory neurons were observed to reenter the host spinal cord. Using combinations of anterograde and retrograde tracers, we observed regeneration of propriospinal neurons up to 2.6 mm beyond grafts. We estimate that 1% of the fibers that enter grafts reenter the host spinal cord by 45 days after grafting. Following retrograde tracing from the distal spinal cord, more labeled neurons were unexpectedly found in the region of the dextran amine anterograde tracer injection site where a marked inflammatory reaction had occurred. Animals with bridging grafts obtained modestly higher scores during open field [(x = 8.2 ± 0.35) vs (x = 6.8 ± 0.42),P = 0.02] and inclined plane testing (x = 38.6 ± 0.542) vs (x= 36.3 ± 0.53),P = 0.006] than animals with similar grafts in distally capped channels. In summary, this study showed that in the nude rat given methylprednisolone in combination with human SC grafts, some regenerative growth occurred beyond the graft and a modest improvement in function was observed.     

Precursor Cell Biology and the Development of Astrocyte Transplantation Therapies: Lessons from Spinal Cord Injury

This review summarizes current progress on development of astrocyte transplantation therapies for repair of the damaged central nervous system. Replacement of neurons in the injured or diseased central nervous system is currently one of the most popular therapeutic goals, but if neuronal replacement is attempted in the absence of appropriate supporting cells (astrocytes and oligodendrocytes), then the chances of restoring neurological functional are greatly reduced. Although the past 20 years have offered great progress on oligodendrocyte replacement therapies, astrocyte transplantation therapies have been both less explored and comparatively less successful. We have now developed successful astrocyte transplantation therapies by pre-differentiating glial restricted precursor (GRP) cells into a specific population of GRP cell-derived astrocytes (GDAs) by exposing the GRP cells to bone morphogenetic protein-4 (BMP) prior to transplantation. When transplanted into transected rat spinal cord, rat and human GDAs^BMP promote extensive axonal regeneration, rescue neuronal cell survival, realign tissue structure, and restore behavior to pre-injury levels on a grid-walk analysis of volitional foot placement. Such benefits are not provided by GRP cells themselves, demonstrating that the lesion environment does not direct differentiation in a manner optimally beneficial for the restoration of function. Such benefits also are not provided by transplantation of a different population of astrocytes generated from GRP cells exposed to ciliary neurotrophic factor (GDAs^CNTF), thus providing the first transplantation-based evidence of functional heterogeneity in astrocyte populations. Moreover, lessons learned from the study of rat cells are strongly predictive of outcomes using human cells. Thus, these studies provide successful strategies for the use of astrocyte transplantation therapies for restoration of function following spinal cord injury.     

Clinical Study of Thirteen Patients with Spinal Cord Infarction

BackgroundA concept of sensory tracts in the spinal cord has been established in relation to a dorsolateral pathway which is located in the posterior part of the lateral column and conveys the deep sense.MethodsThe clinical status at onset, neurological symptoms, and magnetic resonance imaging (MRI) findings in 13 patients of spinal cord infarction were studied.ResultsThe clinical status was acute in 11 patients and subacute in 2 patients. Palsy of the extremities was noted in 11 patients. Segmental sensory disturbance was shown in all patients. One patient showed disturbance of all senses and paraplegia, which indicated transverse myelopathy. In the other 12 patients, 11 patients showed impairment of pain sense although joint position sense was preserved, excluding 1 patient whose sensory disturbance showed dysesthesia alone. In these 11 patients, soft touch and vibration senses were impaired in 7 patients. Abnormality of spinal cord MRI was detected 7 patients. The lesions were located in the cervical cord in 3 patients, cervical to thoracic cord in 1 patient, and thoracic cord in 3 patients.ConclusionsIn the 11 patients in whom pain sense was impaired and joint position sense was preserved, involvement of the anterior spinal cord artery (ASCA) was the mainstay. Impairment of vibration sense was accompanied in 7 patients in patients of ASCA infarction. It was speculated that impairment of vibration sense can occur in patients with ASCA infarction whose ischemia spread to the dorsolateral pathway in the posterior part of the lateral column.     

High-dose Ambroxol Reduces Pulmonary Complications in Patients with Acute Cervical Spinal Cord Injury After Surgery

Background  

Ambroxol has a very high affinity for lung tissues; its concentration is approximately 20 times higher in the lung than in the serum. We aimed to evaluate the effectiveness of high-dose ambroxol (990 mg/day) in the improvement of oxygenation and prevention of postoperative respiratory complications in the patients with acute cervical spinal cord injury (CSCI).     

Brain Activation Evoked by Sensory Stimulation in Patients with Spinal Cord Injury : Functional Magnetic Resonance Imaging Correlations with Clinical Features

Objective

The purpose of this study is to determine whether the changes of contralateral sensorimotor cortical activation on functional magnetic resonance imaging (fMRI) can predict the neurological outcome among spinal cord injury (SCI) patients when the great toes are stimulated without notice.

Methods

This study enrolled a total of 49 patients with SCI and investigated each patient''s preoperative fMRI, postoperative fMRI, American Spinal Injury Association (ASIA) score, and neuropathic pain occurrence. Patients were classified into 3 groups according to the change of blood oxygenation level dependent (BOLD) response on perioperative fMRI during proprioceptive stimulation with repetitive passive toe movements : 1) patients with a response of contralateral sensorimotor cortical activation in fMRI were categorized; 2) patients with a response in other regions; and 3) patients with no response. Correlation between the result of fMRI and each parameter was analyzed.

Results

In fMRI data, ASIA score was likely to show greater improvement in patients in group A compared to those belonging to group B or C (p<0.001). No statistical significance was observed between the result of fMRI and neuropathic pain (p=0.709). However, increase in neuropathic pain in response to the signal change of the ipsilateral frontal lobe on fMRI was statistically significant (p=0.030).

Conclusion

When there was change of BOLD response at the contralateral sensorimotor cortex on perioperative fMRI after surgery, relief of neurological symptoms was highly likely for traumatic SCI patients. In addition, development of neuropathic pain was likely to occur when there was change of BOLD response at ipsilateral frontal lobe.     

Valproic Acid Increases Expression of Neuronal Stem/Progenitor Cell in Spinal Cord Injury

Objective

This study investigates the effect of valproic acid (VPA) on expression of neural stem/progenitor cells (NSPCs) in a rat spinal cord injury (SCI) model.

Methods

Adult male rats (n=24) were randomly and blindly allocated into three groups. Laminectomy at T9 was performed in all three groups. In group 1 (sham), only laminectomy was performed. In group 2 (SCI-VPA), the animals received a dose of 200 mg/kg of VPA. In group 3 (SCI-saline), animals received 1.0 mL of the saline vehicle solution. A modified aneurysm clip with a closing force of 30 grams was applied extradurally around the spinal cord at T9, and then rapidly released with cord compression persisting for 2 minutes. The rats were sacrificed and the spinal cord were collected one week after SCI. Immunohistochemistry (IHC) and western blotting sample were obtained from 5 mm rostral region to the lesion and prepared. We analyzed the nestin immunoreactivity from the white matter of ventral cord and the ependyma of central canal. Nestin and SOX2 were used for markers for NSPCs and analyzed by IHC and western blotting, respectively.

Results

Nestin and SOX2 were expressed significantly in the SCI groups but not in the sham group. Comparing SCI groups, nestin and SOX2 expression were much stronger in SCI-VPA group than in SCI-saline group.

Conclusion

Nestin and SOX2 as markers for NSPCs showed increased expression in SCI-VPA group in comparison with SCI-saline group. This result suggests VPA increases expression of spinal NSPCs in SCI.     

31例脊髓亚急性联合变性临床分析

目的 总结脊髓亚急性联合变性（SCD）的病因、临床特征、诊断及治疗。方法 对31例临床确诊SCD患者的临床资料进行回顾性分析。结果 64.5%（19/31）的SCD患者有贫血,41.9%（13/31）患者血清VitB12水平降低,脊髓MRI检查发现20.0%（4/20）患者可见脊髓后索存在特异性异常信号,84.6%（22/26）患者肌电图有异常改变,体感诱发电位（SEP）检查阳性率100%,经VitB12治疗90.3%（28/31）患者临床症状均有不同程度好转。结论 SCD多由VitB12缺乏引起,试验性VitB12治疗有效,对明确诊断有重要意义;肌电图及SEP等检查可辅助诊断。     

Risk Factors for Organ Dysfunction and Failure in Patients with Acute Traumatic Cervical Spinal Cord Injury

Background  

Traumatic injuries to the cervical spine cause significant disability. Much of the morbidity and mortality that occurs in patients afflicted with cervical spinal cord injury (SCI) occurs early after injury due to primary neurologic dysfunction, systemic inflammation, concomitant injuries, treatments to prevent and ameliorate secondary insults, and prolonged immobilization. This study was undertaken to determine the incidence of organ dysfunction and failure using validated measures: the Multiple Organ Dysfunction Score (MODS) and the Sequential Organ Failure Assessment (SOFA). We also sought to determine if certain patient or injury characteristics were associated with the development of organ dysfunction and failure.     

经皮局部低温治疗兔脊髓损伤后病理与运动诱发电位的研究

目的 :探讨经皮局部低温对兔脊髓损伤的治疗作用。方法 :18只健康家兔随机均分为常温未伤组 ,常温致伤组 ,低温致伤组。保留椎板显露脊髓 ,以Allen法制作脊髓损伤模型。术毕 ,低温致伤组立即予经皮局部低温治疗 ,其他组不予治疗。各组动物分别于术前 ,术后 6、2 4h ,3d ,1、2、4周 7个时间点行Tarlov评分和MEP检查 ,并取材行病理分级。结果 :低温致伤组动物在各个时间点较常温致伤组Tarlov评分分值提高 ,MEP的N1波潜伏期缩短 ,病理损害轻。结论 :经皮局部低温对兔脊髓损伤有治疗作用     

Outcome Evaluation with Signal Activation of Functional MRI in Spinal Cord Injury

Objective

The authors investigated the changes of cortical sensorimotor activity in functional MRI (fMRI) and functional recovery in spinal cord injury (SCI) patients who had been treated by bone marrow cell transplantation.

Methods

Nineteen patients with SCI were included in this study; ten patients with clinical improvement and nine without. The cortical sensorimotor activations were studied using the proprioceptive stimulation during the fMRI.

Results

Diagnostic accuracy of fMRI with neurological improvement was 70.0% and 44.4% for sensitivity and specificity, respectively. Signal activation in the ipsilateral motor cortex in fMRI was commonly observed in the clinically neurological improved group (p-value=0.002). Signal activation in the contralateral temporal lobe and basal ganglia was more commonly found in the neurological unimproved group (p-value<0.001). Signal activation in other locations was not statistically different.

Conclusion

In patients with SCI, activation patterns of fMRI between patients with neurologic recovery and those without varied. Such plasticity should be considered in evaluating SCI interventions based on behavioral and neurological measurements.     

Factors Associated with the Success of Trial Spinal Cord Stimulation in Patients with Chronic Pain from Failed Back Surgery Syndrome

Objective

Spinal cord stimulation (SCS) is an effective means of treatment of chronic neuropathic pain from failed back surgery syndrome (FBSS). Because the success of trial stimulation is an essential part of SCS, we investigated factors associated with success of trial stimulation.

Methods

Successful trial stimulation was possible in 26 of 44 patients (63.6%) who underwent insertion of electrodes for the treatment of chronic pain from FBSS. To investigate factors associated with successful trial stimulation, patients were classified into two groups (success and failure in trial). We investigated the following factors : age, sex, predominant pain areas (axial, limb, axial combined with limbs), number of operations, duration of preoperative pain, type of electrode (cylindrical/paddle), predominant type of pain (nociceptive, neuropathic, mixed), degree of sensory loss in painful areas, presence of motor weakness, and preoperative Visual Analogue Scale.

Results

There were no significant differences between the two groups in terms of age, degree of pain, number of operations, and duration of pain (p>0.05). Univariate analysis revealed that the type of electrode and presence of severe sensory deficits were significantly associated with the success of trial stimulation (p<0.05). However, the remaining variable, sex, type of pain, main location of pain, degree of pain duration, degree of sensory loss, and presence of motor weakness, were not associated with the trial success of SCS for FBSS.

Conclusion

Trial stimulation with paddle leads was more successful. If severe sensory deficits occur in the painful dermatomes in FBSS, trial stimulation were less effective.     

Serotonergic Facilitation of Forelimb Functional Recovery in Rats with Cervical Spinal Cord Injury

Serotonergic agents can improve the recovery of motor ability after a spinal cord injury. Herein, we compare the effects of buspirone, a 5-HT_1A receptor partial agonist, to fluoxetine, a selective serotonin reuptake inhibitor, on forelimb motor function recovery after a C4 bilateral dorsal funiculi crush in adult female rats. After injury, single pellet reaching performance and forelimb muscle activity decreased in all rats. From 1 to 6 weeks after injury, rats were tested on these tasks with and without buspirone (1–2 mg/kg) or fluoxetine (1–5 mg/kg). Reaching and grasping success rates of buspirone-treated rats improved rapidly within 2 weeks after injury and plateaued over the next 4 weeks of testing. Electromyography (EMG) from selected muscles in the dominant forelimb showed that buspirone-treated animals used new reaching strategies to achieve success after the injury. However, forelimb performance dramatically decreased within 2 weeks of buspirone withdrawal. In contrast, fluoxetine treatment resulted in a more progressive rate of improvement in forelimb performance over 8 weeks after injury. Neither buspirone nor fluoxetine significantly improved quadrupedal locomotion on the horizontal ladder test. The improved accuracy of reaching and grasping, patterns of muscle activity, and increased excitability of spinal motor–evoked potentials after buspirone administration reflect extensive reorganization of connectivity within and between supraspinal and spinal sensory-motor netxcopy works. Thus, both serotonergic drugs, buspirone and fluoxetine, neuromodulated these networks to physiological states that enabled markedly improved forelimb function after cervical spinal cord injury.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-020-00974-8.Key Words: Serotonin, Spinal cord injury, Buspirone, Fluoxetine, Forelimb     

Spinal Cord Stimulation for the Treatment of Chronic Pain in Patients with Lumbar Spinal Stenosis

Objective: Chronic back and leg pain associated with lumbar spinal stenosis (LSS) is common in the elderly. Surgical decompression is usually performed when conservative treatments fail. We present an evaluation of the long‐term outcome of patients suffering from symptomatic LSS treated with spinal cord stimulation (SCS). Materials and Methods: Data were collected prospectively in three independent registries in three European centers. Pooled data were analyzed retrospectively. Changes in pain intensity, functional status, and analgesic medication were compared at baseline and at the last available follow‐up. Demographic data as well as details regarding the implantation procedure and any adverse events were systematically recorded. Results: Data were recorded in 69 patients with a mean follow‐up period of 27 months. All patients showed clinically and statistically significant improvement in pain relief, the visual analog scale decreasing from 7.4 ± 2.3 to 2.8 ± 2.4 (p < 0.05). The use of analgesic medication decreased and the functional status improved. Conclusion: Spinal cord stimulation seems to be effective in the treatment of patients suffering from chronic pain associated with LSS. Being less invasive and reversible, SCS should be considered before surgical decompression, particularly in patients with increased risks associated with back surgery.