A shift of brain network hub after spinal cord injury.

Background: Spinal cord injury (SCI) causes severe sequelae and significant social loss, depending on the extent of the damage. Most previous studies have focused on the pathology of the spinal cord to develop treatments for SCI. However, it is now known that the brain, which is not directly damaged, also undergoes morphological changes after spinal cord injury, which could affect natural recovery and treatment. In recent years, magnetic resonance imaging (MRI) has been developed to analyze functional changes in the brain. Resting-state functional MRI (rsfMRI), which captures brain activity at rest, can calculate functional connections between brain areas and identify central hubs by network analysis. Purpose: We aim to investigate functional connectivity in the brain using rsfMRI after SCI and to determine how brain-network main hubs change over time. Methods: We evaluated rsfMRI in 10 mice of the contusional SCI model and calculated connectivity using graph theory. We evaluated "centrality," a representative parameter of network analysis. The subtype of centrality was degree centrality, which indicates the hub function of a single area. The five times of rsfMRI were performed in each individual mouse: before injury and at 1, 3, 7, and 14 weeks post-injury. Results: Before the injury, the degree centralities of the primary and secondary motor cortex were high, suggesting that these motor cortices served as main hubs for motor function. After SCI, the hub function of the motor cortices decreased by 14 weeks. In contrast, hub function in the external capsule and the putamen comparatively increased with time after injury, suggesting that the extrapyramidal/subcortical system, which runs the ventral side of the spinal cord and remains after injury in this model, becomes dominant. Conclusion: We demonstrated the shift of the brain network hub after SCI. The results of this study provide basic information for understanding brain network changes after SCI and would be useful for treatment selection and evaluation of its efficacy in SCI patients.

Does the degree of preoperative gait disturbance remain after tumor resection in patients with intradural extramedullary spinal cord tumors?

STUDY DESIGN: Retrospective comparative study. OBJECTIVE: This study aimed to determine whether the degree of preoperative gait disturbance remains following surgical resection in patients with intradural extramedullary spinal cord tumors (IDEMSCTs), and to investigate any factors that may influence poor improvement in postoperative gait disturbance. SETTING: The single institution in Japan. METHODS: In total, 78 IDEMSCTs patients who required surgical excision between 2010 and 2019 were included. According to the degree of preoperative gait disturbance using modified McCormick scale (MMCS) grade, they were divided into the Mild and Severe groups. The mean postoperative follow-up period was 50.7 ± 17.9 months. Data on demographic and surgical characteristics were compared between the two groups. RESULTS: There was no significant difference in terms of age at surgery, sex, tumor size, surgical time, estimated blood loss, tumor histopathology, and postoperative follow-up period between the Mild and Severe groups. At the final follow-up, 84.6% of IDEMSCTs patients were able to walk without support. Gait disturbance improved after surgery in most of the patients with preoperative MMCS grades II-IV, but remained in approximately half of patients with preoperative MMCS grade V. Age at surgery was correlated with poor improvement in postoperative gait disturbance in the Severe group. CONCLUSIONS: Regardless of the degree of preoperative gait disturbance, it improved after tumor resection in most of the IDEMSCTs patients. However, in the preoperative MMCS grade III-V cases, older age at surgery would be an important factor associated with poor improvement in postoperative gait disturbance.

Effects of Bone Cross-Link Bridging on Fracture Mechanism and Surgical Outcomes in Elderly Patients with Spine Fractures.

STUDY DESIGN: This study adopted a cross-sectional study design. PURPOSE: This study was designed to investigate the effects of bone cross-link bridging on fracture mechanism and surgical outcomes in vertebral fractures using the maximum number of vertebral bodies with bony bridges between adjacent vertebrae without interruption (maxVB). OVERVIEW OF LITERATURE: The complex interplay of bone density and bone bridging in the elderly can complicate vertebral fractures, necessitating a better understanding of fracture mechanics. METHODS: We examined 242 patients (age >60 years) who underwent surgery for thoracic to lumbar spine fractures from 2010 to 2020. Subsequently, the maxVB was classified into three groups: maxVB (0), maxVB (2-8), and maxVB (9-18), and parameters, including fracture morphology (new Association of Osteosynthesis classification), fracture level, and neurological deficits were compared. In a sub-analysis, 146 patients with thoracolumbar spine fractures were classified into the three aforementioned groups based on the maxVB and compared to determine the optimal operative technique and evaluate surgical outcomes. RESULTS: Regarding the fracture morphology, the maxVB (0) group had more A3 and A4 fractures, whereas the maxVB (2-8) group had less A4 and more B1 and B2 fractures. The maxVB (9-18) group exhibited an increased frequency of B3 and C fractures. Regarding the fracture level, the maxVB (0) group tended to have more fractures in the thoracolumbar transition region. Furthermore, the maxVB (2-8) group had a higher fracture frequency in the lumbar spine area, whereas the maxVB (9-18) group had a higher fracture frequency in the thoracic spine area than the maxVB (0) group. The maxVB (9-18) group had fewer preoperative neurological deficits but a higher reoperation rate and postoperative mortality than the other groups. CONCLUSIONS: The maxVB was identified as a factor influencing fracture level, fracture type, and preoperative neurological deficits. Thus, understanding the maxVB could help elucidate fracture mechanics and assist in perioperative patient management.

Normal pressure hydrocephalus due to an iatrogenic giant lumbar pseudomeningocele after posterior lumbar interbody fusion: illustrative case.

BACKGROUND: Iatrogenic pseudomeningocele incidence after lumbar surgery is 0.068%-2%, and most lumbar pseudomeningoceles are smaller than 5 cm; however, in rare cases, "giant" pseudomeningoceles greater than 8 cm in size may develop. Normal pressure hydrocephalus (NPH) is another rare condition in which the ventricles expand despite the presence of normal intracranial pressure. To date, pseudomeningocele associated with NPH has not been reported. OBSERVATIONS: An 80-year-old woman underwent L3-5 laminectomy and posterior lumbar interbody fusion, and her symptoms improved after surgery. However, dementia appeared 1 month after surgery. Repeated brain computed tomography showed ventricular enlargement, and lumbar magnetic resonance imaging showed a long pseudomeningocele in the subcutaneous tissues at the L4 level. Here, the authors report a rare case of an iatrogenic giant pseudomeningocele accompanied by NPH after lumbar surgery. The symptoms of NPH in the present case occurred after spinal surgery and recovered after dural repair surgery, indicating that the changes in cerebrospinal fluid circulation and/or pressure due to pseudomeningoceles may cause NPH. LESSONS: The prevention of dural tears through precise surgical technique and primary repair of dural tears are the best approaches to prevent pseudomeningocele incidence and subsequent events.

Influence of Pedicle Screw Insertion Depth on Posterior Lumbar Interbody Fusion: Radiological Significance of Deeper Screw Placement.

STUDY DESIGN: Retrospective case series. OBJECTIVES: To investigate the influence of screw size on achieving bone fusion in posterior lumbar interbody fusion (PLIF). METHODS: In total, 137 consecutive patients with L4 degenerative spondylolisthesis who underwent single-level PLIF at L4-L5 were evaluated. Factors investigated for their contribution to bone fusion included: 1) age, 2) sex, 3) body mass index, 4) bone mineral density, 5) intervertebral mobility, 6) screw diameter, 7) screw length, 8) screw fitness in the pedicle (%fill), 9) screw depth in the vertebra (%depth), 10) screw angle, 11) facetectomy, 12) crosslink connector, and 13) cage material. RESULTS: Bone fusion was confirmed in 88.2% of patients. The comparison between fusion (+) and fusion (-) groups showed no significant differences in screw size. The %fill and %length were significantly greater in the fusion (+) group than in the fusion (-) group (%fill: 58.5% ± 7.5% vs 52.3% ± 7.3%, respectively, P = .005; %depth: 59.8% ± 9.7% vs 50.3% ± 13.8%, respectively, P = .025). Multivariate logistic regression analysis revealed that %fill (odds ratio [OR]= 1.11, P = .025) and %depth (OR = 1.09, P = .003) were significant independent factors affecting bone fusion. Receiver operating characteristic curve analyses identified a %fill of 60.0% and a %depth of 54.2% as optimal cutoff values for achieving bone fusion. CONCLUSIONS: Screw size should be determined based on the screw fitness in the pedicle (%fill > 60%) and screw insertion depth in the vertebral body (%depth > 54.2%) according to individual vertebral anatomy in L4-L5 PLIF.

Neurorehabilitation using a voluntary driven exoskeletal robot improves trunk function in patients with chronic spinal cord injury: a single-arm study.

Body weight-supported treadmill training with the voluntary driven exoskeleton (VDE-BWSTT) has been shown to improve the gait function of patients with chronic spinal cord injury. However, little is known whether VDE-BWSTT can effectively improve the trunk function of patients with chronic spinal cord injury. In this open-label, single-arm study, nine patients with chronic spinal cord injury at the cervical or thoracic level (six males and three females, aged 37.8 ± 15.6 years, and time since injury 51.1 ± 31.8 months) who underwent outpatient VDE-BWSTT training program at Keio University Hospital, Japan from September 2017 to March 2019 were included. All patients underwent twenty 60-minute gait training sessions using VDE. Trunk muscular strength, i.e., the maximum force against which patient could maintain a sitting posture without any support, was evaluated in four directions: anterior, posterior, and lateral (right and left) after 10 and 20 training sessions. After intervention, lateral muscular strength significantly improved. In addition, a significant positive correlation was detected between the change in lateral trunk muscular strength after 20 training sessions relative to baseline and gait speed. The change in trunk muscular strength after 20 training sessions relative to baseline was greatly correlated with patient age. This suggests that older adult patients with chronic spinal cord injury achieved a greater improvement in trunk muscle strength following VDE-BWSTT. All these findings suggest that VDE-BWSTT can improve the trunk function of patients with chronic spinal cord injury and the effect might be greater in older adult patients. The study was approved by the Keio University of Medicine Ethics Committee (IRB No. 20150355-3) on September 26, 2017.

Influence of body weight-supported treadmill training with voluntary-driven exoskeleton on the quality of life of persons with chronic spinal cord injury: a pilot study.

The aim of this study was to investigate whether body weight-supported treadmill training with voluntary-driven exoskeleton body weight-supported treadmill training (VDE-BWSTT) improves the quality of life (QOL) of persons with chronic spinal cord injury (SCI). Nineteen individuals with chronic SCI with walking limitation underwent a total of 20 sessions of VDE-BWSTT using the hybrid assistant limb. The QOL was measured using the Short Form-36v2 (SF-36v2) questionnaire at preintervention and postintervention. The Walking Index for SCI-II (WISCI-II), Functional Independence Measure (FIM) motor score, and Neuropathic Pain Symptom Inventory (NPSI) self-questionnaire were also administered/completed. In SF-36v2, the mean values of all subscales in our participants were lower than those in healthy individuals. None of the measures showed significant improvement, even in individuals with some residual walking ability (baseline WISCI-II score of 6 or higher). In the correlation analysis between the baselines WISCI-II, FIM, or NPSI values and the mean SF-36v2 subscale changes throughout the training, the baseline FIM motor score was positively correlated with the mean changes in Role Emotional and Mental Health. In addition, NPSI was negatively correlated with the mean change in Vitality and Mental Health. In our protocol, although VDE-BWSTT did not improve the QOL of persons with chronic SCI, those with higher functional independence or lower pain at preintervention likely improved. Further study with combination of task-specific training or pain-targeting treatment with more patients should be considered to more effectively improve their QOL.

Gait ability required to achieve therapeutic effect in gait and balance function with the voluntary driven exoskeleton in patients with chronic spinal cord injury: a clinical study.

STUDY DESIGN: A non-randomized open-label single-arm clinical trial. OBJECTIVES: To analyze the effect of body weight supported treadmill training (BWSTT) with the voluntary driven exoskeleton (VDE) in persons with differing levels and completeness of spinal cord injury (SCI) and differing walking abilities. SETTING: Keio University Hospital, Tokyo, Japan. METHODS: Twenty individuals with chronic SCI (age, 43 ± 17 years) classified as American Spinal Injury Association Impairment Scale grade A (n = 2), B (n = 4), C (n = 8), or D (n = 6) who had reached a plateau in recovery. Participants underwent twenty 60 min sessions of BWSTT with the hybrid assisted limb. The speed, distance, and duration walked in every 60 min training session were recorded. The Walking Index for SCI Scale II (WISCI-II), 10 meters walk test (10MWT), 2 min walk test, timed up and go (TUG) test, Berg Balance Scale (BBS), lower extremity motor score (LEMS), Barthel Index, and Functional Independence Measure were evaluated at pre and post intervention. RESULTS: There was a significant improvement in 10MWT, TUG, and BBS after the intervention. Walking ability significantly improved in participants with high walking ability at baseline (WISCI-II score 6-20; n = 12) but not in participants with low walking ability (WISCI-II score 0-3; n = 8). Significant improvement of BBS was also shown in participants with high walking ability at baseline. CONCLUSIONS: Patients with high walking ability at baseline responded better to the training than those with low walking ability.

Assessing cortical plasticity after spinal cord injury by using resting-state functional magnetic resonance imaging in awake adult mice.

Neural connectivity has recently been shown to be altered after spinal cord injury (SCI) not only in the spinal cord but also in the brain. However, to date, no studies have analyzed the functional alterations after SCI in various areas of the cerebral cortex over time. To examine the plasticity of the neural connectivity in the brain after SCI, we performed resting-state functional magnetic resonance imaging (rs-fMRI) in awake adult mice pre- and post-SCI. After a complete thoracic SCI, the functional connectivity between the primary motor (MOp) and primary sensory (SSp) areas was significantly decreased during the chronic phase. In contrast, the connectivity between the MOp and motivation area was increased. Thus, impairments in sensory and motor connections after SCI led to a time-dependent compensatory upregulation of "motor functional motivation". Moreover, the functional connectivity between the SSp and pain-related areas, such as the caudoputamen (CP) and the anterior cingulate area (ACA), was strengthened during the chronic phase, thus suggesting that rs-fMRI can indicate the presence of neuropathic pain after SCI. Therefore, rs-fMRI is a useful tool for revealing the pathological changes that occur in the brain after SCI.

Low immunogenicity of mouse induced pluripotent stem cell-derived neural stem/progenitor cells.

Resolving the immunogenicity of cells derived from induced pluripotent stem cells (iPSCs) remains an important challenge for cell transplant strategies that use banked allogeneic cells. Thus, we evaluated the immunogenicity of mouse fetal neural stem/progenitor cells (fetus-NSPCs) and iPSC-derived neural stem/progenitor cells (iPSC-NSPCs) both in vitro and in vivo. Flow cytometry revealed the low expression of immunological surface antigens, and these cells survived in all mice when transplanted syngeneically into subcutaneous tissue and the spinal cord. In contrast, an allogeneic transplantation into subcutaneous tissue was rejected in all mice, and allogeneic cells transplanted into intact and injured spinal cords survived for 3 months in approximately 20% of mice. In addition, cell survival was increased after co-treatment with an immunosuppressive agent. Thus, the immunogenicity and post-transplantation immunological dynamics of iPSC-NSPCs resemble those of fetus-NSPCs.

Evaluation of the immunogenicity of human iPS cell-derived neural stem/progenitor cells in vitro.

To achieve the goal of a first-in-human trial for human induced pluripotent stem cell (hiPSC)-based transplantation for the treatment of various diseases, allogeneic human leukocyte antigen (HLA)-matched hiPSC cell banks represent a realistic tool from the perspective of quality control and cost performance. Furthermore, considering the limited therapeutic time-window for acute injuries, including neurotraumatic injuries, an iPS cell bank is of potential interest. However, due to the relatively immunoprivileged environment of the central nervous system, it is unclear whether HLA matching is required in hiPSC-derived neural stem/progenitor cell (hiPSC-NS/PC) transplantation for the treatment of neurodegenerative diseases and neurotraumatic injuries. In this study, we evaluated the significance of HLA matching in hiPSC-NS/PC transplantation by performing modified mixed lymphocyte reaction (MLR) assays with hiPSC-NS/PCs. Compared to fetus-derived NS/PCs, the expression levels of human leukocyte antigen-antigen D related (HLA-DR) and co-stimulatory molecules on hiPSC-NS/PCs were significantly low, even with the addition of tumor necrosis factor-α (TNFα) and/or interferon-γ (IFNγ) to mimic the inflammatory environment surrounding transplanted hiPSC-NS/PCs in injured tissues. Interestingly, both the allogeneic HLA-matched and the HLA-mismatched responses were similarly low in the modified MLR assay. Furthermore, the autologous response was also similar to the allogeneic response. hiPSC-NS/PCs suppressed the proliferative responses of allogeneic HLA-mismatched peripheral blood mononuclear cells (PBMCs) in a dose-dependent manner. Thus, the low antigen-presenting function and immunosuppressive effects of hiPSC-NS/PCs result in a depressed immune response, even in an allogeneic HLA-mismatched setting. It is crucial to verify whether these in vitro results are reproducible in a clinical setting.

Pretreatment with a γ-Secretase Inhibitor Prevents Tumor-like Overgrowth in Human iPSC-Derived Transplants for Spinal Cord Injury.

Neural stem/progenitor cells (NS/PCs) derived from human induced pluripotent stem cells (hiPSCs) are considered to be a promising cell source for cell-based interventions that target CNS disorders. We previously reported that transplanting certain hiPSC-NS/PCs in the spinal cord results in tumor-like overgrowth of hiPSC-NS/PCs and subsequent deterioration of motor function. Remnant immature cells should be removed or induced into more mature cell types to avoid adverse effects of hiPSC-NS/PC transplantation. Because Notch signaling plays a role in maintaining NS/PCs, we evaluated the effects of γ-secretase inhibitor (GSI) and found that pretreating hiPSC-NS/PCs with GSI promoted neuronal differentiation and maturation in vitro, and GSI pretreatment also reduced the overgrowth of transplanted hiPSC-NS/PCs and inhibited the deterioration of motor function in vivo. These results indicate that pretreatment with hiPSC-NS/PCs decreases the proliferative capacity of transplanted hiPSC-NS/PCs, triggers neuronal commitment, and improves the safety of hiPSC-based approaches in regenerative medicine.