REVIEW | doi:10.20944/preprints202307.1409.v1
Subject: Biology And Life Sciences, Life Sciences Keywords: spinal and bulbar muscular atrophy; antisense therapy; oligonucleotide; splice switching; mRNA knockdown; androgen receptor; AR45
Online: 20 July 2023 (09:53:18 CEST)
Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy’s disease, is a debilitating neuromuscular disease characterized by progressive muscular weakness and neuronal degeneration, affecting 1-2 individuals per 100,000 globally. While SBMA is relatively rare, recent studies have shown a significantly higher prevalence of the disease within the indigenous population of Western Canada compared to the general population. The disease is caused by a pathogenic expansion of polyglutamine residues in the androgen receptor protein, which acts as a key transcriptional regulator for numerous genes. SBMA has no cure, and current treatments are primarily supportive and focused on symptom management. Recently, a form of precision medicine known as antisense therapy has gained traction as a promising therapeutic option for numerous neuromuscular diseases. Antisense therapy uses small synthetic oligonucleotides to confer therapeutic benefit by acting on pathogenic mRNA molecules, serving to either degrade pathogenic mRNA transcripts or helping to modulate splicing. Recent studies have explored the suitability of antisense therapy for the treatment of SBMA, primarily focused on antisense-mediated mRNA knockdown approaches. Advancements in understanding the pathogenesis of SBMA and the development of targeted therapies offer hope for improved quality of life for individuals affected by this debilitating condition. Continued research is essential to optimize these genetic approaches, ensuring their safety and efficacy.
BRIEF REPORT | doi:10.20944/preprints202309.1527.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: spinal muscular atrophy; SMN1 gene; SMN2 gene; nuclear gems; antisense oligonucleotides; splicing correction.
Online: 22 September 2023 (09:19:28 CEST)
Spinal muscular atrophy is a neuromuscular disorder caused by mutationsin both copies of the survival motor neuron gene 1 (SMN1) which lead to reduction in the production of the SMN protein. Currently, there are several therapies that have been approved for SMA, with much more undergoing active research. While various biomarkers have been proposed for assessing the effectiveness of SMA treatment, a universally accepted one still hasnot been identified. This study aimed to investigate whether the number of gems in cell nuclei could serve as a potential biomarker for SMA. To gain insight into whether the number of gems in cell nuclei varies based on their SMN genotype and whether the increase in gems number is associated with therapeutic response, we utilized fibroblast cell cultures obtained from a patient with SMA type II and from healthy individual. We have discovered a remarkable difference in the number of gems found in the nuclei of these cells, specifically when counting gems per 100 nuclei. Then the SMA fibroblasts were treated with antisense oligonucleotides the beneficial effects in correcting the abnormal splicing of SMN2 exon 7 have been demonstrated. It was observed that there was a significant increase in the number of gems in the treated cells compared to the intact SMA cells. The results obtained significantly correlate with an increase of full-length SMN transcripts share. Based on our findings, it is evident that the quantity of gems can be regarded as a reliable biomarker for SMA drugs development.
ARTICLE | doi:10.20944/preprints202302.0500.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: spinal muscular atrophy; newborn screening; SMN1; SMN2; real-time PCR; dried blood spots; SMA incidence; carrier frequency
Online: 28 February 2023 (03:45:16 CET)
Spinal muscular atrophy 5q (SMA) is the most common neuromuscular inherited disease in neonates which is associated with homozygous deletion of exon 7 in the SMN1 gene. Recently established drugs can improve the motor functions of SMA infants when treated in the pre-symptomatic stage. With aim of providing an early diagnosis, newborn screening (NBS) for SMA using real-time PCR assay with dried blood spots (DBS) was performed in Saint-Petersburg from January 2022 through November 2022. Here, 36,140 newborns were screened by GenomeX real-time PCR-based screening test, and three genotypes were determined. Homozygous deletion carriers (4 newborns), heterozygous carriers (772 newborns) and wild-type individuals (35,364 newborns) were identified. All four newborns screened positive for homozygous SMN1 deletion were confirmed by alternate methods. Two of the newborns had two copies of SMN2, and two of the newborns had three copies. We determined Saint-Petersburg spinal muscular atrophy incidence of 1 in 9,035 and SMA carrier frequency of 1 in 47. In conclusion, it can be summarized that providing both timely SMN1 information and confirmation along with SMN2 copy number as part of SMA newborn screening algorithm can significantly improve clinical follow-up, family members testing, and SMA patients' treatment.
REVIEW | doi:10.20944/preprints202106.0184.v1
Subject: Medicine And Pharmacology, Pediatrics, Perinatology And Child Health Keywords: SMA; spinal muscular atrophy type 1; SMN1; nutritional management; enteral nutrition; pediatric gastroenterology; dysphagia; neurological disability; endocrine disorders; precocious pubarche
Online: 7 June 2021 (13:14:37 CEST)
The management of patients with spinal muscular atrophy type 1 (SMA1) is constantly evolving. In just a few decades the medical approach has switched from an exclusively palliative therapy to a targeted therapy, transforming the natural history of the disease, improving survival time and quality of life, and creating new challenges and goals. Many nutritional problems, gastrointesti-nal disorders and metabolic and endocrine alterations are commonly identified in patients af-fected by SMA1 during childhood and adolescence. For this reason, a proper pediatric multidis-ciplinary approach is then required in the clinical care of these patients, with a specific focus on the prevention of most common complications. The purpose of this narrative review is to provide the clinician with a practical and usable tool about SMA1 patients care, through a comprehensive insight into the nutritional, gastroenterological, metabolic and endocrine management of SMA1. Considering the possible horizons opened thanks to new therapeutic frontiers, a nutritional and endo-metabolic surveillance is a crucial element to be considered for a proper clinical care of these patients.
ARTICLE | doi:10.20944/preprints201704.0048.v1
Subject: Social Sciences, Behavior Sciences Keywords: stress; transcranial magnetic stimulation; spinal reflex; reaction time; co-contraction
Online: 10 April 2017 (05:59:46 CEST)
The purpose of the present study was to investigate the effects of psychological pressure on corticospinal excitability, the spinal reflex, lower limb muscular activity, and reaction times during a task involving dominant leg movements. Ten healthy participants performed a simple reaction time task by raising the heel of their dominant foot from a switch. After 20 practice trials, participants performed 20 non-pressure and 20 pressure trials in a counterbalanced order. Stress responses were successfully induced, as indexed by significant increases in state anxiety, mental effort, and heart rates under pressure. Significant increases in motor evoked potential (MEP) amplitude of the tibialis anterior muscle (TA) occurred under pressure. In terms of task-related EMG amplitude, the co-contraction rate between the soleus (SOL) and TA muscles significantly increased along with SOL and TA EMG amplitudes under pressure. Hoffmann reflexes for SOL and reaction times did not change under pressure. These results indicate that corticospinal excitability and leg muscle-related EMG activity increase homogeneously during lower limb movements that are performed under psychological pressure.
ARTICLE | doi:10.20944/preprints202308.0804.v1
Subject: Physical Sciences, Biophysics Keywords: Sensorimotor Integration; Spinal muscle atrophy; cognition; Fitts’s Law; Motor; Sensory
Online: 10 August 2023 (03:36:20 CEST)
Previous studies have found that individuals with limited motor capabilities due to acquired neurological injury (e.g., spinal cord injury and stroke) can make accurate action possibility judgements for neurologically healthy individuals. Previous studies have shown that people with limited motor capabilities may rely on previous motor experience (i.e., pre-injury) when making action possibility judgments for others. In the present study, we examined whether having severely limited previous motor experience from birth, as a consequence of spinal muscle atrophy (SMA), alters the action possibility judgments made for neurologically healthy individuals. Participants with SMA and Neurologically Healthy (NH) sex- and age-matched controls performed a perceptual-motor judgment task using the Fitts’s law paradigm (see Fitts, 1954). Participants observed apparent motion videos of reciprocal aiming movements with varying indices of difficulty (ID, see: Manson et al., 2014). For each movement, participants predicted the shortest movement time (MT) at which a neurologically healthy young adult could perform the task while maintaining accuracy. Between-group comparisons revealed that participants with SMA predicted significantly longer MTs compared to controls. Regression analyses revealed that predicted MTs of both NH and SMA participants exhibited a Fitts’s law relationship (i.e., the predicted MTs significantly increased as movement difficulty increased). A supplementary analysis on the SMA group revealed no differences in predicted MTs between the participants with some and no motor function as assessed by the SMA health index. Overall, these results provide evidence that participants with SMA who have limited or no motor experience may make more conservative action possibility judgments for others. Critically, our finding that the pattern of action possibility judgements (e.g., the slopes of the regression lines) were not different between SMA and NH groups provides evidence that limited previous motor experience may not completely impair action possibility judgements.
REVIEW | doi:10.20944/preprints202210.0359.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: Spinal plasticity; spinal neuronal networks; spinal muscular atrophy; amyotrophic lateral sclerosis; spinal cord injury; stroke; spasticity; classical conditioning; instrumental conditioning; operant conditioning
Online: 24 October 2022 (10:05:33 CEST)
In former times, the spinal cord was considered a hard-wired network for spinal reflexes and a conduit for long-range connections. This view has changed dramatically over the past few decades. It is now recognized as a plastic device whose structures and functions adapt to changing circumstances. While such changes also occur under physiological conditions, the most dramatic alterations take place during or after various pathological events. It is astonishing what mechanisms the musculo-skeletal system has evolved to come to grips with the damages. Many of these changes are maladaptive, but some appear to help adapt to the new conditions. Although myriads of studies, using manifold methods, have been devoted to elucidating the underlying mechanisms, in humans and animal models, the etiology and pathophysiology of various diseases are still little understood, due to a number of reasons. We will here try to summarize some results and remaining problems in a selection of diseases, in particular spinal muscular atrophy (SMA), amyotrophic laterals sclerosis (ALS), and predominantly spinal cord injury (SCI) with occasional relations to stroke. Especially the changes in SCI (and stroke) depend on the cause, site and extent of the afflicted damage and are therefore multifarious. At the end, we will briefly summarize results indicating that operant, classical and instrumental conditioning can be used to produce plastic changes in healthy people, with potentials for applications to patients with spinal cord injury. In order not to overload the article, we will not delve deeply into sub-cellular processes.
REVIEW | doi:10.20944/preprints202306.1924.v2
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: spinal cord injury; spinal cord dysfunction; traumatic spinal cord injury; non traumatic spinal cord injury; rehabilitation; neuroregeneration
Online: 29 June 2023 (11:02:29 CEST)
Spinal Cord Injury in children can be a devastating condition in children with profound implications for their overall health and quality of life. In this review we aim to provide a concise overview of the key aspects associated with SCI in pediatric population. Firstly, we discuss the etiology and epidemiology of SCI in children, highlighting the diverse range of causes. We explore the unique anatomical and physiological characteristics of the developing spinal cord that contribute to the specific challenges faced by pediatric patients. Next, we delve into the clinical presentation and diagnostic methods, emphasizing the importance of prompt and accurate diagnosis to facilitate appropriate interventions. Furthermore, we approach the multidisciplinary management of pediatric SCI, encompassing acute medical care, surgical interventions, and ongoing supportive therapies. Finally, we explore emerging research and innovative therapies in the field and we emphasize the need for continued advancements in understanding and treating SCI in children to improve their functional independence and overall quality of life.
REVIEW | doi:10.20944/preprints202010.0011.v1
Subject: Medicine And Pharmacology, Anatomy And Physiology Keywords: Anterior spinal artery syndrome; Spinal cord Infarction; Aortic insufficiency; Aortic surgery; Spinal shock; Quadriplegia; Bowel-bladder incontinence
Online: 1 October 2020 (09:15:58 CEST)
As an uncommon cause of spinal cord infarction, anterior spinal cord syndrome can manifest with motor paralysis, loss of pain, and temperature sensation distal to the site of the lesion. The main pathogenesis of this syndrome is the disruption of blood flow in the anterior spinal artery. Mortality and morbidity differ with the etiology of the syndrome. So knowing the etiology of blood flow disruption is essential for patient management. This review article highlights the important clinical manifestation of Anterior spinal artery syndrome. Also describes etiology, pathogenesis, diagnosis, prognosis, possible management, and complications.
ARTICLE | doi:10.20944/preprints202309.0081.v1
Subject: Medicine And Pharmacology, Other Keywords: ESCC; MSCC; spinal metastasis; decompression surgery; radiotherapy; spinal cord syndrome
Online: 4 September 2023 (04:34:03 CEST)
Background: Surgical decompression (SD) with and without posterior stabilization followed by radiotherapy is an established treatment for patients with metastatic spinal disease with epidural spinal cord compression (ESCC). This study aims to identify risk factors for occurrence of neurologic comprise resulting from local recurrence. Methods: All patients who received surgical treatment for metastatic spinal disease at our center between 2011 and 2022 were included in this study. Cases were evaluated for tumor entity, surgical technique for decompression (decompression, hemilaminectomy, laminectomy, corpectomy) neurological deficits, grade of ESCC, time interval to radiotherapy and perioperative complications. Results: A total of 747 patients were included in the final analysis, with a follow-up of 296.8 days (95% CI (263.5, 330.1)). During the follow-up period 7.5% of patients developed spinal cord/cauda syndrome (SCS). Multivariate analysis revealed prolonged time (> 35 d) to radiation therapy as solitary risk factor (p < 0.001) for occurrence of SCS during follow-up. Conclusion: Surgical treatment of spinal metastatic disease improves patients’ quality of life and Frankel grade but radiation therapy needs to be scheduled within a time frame of few weeks in order to reduce the risk of tumor-induced neurologic comprise.
ARTICLE | doi:10.20944/preprints202312.0036.v1
Subject: Medicine And Pharmacology, Surgery Keywords: Spinal fusion; Interbody cage; Sagittal balance; Artificial intelligence; Machine learning; Spinal parameters
Online: 1 December 2023 (08:12:03 CET)
Transforaminal lumbar interbody fusion (TLIF) is a commonly used technique for treating lumbar degenerative diseases. Here, we developed a fully computer-supported pipeline to predict the cage height and the degree of lumbar lordosis subtraction from the pelvic incidence (PI-LL) after TLIF surgery through preoperative X-ray images. The automated pipeline included two primary stages. First, a deep learning model was used to extract essential features from X-ray images. Second, five machine learning algorithms were trained to identify the optimal models to predict the interbody cage height and postoperative PI-LL. Lasso regression and support vector regression exhibited superior performance for predicting the interbody cage height and postoperative PI-LL, respectively. For cage height prediction, the root mean square error (RMSE) was calculated as 1.01, and the model achieved the highest accuracy at a height of 12 mm, with exact prediction achieved in 54.43% (43/79) of cases. In most of the remaining cases, the prediction error of the model was within 1 mm. In addition, the model demonstrated adequate performance for predicting PI-LL, with an RMSE of 5.19 and an accuracy of 0.81 for PI-LL stratification. In conclusion, the interbody cage height and postoperative PI-LL can be reliably predicted using artificial intelligence and ML models.
ARTICLE | doi:10.20944/preprints201807.0382.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: spinal cord injury; inflammation; plasma
Online: 20 July 2018 (12:49:20 CEST)
While over half of all spinal cord injuries (SCIs) occur in the cervical region, the majority of preclinical studies have focused on models of thoracic injury. However, these two levels are anatomically distinct—with the cervical region possessing a greater vascular supply, grey-white matter ratio and sympathetic outflow relative to the thoracic region. As such, there exists a significant knowledge gap in the secondary pathology at these levels following SCI. In this study, we characterized the systemic plasma markers of inflammation over time (1, 3, 7, 14, 56 days post-SCI) after moderate-severe, clip-compression cervical and thoracic SCI in the rat. Using high-throughput ELISA panels, we observed a clear level-specific difference in plasma levels of VEGF, leptin, IP10, IL18, GCSF, and fractalkine. Overall, cervical SCI had reduced expressions of both pro- and anti-inflammatory proteins relative to thoracic SCI, likely due to sympathetic dysregulation associated with higher level SCIs. However, contrary to the literature, we did not observe level-dependent splenic atrophy with our incomplete SCI model. This is the first study to compare the systemic plasma-level changes following cervical and thoracic SCI using level-matched and time-matched controls. The results of this study provide the first evidence in support of level-targeted intervention and also challenge the phenomenon of high SCI-induced splenic atrophy in incomplete SCI models.
ARTICLE | doi:10.20944/preprints202306.0569.v1
Subject: Public Health And Healthcare, Physical Therapy, Sports Therapy And Rehabilitation Keywords: red flags; clinical reasoning; back pain; cauda equina syndrome; spinal fracture; spinal infection; malignancy; serious pathology; Spinal pain; low back pain; diagnostic triage
Online: 8 June 2023 (07:25:53 CEST)
Background and Objectives: The relevance of red flags in serious spinal pathology (SSP) evolved throughout the last years. Recently, new considerations have been proposed to expand the consideration of red flags. The purpose of this study was to determine, approve and test a model for the triage and manage-ment process of SSP based on the latest data available in the literature. Materials and Methods: The SSP model was initially built on the basis of a literature re-view. The model was further determined and approved by an expert panel us-ing a Delphi process. Finally, clinical scenario were used to test the applicabil-ity of the model. Results: After three rounds of Delphi process, panellists reached a consensus on a final version of the model. The use of clinical scenari-os by experts bring about reflexive elements both on the determined model and on the evocative SSP of the clinical cases. Conclusions: The validation of the model and its implementation in the clinical field could help assess the skills of first-line practitioners managing spinal painful patients. To this end, the devel-opment of additional clinical scenarios fitting with the determined model should be further considered.
COMMUNICATION | doi:10.20944/preprints201907.0002.v1
Subject: Medicine And Pharmacology, Pediatrics, Perinatology And Child Health Keywords: motor evoked potentials lysosomal disorders; cortical-spinal tract; spinal cord compression; cervical myelopathy; clinical neurophysiology
Online: 1 July 2019 (11:05:52 CEST)
Background: Cervical myelopathy (CM) is a common cause of morbidity and disability in patients with mucopolysaccharidosis (MPS) and, therefore, early detection is crucial for best surgical intervention and follow-up. Transcranial Magnetic Stimulation (TMS) non-invasively evaluates the conductivity along the cortico-spinal tract, also allowing preclinical diagnosis and monitoring. Methods: motor evoked potentials (MEPs) to TMS were recorded in a group of 8 patients with MPS-related CM. Responses were obtained during mild tonic contraction through a circular coil applied over the “hot spot” of the first dorsal interosseous and tibialis anterior muscles, bilaterally. Central motor conduction time was estimated as the difference between MEP cortical latency and the peripheral motor conduction time by cervical or lumbar magnetic stimulation. Peak-to-peak MEP amplitude to cortical stimulation and right-to-left difference of each parameter were also measured. Results: TMS revealed abnormal findings from both upper and lower limbs compatible with axonal damage and demyelination in 6 of them. Notably, a subclinical cervical spinal disease was detected before the occurrence of an overt CM in two patients, whereas TMS signs compatible with a CM of variable degree persisted despite surgery in all treated subjects. Conclusions: TMS screening should be performed in MPS patients, before and after surgery.
ARTICLE | doi:10.20944/preprints202304.0046.v2
Subject: Medicine And Pharmacology, Orthopedics And Sports Medicine Keywords: Lumbar spinal stenosis; Spinal decompression; Minimally invasive surgery; Mini-open; Disc herniation; Post-decompression; Instability
Online: 19 June 2023 (15:17:06 CEST)
BackgroundIndex level disc herniation following lumbar spinal decompression is somewhat overlooked as postoperative complication, resulting in return of symptoms. It is proposed that the combination of local instability and degenerated disc is more likely to result in disc herniation. There is no literature comparing post-decompression disc herniation rates between different techniques. This study compares the postoperative disc herniation rates of the "mini-open" laminectomy versus the tubular system decompression.MethodsIn a retrospective comparative study, 563 patient files who underwent primary lumbar spinal decompression, were reviewed and divided into two groups, distinguished by surgical technique. Demographic, clinical, and postoperative data were collected and compared using independent two-tailed t-test and Fisher's exact test with significance set at p<0.05. Primary outcome: comparison of post-decompression surgery, index level, disc herniation occurrence between two surgical techniques.ResultsPostoperative index level disc herniation was significantly lower in the minimally invasive surgery group with 2 cases (0.8%) versus 19 cases (5.8%) in the "mini-open" group [p=0.002]. Disc herniation following single level and multi-level operations were also significantly lower in the minimally invasive group compared with the "mini-open" group (2 versus 11 and 0 versus 8 respectively; p<0.05).ConclusionPostoperative index level disc herniation following lumbar spinal decompression occurs in 3.7% of surgeries. Minimally invasive surgery is found to result in less herniations then "mini-open".
ARTICLE | doi:10.20944/preprints202312.0630.v1
Subject: Medicine And Pharmacology, Medicine And Pharmacology Keywords: spinal cord injury; sarcopenia; immobilization osteoporosis; spasticity
Online: 8 December 2023 (14:40:25 CET)
Background. Sarcopenia and spinal cord injury (SCI) often coexist, but little is known about the associations of these two pathologies. This study aimed to assess the impact of SCI on muscle and bone mass and the correlations between clinical characteristics of SCI patients and sarcopenia. Methods: 136 patients diagnosed with SCI admitted to rehabilitation hospital were included in the study. The type and severity of injury (AIS), the level of spasticity (MAS), bone mineral density and Appendicular Lean Muscle Mass (ALM) were assessed. Sarcopenia was diagnosed according to the recommended EWGSOP2 cut-off points for ALM. Results: There was a statistically significant association between the ALM value and the gender, 75% of women developing sarcopenia. Among men, 42.9% had sarcopenia. Over 55% of AIS Grades A and B cases had sarcopenia. Mean age of sarcopenic patients was 35.8 years and they had multiple comorbidities. 51.6% of the patients with osteoporosis had sarcopenia. 69.7% of MAS level 0 cases had sarcopenia, while this was diagnosed in about 40% of patients with MAS levels 1-4. Conclusions: Gender, type of injury, presence of multiple comorbidities and age were directly associated with sarcopenia, while surprisingly, spasticity level and the presence of immobilization osteoporosis were not.
ARTICLE | doi:10.20944/preprints202107.0042.v1
Subject: Medicine And Pharmacology, Clinical Medicine Keywords: Spinal Cord Injury; Oxidative stress; Antioxidants, Pain
Online: 2 July 2021 (09:05:08 CEST)
Introduction:In this study we evaluated the connivance of oxidative and antioxidative parameters in the pathogenesis of spinal cord injury (SCI). Although the etiology and pathogenesis of SCI remain to be fully understood, it has been suggested that reactive oxygen species (ROS) and oxidative stress may play a significant role in the pathophysiology of SCI. Furthermore, there is little information available in scientific literature about oxidative and antioxidative parameters in SCI patients. Methods:Oxidative stress was determined by measuring the levels of Lipid Peroxides (LPO) and Protein carbonyl in plasma and antioxidative parameters like Glutathione Reductase (GR), catalase and Glutathione peroxidase (GPx) in lysate in 40 SCI patients and 40 healthy subjects without SCI. However, pain was measured by McGill pain questionnaire. Results: Concentrations of catalase (p<0.01), GR (p<0.01) and GPx (p<0.01) were significantly lower in patients with SCI than in controls, and levels of oxidative stress parameters, LPO (p<0.01), Protein carbonyl (p<0.01) were significantly higher in patients than in controls. A significant positive correlation was found between LPO and pain score among SCI patients group. Furthermore, a significant positive correlation was also found between Protein carbonyl and pain score among SCI patients group than in control group. Conclusion: The present results indicate that SCI patients are exposed to oxidative stress and this escalated oxidative stress may play a role in the etiopathogenesis of the disease. Moreover, our results also show that increased oxidative stress parameters are more strongly amalgamated with pain in SCI patients.
ARTICLE | doi:10.20944/preprints202211.0171.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: brain clearance; Qdots; nasal turbinates; subarachnoid space; cervical lymphatics; sympathetic ganglia; cervical spinal cord; thoracic spinal cord
Online: 9 November 2022 (08:57:11 CET)
Unwanted proteins and metabolic waste in cerebral spinal fluid are cleared from the brain by meningeal and nasal lymphatics, and perineural sheath of cranial nerves; however, the distribution and clearance of CSF along the subarachnoid space of the entire spinal cord is not fully understood. It was hypothesized that the anatomical resolution of Cryo-Fluorescence Tomography (CFT) could provide the visual evidence of clearance across the spinal cord at each level of the vertebral column. To that end, isoflurane anesthetized mice were infused into the lateral cerebroventricle with 5.0 µl of quantum dots [QdotR 605 ITKTM amino (PEG)] over two mins. Mice were allowed to recover (ca 2-3 min) and remained awake and ambulatory for 5, 15, 30, 60 and 120 minutes after which they were euthanized, and the entire intact body frozen at -800. The entire mouse was sectioned and imaged to produce an isotropic voxel resolution of 35 µm. Both white light and fluorescent images were captured after each slice to produce high resolution three-dimensional volumes for each mouse. CFT highlighted the circulation of tracer throughout the ventricular system and central canal of the spinal cord and the entire subarachnoid space of the CNS. Signal could be visualized in the nasal cavity, deep cervical lymph nodes, thoracic lymph nodes and more superficial submandibular lymph nodes as early as 15 min post infusion. Fluorescent signal could be visualized along the dorsal root ganglia and down the proximal extension of the spinal nerves of the thoracic and lumbar segments at 30 min. There was significant accumulation of tracer in the lumbar and sacral lymph nodes between 15- 60 min. The dense fluorescent signal in the thoracic vertebrae noted at 5- and 15-mins post infusion was significantly reduced by 30 min. Indeed, all signal in the spinal cord was ostensibly absent by 120 min except for trace amounts in the coccyx. The brain still had some residual signal at 120 min. These data show that Qdots with a hydrodynamic diameter of 16-20 nm rapidly clear from the brain of awake mice. These data also clearly demonstrate the rapid distribution and efflux of trace along a major length of the vertebral column and the potential contribution of the spinal cord in the clearance of brain waste.
ARTICLE | doi:10.20944/preprints202210.0285.v1
Subject: Physical Sciences, Biophysics Keywords: Botulinum toxin; bladder hypertrophy; spinal cord injury
Online: 19 October 2022 (11:08:17 CEST)
Following spinal cord injury (SCI), pathological reflexes develop that result in altered bladder function and sphincter dis-coordination, with accompanying changes in the detrusor. Bladder chemodenervation is known to ablate the pathological reflexes, but the resultant effects on the bladder tissue are poorly defined. In a rodent model of contusion SCI, we examined the effect of early bladder chemodenervation with botulinum toxin A (BoNT-A) on bladder histopathology and collagen deposition. Adult female Long Evans rats were given a severe contusion SCI at spi-nal level T9. The SCI rats immediately underwent open laparotomy and received detrusor injec-tions of either BoNT-A (10 U/animal) or saline. At 8 weeks post injury, the bladders were col-lected, weighed, and examined histologically. BoNT-A injected bladders of SCI rats (SCI-BoNT-A) weighed significantly less than saline injected bladders of SCI rats (SCI-saline) (241 ± 25 mg vs. 183 ± 42 mg; p<0.05). Histological analyses showed that SCI resulted in significantly thicker bladder walls due to detrusor hypertrophy and fibrosis compared to bladders from uninjured animals (339 ± 89.0 m vs. 193 ± 47.9 m; p<0.0001). SCI-BoNT-A animals had significantly thinner bladder walls compared to SCI-saline animals (202 ± 55.4 m vs. 339 ± 89.0 m; p<0.0001). SCI-BoNT-A animals had collagen organization in the bladder walls similar to that of uninjured animals. Detrusor chemodenervation soon after SCI appears to preserve bladder tissue integrity, by reducing the development of detrusor fibrosis and hypertrophy associated with SCI.
COMMUNICATION | doi:10.20944/preprints202303.0542.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: microglia; cortex; spinal cord; morphology; phagocytosis; in vitro studies
Online: 31 March 2023 (04:09:06 CEST)
Regional heterogeneity of microglia was first described a century ago by Pio del Rio Hortega. Currently, new hints on microglia heterogeneity across central nervous system (CNS) regions are still being unraveled by high-throughput techniques. It remains unclear whether these spatial specificities translate into different microglial behaviors in vitro. We cultured microglia isolated from the cortex and spinal cord and analyzed the effect of the CNS spatial source on in vitro behavior by applying the same experimental protocol and culture conditions. We analyzed microglial cell numbers, function, and morphology and found a distinctive in vitro phenotype. We found that microglia were present in higher numbers in spinal cord-derived glial cultures, presenting different expression of inflammatory genes and a lower phagocytosis rate under basal conditions or after activation with LPS and IFN-. Morphologically, cortical microglial cells are more complex and present longer ramifications, which were also observed in vivo in CX3CR1+/GFP transgenic reporter mice. Collectively, our data demonstrated that microglial behavior in vitro is defined according to specific spatial characteristics acquired in the tissue. Thus, our study highlights the importance of microglia as a source of CNS for in vitro studies.
ARTICLE | doi:10.20944/preprints202311.1564.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: effectiveness; nusinersen; real-world data; risdiplam; spinal muscular atrophy
Online: 26 November 2023 (05:27:25 CET)
(1) Background: Aim was to investigate real-world effectiveness (hypothesizing non-inferiority) and safety profile of risdiplam in paediatric and adult nusinersen-risdiplam spinal muscular atrophy (SMA) switch cohort. (2) Methods: A retrospective and anonymous collection of relevant demographic and clinical data for all Croatian SMA patients switched from nusinersen to risdiplam up to September 2023 (reimbursed by Croatian Health Insurance Fund – CHIF) was performed using CHIF database and associated reimbursement documentation. Patients were included in effectiveness and safety analysis if they met the following inclusion criteria: i) risdiplam reimbursed by CHIF; ii) patient received at least 6 doses of nusinersen before switch to risdiplam; iii) no relevant pause between the latter disease modifying drugs (DMDs); iv) availability of all prespecified studied data and parameters. (3) Results: 17 patients met inclusion criteria [58.9% female; median age 12.75 (3.0-44.5) yr.]. In our ‘switch’ cohort, we have demonstrated a non-inferiority of risdiplam to nusinersen, in SMA 1 (+1.0 in CHOP INTEND; p=0.067), SMA 3p (+0.7 in HFMSE; p=0.897) and SMA 3a (+0.8 in RHS; p=0.463) subpopulations, during a one-year follow-up period. There were no reports on respiratory function worsening, feeding worsening, and no lethal events. No new safety concerns were identified, except of the weight gain that arose as a new potential adverse drug reaction ‘signal’ in two patients. (4) Conclusions: We have reported a pivotal real-world findings on switching SMA patients from nusinersen to risdiplam and demonstrated its effectiveness (non-inferiority), safety and tolerability in a heterogenous paediatric and adult ‘switch’ cohort, which will further increase the quality and standards of care as well as safety of a notable portion of SMA patients; especially for those who demand switch from nusinersen to other DMDs from clinical or personal reasons.
REVIEW | doi:10.20944/preprints202302.0448.v1
Subject: Biology And Life Sciences, Cell And Developmental Biology Keywords: dorsal root ganglia; fatty acids; gliopathy; nerve injury; spinal cord
Online: 27 February 2023 (06:35:32 CET)
Preclinical studies have identified glial cells as pivotal players in the genesis and maintenance of neuropathic pain after nerve injury associated with diabetes, chemotherapy, major surgeries, and virus infections. Satellite glial cells (SGCs) in the dorsal root and trigeminal ganglia of the peripheral nervous system (PNS) and astrocytes in the central nervous system (CNS) express similar molecular markers and are protective under physiological conditions. They also serve similar functions in the genesis and maintenance of neuropathic pain, downregulating some of their homeostatic functions and driving pro-inflammatory neuro-glial interactions in the PNS and CNS, i.e. “gliopathy”. However, the role of SGCs in neuropathic pain is not simply as “peripheral astrocytes”. We delineate how these peripheral and central glia participate in neuropathic pain by producing different mediators, engaging different parts of neurons, and becoming active at different stages following nerve injury. Finally, we highlight the recent findings that SGCs are enriched with proteins related to fatty acid metabolism and signaling such as Apo-E, FABP7, and LPAR1. Targeting SGCs and astrocytes may lead to novel therapeutics for the treatment of neuropathic pain.
ARTICLE | doi:10.20944/preprints201808.0035.v1
Subject: Biology And Life Sciences, Animal Science, Veterinary Science And Zoology Keywords: neural; stem cells; compressed; spinal cord; injury; regeneration; rat
Online: 2 August 2018 (06:26:46 CEST)
Background: In spinal cord injury, radical treatment is still a persistent hope for patients and clinicians. Our study aimed to determine the different histological changes in central, cranial and caudal sites of compressed spinal cord as a result of neuroectodermal stem cells (NESCs) transplantation in rats. Material and methods: For extraction of NESCs, future brains were extracted from mice embryos (10-days old) and cultured. Eighty, male rats were divided randomly into control, sham (20 rats each); while 40 rats were subjected to compressed spinal cord injury (CSCI). Seven days after spinal cord injury, rats were subdivided into 2 groups (20 rats each); an untreated and treated with NESCs injected cranial and caudal to the site of the spinal cord injury. Rats were sacrificed 4 weeks after transplantations of NESCs and specimens from the spinal cord at the central, cranial and caudal to site of spinal cord injury were proceeded to be stained with haematoxylin & eosin, osmic acid and Immunohistochemistry of glial fibrillary acidic protein (GFAP). Results: Sections of CSCI revealed areas of hemorrhages, necrosis and cavitation limited by reactive astrocytosis, with upregulation of GFAP expression. Evidence of remyelination and mitigation of histopathological features, reactive astrocytosis in CSCI sections were more pronounced in cranial than in caudal region. Conclusions: NESCs transplantation ameliorated the pathological changes, promoted remyelination.
REVIEW | doi:10.20944/preprints202307.2090.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: spinal cord injury; cell therapy; neuroprotection; supplements; peptides; inflammation
Online: 31 July 2023 (10:24:19 CEST)
Spinal cord injury is a traumatic injury that causes a catastrophic state in patients due to neuronal deficits, loss of motor and sensory function, and this is due to secondary deleterious events subsequent to mechanical damage that expands the death of neural cells beyond the initial trauma. One of the most important events is inflammation, which activates molecules like pro-inflammatory cytokines (IL-1beta, IFN-gamma, TNF-alpha) that provoke a toxic environment, inhibiting axonal growth and exacerbating CNS damage. As there is no effective treatment, one of the strategies developed is neuroprotection to preserve healthy neural tissue and reduce neuroinflammation. Some of the neuroprotective treatments that have been practiced are the use of cell therapy, the administration of peptides and molecules or supplements that have been shown to favor an anti-inflammatory environment, and help to preserve the cells and tissues surrounding the injured area, favoring axonal growth and improving locomotor function. In this review we will explain some of these strategies used in different animal models of spinal cord injury, their activity as modulators of the immune system and the benefits they have shown.
ARTICLE | doi:10.20944/preprints202310.1604.v1
Subject: Medicine And Pharmacology, Complementary And Alternative Medicine Keywords: spinal stenosis; nerve block; acupuncture therapy; comprehensive health care
Online: 25 October 2023 (08:56:14 CEST)
Background: Two types of medicinal systems are available in Korea: Western and oriental. These exist as separate services that independently provide medical care to patients. We determined the utility and benefits of compressive and integrated medical services (CIMS) comprising 12 sessions of acupuncture and healing programs over 6 weeks. Methods: In this two-group parallel single-center randomized controlled assessor-blinded trial, 24 participants were assigned to either the experimental (conventional medical treatment plus CIMS, n = 12) or control (conventional medical treatment, n = 13) group. Spinal nerve root block was performed on the compressed spinal nerve root (identified using magnetic resonance imaging) when no improvement was observed after the initial treatment. The experimental group received 12 cycles of acupuncture and manual therapy for 6 weeks; the control group received conventional medical treatment alone. Results: The average age of participants in the experimental and control groups was 70.73 ± 5.95 and 67.33 ± 8.89 years, respectively. There were no significant differences between the groups in terms of age, body mass index, Leeds Assessment of Neuropathic Symptoms and Signs, sex, and current medical history. We found high compliance for both programs (acupuncture and healing). On exclusion of between-group effects, the visual analog scale (VAS) score improved significantly over time (p = 0.045). Further, comparison of the groups after excluding the effects of visits revealed significantly lower VAS scores in the experimental group than in the control group (p = 0.000). Conclusions: Patients with degenerative lumbar spinal stenosis who mainly complain of radiating pain in the lower leg may benefit from CIMS after spinal nerve root block for ≤3 months after treatment. Our study findings suggest that this treatment improves spinal function and Oswestry Disability Index score. However, CIMS did not improve QoL.
TECHNICAL NOTE | doi:10.20944/preprints202311.0854.v1
Subject: Medicine And Pharmacology, Surgery Keywords: Tethered cord syndrome; Navigation; Spinal shortening osteotomy
Online: 14 November 2023 (11:36:20 CET)
Study design : Technical note. Objectives: To present a new spinal shortening technique for tethered cord syndrome. Background : Tethered cord syndrome (TCS) is a debilitating condition of progressive neurological decline. Surgical detethering for TCS is a gold standard. However, symptomatic retethering of TCS has been reported in 5%–50% of patients after initial release. To solve this problem, posterior spinal shortening osteotomy has been reported. This technique has risks of massive blood loss and neurological deterioration. The authors hereby report a new safe spinal shortening technique for tethered cord syndrome. Materials and Methods : A 31-year-old man with gait disturbance was referred to our hospital. After the delivery, he underwent surgical untethering of spinal cord in another hospital. He had hyperreflexia of Achilles tendon reflex and muscle weakness of bilateral legs (MMT 3-4). He also had urinary and bowel incontinence, and total sensory loss below L5.Anteroposterior lumbar radiogram indicates partial laminectomy of L3 and L4. Lumbar MRI showed retethering of spinal cord. Results: He underwent new spinal shortening technique for tethered cord syndrome under the guidance of O-arm navigation. First, from anterior approach disectomy from T12 to L3 was performed. Second, from posterior Ponte osteotomy was done from T12 to L3, shorten the spinal column 15 mm. The patient was successfully treated surgically. Postoperative lumbar MRI showed the tension of spinal cord was released. Manual muscle testing results and sensory function of the left leg had recovered almost fully on final follow-up at one year. Conclusions/Level of Evidence: Retethered spinal cord after initial untethering was difficult to treat. This new spinal shortening technique was effective and very safe technique to release the tension of spinal cord. Level V.
REVIEW | doi:10.20944/preprints202305.1822.v1
Subject: Biology And Life Sciences, Neuroscience And Neurology Keywords: Glial scar; Spinal cord injury; cell ablation
Online: 26 May 2023 (03:11:31 CEST)
Spinal cord injury (SCI) is a condition that affects between 8.8 and 246 people in a million and, unlike many other neurological disorders, it affects mostly young people, causing deficits in sensory, motor, and autonomic functions. Promoting regrowth of axons is one of the most important goals for the neurological recovery of patients after SCI, but it is also one of the most challenging goals. A key event after SCI is the formation of a glial scar around the lesion core, which is mainly comprised of astrocytes, NG2+-glia, and microglia. Traditionally, the glial scar has been regarded as detrimental for recovery because it may act as a physical barrier for axon regrowth and release various inhibitory factors. However, more and more evidence now suggest that the glial scar is beneficial for the surrounding spared tissue after SCI. Here, we review experimental studies that used genetic and pharmacological approaches to ablate specific populations of glial cells in rodent models of SCI, in order to understand their functional role. The studies showed that ablation of either astrocytes, NG2+-glia or microglia may result in disorganization of glial scar, increased inflammation, extended tissue degeneration and impaired recovery after SCI. Hence, glial cells and glial scar appear as important beneficial players after SCI.
ARTICLE | doi:10.20944/preprints202309.1564.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: nitric oxide, cooper, brain stroke, spinal cord injury, electron paramagnetic resonance
Online: 22 September 2023 (10:21:10 CEST)
Here we performed a comparative experimental analysis by EPR spectroscopy of the intensity of nitric oxide (NO) production and copper content in the injured and uninjured areas of the frontal lobes and the hippocampus of the brain of male Wistar rats, after modeling of combined brain and spinal cord injury. Brain and spinal cord injury were modelled by local destruction of the left precentral region of the brain using a stylet followed by hemorrhage injury at the level of the first lumbar vertebra of the spinal cord. We found a significant decrease in NO production 7 days after injury modeling in the injured and uninjured (contralateral) brain regions, but the copper content remained unchanged one week after injury modeling. Thus, combined brain and spinal cord injury is not accompanied by a radical change in the activity of the antioxidant system in the brain, which is also confirmed by the absence of changes in NO production and copper content in the hippocampus.
ARTICLE | doi:10.20944/preprints201910.0006.v1
Subject: Biology And Life Sciences, Neuroscience And Neurology Keywords: l-type calcium channels; nociception; spinal cord; central sensitization; windup
Online: 2 October 2019 (02:49:04 CEST)
Windup, a progressive increase in spinal response to repetitive stimulations of nociceptive peripheral fibres, is a useful model to study central sensitization to pain. Windup is expressed by neurons in of both dorsal and ventral horn of the spinal cord. In juvenile rats, it has been demonstrated both in vivo and in vitro that windup depends on calcium-dependent intrinsic properties and their modulation by synaptic components. However, the involvement of these two components in the adult remain controversial. In the present study, by means of electromyographic and extracellular recordings, we show that windup in adult, in vivo, depends on a synaptic balance between excitatory NMDA receptors and inhibitory glycinergic receptors. We also demonstrate the involvement of L-type calcium channels in both the dorsal and ventral horn of the spinal cord. These results indicate that windup in adults is similar to juveniles rats and that windup properties are the same regardless spinal network, i.e. sensory or motor.
ARTICLE | doi:10.20944/preprints202310.1143.v1
Subject: Medicine And Pharmacology, Orthopedics And Sports Medicine Keywords: Computed Tomography; Generative Adversarial Networks; Deep learning; 3D reconstruction; Spinal Imaging; Spinal diagnosis; Spine surgery; Quantitative measurement; Clinical application
Online: 18 October 2023 (12:03:13 CEST)
Computed tomography (CT) offers detailed insights into the internal anatomy of patients, partic-ularly for spinal vertebrae examination. However, CT scans are associated with higher radiation exposure and cost compared to conventional X-ray imaging. In this study, we applied a Genera-tive Adversarial Network (GAN) framework to reconstruct 3D spinal vertebrae structures from synthetic biplanar X-ray images, specifically focusing on anterior and lateral views. The synthetic X-ray images were generated using the DRRGenerator module in 3D Slicer, by incorporating segmentations of spinal vertebrae in CT scans for the region of interest focussing. The approach leverages a novel feature fusion technique based on X2CT-GAN to combine information from both views and employs a combination of Mean Squared Error (MSE) loss and adversarial loss to train the generator, resulting in high-quality synthetic 3D spinal vertebrae CTs. A total of n=440 CT data were processed. We evaluated the performance of our model using multiple metrics, in-cluding Mean Absolute Error (MAE) (for each slice of the 3D volume [MAE0] and for the entire 3D volume [MAE]), Cosine Similarity, Peak Signal-to-Noise Ratio (PSNR), 3D Peak Sig-nal-to-Noise Ratio (PSNR-3D), and Structural Similarity Index (SSIM). The average PSNR was 28.394 dB, PSNR-3D was 27.432, SSIM was 0.468, cosine similarity was 0.484, MAE0 was 0.034, and MAE was 85.359. The results demonstrated the effectiveness of the approach in reconstruct-ing 3D spinal vertebrae structures from biplanar X-rays, although some limitations in accurately capturing the fine bone structures and maintaining the precise morphology of the vertebrae were present. This technique has the potential to enhance the diagnostic capabilities of low-cost X-ray machines while reducing radiation exposure and cost associated with CT scans, paving the way for future applications in spinal imaging and diagnosis.
ARTICLE | doi:10.20944/preprints202205.0038.v1
Subject: Public Health And Healthcare, Other Keywords: COVID-19; spinal cord injury; disability; stroke; well-being; social isolation
Online: 5 May 2022 (12:35:32 CEST)
Coronavirus disease 2019 restrictions impacted Canadians' daily living, especially those at higher risk of compromised health conditions. This study aimed to describe the physical, psychological, and social well-being of adults with disabilities, and older adults from May to June 2020. An online survey was used to administer standardized measures of mobility, anxiety and depression, boredom, resilience, technology readiness, social support, social networks, and participation. Seventy-two participants were recruited, with a mean age (SD) of 61.2 (13.8). 69.4% of participants had a disability, and 51.4% were older adults. 27.8% and 16.7% of participants exceeded the anxiety and depression cut-off scores, respectively. Boredom and restriction in participation were experienced by 76.4% and 80.1% of participants, respectively. Participants' mean (SD) resilience and life space scores were 72.4 (14.0) and 51.9 (24.0), respectively. Individuals with disabilities have comparatively higher mean anxiety (5.5 to 3.3), depression (4.8 to 2.9), and boredom (92.2 to 72.3) scores than those without. Individuals with a disability had lower resilience (69.9 to 78.0) and felt more life space restrictions (45.4 to 67.6). Our findings revealed issues with anxiety, boredom, participation, and life space activity. This information may provide supporting evidence when creating policies to mitigate existent health and social inequities.
ARTICLE | doi:10.20944/preprints202309.0167.v1
Subject: Medicine And Pharmacology, Clinical Medicine Keywords: spinal cord injury; robotic rehabilitation; coordinative rehabilitation; depression; mood; anxiety
Online: 5 September 2023 (04:18:22 CEST)
Background: Mood disorders, especially depression, and emotional difficulties such as anxiety are very common problems among patients with spinal cord injury (SCI). The loss of physical training may deteriorate their mental state, which in turn has a significant impact on the improvement of functioning. The aim of the present study was to examine the influence of innovative rehabilitation approaches involving robotic assisted gait therapy (RAGT) on mood and anxiety symptoms in pa-tients with SCI. Methods: To this single-centre, single-blinded, single-arm, prospective study, 110 participants with subacute SCI were enrolled; patients were divided into experimental (robotic assisted gait therapy -RAGT) and control (conventional gait therapy with dynamic parapodium - DPT) groups. They received five training sessions per week over 7- weeks. The severity of de-pression was assessed by Depression Assessment Questionnaire (KPD) and anxiety symptoms by State - Trait Anxiety Inventory (STAI X-1) on the beginning and end of therapy. Results: SCI patients experienced significantly lower levels of anxiety and depression-related symptoms after completing the seven-week rehabilitation program (KPD: Z=6.35; p<0.001; r=0.43; STAI X-1: Z=-6.20; p<0.001; r=0.42) in both group of patients. In the RAGT group, post-rehabilitation measurements also indicated an improvement in psychological functioning, i.e., a decrease in depression and anxiety, and an increase in self-regulation. Significant results were noted for each variable (STAI X-1: Z = -4.93; KPD: Z = -5.26; SR: Z = -3.21). In the control group, there was also a decrease in the effect on the depression, anxiety-state and an increase in self-regulation ability (STAI X-1: Z=-4.01; KPD: Z=-3.65; SR: Z=-2.83). Rehabilitation modality did not appear to have a statistically significant relationship with the magnitude of improvement in KPD (including SR) and STAI scores. However, there were some significant differences when comparing the groups by extent and depth of injury and type of paralysis. The study also did not find a significant rela-tionship between improvements in physical aspects and changes in psychological factors. Conclusion: Subjects in RAGD and DPT groups experienced a decrease in anxiety and depres-sion after a 7-week rehabilitation program. However, the rehabilitation modality (DPT vs. RAGT) did not differentiate patients with SCI in terms of the magnitude of this change. Our results may suggest that individuals with severe neurological condition and complete spinal cord injury (AIS A) may experience more benefit in terms of change in psychological parameters after rehabilitation with RAGT.
ARTICLE | doi:10.20944/preprints202311.1200.v1
Subject: Medicine And Pharmacology, Orthopedics And Sports Medicine Keywords: spinal fusion; mechanical failure; risk factor; spine arthrodesis
Online: 22 November 2023 (15:17:49 CET)
PURPOSE: The aim of this study was to identify the incidence of early mechanical failure in the first post-surgical year in patients who had undergone spinal surgery, and to assess the related risk factors. METHODS: Retrospective observational study of a prognostic cohort was conducted at an orthopaedic hospital, examining all patients with spine degenerative disease who consecutively underwent arthrodesis surgery between March 2018 and March 2019. The incidence of postoperative mechanical failure during the first year was calculated as primary outcome; the time between the date of the implant surgery and diagnosis of the mechanical failure was calculated as secondary outcome. RESULTS: A total of 237 patients were identified for statistical analysis. The median age of the group of patients was 47 years (IQR of 44), and 66.6% were female. The incidence of mechanical failure in the first postoperative year was 5.1% overall with 12 events and the median time between surgery and the need for revision surgery was 5 months (IQR=7.75). ASA score (OR= 2,39; p=0.134), duration of the surgical procedure (OR=1,27; p=0,006) and inability to walk at discharge (OR=7,86; p=0,072) were independent risk of factor associated with the mechanical failure. CONCLUSION: Higher ASA score and longer duration of surgery are risk factors for mechanical failure in the first year in patients who had undergone spinal surgery and must be carefully considered when planning spinal surgery. During hospitalization, recovery of ambulation must be encouraged to prevent mechanical failure. All these factors are useful in identifying patients with a closer follow-up is needed.
ARTICLE | doi:10.20944/preprints202308.1956.v1
Subject: Biology And Life Sciences, Neuroscience And Neurology Keywords: Muse cell; intravenous administration; rat; spinal cord injury
Online: 30 August 2023 (04:06:09 CEST)
Background Multilineage-differentiating stress-enduring (Muse) cells are newly established pluripotent stem cells. The aim of the present study was to examine the potential of the systemic administration of Muse cells as an effective treatment for subacute SCI. Methods: We intravenously administered the clinical product “CL2020” containing Muse cells to a rat model two weeks after mid-thoracic spinal cord contusion. Eight experimental animals received CL2020 and 12 received the vehicle. Behavioral analyses were conducted over 20 weeks. Histological evaluations were performed. After 20 weeks of observation, diphtheria toxin was administered to 3 CL2020-treated animals to selectively ablate human cell functions. Results: Hindlimb motor functions significantly improved from 6 to 20 weeks after the administration of CL2020. The cystic cavity was smaller in the CL2020 group. Furthermore, larger numbers of descending 5-HT fibers were preserved in the distal spinal cord. Muse cells in CL2020 were considered to have differentiated into neuronal and neural cells in the injured spinal cord. Neuronal and neural cells were identified in the gray and white matter, respectively. Importantly, these effects were reversed by the selective ablation of human cells by diphtheria toxin. Conclusions: Intravenously administered Muse cells facilitated the therapeutic potential of CL2020 for severe subacute spinal cord injury.
BRIEF REPORT | doi:10.20944/preprints202306.1409.v1
Subject: Medicine And Pharmacology, Pulmonary And Respiratory Medicine Keywords: Neuromodulation; Spinal cord stimulation; Respiration; Rehabilitation; COVID-19
Online: 20 June 2023 (08:30:47 CEST)
Background: A growing number of studies have reported Coronavirus disease (COVID-19)-related to both respiratory and central nervous system dysfunctions. This study evaluates the neuromodulatory effects of spinal cord transcutaneous stimulation (scTS) on the respiratory functional state in healthy controls and patients with post-COVID-19 respiratory deficits as a step toward the development of a rehabilitation strategy for these patients.; Methods: In this before-after, interventional, case-controlled clinical study, ten individuals with post-acute COVID-19 respiratory deficits and eight healthy controls received a single twenty-minute-long session of modulated monophasic scTS delivered over the T5 and T10 spinal cord segments. Forced Vital Capacity (FVC), Peak Forced Inspiratory Flow (PIF), Peak Expiratory Flow (PEF), Time-To-Peak of Inspiratory Flow (tPIF), and Time-To-Peak of Expiratory Flow (tPEF) were assessed before and after the intervention; Results: In COVID-19 group, the scTS intervention led to significantly increased PIF (p= .040) and PEF (p= .049) in association with significantly decreased tPIF (p= .035) and tPEF (p= .013). In the Control Group, the exposure to scTS also resulted in significantly increased PIF (p= .010) and significantly decreased tPIF (p= .031). Unlike the results in COVID-19 group, there was significantly decreased PEF (p= .028) in association with significantly increased tPEF (p= .036). There were no changes for FVC after scTS in both groups (p= .67 and p= .503); Conclusions: In post-COVID-19 patients scTS facilitates excitation of both inspiratory and expiratory spinal neural networks leading to an immediate improvement of respiratory functional performance. This neuromodulation approach could be utilized in rehabilitation programs for patients with COVID-19 respiratory deficits.
ARTICLE | doi:10.20944/preprints201712.0138.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: multiple sclerosis; spinal cord; transforming growth factor beta 1; active plaques
Online: 20 December 2017 (07:04:10 CET)
We recently reported that in the spinal cord of PPMS or SPMS patients, large areas of periplaque demyelinating lesions extend distance away from plaque borders. Such lesions are characterized by a progliotic TGF-beta 1 signature accompanied by: i) a low-grade inflammatory reaction, ii) an extensive astrocytosis and iii) a process of incomplete demyelination. It was proposed that, while efficiently dampening inflammation in MS spinal cords, TGF-beta 1 could promote astrocytosis, prevent remyelination and possibly trigger alterations of myelin synthesis. In light of these findings, a re-interpretation of two large neuropathological studies performed on MS brains and spinal cords is provided here. While results from these studies clearly showed that active plaques do not display any region-specific distribution, an important point was apparently overlooked and not discussed by the authors: a significantly higher percentage of inactive plaques was found in MS spinal cords as compared to brains and, conversely, the percentage of slowly-expanding (or smoldering) lesions was significantly lower in the spinal cord as compared to the brain. These data indicate that the spinal cord environment may be more favorable to the resolution of inflammation. Downstream of the autoimmune process leading to plaque formation, region-specific mechanisms may thus drive the outcome of active plaques. While inflammation triggers tissue destruction, inflammation may also be needed for effective tissue repair and an inappropriate dampening of inflammatory events may possibly translate into a poor level of remyelination in MS spinal cords. It is proposed here that TGF-beta 1 is involved in such a brain-spinal cord dissociation of active plaques outcome.
ARTICLE | doi:10.20944/preprints202308.0723.v1
Subject: Biology And Life Sciences, Neuroscience And Neurology Keywords: spinal cord injury; polysialic acid; Schwann cell; transplantation; corticospinal axon; axonal regeneration
Online: 9 August 2023 (08:11:09 CEST)
Providing cellular support and modifying the glial scar around the lesion are two key strategies for promoting axonal regeneration after spinal cord injury. We showed before that over-expressing polysialic acid (PSA) on Schwann cells (SCs) by lentiviral vector (LV)-mediated expression of polysialyltransferase (PST) facilitated their integration and migration in the injured spinal cord. We also showed that PSA over-expression in the injured spinal cord modified the glial scar and promoted the growth of ascending sensory axons. In this study, we combined the PST/SC transplantation with LV/PST injection in spinal cords after dorsal column transection and found the combined treatments led to faster and more profound locomotor functional recovery compared with animals receiving combined GFP/SC transplantation with LV/GFP injection. Histological examination showed significantly more injured corticospinal axons growing close to the lesion/transplant borders and into the caudal spinal cord in the PST group than in the GFP group. We also found over-expressing PSA around the lesion site did not cause allodynia and hyperalgesia in our injury model. These results demonstrate the promising therapeutic benefit of over-expressing PSA in transplanted SCs and spinal cord in promoting axonal growth and restoring motor function.
TECHNICAL NOTE | doi:10.20944/preprints202306.0210.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: Percutaneous spinal biopsy; Imaging-guided biopsy; O-arm CT navigation; Spinal tumors; Diagnostic accuracy; Biopsy efficiency; O-arm CT-MRI fusion
Online: 2 June 2023 (14:11:00 CEST)
Classifying spinal tumors can be challenging due to nonspecific clinical and radiological qualities, and a precise biopsy is crucial for an accurate diagnosis and treatment planning. This study aimed to enhance the accuracy and efficiency of spinal biopsies integrating Cone Beam Computed Tomography (CBCT) and magnetic resonance imaging (MRI) modalities using an O-arm CT navigation system. Eighteen patients with diverse spinal lesions underwent 18 biopsies following the Stealth Station navigation system Spine 8 protocol. Preoperative MRI scans were merged with intraoperative CT navigation systems for continuous monitoring during the biopsy process. The combined imaging technique accurately identified the diseased lesion type in all biopsies, demonstrating 100% sensitivity and specificity. In conclusion, combining MRI and CT imaging modalities significantly improved spinal biopsy accuracy and efficiency, differentiating between pathological entities. However, large-scale studies are desired to validate these findings and investigate potential benefits in different clinical scenarios. Although this method requires general anesthesia, its potential profits in avoiding misdiagnosed lesions and decreasing the need for further invasive procedures make it a promising approach for improving spinal biopsy accuracy and efficiency.
ARTICLE | doi:10.20944/preprints202307.0365.v1
Subject: Medicine And Pharmacology, Surgery Keywords: Intramedullary spinal cord tumours (IMSCT), upper cervical spine, neurological deterioration, respiratory insufficiency
Online: 6 July 2023 (07:45:05 CEST)
Background and Objectives: Intramedullary spinal cord tumors (IMSCT) are rare entities. Especially, a location in the upper cervical spine as a highly eloquent region carries the risk of postoperative neurological deficits, such as tetraparesis or respiratory dysfunction. Evidence for respiratory dysfunction is scarce. The aim of this study was to describe the early and late postoperative clinical course of this highly eloquent tumours. Patients and Methods: This is a single-centre retrospective cohort study. We included 35 patients with IMSCT at levels of craniocervical junction to C4 who underwent surgical treatment between January 2008 and December 2022. The authors analysed the patients' preoperative status, tumour- and surgery-specific characteristics, and follow-up functional status. Results: The study cohort included 22 patients with grade II ependymoma (62.9%), 2 low-grade astrocytomas (5.7%), 2 glioblastomas (5.7%), 6 hemangioblastomas (17.1%), 2 metastases (5.7%), and 1 patient with partially intramedullary schwannoma (2.9%). Gross total resection was achieved in 76% of patients. Early dorsal column related symptoms and motor deterioration occurred in 64% and 44% of patients, respectively. At a follow-up of 3.27 ± 3.83 years, 43% and 33% of patients preserved postoperative sensory and motor deterioration, respectively. The median McCormick Scale grade was 2 in the preoperative and late postoperative periods, respectively (p=0.0897, α=0.05). Only two out of 35 patients (5.7%) developed new intermittent respiratory dysfunction, of whom two were transient. There were no surgery-related deaths. Conclusions: The surgery of IMSCT of the upper cervical spine could be performed without major procedure-related risk. Roughly a half of the patients develop new neurological deficit in the immediate postoperative period. However, most of the patients still maintain functional independence. The rate of respiratory insufficiency is low and is strongly influenced by the rapid neurological deterioration in high-grade tumours.
ARTICLE | doi:10.20944/preprints202307.1542.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: Metastatic spinal cord compression; Lung cancer; Survivor; Prognostic factors
Online: 24 July 2023 (09:32:54 CEST)
Purpose: Metastatic spinal cord compression (MSCC) is a severe complication of cancer that can lead to irreversible neurological impairment, necessitating prompt recognition and intervention. This retrospective, single-center study aimed to determine the prognostic factors and survival rates among patients presenting with MSCC secondary to lung cancer. Methods and Materials: We identified 74 patients with epidural metastases-related spinal cord compression and a history of lung cancer, through the electronic database of Medway Maritime Hospital in United Kingdom (UK), spanning the period from April 2016 to September 2021. Among them, 39 were below 55 years old, while 35 were aged 55 years or older, whereas 24 patients were diagnosed with small cell lung cancer (SCLC), and 50 patients had non-small cell lung cancer (NSCLC). Results: The median overall survival (OS) was 5.5 months, with 52 out of 74 patients dying within 6 months of the diagnosis of MSCC. For the entire cohort, the statistically significant variables on multi-variate analysis were: cancer type (NSCLC had improved OS), number of involved vertebrae (one to two vertebrae involvement had improved OS) and time taken to develop motor deficits (≤10 days to develop motor deficits had worsened OS). For the NSCLC cohort, the statistically significant variables on multivariate analysis were: molecular alterations (patients with epidermal growth factor receptor (EGFR) mutation), pre-treatment ambulatory status, Eastern Cooperative Oncology Group (ECOG) performance status, and time taken to develop motor deficits. Conclusions: Within the entire cohort, patients diagnosed with NSCLC and spinal metastases affecting one to two vertebrae exhibited enhanced OS. Within the NSCLC subgroup, those with EGFR mutations, who were ambulatory, and possessed an ECOG performance status of 1-2, demonstrated improved OS. In both the entire cohort and NSCLC subgroup, the development of motor deficits within a period of ≤10 days was associated with poorer OS.
ARTICLE | doi:10.20944/preprints202305.0654.v1
Subject: Medicine And Pharmacology, Orthopedics And Sports Medicine Keywords: neuromuscular diseases; scoliosis; posterior spinal fusion surgery; Cobb angle
Online: 9 May 2023 (12:35:41 CEST)
Patients with neuromuscular diseases usually have progressive neuromuscular scoliosis (NMS), requiring invasive surgery. Some patients present with severe scoliosis at the time of consultation and are difficult to treat. Posterior spinal fusion (PSF) surgery combined with anterior release and pre or intraoperative traction would be effective for severe spinal deformity, but invasive. This study aimed to evaluate the outcomes of PSF only surgery for patients with severe NMS with Cobb angle >100 °. Thirty NMS patients (13 boys and 17 girls; mean age 13.8 years) who underwent PSF only surgery for scoliosis with Cobb angle >100 ° were included. We reviewed the lower instrumented vertebra (LIV), duration of surgery, blood loss, perioperative complications, preoperative clinical findings, and radiographic findings including Cobb angle and pelvic obliquity (PO) in the sitting position pre and postoperatively. The correction rate and correction loss of the Cobb angle and PO were also calculated. The mean duration of surgery was 338 min, intraoperative blood loss was 1,440 mL, preoperative %VC was 34.1%, FEV1.0 (%) was 91.5%, and EF was 66.1%. There were eight cases of perioperative complications. The Cobb angle and PO correction rates were 48.5% and 42.0%, respectively. We divided the patients into two groups: the L5 group, in which the LIV was L5, and the pelvis group, in which the LIV was the pelvis. The duration of surgery and PO correction rate in the pelvis group was significantly higher than that of the L5 group. Patients with severe NMS demonstrated severe preoperative restrictive ventilatory impairments. PSF only surgery for severe NMS showed satisfactory outcomes, although highly invasive. Instrumentation and fusion to the pelvis for severe scoliosis in patients with NMS showed good PO correction and low correction loss of Cobb angle and PO, but a longer duration of surgery.
REVIEW | doi:10.20944/preprints202103.0261.v1
Subject: Social Sciences, Psychology Keywords: Evolution of sleep, NREM sleep, REM sleep, Rhombencephalic-spinal wake, Diencephalic wake, Cortical wake
Online: 9 March 2021 (11:12:11 CET)
Three types of wakefulness appeared along the vertebrate’s phylogeny and ontogeny: spinal-rhombencephalic in fish, brainstem-diencephalic in reptiles and cortical in mammals, in which the paralyzed spinal-rhombencephalic wake and the brainstem-diencephalic wake remain as REMS and NREMS The spinal-rhombencephalic and cortical types of wake are inherently anti-homeostatic. Animals must forage, reproduce, and survive to predation disregarding the environmental circumstances, hence temporarily forgetting the homeostatic regulation. After fulfilling the vital functions, the brainstem-diencephalic wake recovers the homeostatic control. The phasic signs of REMS are adaptive in immature mammals, serving for demanding heat, milk and defense to their mother. These advantages outweigh the REMS' poikilostasis in infants. The adults’ poikilostasis of REMS is harmless in thermoneutral environments but is mal-adaptive in aquatic environments in which REMS is reduced or even disappears. These exceptions explain the anomalous examples of REMS. An on-off hypothalamic switch homeostatically regulates the entrance and exit from REMS. Furthermore, the vital phasic signs of REMS depend on a second pontine proportional homeostatic control. Altogether, they regulate the expression of REMS.
ARTICLE | doi:10.20944/preprints202203.0409.v1
Subject: Engineering, Bioengineering Keywords: cervical alignment; cervical laminoplasty; spinal cord; finite element analysis; cervical spine biomechanics
Online: 31 March 2022 (13:58:12 CEST)
Background: Cervical laminoplasty is a useful for treatment of cervical myelopathy. However, this procedure has limitations for kyphotic cervical alignments. We used the finite element (FE) analysis and investigated the biomechanical changes in an intact and laminoplasty models with lordosis, straight, and kyphosis cervical alignments. Methods: A three-dimensional FE model of the cervical spine (C2-C7) with ligaments was created from computed tomography. The model was modified with the following cobb angles and the C3-C6 laminoplasty was conducted; a) laminoplasty-lordotic model (LM-L; C2-C7 angle: -10°), b) laminoplasty-straight model (LM-S; C2-C7 angle: 0°), and c) laminoplasty-kyphotic model (LM-K; C2-C7 angle: 10°). A pure moment with a compressive follower load of 100N to represent the weight of the head/cranium and cervical muscle stabilization was applied to these models. The range of motion (ROM), annular stress, nucleus stress and facet forces were analyzed. Results: ROM of LM-K increased when compared to the other models except for flexion. The LM-K had the highest mobility with 49% increase in ROM observed under extension, compared to the intact model. In all motion except for flexion, LM-L models’ ROM decreased by more than 10%, and LM-S and LM-K models’ ROM increased by more than 10% at C2-C7 compared to the intact model. The annular stresses and nucleus stresses in LM-K were higher compared to the other models. The maximum increase in annular stresses was about 194% in LM-K compared to the intact model, observed at the C3-C4 segment. The facet contact forces were lowest in the LM-K, compared to the other models.Conclusions: Patients with a cervical kyphosis alignment are at a disadvantage of increased kyphosis compared to cases with lordosis or straight alignment and should be treated with caution.
ARTICLE | doi:10.20944/preprints202306.0550.v1
Subject: Medicine And Pharmacology, Orthopedics And Sports Medicine Keywords: Global sagittal balance; Transforaminal epidural steroids injections; Lumbar spinal stenosis
Online: 7 June 2023 (12:10:35 CEST)
Patients' functional adaptation to pain can affect global sagittal alignment. This study evaluated the short-term spinal sagittal alignment change after Transforaminal Epidural Steroid Injection (TFESI) in lumbar spinal stenosis patients. Patients with lumbar spinal stenosis who underwent TFESI were retrospectively examined. Clinical outcomes were Visual Analog Scale (VAS) and Oswestry Disability Index (ODI). Before and two weeks after the intervention, whole spine lateral standing view radiographs were taken. Radiographic parameters, e.g., Sagittal Vertical Axis (SVA), C2C7 Cobb, Thoracic Kyphosis (TK), Lumbar Lordosis (LL), Pelvic Incidence (PI), Pelvic Tilt (PT), Sacral Slope (SS), and Lumbopelvic Mismatch (PI-LL), were measured. Ninety-nine patients (mean age 64.3 ± 9.2 years) were included in this study. Both VAS and ODI outcomes were statistically improved after two weeks of intervention. Radiographic parameters showed that SVA, PT, and PI-LL mismatch were significantly decreased, while C2C7 Cobb, TK, SS, and LL were significantly increased after the intervention. SVA was improved by 29.81% (52.76 ± 52.22 mm to 37.03 ± 41.07 mm, P < 0.001). PT was also decreased significantly from 28.71° ± 10.22° to 23.84° ± 9.96° (P < 0.001). Transforaminal Epidural Steroid Injection (TFESI) significantly improves VAS, ODI, and global sagittal parameters in lumbar spinal stenosis patients.
ARTICLE | doi:10.20944/preprints202106.0488.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: neurodegeneration; serum; spinal cord; dog; Degenerative myelopathy; amyotrophic lateral sclerosis
Online: 18 June 2021 (15:26:13 CEST)
Blood-based biomarkers are much-needed diagnostic and prognostic tools for ALS. Canine degenerative myelopathy (DM) is recognized animal disease model to study the biology of human ALS. Serum derived exosomes are potential carrier that transport intercellular hormone-like messengers, together with their stability as carrier of proteins and RNA, make them ideal as biomarkers for a variety of diseases and biological processes. We study exosomal TDP-43 pattern as a surrogate biomarker that reflects biochemical changes in central nervous system. We isolated exosomes from canine serum using commercial exosome isolation reagents. TDP-43 and SOD1 profile in spinal cord homogenate lysate and that of serum-derived exosomes were found elevated in dogs with DM. We conclude levels of spinal cord TDP-43 and serum-derived exomes were similar in TDP-43 profiling, which warrant further investigation of disease sensitivity and specificity for establishing as a blood-based biomarker in canine DM.
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: peripheral blood mononuclear cells; spinal cord injury; pigs; fibrin matrix
Online: 18 November 2020 (13:00:26 CET)
Peripheral blood is an available source of adult stem cells for both fundamental research and clinical use. Peripheral blood mononuclear cells (PBMCs) contain a number of different multipotent populations of progenitor cells and possess a potential to differentiate into various types of cells under appropriate conditions. We have evaluated a regenerative potential of PBMCs embedded into fibrin matrix (FM) in a model of pig spinal cord injury. The distribution of transplanted PBMCs in the injured spinal cord was previously evaluated, which demonstrated the ability of these cells to penetrate into deep layers of the spinal cord and to concentrate mainly in the grey matter. The pilot study conducted demonstrated that the tissue structure could be improved and the conduction along posterior columns of the spinal cord could be partially recovered in animals in the setting of FM+РВМCs application. The multiplex analysis of blood serum and cerebrospinal fluid (CSF) showed the cytokine imbalance to occur without significantly shifting towards pro-inflammatory or anti-inflammatory cytokine cascades in the setting therapy provided.
ARTICLE | doi:10.20944/preprints202210.0250.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: anatomy; neuroanatomy; conus medullaris; Multicolumn Spinal Cord Stimulation (SCS); soma-totopy; dorsal columns; Computerized Electrical Modeling; Neuro-Fiber-Mapping; super-selective spinal cord stimulation
Online: 18 October 2022 (05:29:38 CEST)
Spinal Cord (SC) Anatomy is often assimilated to a morphologically encapsulated neural entity, but its functional anatomy remains only partially understood. We hypothesized that it could be possible to reexplore SC neural networks by performing live electrostimulation mapping, based on “super-selective” Spinal Cord Stimulation (SCS), originally designed as a therapeutical tool to address chronic refractory pain. As a starting point, we initiated a systematic SCS lead programming approach using live electrostimulation mapping on a chronic refractory perineal pain patient, previously implanted with multicolumn SCS at the level of the conus medullaris (T12-L1). It appeared possible to (re)explore the classical anatomy of the conus medullaris using statistical correlations of paresthesia coverage mappings, resulting from 165 different electrical configurations tested. We highlighted that sacral dermatomes were not only located more medially but also deeper than lumbar dermatomes at the level of the conus medullaris, in contrast with classical anatomical descriptions of SC somatotopical organization. As we were finally able to find a morpho-functional description of ‘Philippe-Gombault’s triangle’, in 19th century historical textbooks of neuroanatomy, matching remarkably with these conclusions, the concept of “Neuro-Fiber-Mapping” was introduced.
ARTICLE | doi:10.20944/preprints202009.0188.v1
Subject: Biology And Life Sciences, Anatomy And Physiology Keywords: Pain; spinal cord; dopamine receptors; clock gene; dopaminergic A11 nuclei; paw withdrawal threshold
Online: 8 September 2020 (11:26:08 CEST)
Patients with degenerative diseases refer to feeling more pain during the night. However, it is unknown whether spinal nociception can be circadian and how is it controlled. We investigated whether the paw withdrawal threshold (PWT) could exhibit physiological circadian behavior as well as the contribution of the dopaminergic A11 nucleus and the spinal dopamine (DA) receptors (DRs) on the circadian PWT and the spinal clock gene transcription. Results revealed that control rats present a circadian PWT. Injecting 6-hydroxidopamine (6-OHDA) into the dopaminergic A11 nucleus reduced DA tissue content in the lumbar spinal cord, abolished the circadian PWT, induced allodynia, and reduced Period 1 and 2 (Per1 and 2), retinoid-related orphan receptor α (Rorα), Cryptochrome 1 (Cry1), and brain and muscle aryl-hydrocarbon receptor nuclear translocator-like protein (Bmal) mRNA. Likewise, administration of D1-like and D2-like DR antagonists blunted circadian PWT, producing allodynia, and altered the clock genes mRNA. In contrast, administration of D1-like or D2-like DR agonists blocked 6-OHDA-induced allodynia. This study shows that the spinal cord has physiological circadian PWT, which is modulated by the descending dopaminergic A11 through differential activation of the spinal DRs. Also, A11 nuclei and spinal DRs can regulate the clock gene transcription, which can likely modulate the circadian PWT.
ARTICLE | doi:10.20944/preprints202212.0023.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: spinal cord injury; X-linked inhibitor of apoptosis protein; neuroprotection; apoptosis; transgenic mice
Online: 1 December 2022 (09:59:17 CET)
Trauma to the spinal cord causes extensive neuronal death contributing to the loss of sensory-motor and autonomic functions below the injury level. Apoptosis affects neurons after spinal cord injury (SCI) and is associated with increased caspase activity. Cleavage of X-linked inhibitor of apoptosis protein (XIAP) after SCI may contribute to this rise of caspase activity. Accordingly, we have shown that the elevation of XIAP resulted in increased neuronal survival after SCI and improved functional recovery. Therefore, we hypothesize that neuronal overexpression of XIAP can be neuroprotective after SCI with improved functional recovery. In line with this, studies of a transgenic mouse with overexpression of XIAP in neurons revealed that higher levels of XIAP after spinal cord trauma favours neuronal survival, tissue preservation, and motor recovery after the spinal cord trauma. Using the human SH-SY5Y cells overexpressing XIAP we show further that XIAP reduced caspase activity and apoptotic cell death after pro-apoptotic stimuli. In conclusion, this study shows that the levels of XIAP expression are an important factor for the outcome after spinal cord trauma and identifies XIAP as an important therapeutic target for alleviating the deleterious effects of SCI.
Subject: Medicine And Pharmacology, Pediatrics, Perinatology And Child Health Keywords: body posture defects; the shape of anterior-posterior spinal curvatures; body composition; school-children
Online: 11 April 2020 (05:38:01 CEST)
The aim of the study was to assess the relationship between the shape of the anterior-posterior curvature of the spine and body composition in school-children. The study included 257 children, aged 11-12. Correct spinal curvature was established in 106 (41.08%) subjects. Other types included: decreased kyphosis and correct lordosis - 40 participants (15.50%), correct kyphosis and decreased lordosis - 24 individuals (9.30%), increased kyphosis and correct lordosis - 17 subjects (6.59%), correct kyphosis and increased lordosis - 22 children (8.53%), decreased kyphosis and decreased lordosis - 32 people (12.40%), decreased kyphosis and increased lordosis - 4 of the examined subjects (1.55%), increased kyphosis and lordosis - 13 people (5.04%). In addition, 134 (51.94%) demonstrated scoliotic posture and 8 (3.10%) scoliosis. There were significant relationships between the shape of the anterior-posterior curvatures and body composition in school-children. Those with a strong body build (predominance of mesomorphs) were generally characterised by the correct formation of these curvatures. In contrast, lean people (with the predominance of ectomorphic factors) were more likely to experience abnormalities. No correlations with body composition were observed in the group with scoliotic posture or scoliosis.
ARTICLE | doi:10.20944/preprints202109.0031.v1
Subject: Medicine And Pharmacology, Clinical Medicine Keywords: spinal cord stimulation (SCS); peripheral nerve field stimulation (PNfS); SubQ-stimulation; hybrid stimulation; multidimensional pain assessment; pain mapping; pain software; persistent spinal pain syndrome - T2 (PSPS-T2); failed back surgery syndrome; failed spinal cord stimulation syndrome (FSCSS); salvage therapy; salvage algorithm
Online: 1 September 2021 (18:16:10 CEST)
While Spinal Cord Stimulation (SCS) provides satisfaction to almost 2/3 of Persistent Spinal Pain Syndrome-Type 2 (PSPS-T2) patients implanted for refractory chronic back and/or leg pain when not adequately addressed the back pain component, leaves patients in a therapeutic cul-de-sac. Peripheral Nerve field Stimulation (PNfS) has shown interesting results addressing back pain in the same population. Far from placing these two techniques in opposition, we suggest that these approaches could be combined to better treat PSPS-T2 patients. We designed a RCT (CUMPNS), with a 12-month follow-up, to assess the potential added value of PNfS, as a salvage therapy, in PSPS-T2 patients experiencing a “Failed SCS Syndrome” in the back pain component. Fourteen patients were included in this study and randomized into 2 groups (“SCS + PNfS” group/n=6 vs “SCS only” group/n=8). The primary objective of the study was to compare the percentage of back pain surface decrease after 3 months, using a computerized interface to obtain quantitative pain mappings, combined with multi-dimensional SCS outcomes. Back pain surface decreased significantly greater for the ”SCS+PNfS” group (80.2% ± 21.3%) compared to the “SCS only” group (13.2% ± 94.8%) (p=0.012), highlighting the clinical interest of SCS+PNfS, in cases where SCS fails to address back pain.
ARTICLE | doi:10.20944/preprints202212.0020.v2
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: spinal cord injury; apoptotic cell death; XIAP; neuroprotection; miRNA-based therapies
Online: 11 January 2023 (11:39:24 CET)
Altered expression of microRNAs (miRNAs) after spinal cord injury (SCI) has been described as being responsible for the main secondary responses, such as apoptosis. X-linked inhibitor apoptosis protein (XIAP) is a key apoptotic component involved in the progression of apoptotic programmed cell death. Several regulators have been described to modulate the XIAP's function, including the post-transcriptional regulator's miRNAs. The main aim of the present work is to identify miRNAs with altered expression after SCI which can regulate XIAP expression. Our bioinformatic analyses identified several candidate miRNAs that may regulate XIAP, among which miR-199a-5p may be involved in the downregulation of XIAP after SCI. Gene reporter assays and in vitro analyses in the neural C6 cell line confirmed the targeting of miR-199a-5p on the 3-UTR of the rat XIAP and its post-transcriptional regulation of XIAP protein level, but not at mRNA level. Analyses in a rat model of SCI revealed a trend towards increased expression of miR-199a-5p and a decrease in XIAP protein level at 3 days after injury. Finally, using a specific fluorescent in situ hybridization (FISH) probe for miR-199a-5p, we characterized the expression pattern of miR-199a-5p in cells of uninjured and rat-contused spinal cords. These findings provide new insights into apoptotic miRNA-mediated mechanisms after SCI, which will help us develop therapeutic strategies based on miRNAs for treating SCI.
ARTICLE | doi:10.20944/preprints202210.0087.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Echinoderm; Heat shock proteins; Ubiquitin; Regeneration; RNA-seq; Spinal cord injury
Online: 8 October 2022 (03:02:32 CEST)
Injury to the central nervous system (CNS), in most vertebrate animals, results in permanent damage and lack of function, due to their limited regenerative capacities. In contrast, echinoderms can fully regenerate their radial nerve cord (RNC) following transection, with little or no scarring. Investigators have associated the regenerative capacity of some organisms with the stress response and inflammation produced by the injury. Here we explore the gene activation profile of the stressed holothurian CNS. To do this, we performed RNA sequencing on isolated RNC explants submitted to the stress of transection and enzyme dissection and compared them to explants kept in culture for 3 days following dissection. We describe stress-associated genes, including members of heat-shock families, ubiquitin-related pathways, transposons, and apoptosis that were differentially expressed. Surprisingly, the stress response does not induce apoptosis in this system. Other genes associated with stress in other animal models, such as hero proteins and those associated with the integrated stress response, were not found to be differentially expressed either. Our results provide a new viewpoint on the stress response in the nervous system of an organism with an amazing regenerative capacity. This is the first step to deciphering the molecular processes that allow echinoderms to undergo fully functional CNS regeneration while also providing a comparative view for students of the stress response in other organisms.
ARTICLE | doi:10.20944/preprints202201.0363.v1
Subject: Engineering, Mechanical Engineering Keywords: multibody simulation; multi-way sensitivity analysis; spinal implant anchor screw; stiffness and damping parameters
Online: 24 January 2022 (14:56:06 CET)
Finite element (FE) modeling is commonly used as a method to investigate the influence of medical devices, such as implants and screws and their effects on the biomechanical behavior of the spine. Another simulation method is a multi-body simulation (MBS), where the model is composed of several non-deformable bodies. MBS solvers generally require a very short computing time for dynamic tasks compared to an FE analysis. Considering this computational advantage, in this study, we examine whether parameters whose values are not known a priory can be determined with sufficient accuracy using MBS model. Therefore, we propose a Many-at-a-time sensitivity analysis method that allows approximating these a priory unknown parameters without requiring long simulation times. This method enables a high degree of MBS model optimization to be achieved in an iterative process. The sensitivity analysis method is applied to a simplified screw-vertebra model, consisting of an anterior anchor implant screw and vertebral body of C4. An experiment described in the literature is used as a basis for developing and assessing the potential of the method for sensitivity analysis and to validate the models action. The optimal model parameters for the MBS model were determined to be c=823224N/m for stiffness and d=488Ns/m for damping. The presented method of parameter identification can be used in studies including more complex MBS spine models or to set initial parameter values that are not available as initial values for FE models.
ARTICLE | doi:10.20944/preprints202308.1296.v1
Subject: Biology And Life Sciences, Neuroscience And Neurology Keywords: mammalians; spinal cord; central canal; CSF; CSF-cNs; intrinsic sensory neurons; transient receptor potential channels
Online: 18 August 2023 (10:59:31 CEST)
Cerebrospinal fluid contacting neurons (CSF-cNs) are a specific type of neurons located around the ventricles in the brain and the central canal in the spinal cord and have been demonstrated to be intrinsic sensory neurons in the central nervous system (CNS). One of the important channels responsible for the sensory function is polycystic kidney disease 2-like 1 (PKD2L1) channel. Most of the studies concerning the distribution and function of the PKD2L1-expressing CSF-cNs in the spinal cord have previously been performed in non-mammalian vertebrates. In the present study immunohistochemistry was performed to determine the distribution of PKD2L1-immunoreactive (IR) CSF-cNs in the spinal cords of 4 mammalian species: mouse, rat, cat, and macaque monkey. Here, we found that PKD2L1-expressing CSF-cNs were present at all levels of the spinal cord in these animal species. Although the distribution pattern was similar across these species, differences existed. Mice and rats presented a clear PKD2L1-IR cell body labeling, whereas in cats and macaques the PKD2L1-IR cell bodies were more weakly labeled. Ectopic PKD2L1-IR neurons away from the ependymal layer were observed in all the animal species although the abundance and the detailed locations varied. The apical dendritic protrusions towards the lumen of the central canal were clearly seen in all the animal species, but the sizes of protrusion bulbs were different among the species. PKD2L1-IR cell bodies/dendrites were co-expressed with doublecortin, MAP2 (microtubule-associated protein 2) and aromatic L-amino acid decarboxylase, but not with NeuN (neuronal nuclear protein), indicating their immature property and ability to synthesis monoamine transmitters. In addition, in-situ hybridization performed in rats revealed PKD2L1 mRNA expression in the cells around the central canal. Our results indicate that the intrinsic sensory neurons are conserved across non-mammalian and mammalian vertebrates, and that this may play an essential role in the regulation of motor and sensory functions as well as in the maintenance of homeostasis in the CNS.
ARTICLE | doi:10.20944/preprints202310.0586.v1
Subject: Medicine And Pharmacology, Anesthesiology And Pain Medicine Keywords: rectus sheath block; foal; ultrasound guided regional anaesthesia; spinal nerves; umbilical surgery
Online: 10 October 2023 (08:23:17 CEST)
In neonatal equines, pathologies involving umbilical structures are an important cause of morbidity, and surgical removal of urachal remnants is a common procedure in clinical practice. Surgery involving the ventral abdominal wall can cause substantial pain, leading to complications and prolonged recovery. The objectives of this study were to describe a two-point bilateral ultrasound-guided rectus sheath block at the level of the umbilicus and to evaluate the extent of dye distribution in foal cadavers. Ten foal cadavers were included in the study, in which a bilateral two-point ultrasound-guided rectus sheath block was performed—one injection cranially and a second one caudally to the umbilicus. The injectate consisted of a mixture of iodinated contrast medium and blue dye at a volume of 0.25 mL kg-1 per injection point (total 1 mL kg-1). After the injection, computer tomography and subsequent dissection of the ventral abdominal wall were performed. The extension of the contrast medium, the number of stained nerves, and contamination of the abdominal cavity were evaluated. The cranio-caudal extension of the contrast ranged from 0.8 to 1.4 centimeters per milliliter of injectate. The most commonly stained ventral branches of spinal nerves were thoracic (Th) nerves 16, 17, and 18 (95%, 85%, and 80% of the nerves, respectively). Abdominal contamination was found in 4 animals. The results suggest that the block could provide periumbilical analgesia. Further studies with different volumes of injectate and living animals are warranted.
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: adult spinal deformity; lumbosacral junction; anterior lumbar interbody fusion; bone morphogenetic protein; beta-tricalcium phosphate
Online: 28 December 2020 (12:06:09 CET)
Achievement of solid fusion of the lumbosacral junction (L5-S1 level) is an important factor in adult spinal deformity (ASD) surgery. The purpose of this study is to explore the effectiveness and feasibility of injectable rhBMP-2 (a combination of Eschericia coli-derived rhBMP-2 and hydrogel type β-TCP carrier; NOVOSIS Inject) as a bone substitute for the fusion of lumbosacral junction. 20 patients (average age 69.1 years) diagnosed with ASD with sagittal imbalance who underwent surgical treatment including anterior lumbar interbody fusion (ALIF) in the L5-S1 level were evaluated. Injectable rhBMP-2 was applied in L5-S1 ALIF and followed-up for 1-year. Solid fusion rates and changes of clinical outcomes (Oswestry Disability Index [ODI], Visual Analog Scale [VAS] of back and leg) were measured and analyzed at 6 and 12 months after surgery. All postoperative adverse events were evaluated about the association with injectable rhBMP-2. Fusion rates were 68.4% and 100% at 6 and 12 months after surgery. Compared to baseline, ODI were improved to 45.8% and 63.7%, VAS(back) were improved to 69.2% and 72.8%, and VAS(leg) were improved to 49.2% and 64.8% at 6 and 12 months after surgery (p<0.001, respectively). There were no adverse events associated with injectable rhBMP-2. Thus, injectable rhBMP-2 may be a suitable choice of a bone graft substitute when achieving solid interbody fusion in the lumbosacral junction.
ARTICLE | doi:10.20944/preprints202309.1953.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: chronic spinal cord injury; sensorimotor rehabilitation; transcutaneous electrical stimulation; neuromodulation; over-ground walking
Online: 28 September 2023 (06:28:20 CEST)
Spinal cord injuries (SCI) can result in sensory and motor dysfunctions, which were long-considered permanent. Recent advancement in electrical neuromodulation has been proven to restore sensorimotor function in people with SCI. These stimulation protocols, however, were mostly invasive, expensive, and difficult to implement. In this study, transcutaneous electrical stimulation (tES) was used to restore over-ground walking of an individual with 21 years of chronic paralysis from a cervical SCI. After a total of 66 weeks of rehabilitation training with tES, which included standing, functional reaching, reclined sit-up, treadmill walking and active biking, significant improvement in lower-limb volitional movements and overall light touch sensation were shown by International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) score. By the end of the study, the participant could walk in a 4-meter walking test with the aid of a walking frame and ankle foot orthoses. The success in the sensorimotor recovery of our study participant sheds light on the future of non-invasive neuromodulation treatment for SCI paralysis.
ARTICLE | doi:10.20944/preprints202308.0726.v1
Subject: Biology And Life Sciences, Anatomy And Physiology Keywords: postural control; spinal cord; transcutaneous electrical stimulation; healthy subjects; cognitive style; supporting leg
Online: 9 August 2023 (08:10:14 CEST)
Transcutaneous electrical stimulation of the spinal cord is used to restore locomotion and body weight support in patients with severe motor disorders. We studied effects of this non-invasive stimulation on postural control in healthy subjects. Stimulation at the L1-L2 vertebrae was performed to activate the extensor muscles of the lower limbs. Because postural regulation depends on the cognitive style, the effects of the stimulation were analyzed separately in field-dependent (FD) and field-independent (FI) participants. During the study young adults (N=16, half FD and half FI participants, all right dominant leg) stood on a force platform in a soundproof chamber with their eyes closed. Stimulation was applied in the midline between the L1-L2 vertebrae or over the left or right dorsal roots of the spinal cord; under control condition there was no stimulation. Stimulation destabilized posture in healthy subjects, whereas patients with movement disorders usually showed an improvement in postural control. In FD participants, left dorsal root and midline stimulation increased several postural parameters by up to 30%. Dorsal root stimulation on the side of the supporting leg reduced postural control, while stimulation on the side of the dominant leg did not. No significant changes were observed in the FI participants.
REVIEW | doi:10.20944/preprints202111.0065.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: Cervical spinal cord injury; Arm function; Exoskeleton; Robot-assisted therapy; Robotic therapy; Rehabilitation.
Online: 3 November 2021 (08:35:46 CET)
The upper extremities limitation represents one of the essential functional impairments in patients with cervical spinal cord injury. Electromechanics assisted devices and robots are increasingly used in neurorehabilitation to help functional improvement in patients with neurological diseases. This review aimed to systematically report the evidence-based, state-of-art on clinical applications and robotic-assisted arm training (RAT) in motor and functional recovery in subjects affected by cervical spinal cord injury. The present study has been carried out within the framework of the Italian Consensus Conference on "Rehabilitation assisted by robotic and electromechanical devices for persons with disability of neurological origin" (CICERONE). PubMed/MEDLINE, Cochrane Library, and Physiotherapy Evidence Database (PEDro) databases were systematically searched from inception to September 2021. The 10-item PEDro scale assessed the study quality for the RCT and the AMSTAR-2 for the systematic review. Two different authors rated the studies included in this review. If consensus was not achieved after discussion, a third reviewer was interrogated. The 5-item Oxford CEBM scale was used to rate the level of evidence. A total of 11 studies were included. The selected studies were: two systematic reviews, two RCTs, one parallel-group controlled trial, one longitudinal intervention study and five case series. One RCT was scored as a high-quality study, while the systematic review was of low quality. RAT was reported as feasible and safe. Initial positive effects of RAT were found for arm function and quality of movement in addition to conventional therapy. The high clinical heterogeneity of treatment programs and the variety of robot devices could severely affect the generalizability of the study results; therefore, future studies are warranted to standardize the type of intervention and evaluate the role of robotic-assisted training in subjects affected by cervical spinal cord injury.
ARTICLE | doi:10.20944/preprints201809.0424.v1
Subject: Medicine And Pharmacology, Pharmacy Keywords: Genistein; nanofibers; spinal cord injury; inflammation; SOD; NO; MDA; IL-10; TNF-α
Online: 20 September 2018 (17:11:18 CEST)
Implantable drug-delivery systems provide new means for achieving therapeutic drug concentration over a prolonged time to achieve better tissue protection and enhanced recovery. The hypothesis of the current study was to test the antioxidant and anti-inflammatory effects of genistein and nanofibers on the spinal cord tissue following experimental spinal cord injury (SCI). Rats were treated post SCI with genistein loaded on chitosan/polyvinyl alcohol (CS/PVA) nanofibers as an implantable drug-delivery system. SCI caused marked oxidative damage and inflammation as evident by the reduction in the super oxide dismutase (SOD) activity and the level of interleukin-10 (IL-10) in injured spinal cord tissue, as well as, the significant increase in the levels of nitric oxide (NO), malondialdehyde (MDA) and tumor necrosis factor-alpha (TNF-α). Treatment of rats post SCI with genistein and CS/PVA nanofibers improved most of the above mentioned biochemical parameters and shifted them toward the control group values. Genistein induced an increase in the activity of SOD and the level of IL-10, while causing a decrease in the levels of NO, MDA and TNF-α in injured spinal cord tissue. Genistein and CS/PVA nanofibers provide a novel combination for treating inflammatory nervous tissue conditions, especially when combined as an implantable drug-delivery system.
REVIEW | doi:10.20944/preprints202011.0721.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: Non-invasive direct current stimulation; Cortical, Suboccipital and Spinal stimulation; Quantitative sensory testing, Pain outcome measures, Endogenous pain modulation.
Online: 30 November 2020 (11:44:44 CET)
Background: Objectives. The objective of this study was to compare the efficacy of direct current stimulation (DCS) applied at the transcranial, suboccipital and spinal level on experimental sensory modalities and pain outcome measures in healthy subjects. The hypothesis of this study was that systematic analysis of the efficacy of DCS on modulating evoked thermal and mechanical pain modalities and mechanisms such as endogenous pain modulation in healthy individuals would reveal sensitive outcome measures help develop this technique for the control of chronic pain. Materials and Methods. Database searches were conducted up to December 2019 for randomized controlled trials that performed sham-controlled DCS of experimental sensory modalities and pain outcomes following transcranial, suboccipital and spinal locations in healthy participants. Standardized mean differences with 95% confidence intervals were calculated for sensory modalities, including random-effect metanalysis. Results: Thirty-one studies were included for analysis (647 participants). A significant decrease in pain intensity for active vs sham transcranial stimulation was identified for pain intensity (n=158; SMD=0.79; 95% CI=0.56 to 1.02), a significant increase in heat pain threshold (n=222; SMD=1.16; 95% CI=0.95 to 1.37), and a significant increase in cold pain threshold (n = 155; SMD = 0.77, 95% CI 0.53 to 1.01). No significant modulation of pressure pain threshold was identified with DCS and only a limited number of studies focused on experimental pain modulation following neuromodulation at the suboccipital or spinal level. Conclusions: These results show significant transcranial DCS neuromodulation of pain intensity and on thermal pain modalities. Future studies should focus on endogenous pain and sensory modality modulation with sham-controlled DCS applied at transcranial, suboccipital and spinal locations.
ARTICLE | doi:10.20944/preprints202109.0010.v1
Subject: Medicine And Pharmacology, Anesthesiology And Pain Medicine Keywords: spinal cord stimulation; screening trial; infection; supervised learning; machine learning; predictive modeling; patient outcome
Online: 1 September 2021 (12:05:18 CEST)
Persistent Pain after Spinal Surgery can be successfully addressed by Spinal Cord Stimulation (SCS). International guidelines strongly recommend that a lead trial be performed before any permanent implantation. Recent clinical data highlight some major limitations of this approach. First, it appears that patient outcomes, WITH OR WITHOUT lead trial, are similar. In contrast, during trialing, infection rate drops drastically within time and can compromise the therapy. Using composite pain assessment experience and previous research, we hypothesized that ma-chine learning models could be robust screening tools and reliable predictors of long-term SCS efficacy. We developed several algorithms including logistic regression, Regularized Logistic Regression (RLR), naive Bayes classifier, artificial neural networks, random forest and gradient boosted trees to test this hypothesis and to perform internal and external validations, the objec-tive being to confront model predictions with lead trial results using a 1-year composite out-come from 103 patients. While almost all models have demonstrated superiority on lead trial-ing, the RLR model appears to represent the best compromise between complexity and inter-pretability in prediction of SCS efficacy. These results underscore the need to use AI based-predictive medicine, as a synergistic mathematical approach, aimed at helping implanters to optimize their clinical choices on daily practice.
REVIEW | doi:10.20944/preprints202106.0449.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Central Nervous System; Ependymal Cells; Neural Stem and Progenitor Cells; NG2+ Cells; Regenerative Medicine; Retina Injury; Spinal Cord Injury; Traumatic Brain Injury.
Online: 16 June 2021 (15:02:02 CEST)
Adult neural stem and progenitor cells (NSPCs) contribute to learning, memory, maintenance of homeostasis, energy metabolism and many other essential processes. They are highly heterogeneous populations that require input from a regionally distinct microenvironment including a mix of neurons, oligodendrocytes, astrocytes, ependymal cells, NG2+ glia, vasculature, cerebrospinal fluid (CSF), and others. The diversity of NSPCs is present in all three major parts of the CNS, i.e., the brain, spinal cord, and retina. Intrinsic and extrinsic signals, e.g., neurotrophic and growth factors, master transcription factors, and mechanical properties of the extracellular matrix (ECM), collectively regulate activities and characteristics of NSPCs: quiescence/survival, proliferation, migration, differentiation, and integration. This review discusses the heterogeneous NSPC populations in the normal physiology and highlights their potentials and roles in injured/diseased states for regenerative medicine.
ARTICLE | doi:10.20944/preprints202108.0023.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: Nicotine toxicity; Wnt1 pathway; spinal cord injury; locomotor networks; excitotoxicity; fictive locomotion; postnatal; rat; mice
Online: 2 August 2021 (11:52:54 CEST)
The postnatal rodent spinal cord in-vitro is a useful model to investigate early pathophysiological changes after injury. While low dose nicotine (1µM) induces neuroprotection, how higher doses affect spinal networks is unknown. Using spinal preparations of postnatal wild-type Wistar rat and Wnt1Cre2:Rosa26Tom double-transgenic mouse, we studied the effect of nicotine (0.5-10µM) on locomotor networks in-vitro. Nicotine 10µM induced motoneuron depolarization, suppressed monosynaptic reflexes, and decreased fictive locomotion in rat spinal cord. Delayed fall in neuronal numbers (including motoneurons) of central and ventral regions emerged without loss of dorsal neurons. Conversely, nicotine (0.5-1µM) preserved neurons throughout the spinal cord and strongly activated the Wnt1 signaling pathway. High-dose nicotine enhanced expression of S100 and GFAP in astrocytes suggesting their response to stress. Excitotoxicity induced by kainate was contrasted by nicotine (10µM) in the dorsal area and persisted in central and ventral regions with no change basal Wnt signaling. When combining nicotine with kainate, the activation of Wnt1 was reduced compared to kainate/sham. The present results suggest that high dose nicotine was neurotoxic to central and ventral spinal neurons as the neuroprotective role of Wnt signaling became attenuated. This also corroborates the risk of cigarette smoking for the foetus/newborn since tobacco contains nicotine.
CASE REPORT | doi:10.20944/preprints202002.0280.v1
Subject: Medicine And Pharmacology, Veterinary Medicine Keywords: spinal disc herniation, dog, NADPH diaphorase, the aging-related NADPH diaphorase body, megaloneurite, homogeneous formazan globule, intermedial collateral pathway
Online: 19 February 2020 (11:47:26 CET)
Neuronal lesion or injury is a traditional approach to investigate neural circuit. Is any new neural pathway or new neurodegeneration related central nerve system injury? Spinal disc herniation can cause the spinal cord injury. However, the histological examination is still lack. It happened that a case of spinal disc herniation of a 10-year old dog was examined with NADPH diaphorase (N-d) histology. We did not find the N-d neurodegenerative aberrant in the tissue of the mid-rostral lumber segment besides the metamorphoses by the compression of the disc herniation. However, the severe neuropathological changes majorly occurred in the lumbosacral spinal cord. We found more diverse neurodegenerative alterations: the aging-related N-d body (ANB), megaloneurite and N-d homogeneous formazan globule in the lumbosacral spinal cord. We also found that a new circuit pathway (intermedial collateral pathway) showed by a megaloneurite between the lateral collateral pathway and the medial collateral pathway. The enormous notch caused by spinal disc herniation located at the mid-rostral lumber segments. The aging-related neurodegeneration occurred the specific lumbosacral segments. The homogeneous formazan globule was round or oval homogeneous N-d positivity which distributed in the gray matter and dorsal column. In the medulla oblongata, ANBs were revealed in the gracile nucleus, nucleus reticularis lateralis (ventrolateral spinal trigeminal nucleus) and middle of the spinal trigeminal nucleus.
ARTICLE | doi:10.20944/preprints202310.1718.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: percutaneous thermal ablation; image-guided procedures; Cone Beam Computed Tomography (CBCT); fusion imaging; thermal ablation techniques; secondary spinal tumors; interventional radiology
Online: 26 October 2023 (11:35:31 CEST)
Spinal metastatic tumors are common and often cause debilitating symptoms. Image-guided percutaneous thermal ablation (IPTA) has gained significant recognition in managing spinal column tumors due to its exceptional precision and effectiveness. Conventional guidance modalities, including computed tomography, fluoroscopy, and ultrasound, have been important in targeting spinal column tumors while minimizing harm to adjacent critical structures. This study presents a novel approach utilizing a fusion of Cone Beam Computed Tomography with Magnetic Resonance Imaging to guide percutaneous thermal ablation for four patients with secondary spinal column tumors. The visual analog scale (VAS) evaluated procedure effectiveness during an 18-month follow-up. Percutaneous vertebroplasty was performed in two cases, and a thermostat was used during all procedures. Imaging was performed using the Stealth Station navigation system Spine 8 (SSS8) and a 1.5T MRI machine. The fusion of CBCT with MRI allowed precise tumor localization and guidance for thermal ablation. Initial results indicate successful tumor ablation and symptom reduction, emphasizing the potential of CBCT-MRI fusion in spinal column tumor management. This innovative approach is promising in optimizing therapy for secondary spinal column tumors. Further studies are necessary to validate its efficacy and applicability.
ARTICLE | doi:10.20944/preprints202108.0527.v1
Subject: Medicine And Pharmacology, Clinical Medicine Keywords: PSPS; FBSS; chronic pain; health-related quality of life; mixture models analysis; personalized pain management; chronic pain after spinal surgery
Online: 27 August 2021 (15:23:27 CEST)
Persistent Spinal Pain Syndrome Type 2 (PSPS-T2), (Failed Back Surgery Syndrome), dramatically impacts on patient quality of life, as evidenced by Health-Related Quality of Life (HRQoL) assessment tools. However, the importance of functioning, pain perception and psychological status in HRQoL can substantially vary between subjects. Our goal was to extract patient profiles based on HRQoL dimensions in a sample of PSPS-T2 patients and to identify factors associated with these profiles. Two classes were clearly identified using a mixture of mixed effect models from a clinical data set of 200 patients enrolled in “PREDIBACK”, a multicenter observational prospective study including PSPS-T2 patients with 1-year follow-up. We observed that HRQoL was more impacted by functional disability for first class patients (n=136) and by pain perception for second class patients (n=62). Males that perceive their work as physical were more impacted by disability than pain intensity. Lower education level, lack of adaptive coping strategies and higher pain intensity were significantly associated with HRQoL being more impacted by pain perception. The identification of such classes allows for a better understanding of HRQoL dimensions and opens the gate towards optimized health-related quality of life evaluation and personalized pain management.
REVIEW | doi:10.20944/preprints202202.0355.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: non-myelopathic cervical spinal cord compression; degenerative cervical myelopathy; diffusion magnetic resonance imaging; quantitative magnetic resonance imaging
Online: 28 February 2022 (10:20:37 CET)
Degenerative spinal cord (SC) compression is a frequent pathological condition with increasing prevalence throughout aging. Initial non-myelopathic cervical SC compression (NMDC) might progress over time into potentially irreversible degenerative cervical myelopathy (DCM). While quantitative MRI (qMRI) techniques demonstrated the ability to depict intrinsic tissue properties, longitudinal in-vivo biomarkers to identify NMDC patients who will eventually develop DCM are still missing. Thus, we aim to review the ability of qMRI techniques (such as diffusion MRI, diffusion tensor imaging (DTI), magnetization transfer (MT) imaging, magnetic resonance spec-troscopy (1H-MRS)) to serve as prognostic markers in NMDC. While DTI in NMDC patients con-sistently detected lower fractional anisotropy and higher mean diffusivity at compressed levels caused by demyelination and axonal injury, MT and 1H-MRS along with advanced and tract-specific diffusion MRI recently revealed microstructural alterations also rostrally pointing to Wallerian degeneration. Recent studies also disclosed significant relationship between micro-structural damage and functional deficits, assessed by qMRI and electrophysiology, respectively. Thus, tract-specific qMRI in combination with electrophysiology critically extend our under-standing of the underlying pathophysiology of degenerative SC compression and may provide predictive markers of DCM development for accurate patient management. However, the prog-nostic value must be validated in longitudinal studies.
REVIEW | doi:10.20944/preprints202308.2156.v1
Subject: Medicine And Pharmacology, Orthopedics And Sports Medicine Keywords: C-arm free; minimally invasive spine surgery; adult spinal deformity; lateral access spine surgery; oblique lumbar interbody fusion
Online: 31 August 2023 (09:51:02 CEST)
Background and Objectives: C-arm free MIS techniques can offer significantly reduced rates of postoperative complications such as blood loss and hospitalization time. Another advantageous long-term aspect is the notably diminished exposure to radiation which is known to cause ma-lignant changes. This study emphasizes that, in some cases of spinal conditions which require a procedural intervention, C-arm free MIS techniques hold stronger indications than open surgeries guided by image intensifier. Materials and Methods: In this research, a retrospective analysis and review of various cervical and thoracic spinal procedures, performed in our hospital, by applying C-arm free techniques. The course of the study explains the basic steps of the procedures and demonstrating postoperative or intra-operative results. For anterior cervical surgery, we performed OPLL resection, while for posterior cervical surgery, we performed posterior fossa decompression for Chiari malformation, minimally invasive cervi-cal pedicle screw fixation (MICEPS) and modified Goel technique with C1 lateral mass screw for atlantoaxial subluxation. Re-garding the thoracic spine, we performed anterior correction for Lenke type 5 scoliosis, and transdiscal screw fixation for DISH fractures. Results: C-arm free techniques are safe procedures that offer precise and high-quality postoperative results by offering sufficient spine alignment and adequate decompression depending on the case. Blood loss, postoperative pain and wound infection are other important aspects of spine surgery that must be always taken into consideration. Conclusions: Navigated C-arm free techniques are safe and precise procedures implemented in the treatment of surgically demanding conditions. They can significantly increase accuracy while decreasing the operative time. They represent the advancement in the field spine surgery and are hailed as the future of the same
ARTICLE | doi:10.20944/preprints202308.0796.v1
Subject: Biology And Life Sciences, Neuroscience And Neurology Keywords: anesthesia neurotoxicity; neuropathic pain; neural activity; mammalian target of rapamycin (mTOR); dorsal spinal cord (DSC), dorsal root ganglion (DRG).
Online: 10 August 2023 (08:17:30 CEST)
Patients who have undergone surgery in early life may be at elevated risk for neuropathic pain in later life. The risk factors for this susceptibility are not fully understood. Here, we used a mouse chronic pain model to test the hypothesis that early exposure to general anesthetic (GA) causes cellular and molecular alterations in dorsal spinal cord (DSC) and dorsal root ganglion (DRG) that produces a predisposition to neuropathic pain via an upregulation of the mammalian target of the rapamycin (mTOR) signaling pathway. Mice were exposed to isoflurane at postnatal day 7 (P7) and underwent spared nerve injury at P28 which causes chronic pain. Selected groups were treated with rapamycin, an mTOR inhibitor, for eight weeks. Behavioral tests show early isoflurane exposure enhances susceptibility to chronic pain, and rapamycin treatment improves outcomes. Immunohistochemistry, Western blotting, and q-PCR indicates that isoflurane upregulates mTOR expression and neural activity in DSC and DRG. Accompanying upregulation of mTOR and rapamycin-reversible changes in chronic pain-associated markers, including N-cadherin, cAMP response element-binding protein (CREB), purinergic P2Y12 receptor, glial fibrillary acidic protein (GFAP) in DSC; and connexin 43, phospho-extracellular signal-regulated kinase (p-ERK), GFAP, Iba1 in DRG, were observed. We conclude that early GA exposure alters the development of pain circuits such that mice are subsequently more vulnerable to chronic neuropathic pain states.
REVIEW | doi:10.20944/preprints202103.0636.v2
Subject: Chemistry And Materials Science, Biomaterials Keywords: Silicon nitride; structure; properties; processing; coatings; spinal implants; arthroplastic implants; bone scaffolds; dental implants; neural circuits; biosensors; medical diagnostics.
Online: 15 April 2021 (12:55:38 CEST)
This topical review describes the results of recent research into and development of silicon nitride, a ceramic material with unique properties. The outcome of this ongoing research strongly encourages the use of monolithic silicon nitride and coatings as contemporary and future biomaterial for a variety of medical applications. Crystallographic structure, synthesis and processing of monolithic structures and coatings, and examples of their medical applications are covered that relate to spinal, orthopedic and dental implants, bone grafts and scaffolds, platforms for intelligent synthetic neural circuits, antibacterial and antiviral particles and coatings, optical biosensors, and nano-photonic waveguides for sophisticated medical diagnostic devices. The examples provided show convincingly that silicon nitride is destined to become a leader to replace titanium and other entrenched biomaterials in many fields of medicine.
REVIEW | doi:10.20944/preprints201805.0247.v1
Subject: Medicine And Pharmacology, Orthopedics And Sports Medicine Keywords: spinal cord injury; glial cell line-derived neurotrophic factor (GDNF), GFRα-1; cRET; Schwann cells; Astrogliosis; neuroprotection; axonal regeneration; combinational therapies; neurotrauma
Online: 17 May 2018 (12:54:50 CEST)
Following an initial mechanical insult, traumatic spinal cord injury (SCI) induces a secondary wave of injury, resulting in a toxic lesion environment inhibitory to axonal regeneration. This review focuses on the glial cell line-derived neurotrophic factor (GDNF) and its application, also in combination with other factors and cell transplantations, for repairing the injured spinal cord. As recent decades of studies strongly suggest combinational treatment approaches hold the greatest therapeutic potential for the central nervous system (CNS) trauma, future directions of combinational therapies will also be discussed.
ARTICLE | doi:10.20944/preprints202307.0052.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: Chiari malformation; corticospinal tract mapping; dorsal column mapping; D-wave; intraoperative neurophysiological monitoring; motor evoked potentials; root mapping; somatosensory evoked potentials; spinal cord; syringomyelia
Online: 3 July 2023 (11:53:52 CEST)
Syringomyelia can be associated with multiple etiologies. The treatment of the underlying causes is the first-line therapy, however, a direct approach to the syrinx is accepted as rescue treatment. Any direct intervention on the syrinx requires a myelotomy, posing a significant risk of iatrogenic spinal cord (SC) injury. Intraoperative neurophysiological monitoring (IONM) is crucial to detect and prevent surgically induced damage in neural SC pathways. We retrospectively reviewed the perioperative and intraoperative neurophysiological data and perioperative neurological examinations in ten cases of syringomyelia surgery. All monitored modalities remained stable throughout the surgery in six cases, correlating with no new postoperative neurological deficits. In two patients, significant transitory attenuation, or loss of motor evoked potentials (MEPs), were observed and recovered after a corrective surgical maneuver, with no new postoperative deficit. In two cases, a significant MEP decrement was noted, which lasted until the end of the surgery and was associated with postoperative weakness. A transitory train of neurotonic electromyography (EMG) discharges was reported in one case, the surgical plan was adjusted and the patient showed no postoperative deficit. The dorsal nerve roots were stimulated and identified in the seven cases where the myelotomy was performed via the dorsal root entry zone. Dorsal column mapping guided the myelotomy entry zone in four cases. In conclusion, multimodal IONM is feasible and reliable and may help prevent iatrogenic SC injury during syringomyelia surgery.
REVIEW | doi:10.20944/preprints201805.0303.v1
Subject: Biology And Life Sciences, Cell And Developmental Biology Keywords: glial bridge; ctgfa; Fgf signaling; MAPK signaling; shh; slit2/3; Wnt signaling; genetic compensation; glial bridge cycle; spinal cord regeneration; termination signal; central nervous system; peripheral nervous system; zebrafish
Online: 22 May 2018 (12:09:09 CEST)
Zebrafish have been found to be the premier model organism in biological and biomedical research, specifically offering many advantages in developmental biology and genetics. This unique aquatic species has been found to have the capacity to regenerate their spinal cord after injury. However, the complete molecular and cellular mechanisms behind glial bridge formation in the central and peripheral nervous systems upon glial cell injury remains unclear. This review paper focuses on the molecular mechanisms and cellular processes that underlie spinal cord regeneration in four initial phases: proliferation and initial migration; migration and differentiation; glial bridge formation; and remodeling. We propose that within these four phases the cellular mechanisms that underlie spinal cord regeneration each express a terminating signal that aborts one step of the process and initiates the next. Specifically, future studies would be devoted to investigate transmitting signals in the spinal cord injury micro-environment in hope to contribute to the understanding of underlying cellular mechanisms by connecting each process of spinal cord regeneration in zebrafish.
ARTICLE | doi:10.20944/preprints202110.0235.v1
Subject: Medicine And Pharmacology, Clinical Medicine Keywords: Spinal Cord Stimulation; rescue therapy; salvage therapy; new waveforms; paresthesia-free waveforms; High-Frequency stimulation; Burst stimulation; spatial neural targeting; temporal neural targeting; SCS programming; adapter; mapping software; paresthesia coverage; patient outcome; salvage algorithm
Online: 18 October 2021 (10:04:52 CEST)
While paresthesia-based spinal cord stimulation (SCS) has been proven effective to treat chronic neuropathic pain, initial benefits may lead to the development of “Failed SCS Syndrome’ (FSCSS) defined as decrease over time related to Loss of Efficacy (LoE) with or without Loss of Coverage (LoC). Development of technologies associating new paresthesia-free stimulation waveforms and implanted pulse generator adapters provide opportunities to manage patients with LoE. The main goal of our study was to investigate salvage procedures, through neu-rostimulation adapters, in patients already implanted with SCS and experienced LoE. We retro-spectively analyzed a cohort of patients who were offered new SCS programs/waveforms through an implanted adapter between 2018 and 2021. Patients were evaluated before, and at 1, 3, 6 and 12-month follow-up. Outcomes included pain intensity rating with Visual Analog Scale (VAS), pain/coverage mappings and stimulation preferences. Last follow-up evaluations (N=27) showed significant improvement in VAS (p = 0.0001), ODI (p = 0.021) and Quality of Life (p=0.023). In the 11/27 patients with LoC, SCS efficacy on pain intensity (36.89%) was accompa-nied by paresthesia coverage recovery (55.57%) and pain surface decrease (47.01%). At 12-month follow-up, 81.3% preferred to keep tonic stimulation in their waveform portfolio. SCS conver-sion using adapters appears promising as a salvage solution, with an emphasis on paresthesia recapturing enabled by spatial retargeting. In light of these results, adapters could be integrated to SCS rescue algorithms or should be considered in SCS rescue.