Effect of Long-term Peripheral Nerve Stimulation on Neuro-Muscular Complex Morphologic Recovery in Experiment / Efecto de la Estimulación del Nervio Periférico a Largo Plazo sobre la Recuperación Morfológica del Complejo Neuromuscular en Experimento

SUMMARY: Peripheral nerve injury is an extremely important medical and socio-economic problem. It is far from a solution, despite on rapid development of technologies. To study the effect of long-term electrical stimulation of peripheral nerves, we used a domestically produced electrical stimulation system, which is approved for clinical use. The study was performed on 28 rabbits. Control of regeneration was carried out after 3 month with morphologic techniques. The use of long-term electrostimulation technology leads to an improvement in the results of the recovery of the nerve trunk after an injury, both directly at the site of damage, when stimulation begins in the early period, and indirectly, after the nerve fibers reach the effector muscle.

La lesión de los nervios periféricos es un problema médico y socioeconómico extremadamente importante. Sin embargo, y a pesar del rápido desarrollo de las tecnologías, aún no tiene solución. Para estudiar el efecto de la estimulación eléctrica a largo plazo de los nervios periféricos, utilizamos un sistema de estimulación eléctrica de producción nacional, que está aprobado para uso clínico. El estudio se realizó en 28 conejos. El control de la regeneración se realizó a los 3 meses con técnicas morfológicas. El uso de tecnología de electro estimulación a largo plazo conduce a una mejora en los resultados de la recuperación del tronco nervioso después de una lesión, tanto directamente en el lugar del daño, cuando la estimulación comienza en el período temprano, como indirectamente, después de que las fibras nerviosas alcanzan el músculo efector.

Redefining the Inclusion Criteria for Successful Steindler Flexorplasty Based on the Outcomes of a Case Series in Eight Patients.

Background (rationale) Steindler flexorplasty (SF) is aimed at restoring independent elbow flexion in the late stages of dysfunction of the primary elbow flexors. Selection criteria for successful SF have been defined. Objectives The purpose of this study was to redefine the inclusion criteria for successful SF based on functional outcomes. Methods Eight patients received SF after an average of 50.8 months after injury or dysfunction. Three patients (37.5%) met all five Al-Qattan inclusion criteria (AQIC), and another five patients (62.5%) met four or less AQIC. Patients were followed up for at least 9 months, and the maximum range of active elbow flexion (REF) was measured. Functional results of SF were assessed using the Al-Qattan scale (in accordance with Al-Qattan's scale). Results The mean maximum REF was 100 degrees (70 to 140 degrees). Five patients reached REF greater than 100 degrees. One patient had a poor outcome, two patients (25%) had a fair outcome, three patients (37.5%) had a good outcome, and two patients (25%) had an excellent outcome of SF on the Al-Qattan scale. The impact of each AQIC on functional outcome has been critically reviewed from a biomechanical point of view. Conclusions The sufficient number of inclusion criteria required for successful SF can be reduced from five (according to AQIC) to two; Normal or near-normal function (M4 or greater on the MRC scale) of the muscles of the flexor-pronator mass should be considered an obligatory inclusion criterion, while primary wrist extensors may be considered an optional inclusion criterion.

Neuronal differentiation and inhibition of glial differentiation of murine neural stem cells by pHPMA hydrogel for the repair of injured spinal cord.

Currently, several therapeutic methods of treating the effects of spinal cord injury (SCI) are being considered. On the one hand, transplantation of stem cells (SCs), in particular, neural stem/progenitor cells (NSPCs), is promising, as these cells have the potential to differentiate into nervous tissue cells, able to enhance endogenous regeneration and prevent the development of inflammatory processes. On the other hand, it is quite promising to replace the damaged nervous tissue with synthetic matrices, in particular hydrogels, which can create artificial conditions for the regenerative growth of injured nerve fibers through the spinal cord injury area, i.e. stimulate and support axonal regeneration and myelination. In this work, we combined both of these novel approaches by populating (injecting or rehydrating) a heteroporous pHPMA hydrogel (NeuroGel) with murine hippocampal NSPCs. Being inside the hydrogel (10 days of cultivation), NSPCs were more differentiated into neurons: 19.48% ± 1.71% (the NSPCs injection into the hydrogel) and 36.49% ± 4.20% (the hydrogel rehydration in the NSPCs suspension); in control cultures, the level of differentiation in neurons was only 2.40% ± 0.31%. Differentiation of NSPCs into glial cells, in particular into oligodendrocyte progenitor cells, was also observed - 8.89% ± 2.15% and 6.21% ± 0.80% for injection and rehydration variants, respectively; in control - 28.75% ± 2.08%. In the control NSPCs culture, there was a small number of astrocytes - 2.11% ± 0.43%. Inside the hydrogel, NSPCs differentiation in astrocytes was not observed. In vitro data showed that the hydrogel promotes the differentiation of NSPCs into neurons, and inhibits the differentiation into glial cells. And in vivo showed post-traumatic recovery of rat spinal cord tissue after injury followed by implantation of the hydrogel+NSPCs complex (approximately 7 months after SCI). The implant area was closely connected with the recipient tissue, and the recipient cells freely grew into the implant itself. Inside the implant, a formed dense neuronal network was visible. In summary, the results are primarily an experimental ground for further studies of implants based on pHPMA hydrogel with populated different origin SCs, and the data also indicate the feasibility and efficiency of using an integrated approach to reduce possible negative side effects and facilitate the rehabilitation process after a SCI.

Matrix Metalloproteinase-9 is Involved in the Fibrotic Process in Denervated Muscles after Sciatic Nerve Trauma and Recovery.

Fibrosis of the injured muscles is a problem of recovery from trauma and denervation. The aim of the work was to investigate the interconnection of matrix metalloproteinase-9 (ММР-9) activity in denervated muscles with fibrosis and to estimate its role in nerve restoration by the epineurial suture, fibrin-based glue, and polyethylene glycol hydrogel. The activity of matrix metalloproteinases was estimated by gelatin zymography. Collagen density in muscles was determined histochemically. An increased level of the active MMP-9 is associated with the fibrous changes in the denervated skeletal muscles and after an epineurial suture. The use of fibrin glue and polyethylene glycol hydrogel resulted in a lower level of collagen and ММР-9 activity, which may be a therapeutic target in the treatment of neuromuscular lesions, and has value in fibrosis analysis following microsurgical intervention for peripheral nerve reconstruction.

Nerve transfers in a patient with asymmetrical neurological deficit following traumatic cervical spinal cord injury: simultaneous bilateral restoration of pinch grip and elbow extension. Illustrative case.

BACKGROUND: Cervical spinal cord injury (CSCI) causes severe motor deficit in upper extremities. The mixed segmental CSCI pattern is reflected in the combination of time-sensitive (TS) and non-TS myotomes in the upper extremities. Nerve transfers (NTs) restore upper extremity function yet remain TS procedures. A combination of neurological, magnetic resonance imaging (MRI), and electromyography (EMG) studies allows the identification of TS and non-TS myotomes in the upper extremities. OBSERVATIONS: Nineteen months after NTs, flexor pollicis longus (FPL) and deep flexor of the index finger (FDP2) recovered to M4 (right UE), FPL recovered to M3 and FDP2 to M2 (left EU). The long head of the triceps brachii muscle recovered to M4 bilaterally. The Capabilities of Upper Extremity Questionnaire (CUE-Q) score for unilateral arm functionality increased by 44% (right) and 112.5% (left) and for bilateral arm functionality by 400%; the CUE-Q score for unilateral hand and finger function increased by 283% (right) and 166% (left). LESSONS: The combination of neurological, MRI, and EMG studies before surgery and data obtained during surgery provides reliable information on the CSCI pattern, specifically the availability of motor donor nerves. Simultaneous bilateral restoration is required in the event of CSCI and significantly improves the unilateral and bilateral function of the UEs.

Phenotypes of Motor Deficit and Pain after Experimental Spinal Cord Injury.

Motor disability is a common outcome of spinal cord injury (SCI). The recovery of motor function after injury depends on the severity of neurotrauma; motor deficit can be reversible, at least partially, due to the innate tissue capability to recover, which, however, deteriorates with age. Pain is often a comorbidity of injury, although its prediction remains poor. It is largely unknown whether pain can attend motor dysfunction. Here, we implemented SCI for modelling severe and moderate neurotrauma and monitored SCI rats for up to 5 months post-injury to determine the profiles of both motor deficit and nociceptive sensitivity. Our data showed that motor dysfunction remained persistent after a moderate SCI in older animals (5-month-old); however, there were two populations among young SCI rats (1 month-old) whose motor deficit either declined or exacerbated even more over 4-5 weeks after identical injury. All young SCI rats displayed changed nociceptive sensitivity in thermal and mechanical modalities. The regression analysis of the changes revealed a population trend with respect to hyper- or hyposensitivity/motor deficit. Together, our data describe the phenotypes of motor deficit and pain, the two severe complications of neurotrauma. Our findings also suggest the predictability of motor dysfunction and pain syndromes following SCI that can be a hallmark for long-term rehabilitation and recovery after injury.

Efficiency and safety of umbilical cord mesenchymal stromal/ stem cells in multiple sclerosis combined treatment / Eficacia y seguridad de las células madre / estromales mesenquimales del cordón umbilical en el tratamiento combinado de la esclerosis múltiple

SUMMARY: Multiple sclerosis is a demyelinating disease of the nervous system that affects young people of working age and quickly leads to disability. Treatment of this pathology with umbilical cord mesenchymal stem cells is promising, given their immunomodulatory and neurotrophic properties. The study involved 27 patients diagnosed with multiple sclerosis, 12 of whom underwent combined treatment (intravenous and intrathecal administration) of umbilical cord multipotent mesenchymal stromal/stem cells. The effectiveness of treatment was determined by the degree of neurological deficit and spasticity. Combined treatment with umbilical cord mesenchymal stem cells significantly improves the condition of patients with multiple sclerosis and promotes the regression of neurological deficits and spasticity. This treatment is safe, but for a deeper study, it is necessary to continue research in this area.

RESUMEN: La esclerosis múltiple es una enfermedad desmielinizante del sistema nervioso que afecta a los jóvenes en edad laboral y conduce rapidamente a la discapacidad. El tratamiento de esta patología con células madre mesenquimales de cordón umbilical es prometedor, debido a sus propiedades inmunomoduladoras y neurotróficas. En el estudio participaron 27 pacientes diagnosticados de esclerosis múltiple, 12 de los cuales fueron sometidos a un tratamiento combinado (administración intravenosa e intratecal) de células madre / estromales mesenquimales multipotentes del cordón umbilical. La efectividad del tratamiento estuvo determinada por el grado de déficit neurológico y espasticidad. El tratamiento combinado con células madre mesenquimales del cordón umbilical mejora significativamente la condición de los pacientes con esclerosis múltiple y promueve la regresión de los déficits neurológicos y la espasticidad. Este tratamiento es seguro, sin embargo, es necesario continuar investigando en esta area.

Opposite, bidirectional shifts in excitation and inhibition in specific types of dorsal horn interneurons are associated with spasticity and pain post-SCI.

Spasticity, a common complication after spinal cord injury (SCI), is frequently accompanied by chronic pain. The physiological origin of this pain (critical to its treatment) remains unknown, although spastic motor dysfunction has been related to the hyperexcitability of motoneurons and to changes in spinal sensory processing. Here we show that the pain mechanism involves changes in sensory circuits of the dorsal horn (DH) where nociceptive inputs integrate for pain processing. Spasticity is associated with the DH hyperexcitability resulting from an increase in excitation and disinhibition occurring in two respective types of sensory interneurons. In the tonic-firing inhibitory lamina II interneurons, glutamatergic drive was reduced while glycinergic inhibition was potentiated. In contrast, excitatory drive was boosted to the adapting-firing excitatory lamina II interneurons while GABAergic and glycinergic inhibition were reduced. Thus, increased activity of excitatory DH interneurons coupled with the reduced excitability of inhibitory DH interneurons post-SCI could provide a neurophysiological mechanism of central sensitization and chronic pain associated with spasticity.

Biocompatible heterogeneous porous gel matrix NeuroGel(TM) promotes regeneration of rat sciatic nerve within tubular silicone prosthesis (experimental study).

BACKGROUND: The purpose of this study was to investigate the ability of NeuroGel™ to promote and enhance the regeneration of rat sciatic nerve within a 10-mm gap using silicone tubular prosthesis, and to evaluate and compare the regeneration outcomes versus autologous grafting. METHODS: The 10-mm gap of rat sciatic nerve was bridged through silicone tubular prosthesis filled with dehydrated NeuroGel™, and NeuroGel™ saturated with rat NGF-B (NG30-NGG60, NGgfB30-NGgfB60). To assess the regeneration of the peripheral nerve we utilized three general and most commonly applied methods: electrophysiologic, hystomorphometric, and functional methods. RESULTS: The average M-wave amplitude (AMW index), or the intermediary index of the number of regenerated axons, in animal groups NGG60 and NGgfB60 60 days post-op was: 2.44 ± 0.57 mV and 1.87 ± 0.48 mV. These indices were statistically lower compared to the indices obtained after autologous grafting. The average impulse conduction velocity along motor fibers (VMF index), or the intermediary index of myelination rate, was: 13.3 mm/ms and 13.3 mm/ms, respectively, statistically equal to indices obtained after autologous grafting. The average density (D) of regenerated fibers (direct numerical indicator in contrast to intermediary AMW index) in animal groups NGG60 and NGgfB60 was: 4,920 ± 178.88 and 5,340 ± 150.33 per mm(2), respectively. These indices were statistically higher versus indices obtained after autologous grafting. Myelination rates of regenerated fibers in animal groups NGG60 and NGgfB60 were 73 and 86 %, respectively. They were also statistically higher. The average sciatic functional index (SFI) in NGG60 and NGgfB60 was: -25.57 ± 3.05 and -24.124 ± 4.8, respectively, which is statistically equal to indices obtained after autologous grafting. CONCLUSIONS: Neurogel™ strongly promotes the regeneration of rat sciatic nerve within silicone tubular prosthesis. After bridging a 10-mm gap through silicone prosthesis with Neurogel™ or Neurogel™ +NGF-B-modified intraluminal space, the myelination rate of regenerated axons of rat sciatic nerve appeared to be higher, and the axon count and functional recovery is similar to results seen with the autografting technique.

The discovery of the pyramidal neurons: Vladimir Betz and a new era of neuroscience.

As a consequence of nascent technology, the 19th century witnessed a profound change in orientation to the nervous system. For example, improved microscopy in the first half of the 19th century allowed high magnification without blurring. The subsequent observation of nucleated cells led to the identification of individual brain cells. Philosophical changes in approach to the natural sciences took their lead from those applied to physical observations. The Ukrainian anatomist and histologist, Vladimir Alekseyevich Betz (1834-94) played a pivotal role in reshaping scientific and philosophical approaches to the brain, connecting cerebral localization, function and brain microstructure. Betz revolutionized methods of cell fixation and staining. Sometimes his efforts yielded enormously complicated technological improvements. Betz's greatest contribution, however, was connecting his discovery of the function of giant pyramidal neurons of the primary motor cortex ('cells of Betz') with the cortical organization. Considering cortical cytoarchitectonics in relation with physiological function, Betz recognized this organization in two areas: motor and sensory. He defined a functional area on histological grounds and thereby opened the way to study precise cortical areas. Betz participated in the scientific transformation of cytoarchitectonics based on macro- and microscopic studies of the cortical surface, enabling him to view the paths of nerve cells in the brain. Betz's influence allowed systemization of scattered scientific findings. The discovery of pyramidal cells was a turning point in the prevailing philosophical and scientific approach to the brain, linking cytoarchitecture, neurophysiology and cerebral localization.