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Natalia M Yudintceva,1 Yulia A Nashchekina,1,2 Miralda I Blinova,1 Nadezhda V Orlova,3 Alexandr N Muraviov,3 Tatiana I Vinogradova,3 Magomed G Sheykhov,3 Elena Y Shapkova,3 Dmitriy V Emeljannikov,3 Petr K Yablonskii,3,4 Igor A Samusenko,5 Anastasiya L Mikhrina,6 Artem V Pakhomov,7 Maxim A Shevtsov1,7,8 1Department of Cell Culture, Institute of Cytology of the Russian Academy of Sciences (RAS), 2Nanotechnology and Telecommunications, Institute of Physics, Peter the Great St Petersburg Polytechnic University, 3Department of Urology, Federal State Institution Saint Petersburg Research Institute of Phthisiopulmonology, Ministry of Health of Russia, 4Faculty of Medicine, Federal State Budgetary Institute, 5Department of Pathology, Federal State Budgetary Institute “Nikiforov Russian Centre of Emergency and Radiation Medicine” of the Ministry of Health of Russia, 6Department of Pathomorphology, I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Science, 7Department of Radiology, Federal Almazov North-West Medical Research Center, 8Department of Experimental Medicine, First I.P. Pavlov State Medical University of St Petersburg, St Petersburg, Russia Abstract: In the present study, a poly-L-lactide/silk fibroin (PL-SF) bilayer scaffold seeded with allogenic bone marrow stromal cells (BMSCs) was investigated as a potential approach for bladder tissue engineering in a model of partial bladder wall cystectomy in rabbits. The inner porous layer of the scaffold produced from silk fibroin was designed to promote cell proliferation and the outer layer produced from poly-L-lactic acid to serve as a waterproof barrier. To compare the feasibility and efficacy of BMSC application in the reconstruction of bladder defects, 12 adult male rabbits were divided into experimental and control groups (six animals each) that received a scaffold seeded with BMSCs or an acellular one, respectively. For BMSC tracking in the graft in in vivo studies using magnetic resonance imaging, cells were labeled with superparamagnetic iron oxide nanoparticles. In vitro studies demonstrated high intracellular incorporation of nanoparticles and the absence of a toxic influence on BMSC viability and proliferation. Following implantation of the graft with BMSCs into the bladder, we observed integration of the scaffold with surrounding bladder tissues (as detected by magnetic resonance imaging). During the follow-up period of 12 weeks, labeled BMSCs resided in the implanted scaffold. The functional activity of the reconstructed bladder was confirmed by electromyo­graphy. Subsequent histological assay demonstrated enhanced biointegrative properties of the PL-SF scaffold with cells in comparison to the control graft, as related to complete regener­ation of the smooth muscle and urothelium tissues in the implant. Confocal microscopy studies confirmed the presence of the superparamagnetic iron oxide nanoparticle-labeled BMSCs in newly formed bladder layers, thus indicating the role of stem cells in bladder regeneration. The results of this study demonstrate that application of a PL-SF scaffold seeded with allogenic BMSCs can enhance biointegration of the graft in vivo and support bladder tissue regeneration and function. Keywords: bladder, bone marrow stromal cells, scaffold, superparamagnetic iron oxide nanoparticles, tissue engineering, stem cells

Neuromodulating the locomotor network through spinal cord electrical stimulation (SCES) is effective for restoring function in individuals with gait deficits. However, SCES alone has limited effectiveness without concurrent locomotor function training that enhances activity-dependent plasticity of spinal neuronal networks by sensory feedback. This mini review discusses recent developments in using combined interventions, such as SCES added to exoskeleton gait training (EGT). To develop personalized therapies, it is crucial to assess the state of spinal circuitry through a physiologically relevant approach that identifies individual characteristics of spinal cord function to develop person-specific SCES and EGT. The existing literature suggests that combining SCES and EGT to activate the locomotor network can have a synergistic rehabilitative effect on restoring walking abilities, somatic sensation, and cardiovascular and bladder function in paralyzed individuals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ivanenko, Shapkova, Petrova, Kleeva and Lebedev.)

In recent years, advanced technologies featuring wearable powered exoskeletons and neuromodulation of lumbosacral spinal networks have been developed to facilitate stepping and promote motor recovery in humans with paralysis. Here we studied a combined effect of spinal cord electrical stimulation (SCES) and exoskeleton walk training (EWT) during an intensive 2-week rehabilitative protocol in spinal cord injury individuals ( n = 19, American Spinal Injury Association Impairment Scale (AIS) A-11, B-5, C-3). The purpose of this study was to evaluate the compatibility of methods and to explore the main effects of combined SCES and EWT. All participants had a chronic state of paralysis (1-11 years after trauma). In addition, in the control group ( n = 16, AIS A-7, B-5, C-4), we performed EWT without SCES. For EWT, we used a powered exoskeleton (ExoAtlet), while stability was assisted by crutches, with automatic arrest of stepping if excessive torques were detected. SCES was applied to the level of the mid-lumbar cord over the Th12 vertebra at 1 or 3 pulses/s (4 individuals with severe spasticity were also stimulated in an anti-spastic mode 67 pulses/s). The vertical component of the ground reaction force was recorded using the F-Scan system at the onset and after training with SCES. EWT with SCES significantly increased the foot loading forces, could decrease their asymmetry and 8 out of 19 subjects improved their Hauser Ambulation Index. The anti-spastic mode of stimulation also allowed individuals with severe spasticity to walk with the aid of the exoskeleton. Participants reported facilitation when walking with SCES, paresthesia in leg muscles and new non-differential sensation of passive motion in leg joints. Neurological examination showed an increase of tactile (7) and/or pain (7) sensation and an increase of the AIS motor scale in 9 individuals, including both incomplete and complete paralysis. Improvements in the neurological scores were, however, limited in the control group (EWT without SCES). The results suggest that SCES may facilitate training and walking in the exoskeleton by activating the locomotor networks and augmenting compensative sensitivity., (Copyright © 2020 Shapkova, Pismennaya, Emelyannikov and Ivanenko.)

We analyzed the efficiency of percutaneous electrical stimulation of the spinal cord and serotonin receptor activation in rehabilitation of paralyzed patients. Four-week course of spinal cord electrical stimulation combined with mechanotherapy produced positive shifts in the status of chronically paralyzed patients. Serotonin receptor activation potentiated the effect of spinal cord stimulation and can be regarded as an additional neurorehabilitation option.

Multisegmental muscle responses (MMR) are reflexes in the leg muscles evoked by transcutaneous electrical spinal cord stimulation over the Th11–Th12 vertebrae. We have used MMR to evaluate the excitability of lumbosacral motor neurons in individuals suffering lower paraplegia. Ten individuals were tested using H-reflexes and MMR bilaterally before (n 0 = 20) and during 4-weeks course of rehabilitation (n=76). The H-reflex and MMR of m. gastrocnemius lateralis were obtained in: 15 and 13 cases out of 20, respectively. Both reflexes were recorded in 11 and were absent in 3 cases, matched up to 70% of recordings. In dynamic, the both methods were 100% reproducible and the responses’ amplitude varied in similar directions in 67% of records. The data confirm the validity and reproducibility of the MMR for evaluation of the motor neurons excitability in lumbosacral cord. The H-reflex magnitude shows moderate correlation with MMR in m. gastrocnemius lateralis (r = 0.59, p < 0.001), and low correlation with MMR in mm. rectus femoris, biceps femoris, and tibialis anterior (r < 0.40, p < 0.001). These findings do not allow extrapolate the results from the H-reflex measurement on the state of lumbosacral cord. At the same time, measurements of the MMR allow estimate simultaneously the excitability of motor pools innervating several muscle groups. This makes advantageous to assess the functional state of the motor neurons in the lumbosacral spinal cord for clinical and experimental studies, including the spinal cord damage.

We studied the coordination of arm movements in standing persons who performed an out-of-phase arm-swinging task while stepping in place or while standing. The subjects were instructed to stop one of the arms in response to an auditory signal while trying to keep the rest of the movement pattern unchanged. A significant increase was observed in the amplitude of the arm that continued swinging under both the stepping and standing conditions. This increase was similar between the right and left arms. A dynamic model was developed including two coupled nonlinear van der Pol oscillators. We assumed that stopping an arm did not eliminate the coupling but introduced a new constraint. Within the model, superposition of two factors, a command to stop the ongoing movement of one arm and the coupling between the two oscillators, has been able to account for the observed effects. The model makes predictions for future experiments.

We studied the organization of leg and trunk muscles into groups (M-modes) and co-variation of M-mode involvement (M-mode synergies) during whole-body tasks associated with large variations of the moment of force about the vertical body axis. Our major questions were: (1) can muscle activation patterns during such tasks be described with a few M-modes common across tasks and subjects? (2) do these modes form the basis for synergies stabilizing M(z) time pattern? (3) will this organization differ between an explicit body-rotation task and a task associated with locomotor-like alternating arm movements? Healthy subjects stood barefoot on the force platform and performed two motor tasks while paced by the metronome at 0.7, 1.0, and 1.4 Hz: cyclic rotation of the upper body about the vertical body axis (body-rotation task), and alternating rhythmic arm movements imitating those during running or quick walking (arm-movement task). Principal component analysis was used to identify three M-modes within the space of integrated indices of muscle activity. The M-mode vectors showed clustering neither across subjects nor across frequencies. Variance in the M-mode space across sway cycles was partitioned into two components, one that did not affect the average value of M(z) shift ("good variance") and the other that did. An index was computed reflecting the relative amount of the "good variance"; positive values of this index have been interpreted as reflecting a multi-M-mode synergy stabilizing the M(z) trajectory. On average, the index was positive for both tasks and across all frequencies studied. However, the magnitude of the index was smaller for the intermediate frequency (1 Hz). The results show that the organization of muscles into groups during relatively complex whole-body tasks can differ significantly across both task variations and subjects. Nevertheless, the central nervous system seems to be able to build M(z) stabilizing synergies based on different sets of M-modes, within the approach accepted in this study. The drop in the synergy index at the frequency of 1 Hz, which was close to the preferred movement frequency, may be interpreted as corroborating the neural origin of the M-mode co-variation.

We tested a hypothesis that force production by multi-finger groups leads to lower indices of force variability as compared to similar single-finger tasks. Three experiments were performed with quick force production, steady-state force production under visual feedback, and steady-state force production without visual feedback. In all experiments, a range of force levels was used computed as percentages of the maximal voluntary contraction force for each involved finger combination. Force standard deviation increased linearly with force magnitude across all three experiments and all finger combinations. There were modest differences between multi-finger and single-finger tasks in the indices of force variability, significant only in the tasks with steady-state force production under visual feedback. When fingers acted in groups, each finger showed significantly higher force variability as compared to its single-finger task and as compared to the multi-finger group as a whole. Fingers that were not instructed to produce force also showed close to linear relations between force standard deviation and force magnitude. For these fingers, indices of force variability were much higher as compared to those computed for the forces produced by instructed fingers. We interpret the findings within a feed-forward scheme of multi-finger control with two inputs only one of which is related to the explicit task. The total force variability reflects variability in only the task-related component, while variability of the finger forces is also due to variability of the component that is not related to the task. The findings tentatively suggest that total force variability originates at an upper level of the control hierarchy in accordance to the Weber-Fechner law rather than reflects a "neural noise" at the segmental level.

The study addresses postural preparation to stepping. In particular, it tests a hypothesis that such preparation involves adjustments in the activity of ankle plantarflexors to produce shifts of the center of pressure. We investigated the initiation of a step from quiet stance when the subjects stood on boards with a decreased dimension of the support area in the anterior-posterior direction ("unstable boards"). Stepping from an unstable board was associated with decreased preparatory shifts of the center of pressure (COP) in the anterior-posterior direction from about 3 cm to 0.9 cm and further to 0.1cm when the support narrowed from comfortable standing to 3.3 cm and to nearly 0 cm. There was a smaller decrease in the COP shift in the medio-lateral direction. When the subjects stood on a board which rested on a very narrow ridge ("zero-support"), they showed an increase in the magnitude of changes in the horizontal force immediately prior to making a step. There was a general increase in the level of activation of leg and trunk muscles during stepping from unstable boards. The modulation of the activity of ankle plantarflexors increased during stepping from unstable boards. We conclude that, to initiate a step, COP shifts and changes in shear force can be modulated independently of each other in a constraint-specific manner. The results speak against the hypothesis that modulation of ankle plantarflexor activity during postural adjustments is directly related to the production of COP shifts.

The aim of the studies reported here was to quantify changes in balance control for stance and gait tasks with age and to pinpoint possible advantages and difficulties in using these tasks and measures derived from them to identify pathological balance control in patients. Some 470 normal subjects in the age range 6 to 82 were examined for a battery of 14 stance and gait tasks. During the tasks, angular velocity transducers mounted at lumbar 1-3 measured pitch and roll angular velocities of the body. A combination of outcome measures from several tasks was used to create an overall balance control index. Three types of sensory analyses on pitch angle and velocity amplitudes for stance trials were used to quantify possible changes in the contributions of visual, somatosensory and vestibular inputs to balance control with age for 2-legged stance tasks. Correlation analysis on task variables was used to determine the relationship of subjects' age and height on outcome measures. Outcome measures showed a characteristic "L" or "U" shaped profile with a rapid decrease in values between 7 and 25 years of age, a plateau until 55 then a gradual increase with age after 55 years of age for most stance and gait tasks. The sensory analysis technique using differences between stance tests indicated that visual contributions to balance control continuously increased with age between the ages of 15 and 80, and vestibular and lower leg somatosensory contributions remain relatively constant with age. Sensory analysis calculated as commonly-used quotients of outcome measures revealed large variance across all ages, asymmetric distributions, and no clear trends in sensory contributions to stance with age. A third technique based on a discriminant function analysis using measures from model patient populations indicated that proprioceptive but not vestibular contributions first increased with age and then decreased after 55 years of age. Correlations of outcome measures with age and height indicated that both contributed equally to changes in outcome measures between the ages of 7 and 25, otherwise height had no effect. We conclude that both stance and gait tasks should be selected for identifying changes in balance control from that of healthy persons with a preference for gait tasks as these show less variation with age. Because of the large increases in variance in the elderly and those younger than 20 years, appropriate age-matched reference values should be employed to ascertain if trunk sway is out of normal ranges.

The EMG-activity during stepping-like movements evoked by spinal cord electrical stimulation (SCES) was studied in paraplegic patients. Both typical locomotor EMG-pattern with rhythmically, bilaterally alternating flexor-extensor activity ("locomotor stepping") as well as a rhythmic, bilaterally alternating modulation of short latency stimulus coupled reflexes ("reflexogenic stepping") and mixed pattern were observed. While the frequency of "locomotor stepping" could be independent from the stimulus frequency and the stepping was continuing after the end of stimulation for several cycles, the "reflexogenic stepping" was largely somehow coupled to the stimulus frequency and ended with the end of stimulation. It is assumed that both types of rhythmic motor activity reflect the activity of a spinal locomotor generator, but that the activity of the locomotor generator is subthreshold for fully activating the motoneuronal pools in cases with "reflexogenic stepping".