High-Resolution Magic-Angle Spinning NMR Spectroscopy for Evaluation of Cell Shielding by Virucidal Composites Based on Biogenic Silver Nanoparticles, Flexible Cellulose Nanofibers and Graphene Oxide.

Antiviral and non-toxic effects of silver nanoparticles onto in vitro cells infected with coronavirus were evaluated in this study using High-Resolution Magic-Angle Spinning Nuclear Magnetic Resonance (HR-MAS NMR) spectroscopy. Silver nanoparticles were designed and synthesized using an orange flavonoid-hesperetin (HST)-for reduction of silver(I) and stabilization of as obtained nanoparticles. The bio-inspired process is a simple, clean, and sustainable way to synthesize biogenic silver nanoparticles (AgNP@HST) with diameters of ∼20 nm and low zeta potential (-40 mV), with great colloidal stability monitored for 2 years. The nanoparticles were used for the fabrication of two types of antiviral materials: colloids (AgNP@HST spray) and 3D flexible nanostructured composites. The composites, decorated with AgNP@HST (0.05 mmol L-1), were made using cellulose nanofibers (CNF) obtained from orange peel and graphene oxide (GO), being denominated CNF@GO@AgNP@HST. Both materials showed high virucidal activity against coronaviruses in cell infection in vitro models and successfully inhibited the viral activity in cells. HR-MAS 1H-NMR technique was used for determining nanomaterials' effects on living cells and their influences on metabolic pathways, as well as to study viral effects on cells. It was proven that none of the manufactured materials showed toxicity towards the intact cells used. Furthermore, viral infection was reverted when cells, infected with the coronavirus, were treated using the as-fabricated nanomaterials. These significant results open possibilities for antiviral application of 3D flexible nanostructured composite such as packaging papers and filters for facial masks, while the colloidal AgNP@HST spray can be used for disinfecting surfaces, as well as a nasal, mouth, and eye spray.

Effects of light finger touch on the regularity of center-of-pressure fluctuations during quiet bipedal and single-leg postural tasks.

BACKGROUND: The use of extra sources of sensory information associated with light fingertip touch to enhance postural steadiness has been associated with increased attentional demands, whereas the regularity of center of pressure (COP) fluctuations has been interpreted as a marker of the amount of attention invested in posture control. RESEARCH QUESTION: This study addressed whether increased attentional demands associated with postural tasks involving light finger touch might be reflected by measures of COP regularity. METHODS: The experiments involved quiet bipedal stance (n = 8 participants) and single-legged stance (n = 14 participants). Each participant was instructed to stand as quietly as possible on a force plate, either touching an external rigid surface (applied force < 1 N, light touch condition), or not (no touch condition). Postural steadiness was assessed by traditional COP measurements (COP Area, RMS, and velocity), whereas the regularity of postural sway was based on estimates of the sample entropy (SaEn) of the COP time series. RESULTS: Traditional parameters of postural sway and COP regularity (inversely related to SaEn COP measurements) were reduced during the touch conditions as compared to the no-touch conditions, for both bipedal quiet stance and single-legged stance. Decreased COP regularity with light touch was mainly reflected in the direction of the largest postural sway (i.e. in the sagittal plane for bipedal stance and in the frontal plane for single-legged stance). SIGNIFICANCE: The present results suggest that actively touching an external surface with the fingertip, besides increasing postural steadiness, generated an externally oriented (presumably cognitive-dependent) focus of attention, so that participants invested less attention on the postural task per se (as suggested by increased SaEn), which might be associated with a more "automatic" control of posture.

Influence of central and peripheral motor unit properties on isometric muscle force entropy: A computer simulation study.

Approximate entropy of isometric force is a popular measure to characterize behavioral changes across muscle contraction conditions. The degree to which force entropy characterizes the randomness of the motor control strategy, however, is not known. In this study, we used a computational model to investigate the correlation between approximate entropy of the synaptic input to a motor neuron pool, the neural drive to muscle (cumulative spike train; CST), and the force. This comparison was made across several simulation conditions, that included different synaptic command signal bandwidths, motor neuron pool sizes, and muscle contractile properties. The results indicated that although force entropy to some degree reflects the entropy of the synaptic command to motor neurons, it is biased by changes in motor unit properties. As a consequence, there was a low correlation between approximate entropy of force and the motor neuron input signal across all simulation conditions (r2 = 0.13). Therefore, force entropy should only be used to compare motor control strategies across conditions where motor neuron properties can be assumed to be maintained. Instead, we recommend that the entropy of the descending motor commands should be estimated from CSTs comprising spike trains of multiple motor units.

Effects of voluntary contraction on the soleus H-reflex of different amplitudes in healthy young adults and in the elderly.

A number of H-reflex studies used a moderate steady voluntary contraction in an attempt to keep the motoneuron pool excitability relatively constant. However, it is not clear whether the voluntary muscle activation itself represents a confounding factor for the elderly, as a few ongoing mechanisms of reflex modulation might be compromised. Further, it is well-known that the amount of either inhibition or facilitation from a given conditioning depends on the size of the test H-reflex. The present study aimed at evaluating the effects of voluntary contraction over a wide range of reflex amplitudes. A significant reflex facilitation during an isometric voluntary contraction of the soleus muscle (15% of the maximal voluntary isometric contraction-MVC) was found for both young adults and the elderly (p < 0.05), regardless of their test reflex amplitudes (considering the ascending limb of the H-reflex recruitment curve-RC). No significant difference was detected in the level of reflex facilitation between groups for all the amplitude parameters extracted from the RC. Simulations with a computational model of the motoneuron pool driven by stationary descending commands yielded qualitatively similar amount of reflex facilitation, as compared to human experiments. Both the experimental and modeling results suggest that possible age-related differences in spinal cord mechanisms do not significantly influence the reflex modulation during a moderate voluntary muscle activation. Therefore, a background voluntary contraction of the ankle extensors (e.g., similar to the one necessary to maintain upright stance) can be used in experiments designed to compare the RCs of both populations. Finally, in an attempt to elucidate the controversy around changes in the direct motor response (M-wave) during contraction, the maximum M-wave (Mmax) was compared between groups and conditions. It was found that the Mmax significantly increases (p < 0.05) during contraction and decreases (p < 0.05) with age arguably due to muscle fiber shortening and motoneuron loss, respectively.

Neurophysiological correlates of force control improvement induced by sinusoidal vibrotactile stimulation.

OBJECTIVE: An optimal level of vibrotactile stimulation has been shown to improve sensorimotor control in healthy and diseased individuals. However, the underlying neurophysiological mechanisms behind the enhanced motor performance caused by vibrotactile stimulation are yet to be fully understood. Therefore, here we aim to evaluate the effect of a cutaneous vibration on the firing behavior of motor units in a condition of improved force steadiness. APPROACH: Participants performed a visuomotor task, which consisted of low-intensity isometric contractions of the first dorsal interosseous (FDI) muscle, while sinusoidal (175 Hz) vibrotactile stimuli with different intensities were applied to the index finger. High-density surface electromyogram was recorded from the FDI muscle, and a decomposition algorithm was used to extract the motor unit spike trains. Additionally, computer simulations were performed using a multiscale neuromuscular model to provide a potential explanation for the experimental findings. MAIN RESULTS: Experimental outcomes showed that an optimal level of vibration significantly improved force steadiness (estimated as the coefficient of variation of force). The decreased force variability was accompanied by a reduction in the variability of the smoothed cumulative spike train (as an estimation of the neural drive to the muscle), and the proportion of common inputs to the FDI motor nucleus. However, the interspike interval variability did not change significantly with the vibration. A mathematical approach, together with computer simulation results suggested that vibrotactile stimulation would reduce the variance of the common synaptic input to the motor neuron pool, thereby decreasing the low frequency fluctuations of the neural drive to the muscle and force steadiness. SIGNIFICANCE: Our results demonstrate that the decreased variability in common input accounts for the enhancement in force control induced by vibrotactile stimulation.

Sinusoidal vibrotactile stimulation differentially improves force steadiness depending on contraction intensity.

Studies have reported the benefits of sensory noise in motor performance, but it is not clear if this phenomenon is influenced by muscle contraction intensity. Additionally, most of the studies investigated the role of a stochastic noise on the improvement of motor control and there is no evidence that a sinusoidal vibrotactile stimulation could also enhance motor performance. Eleven participants performed a sensorimotor task while sinusoidal vibrations were applied to the finger skin. The effects of an optimal vibration (OV) on force steadiness were evaluated in different contraction intensities. We assessed the standard deviation (SD) and coefficient of variation (CoV) of force signals. OV significantly decreased force SD irrespective of contraction intensity, but the decrease in force CoV was significantly higher for low-intensity contraction. To the best of our knowledge, our findings are the first evidence that sinusoidal vibrotactile stimulation can enhance force steadiness in a motor task. Also, the significant improvement caused by OV during low-intensity contractions is probably due to the higher sensitivity of the motor system to the synaptic noise. These results add to the current knowledge on the effects of vibrotactile stimulation in motor control and have potential implications for the development of wearable haptic devices. Graphical abstract In this work the effects of a sinusoidal vibrotactile stimulation on force steadiness was investigated. Index finger sensorimotor tasks were performed in three levels of isometric contraction of the FDI muscle: 5, 10 and 15 %MVC. An optimal level of vibration significantly improved force steadiness, but the decrease in force CoV caused by vibration was more pronounced in contractions at 5 %MVC.

Perspectives on the modeling of the neuromusculoskeletal system to investigate the influence of neurodegenerative diseases on sensorimotor control

Abstract Introduction The understanding of the neurophysiological mechanisms underlying movement control can be much furthered using computational models of the neuromusculoskeletal system. Biologically based multi-scale neuromusculoskeletal models have a great potential to provide new theories and explanations related to mechanisms behind muscle force generation at the molecular, cellular, synaptic, and systems levels. Albeit some efforts have been made to investigate how neurodegenerative diseases alter the dynamics of individual elements of the neuromuscular system, such diseases have not been analyzed from a systems viewpoint using multi-scale models. Overview and Perspectives This perspective article synthesizes what has been done in terms of multi-scale neuromuscular development and points to a few directions where such models could be extended so that they can be useful in the future to discover early predictors of neurodegenerative diseases, as well as to propose new quantitative clinical neurophysiology approaches to follow the course of improvements associated with different therapies (drugs or others). Concluding Remarks Therefore, this article will present how existing biologically based multi-scale models of the neuromusculoskeletal system could be expanded and adapted for clinical applications. It will point to mechanisms operating at different levels that would be relevant to be considered during model development, along with implications for interpreting experimental results from neurological patients.

D1 and D2 Inhibitions of the Soleus H-Reflex Are Differentially Modulated during Plantarflexion Force and Position Tasks.

Presynaptic inhibition (PSI) has been shown to modulate several neuronal pathways of functional relevance by selectively gating the connections between sensory inputs and spinal motoneurons, thereby regulating the contribution of the stretch reflex circuitry to the ongoing motor activity. In this study, we investigated whether a differential regulation of Ia afferent inflow by PSI may be associated with the performance of two types of plantarflexion sensoriomotor tasks. The subjects (in a seated position) controlled either: 1) the force level exerted by the foot against a rigid restraint (force task, FT); or 2) the angular position of the ankle when sustaining inertial loads (position task, PT) that required the same level of muscle activation observed in FT. Subjects were instructed to maintain their force/position at target levels set at ~10% of maximum isometric voluntary contraction for FT and 90° for PT, while visual feedback of the corresponding force/position signals were provided. Unconditioned H-reflexes (i.e. control reflexes) and H-reflexes conditioned by electrical pulses applied to the common peroneal nerve with conditioning-to-test intervals of 21 ms and 100 ms (corresponding to D1 and D2 inhibitions, respectively) were evoked in a random fashion. A significant main effect for the type of the motor task (FT vs PT) (p = 0.005, η2p = 0.603) indicated that PTs were undertaken with lower levels of Ia PSI converging onto the soleus motoneuron pool. Additionally, a significant interaction between the type of inhibition (D1 vs D2) and the type of motor task (FT vs PT) (p = 0.038, η2p = 0.395) indicated that D1 inhibition was associated with a significant reduction in PSI levels from TF to TP (p = 0.001, η2p = 0.731), whereas no significant difference between the tasks was observed for D2 inhibition (p = 0.078, η2p = 0.305). These results suggest that D1 and D2 inhibitions of the soleus H-reflex are differentially modulated during the performance of plantarflexion FT and PT. The reduced level of ongoing PSI during PT suggests that, in comparison to FT, there is a larger reliance on inputs from muscle spindles primary afferents when the neuromuscular system is required to maintain position-controlled plantarflexion contractions.

Enhanced D1 and D2 inhibitions induced by low-frequency trains of conditioning stimuli: differential effects on H- and T-reflexes and possible mechanisms.

Mechanically evoked reflexes have been postulated to be less sensitive to presynaptic inhibition (PSI) than the H-reflex. This has implications on investigations of spinal cord neurophysiology that are based on the T-reflex. Preceding studies have shown an enhanced effect of PSI on the H-reflex when a train of ~10 conditioning stimuli at 1 Hz was applied to the nerve of the antagonist muscle. The main questions to be addressed in the present study are if indeed T-reflexes are less sensitive to PSI and whether (and to what extent and by what possible mechanisms) the effect of low frequency conditioning, found previously for the H-reflex, can be reproduced on T-reflexes from the soleus muscle. We explored two different conditioning-to-test (C-T) intervals: 15 and 100 ms (corresponding to D1 and D2 inhibitions, respectively). Test stimuli consisted of either electrical pulses applied to the posterior tibial nerve to elicit H-reflexes or mechanical percussion to the Achilles tendon to elicit T-reflexes. The 1 Hz train of conditioning electrical stimuli delivered to the common peroneal nerve induced a stronger effect of PSI as compared to a single conditioning pulse, for both reflexes (T and H), regardless of C-T-intervals. Moreover, the conditioning train of pulses (with respect to a single conditioning pulse) was proportionally more effective for T-reflexes as compared to H-reflexes (irrespective of the C-T interval), which might be associated with the differential contingent of Ia afferents activated by mechanical and electrical test stimuli. A conceivable explanation for the enhanced PSI effect in response to a train of stimuli is the occurrence of homosynaptic depression at synapses on inhibitory interneurons interposed within the PSI pathway. The present results add to the discussion of the sensitivity of the stretch reflex pathway to PSI and its functional role.

Spinal mechanisms may provide a combination of intermittent and continuous control of human posture: predictions from a biologically based neuromusculoskeletal model.

Several models have been employed to study human postural control during upright quiet stance. Most have adopted an inverted pendulum approximation to the standing human and theoretical models to account for the neural feedback necessary to keep balance. The present study adds to the previous efforts in focusing more closely on modelling the physiological mechanisms of important elements associated with the control of human posture. This paper studies neuromuscular mechanisms behind upright stance control by means of a biologically based large-scale neuromusculoskeletal (NMS) model. It encompasses: i) conductance-based spinal neuron models (motor neurons and interneurons); ii) muscle proprioceptor models (spindle and Golgi tendon organ) providing sensory afferent feedback; iii) Hill-type muscle models of the leg plantar and dorsiflexors; and iv) an inverted pendulum model for the body biomechanics during upright stance. The motor neuron pools are driven by stochastic spike trains. Simulation results showed that the neuromechanical outputs generated by the NMS model resemble experimental data from subjects standing on a stable surface. Interesting findings were that: i) an intermittent pattern of muscle activation emerged from this posture control model for two of the leg muscles (Medial and Lateral Gastrocnemius); and ii) the Soleus muscle was mostly activated in a continuous manner. These results suggest that the spinal cord anatomy and neurophysiology (e.g., motor unit types, synaptic connectivities, ordered recruitment), along with the modulation of afferent activity, may account for the mixture of intermittent and continuous control that has been a subject of debate in recent studies on postural control. Another finding was the occurrence of the so-called "paradoxical" behaviour of muscle fibre lengths as a function of postural sway. The simulations confirmed previous conjectures that reciprocal inhibition is possibly contributing to this effect, but on the other hand showed that this effect may arise without any anticipatory neural control mechanism.

Web-based neuromuscular simulator applied to the teaching of principles of neuroscience

INTRODUCTION: The learning of core concepts in neuroscience can be reinforced by a hands-on approach, either experimental or computer-based. In this work, we present a web-based multi-scale neuromuscular simulator that is being used as a teaching aid in a campus-wide course on the Principles of Neuroscience. METHODS: The simulator has several built-in individual models based on cat and human biophysics, which are interconnected to represent part of the neuromuscular system that controls leg muscles. Examples of such elements are i) single neurons, representing either motor neurons or interneurons mediating reciprocal, recurrent and Ib inhibition; ii) afferent fibers that can be stimulated to generate spinal reflexes; iii) muscle unit models, generating force and electromyogram; and iv) stochastic inputs, representing the descending volitional motor drive. RESULTS: Several application examples are provided in the present report, ranging from studies of individual neuron responses to the collective action of many motor units controlling muscle force generation. A subset of them was included in an optional homework assignment for Neuroscience and Biomedical Engineering graduate students enrolled in the course cited above at our University. Almost all students rated the simulator as a good or an excellent learning tool, and approximately 90% declared that they would use the simulator in future projects. CONCLUSION: The results allow us to conclude that multi-scale neuromuscular simulator is an effective teaching tool. Special features of this free teaching resource are its direct usability from any browser (http://remoto.leb.usp.br/), its user-friendly graphical user interface (GUI) and the preset demonstrations.

Models of passive and active dendrite motoneuron pools and their differences in muscle force control.

Motoneuron (MN) dendrites may be changed from a passive to an active state by increasing the levels of spinal cord neuromodulators, which activate persistent inward currents (PICs). These exert a powerful influence on MN behavior and modify the motor control both in normal and pathological conditions. Motoneuronal PICs are believed to induce nonlinear phenomena such as the genesis of extra torque and torque hysteresis in response to percutaneous electrical stimulation or tendon vibration in humans. An existing large-scale neuromuscular simulator was expanded to include MN models that have a capability to change their dynamic behaviors depending on the neuromodulation level. The simulation results indicated that the variability (standard deviation) of a maintained force depended on the level of neuromodulatory activity. A force with lower variability was obtained when the motoneuronal network was under a strong influence of PICs, suggesting a functional role in postural and precision tasks. In an additional set of simulations when PICs were active in the dendrites of the MN models, the results successfully reproduced experimental results reported from humans. Extra torque was evoked by the self-sustained discharge of spinal MNs, whereas differences in recruitment and de-recruitment levels of the MNs were the main reason behind torque and electromyogram (EMG) hysteresis. Finally, simulations were also used to study the influence of inhibitory inputs on a MN pool that was under the effect of PICs. The results showed that inhibition was of great importance in the production of a phasic force, requiring a reduced co-contraction of agonist and antagonist muscles. These results show the richness of functionally relevant behaviors that can arise from a MN pool under the action of PICs.