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Control of posture is a prerequisite for efficient motor performance. Posture depends on muscles capable of enduring contractions, whereas movements often require quick, forceful muscle actions. To serve these different goals, muscles contain fibers that meet these different tasks. Muscles with strong postural functions mainly consist of slow muscle fibers with a great resistance against fatigue. Flexor muscles in the leg and arm muscles are mainly composed of fast muscle fibers producing relatively large forces that are rapidly fatigable. Development of the neuromuscular system continues after birth. We discuss in the human baby and in animal experiments changes in muscle fiber properties, regression from polyneural into mononeural innervation, and developmental changes in the motoneurons of postural muscles during that period. The regression of poly-neural innervation in postural muscles and the development of dendrite bundles of their motoneurons seem to be linked to the transition from the immature into the adult-like patterns of moving and postural control.

Biomaterial-assisted therapeutic strategies enable precise modulation to direct endogenous cellular responses and harness regenerative capabilities for nerve repair. However, achieving effective cellular engagement during nerve remodeling remains challenging. Herein, a novel composite nerve guidance conduit (NGC), the GelMA/PLys@PDA-Fe@PLCL conduit is developed by combining aligned poly(l-lactide-co-caprolactone) (PLCL) nanofibers modified with polydopamine (PDA), ferrous iron (Fe 3 ⁺), and polylysine (PLys) with aligned methacrylate-anhydride gelatin (GelMA) hydrogel nanofibers. PDA films exhibit strong adhesion and metal coordination properties, allowing Fe 3 ⁺ irons to chelate with phenolic hydroxyl groups of dopamine derivatives, forming a metal-phenolic network on PLCL. PLys molecules are then grafted onto PDA-Fe 3 ⁺ coating via Schiff base and Michael addition reactions. This multifunctional coating enhances surface roughness and zeta potential of PLCL nanofibers, imparts superhydrophilicity with anisotropic wetting behavior, and maintains wet tensile properties of substrates. In vitro studies show that the PLys@PDA-Fe coating significantly promotes aligned distribution of Schwann cells, improves cell adhesion and differentiation, and demonstrates notable antioxidant and anti-inflammatory properties. When implanted into nerve defects in rats, the multifunctional coating conduit combined with aligned GelMA hydrogel effectively accelerates axonal regeneration, remyelination, and angiogenesis, leading to enhanced motor function recovery. Overall, the GelMA/PLys@PDA-Fe@PLCL conduit presents a promising strategy for advancing peripheral nerve repair., (© 2024 Wiley‐VCH GmbH.)

Clinically, conventional sutures for repair of short-distance nerve injuries (< 5 mm) may contribute to uncontrolled inflammation and scar formation, thus negatively impacting nerve regeneration. To repair transected peripheral nerves with short distances, a rapid-forming, robust adhesive chitosan hydrogel is prepared by synthesizing maleic and dopamine bi-functionalized fungal-sourced chitosan (DM) and subsequently photopolymerizing DM precursor solution. The hydrogel rapidly polymerized under UV light irradiation (≈2 s) and possessed a strong adhesive strength (273.33 ± 55.07 kPa), facilitating a fast bonding of nerve stump. Especially, its tailored degradation profile over 28 days supported both early gap bridging and subsequent nerve regeneration. Furthermore, deferoxamine (DFO), a pro-angiogenic drug, is loaded into the hydrogel to reach sustainable release, accelerating axonal growth synergistically. A 3 mm long sciatic nerve defects model in rats is used to investigate the efficacy of DM@DFO hydrogel for repairing peripheral nerve defects. After 60 days, the DM@DFO hydrogel significantly outperformed conventional sutures and fibrin glue, improving motor and sensory recovery by reducing inflammation, inhibiting scar formation, and accelerating vascular regeneration within 14 days post-repair. This work highlights the DM@DFO hydrogel as a promising tissue adhesive for effective short-distance peripheral nerve repair., (© 2024 Wiley‐VCH GmbH.)

Peripheral nerve transection has a high prevalence and results in functional loss of affected limbs. The current clinical treatment using suture anastomosis significantly limits nerve recovery due to severe inflammation, secondary damage, and fibrosis. Fibrin glue, a commercial nerve adhesive as an alternative, avoids secondary damage but suffers from poor adhesion strength. To address their limitations, a highly efficacious nerve adhesive based on dual‐cross‐linking of dopamine‐isothiocyanate modified hyaluronic acid and decellularized nerve matrix is reportedr. This dual‐network nerve adhesive (DNNA) shows controllable gelation behaviors feasible for surgical applications, robust adhesion strength, and promotes axonal outgrowth in vitro. The in vivo therapeutic efficacy is tested using a rat‐based sciatic nerve transection model. The DNNA decreases fibrosis and accelerates axon/myelin debris clearance at 10 days post‐surgery, compared to suture and commercial fibrin glue treatments. At 10 weeks post‐surgery, the strong adhesion and bioactivity allow DNNA to significantly decrease intraneural inflammation and fibrosis, enhance axon connection and remyelination, aid motor and sensory function recovery, as well as improve muscle contraction, compared to suture and fibrin treatments. Overall, this dual‐network hydrogel with robust adhesion provides a rapid and highly efficacious nerve transection treatment to facilitate nerve repair and neuromuscular function recovery. [ABSTRACT FROM AUTHOR]

Paralysis of the trunk results in seated instability leading to difficulties performing activities of daily living. Functional neuromuscular stimulation (FNS) combined with control systems have the potential to restore some dynamic functions of the trunk. However, design of multi-joint, multi-muscle control systems requires characterization of the stimulation-driven muscles responsible for movement. Objective: This study characterizes the input-output properties of paralyzed trunk muscles activated by FNS, and explores co-activation of muscles. Methods: Four participants with various spinal cord injuries (C7 AIS-B, T4 AIS-B, T5 AIS-A, C5 AIS-C) were constrained so lumbar forces were transmitted to a load cell while an implanted neuroprosthesis activated otherwise paralyzed hip and paraspinal muscles. Isometric force recruitment curves in the nominal seated position were generated by inputting the level of stimulation (pulse width modulation) while measuring the resulting muscle force. Two participants returned for a second experiment where muscles were co-activated to determine if their actions combined linearly. Results: Recruitment curves of most trunk and hip muscles fit sigmoid shaped curves with a regression coefficient above 0.75, and co-activation of the muscles combined linearly across the hip and lumbar joint. Subject specific perturbation plots showed one subject is capable of resisting up to a 300N perturbation anteriorly and 125N laterally; with some subjects falling considerably below these values. Conclusion: Development of a trunk stability control system can use sigmoid recruitment dynamics and assume muscle forces combine linearly. Significance: This study informs future designs of multi-muscle, and multi-dimensional FNS systems to maintain seated posture and stability. [ABSTRACT FROM AUTHOR]

Some experimental research indicates that low-frequency pulsed electromagnetic field (PEMF) stimulation may accelerate regeneration in sciatic nerve injury. However, little research has examined the electrophysiological and functional properties of regenerating peripheral nerves under PEMF. The main aim of the present study is to investigate the effects of PEMF on sciatic nerve regeneration in short- and long-term processes with electrophysiologically and functionally after crushing damage. Crush lesions were performed using jewelery forceps for 30 s. After crush injury of the sciatic nerves, 24 female Wistar-Albino rats were divided into 3 groups with 8 rats in each group: SH(Sham), SNI (Sciatic Nerve Injury), SNI+PEMF(Sciatic Nerve Injury+Pulsed Electromagnetic Field). SNI+PEMF group was exposed to PEMF (4 h/day, intensity; 0.3mT, low-frequency; 2 Hz) for 40-days. Electrophysiological records (at the beginning and 1st, 2nd, 4th and 6th weeks post-crush) and functional footprints (at 1st, 2nd, 3rd, 4th, 5th and 6th weeks post crush) were measured from all groups during the experiment. The results were compared to SNI and SNI+PEMF groups, it was found that amplitude and area parameters in the first-week were significantly higher and latency was lower in the SNI+PEMF group than in the SNI group (p < 0,05). However, the effect of PEMF was not significant in the 2nd, 4th, 6th weeks. In addition, in the 1st and 2nd weeks, the SSI parameters were significantly higher in SNI+PMF group than SNI group (p <.05). These results indicate that low-frequency PEMF is not effective for long-periods of application time while PEMF may be useful during the short-term recovery period. [ABSTRACT FROM AUTHOR]

Peripheral nerve injuries are serious conditions, and surgical treatment has critical limitations. Therefore, nerve guidance conduits (NGCs) are proposed as an alternative. In this study, multifunctional NGCs are fabricated for the regeneration of injured peripheral nerves. Graphene oxide (GO) and gelatin‐methacrylate (GelMA) are polymerized and chemically reduced to form reduced (GO/GelMA) (r(GO/GelMA)). The prepared materials present good electrical conductivity, flexibility, mechanical stability, and permeability, which are suitable for use as NGCs. In vitro studies show 2.1‐ and 1.4‐fold promotion of neuritogenesis of PC12 neuronal cells on r(GO/GelMA) compared to GelMA and unreduced GO/GelMA, respectively. Animal studies using a rat sciatic nerve injury model with a 10 mm gap between the proximal and distal regions of the defect reveal that r(GO/GelMA) NGCs significantly enhance peripheral nerve regeneration, indicated by improved muscle weight increase, electro‐conduction velocity, and sciatic nerve function index. Specifically, r(GO/GelMA) NGCs are utilized to potentiate regrowth with myelination in rat sciatic nerves followed by histological, immunohistological, and morphometrical analyses. This study successfully shows the feasibility of electrically conductive hydrogel NGCs as functional conduits for improved nerve regeneration in a preclinical study, where these NGCs can not only mimic nerve tissues but also strongly promote nerve regeneration. [ABSTRACT FROM AUTHOR]

Tracing of neurons plays an essential role in elucidating neural networks in the brain and spinal cord. Cholera toxin B subunit (CTB) is already widely used as a tracer although its use is limited by the need for immunohistochemical detection. A new construct incorporating non-canonical azido amino acids (azido-CTB) offers a novel way to expand the range and flexibility of this neuronal tracer. Azido-CTB can be detected rapidly in vivo following intramuscular tongue injection by 'click' chemistry, eliminating the need for antibodies. Cadmium selenide/zinc sulfide (CdSe/ZnS) core/shell nanoparticles were attached to azido-CTB by strain-promoted alkyne–azide cycloaddition to make a nano-conjugate. Following tongue injections the complex was detected in vivo in the brainstem by light microscopy and electron microscopy via silver enhancement. This method does not require membrane permeabilization and so ultrastructure is maintained. Azido-CTB offers new possibilities to enhance the utility of CTB as a neuronal tracer and delivery vehicle by modification using 'click' chemistry. [ABSTRACT FROM AUTHOR]

This paper demonstrates flexible epineural strip electrodes (FLESE) for recording from small nerves. Small strip-shaped FLESE enables us to easily and closely stick on various sized nerves for less damage in a nerve and optimal recording quality. In addition, in order to enhance the neural interface, the gold electrode contacts were coated with carbon nanotubes, which reduced the impedance of the electrodes. We used the FLESEs to record electrically elicited nerve signals (compound neural action potentials) from the sciatic nerve in rats. Bipolar and differential bipolar configurations for the recording were investigated to optimize the recording configuration of the FLESEs. The successful results from differential bipolar recordings showed that the total length of FLESEs could be further reduced, maintaining the maximum recording ability, which would be beneficial for recording in very fine nerves. Our results demonstrate that new concept of FLESEs could play an important role in electroceuticals in near future. [ABSTRACT FROM PUBLISHER]

A novel chitosan adhesive film that incorporates the dye 'Rose Bengal' (RB) was used in conjunction with a green laser to repair transected rat median nerves in vivo. Histology and electrophysiological recording assessed the impact of the laser-adhesive technique on nerves. One week post-operatively, the sham-control group (laser-adhesive technique applied on un-transected nerves) conserved the average number and size of myelinated fibres in comparison to its contralateral side and electrophysiological recordings demonstrated no significant difference with un-operated nerves. Twelve weeks after the laser-adhesive anastomoses, nerves were in continuity with regenerated axons that crossed the anastomotic site. (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [ABSTRACT FROM AUTHOR]

Estimation of on–off timing of human skeletal muscles during movement is an ongoing issue in surface electromyography (sEMG) signal processing for relevant clinical applications. Widely used single threshold methods still rely on the experience of the operator to manually establish a threshold level. In this paper, a novel approach to address this issue is presented. Based on the generalized likelihood ratio test, the maximum likelihood (ML) method is improved with an adaptive threshold technique based on the signal-to-noise ratio (SNR) estimate in the initial time before accurate sEMG analyses. The dependence of optimal threshold on SNR is determined by minimizing the onset/offset estimate error on a large set of simulated signals with well-known signal parameters. Accuracy and precision of the algorithm were assessed by using a set of simulated signals and real sEMG signals recorded from two healthy subjects during elbow flexion-extension movements with and without workload. Comparison with traditional algorithms shows that with a moderate increase in the computational effort the ML algorithm performs well even for low levels of EMG activity, while the proposed adaptive method is most robust with respect to variations in SNRs. Also, we discuss the results of analyzing the sEMG recordings from the selected proximal muscles of the upper limb in two hemiparetic subjects. The detection algorithm is automatic and user-independent, managing the detection of both onset and offset activation, and is applicable in presence of noise allowing use by skilled and unskilled operators alike. [ABSTRACT FROM AUTHOR]

Corticotropin-releasing hormone (CRH) has been implicated to be involved in the development of dendrites in brain. In the present study, we examined the effect of CRH on dendrite outgrowth in primary cultured hippocampal neurons and defined the specific CRH receptor subtype involved. Treatment of neurons with increasing concentration of CRH resulted in an increase in the total dendritic branch length (TDBL) of neurons compared with untreated neurons over 2-4 days period of treatment. These effects can be reversed by the specific CRH-R1 antagonist antalarmin but not by the CRH-R2 antagonist astressin 2B. Treatment of neurons with urocortin II, the exclusive CRH-R2 agonist, significantly decreased TDBL of the cultured neurons. These effects can be reversed by the CRH-R2 antagonist astressin 2B. Our results suggest that CRH-R1 and CRH-R2 differentially modulate the dendritic growth of hippocampal neurons in culture. [ABSTRACT FROM AUTHOR]

Important basic science research is being conducted that has direct implications for the rehabilitation of patients, but the translation of this research to change clinical practice does not occur automatically. Advisory panels to the National Center for Medical Rehabilitation Research acknowledge a need for basic and applied research related to the factors underlying coordinated movements, such as the interactions of the neuromuscular and musculoskeletal systems. In this paper, we briefly describe recent studies that have examined the preceding interaction and discuss some basic issues related to the translation of these experiments to the clinic. More importantly, the main purpose of this paper is to discuss models/ways to translate basic science to clinical practice in a two-way and informed interaction between basic scientists and clinicians. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

In this study, patterns of activity in the soleus (Sol) and tibialis anterior (TA) muscles and hindlimb kinematics were evaluated during slope walking in rats after transection and surgical repair either of the entire sciatic nerve (Sci group) or of its two branches separately, the tibial and common fibular nerves (T/CF group). With the latter method, axons from the tibial and common fibular nerves could not reinnervate targets of the other nerve branch after injury, reducing the opportunity for misdirection. Activity in the TA shifted from the swing phase in intact rats to nearly the entire step cycle in both injured groups. Since these changes occur without misdirection of regenerating axons, they are interpreted as centrally generated. Sol activity was changed from reciprocal to that of TA in intact rats to coactivate with TA, but only in the Sci group rats. In the T/CF group rats, Sol activity was not altered from that observed in intact rats. Despite effects of injury that limited foot movements, hindlimb kinematics were conserved during downslope walking in both injury groups and during level walking in the T/CF group. During level walking in the Sci group and during upslope walking in both groups of injured rats, the ability to compensate for the effects of the nerve injury was less effective and resulted in longer limb lengths held at more acute angles throughout the step cycle. Changes in limb movements occur irrespective of axon misdirection and reflect compensatory changes in the outputs of the neural circuits that drive locomotion. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

There is an urgent need to generate new drugs or improve existing ones in the pharmacology of mood disorders. The corticotropin-releasing hormone (CRH) system is closely involved in the development and course of depression, and drugs targeting this system arguably offer hope to improve the current tools for drug treatment of depression. Recent clinical studies in depressed patients showed that CRHR1 antagonists improve clinical symptoms of anxiety and depression and reduce stress hormone release following psychosocial stress. These effects of CRHR1 antagonists were not associated with reduced secretory capacity of corticotrophic cells because of CRH receptor abundance at the pituitary level, which contrasts with CRH receptors in the brain. This is in accordance with previous studies showing that CRH injections into the mouse brain activate MAPK pathways in a brain region–specific manner pointing toward differences in signaling pathways beyond the receptor level. We will highlight this and discuss how these brain area–specific differences may offer opportunities for drug discovery. An additional puzzle in the search of new targets for depression is the lack of bona fide animal models helping to discover the antidepressants that are not monoamine based. We recently developed a conditional mouse model that overexpresses CRH in a spatio-temporal–regulated fashion and permits to dissect precisely the contribution of different brain areas to the CRH-dependent behaviors. Recent findings obtained with this mouse model and its usefulness in the context of the CRH-dependent, region-specific changes in depression will be discussed. [ABSTRACT FROM AUTHOR]

A classical view of the neuroendocrine–immune network assumes bidirectional interactions where pro-inflammatory cytokines influence hypothalamic–pituitary–adrenal (HPA) axis-derived hormones that subsequently affect cytokines in a permanently servo-controlled circle. Nevertheless, this picture has been continuously evolving over the last years as a result of the discovery of redundant expression and extended functions of many of the molecules implicated. Thus, cytokines are not only expressed in cells of the immune system but also in the central nervous system, and many hormones present at hypothalamic–pituitary level are also functionally expressed in the brain as well as in other peripheral organs, including immune cells. Because of this intermingled network of molecules redundantly expressed, the elucidation of the unique roles of HPA axis-related molecules at every level of complexity is one of the major challenges in the field. Genetic engineering in the mouse offers the most convincing method for dissecting in vivo the specific roles of distinct molecules acting in complex networks. Thus, various immunological, behavioral, and signal transduction studies performed with different HPA axis-related mutant mouse lines to delineate the roles of β-endorphin, the type 1 receptor of corticotropin-releasing hormone (CRHR1), and its ligand CRH will be discussed here. [ABSTRACT FROM AUTHOR]

The effects of unilateral transection of the Achilles tendon (tenotomy) on the electromyographic characteristics of the gastrocnemius muscle on the contralateral side were studied in rats. Motor responses, reflex responses, and motor unit spike activity in the contralateral gastrocnemius muscle were studied in baseline conditions and on afferent stimulation before and 10 days after tenotomy. Changes in the nature of motor unit spike activity and responses to afferent stimulation were observed. The results obtained here demonstrate increases in the excitability of individual motoneurons in the contralateral motor center of the gastrocnemius muscle after exclusion of the symmetrical gastrocnemius muscle from the overall pattern of movement activity. [ABSTRACT FROM AUTHOR]

The precise outgrowth and arborization of dendrites is crucial for their function as integrators of signals relayed from axons and, hence, the functioning of the brain. Proper dendritic differentiation is particularly resonant for Purkinje cells as the intrinsic activity of this cell-type is governed by functionally distinct regions of its dendritic tree. Activity-dependent mechanisms, driven by electrical signaling and trophic factors, account for the most active period of dendritogenesis. An as yet unexplored trophic modulator of Purkinje cell dendritic development is corticotropin-releasing factor (CRF) and family member, urocortin, both of which are localized in climbing fibers. Here, we use rat organotypic cerebellar slice cultures to investigate the roles of CRF and urocortin on Purkinje cell dendritic development. Intermittent exposure (12 h per day for 10 days in vitro) of CRF and urocortin induced significantly more dendritic outgrowth (45% and 70%, respectively) and elongation (25% and 15%, respectively) compared with untreated cells. Conversely, constant exposure to CRF and urocortin significantly inhibited dendritic outgrowth. The trophic effects of CRF and urocortin are mediated by the protein kinase A and mitogen-activating protein kinase pathways. The study shows unequivocally that CRF and urocortin are potent regulators of dendritic development. However, their stimulatory or inhibitory effects are dependent upon the degree of expression of these peptides. Furthermore, the effects of CRF and urocortin on neuronal differentiation and re-modeling may provide a cellular basis for pathologies such as major depression, which show perturbations in the expression of these stress peptides. [ABSTRACT FROM AUTHOR]

Summary The functional recovery after peripheral nerve lesions is generally poor. We studied whether changes in muscles after reinnervation might explain such disappointing results. The functional recovery after peripheral nerve lesions is generally poor. Changes in muscle morphology and neuromuscular innervation might partly explain this lack of compensation. In order to test this hypothesis, we studied muscular differentiation in the soleus, gastrocnemius and tibialis anterior muscles at 7, 15 and 21 weeks after a sciatic nerve lesion in adult rats. In the gastrocnemius and tibialis muscles the percentages of type II muscles fibres were decreased at 7 and 15 weeks but at 21 weeks they again approached normal values. The soleus muscle, however, was permanently decreased in size and this muscle, in contrast to the normal soleus muscle, contained mainly type II fibres. The morphology of the endplates showed distinct stages of degeneration and reinnervation. Two weeks after denervation, in rats in which reinnervation was prevented, all 3 muscles contained considerable numbers of morphologically abnormal endplates and, after 7 weeks, no endplates were detected. During reinnervation, endplates showing signs of acetylcholinesterase activity were observed in all 3 muscles from 7 weeks. At later ages a shift towards morphologically normal endplates occurred, but complete recovery was not observed. Endplates in all 3 muscles were polyneurally innervated at 7 weeks. Although these percentages decreased over age, polyneural innervation was still present at 21 weeks. We conclude that the changes in the distribution of fibre types, abnormal endplate morphology and polyneural innervation may in part explain the poor functional recovery after peripheral nerve lesions. [ABSTRACT FROM AUTHOR]