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A deep understanding of how the brain controls behaviour requires mapping neural circuits down to the muscles that they control. Here, we apply automated tools to segment neurons and identify synapses in an electron microscopy dataset of an adult female Drosophila melanogaster ventral nerve cord (VNC) 1 , which functions like the vertebrate spinal cord to sense and control the body. We find that the fly VNC contains roughly 45 million synapses and 14,600 neuronal cell bodies. To interpret the output of the connectome, we mapped the muscle targets of leg and wing motor neurons using genetic driver lines 2 and X-ray holographic nanotomography 3 . With this motor neuron atlas, we identified neural circuits that coordinate leg and wing movements during take-off. We provide the reconstruction of VNC circuits, the motor neuron atlas and tools for programmatic and interactive access as resources to support experimental and theoretical studies of how the nervous system controls behaviour., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Animal movement is controlled by motor neurons (MNs), which project out of the central nervous system to activate muscles 1 . MN activity is coordinated by complex premotor networks that facilitate the contribution of individual muscles to many different behaviours 2-6 . Here we use connectomics 7 to analyse the wiring logic of premotor circuits controlling the Drosophila leg and wing. We find that both premotor networks cluster into modules that link MNs innervating muscles with related functions. Within most leg motor modules, the synaptic weights of each premotor neuron are proportional to the size of their target MNs, establishing a circuit basis for hierarchical MN recruitment. By contrast, wing premotor networks lack proportional synaptic connectivity, which may enable more flexible recruitment of wing steering muscles. Through comparison of the architecture of distinct motor control systems within the same animal, we identify common principles of premotor network organization and specializations that reflect the unique biomechanical constraints and evolutionary origins of leg and wing motor control., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: Sympathetic nerve activity towards muscle (MSNA) and skin (SSNA) regulates various physiological parameters. MSNA primarily functions in blood pressure and flow, while SSNA operates in thermoregulation. Physical and cognitive stressors have been shown to have effects on both types of sympathetic activity, but there are inconsistencies as to what these effects are. This article aims to address the discrepancies in the literature and compare MSNA and SSNA responses., Methods: Microelectrode recordings were taken from the common peroneal nerve in 29 participants: MSNA (n = 21), SSNA (n = 16) and both MSNA and SSNA (n = 8). Participants were subjected to four different 2-min stressors: two physical (isometric handgrip task, cold pressor test) and two cognitive (mental arithmetic task, Stroop colour-word conflict test), the latter of which saw participants separated into responders and non-responders to the stressors. It was hypothesised that the physical stressors would have a greater effect on MSNA than SSNA, while the cognitive stressors would operate conversely., Results: Peristimulus time histogram (PSTH) analysis showed the mental arithmetic task to significantly increase both MSNA and SSNA; the isometric handgrip task and cold pressor test to increase MSNA, but not SSNA; and Stroop test to have no significant effects on changing MSNA or SSNA from baseline. Additionally, stress responses did not differ between MSNA and SSNA in participants who had both sets of data recorded., Conclusions: This study has provided evidence to support the literature which claims cognitive stressors increase sympathetic activity, and provides much needed SSNA data in response to stressors., (© 2024. The Author(s).)

Objective: This study aimed to introduce a reliable and useful model of selective sensorial or motor denervations of the sciatic nerve in rats with clinical and laboratory outcomes., Methods: The surgical technique was determined via detailed cadaveric dissections of rat sciatic nerve roots and cross-sectional histoanatomy. Forty animals were divided into the sham, sensorial denervation (SD), motor denervation (MD), and combined denervation (CD) groups and evaluated clinically via the pinch test and observation. Electrophysiological tests, retrograde neuronal labeling, and histologic and radiographic studies were performed. The weights of the muscles innervated by the sciatic nerve were measured., Results: The nerve root topography at the L4 level was consistent. Hemilaminectomy satisfactorily exposed all the roots contributing to the sciatic nerve and selectively denervated its sensorial and motor zones. Sensorial denervation caused foot deformities and wound problems, which were more severe in SD than in MD and CD. Nerve histomorphometry, electrophysiological tests, retrograde neuronal labeling studies, and measurements of the muscle weights also verified the denervations., Conclusion: This study has shown the feasibility of selective (sensory or motor) sciatic nerve denervation through a single-level hemilaminectomy. The surgical technique is reliable and has a confounding effect on gait. Sensorial denervation had more severe foot problems than motor and combined denervation in rats.

To construct tissue-like prosthetic materials, soft electroactive hydrogels are the best candidate owing to their physiological mechanical modulus, low electrical resistance and bidirectional stimulating and recording capability of electrophysiological signals from biological tissues 1,2 . Nevertheless, until now, bioelectronic devices for such prostheses have been patch type, which cannot be applied onto rough, narrow or deep tissue surfaces 3-5 . Here we present an injectable tissue prosthesis with instantaneous bidirectional electrical conduction in the neuromuscular system. The soft and injectable prosthesis is composed of a biocompatible hydrogel with unique phenylborate-mediated multiple crosslinking, such as irreversible yet freely rearrangeable biphenyl bonds and reversible coordinate bonds with conductive gold nanoparticles formed in situ by cross-coupling. Closed-loop robot-assisted rehabilitation by injecting this prosthetic material is successfully demonstrated in the early stage of severe muscle injury in rats, and accelerated tissue repair is achieved in the later stage., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Since taking flight, insects have undergone repeated evolutionary transitions between two seemingly distinct flight modes 1-3 . Some insects neurally activate their muscles synchronously with each wingstroke. However, many insects have achieved wingbeat frequencies beyond the speed limit of typical neuromuscular systems by evolving flight muscles that are asynchronous with neural activation and activate in response to mechanical stretch 2-8 . These modes reflect the two fundamental ways of generating rhythmic movement: time-periodic forcing versus emergent oscillations from self-excitation 8-10 . How repeated evolutionary transitions have occurred and what governs the switching between these distinct modes remain unknown. Here we find that, despite widespread asynchronous actuation in insects across the phylogeny 3,6 , asynchrony probably evolved only once at the order level, with many reversions to the ancestral, synchronous mode. A synchronous moth species, evolved from an asynchronous ancestor, still preserves the stretch-activated muscle physiology. Numerical and robophysical analyses of a unified biophysical framework reveal that rather than a dichotomy, these two modes are two regimes of the same dynamics. Insects can transition between flight modes across a bridge in physiological parameter space. Finally, we integrate these two actuation modes into an insect-scale robot 11-13 that enables transitions between modes and unlocks a new self-excited wingstroke strategy for engineered flight. Together, this framework accounts for repeated transitions in insect flight evolution and shows how flight modes can flip with changes in physiological parameters., (© 2023. The Author(s).)

Few studies considered the anatomy of the nerve plexuses and musculature associated with them in ectothermic sauropsids. Based on differentiated Sudan Black B staining and conventional dissections, we describe the neuroanatomy of the brachial plexus, its main associated nerves, and muscles. For that, representatives of the genera Diplolaemus, Liolaemus, Phymaturus, and Tropidurus were selected. Based on this, potentially useful characters for phylogenetic analysis were described. Our results show that the brachial plexus can be formed by four, five, or six nerve branches. The brachial flexor trunk, circumflex, interosseous, median, radial, subscapulocoracoid, supracoracoid, and ulnar nerves were identified. Regarding the muscles innervated by the main nerves, the following muscles were identified: biceps brachii, deltoideus scapularis, latissimus dorsi, levator scapulae, pectoralis, serratus thoracis, trapezius, triceps longus caudalis, and triceps longus lateralis. Phylogenetic analyzes revealed 31 potential synapomorphies. There exists evidence that neuroanatomy studies in a phylogenetic context could provide useful information helping to elucidate the relationships between taxonomic groups., (© 2023 Wiley Periodicals LLC.)

The extracellular waveform manifestations of the intracellular action potential are the quintessential diagnostic foundation of electrodiagnostic medicine, and clinical neurophysiology in general. Volume conduction is the extracellular current flow and associated voltage distributions in an ionic conducting media, such as occurs in the human body. Both surface and intramuscular electrodes, in association with contemporary digital electromyographic systems, permit very sensitive detection and visualization of this extracellular spontaneous, voluntary, and evoked nerve/muscle electrical activity. Waveform configuration, with its associated discharge rate/rhythm, permits the identification of normal and abnormal waveforms, thereby assisting in the diagnosis of nerve and muscle pathology. This monograph utilizes a simple model to explain the various waveforms that may be encountered. There are a limited number of waveforms capable of being generated in excitable tissues which conform to well-known volume conductor concepts. Using these principles, such waveforms can be quickly identified in real time during clinical studies., (Copyright ©2023 by the American Association of Neuromuscular & Electrodiagnostic Medicine, Inc. All rights reserved.)

Muscular hydrostats are organs composed entirely of packed arrays of incompressible muscles and lacking any skeletal support. Found in both vertebrates and invertebrates, they are of great interest for comparative biomechanics from engineering and evolutionary perspectives. The arms of cephalopods (e.g. octopus and squid) are particularly interesting muscular hydrostats because of their flexibility and ability to generate complex behaviors exploiting elaborate nervous systems. Several lines of evidence from octopus studies point to the use of both brain and arm-embedded motor control strategies that have evolved to simplify the complexities associated with the control of flexible and hyper-redundant limbs and bodies. Here, we review earlier and more recent experimental studies on octopus arm biomechanics and neural motor control. We review several dynamic models used to predict the kinematic characteristics of several basic motion primitives, noting the shortcomings of the current models in accounting for behavioral observations. We also discuss the significance of impedance (stiffness and viscosity) in controlling the octopus's motor behavior. These factors are considered in light of several new models of muscle biomechanics that could be used in future research to gain a better understanding of motor control in the octopus. There is also a need for updated models that encompass stiffness and viscosity for designing and controlling soft robotic arms. The field of soft robotics has boomed over the past 15 years and would benefit significantly from further progress in biomechanical and motor control studies on octopus and other muscular hydrostats., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)

Cerebral Function and Muscle Afferent Activity Following Intravenous Succinylcholine in Dogs Anesthetized with Halothane: The Effects of Pretreatment with a Defasciculating Dose of Pancuronium. By WL Lanier, PA Iaizzo, and JH Milde. Anesthesiology 1989; 71:87-95. Reprinted with permission. By the mid-1980s, it was widely assumed that if the depolarizing muscle relaxant, succinylcholine, given IV, produced increases in intracranial pressure, it did so because fasciculations produced increases in intrathoracic and central venous pressures that were transferred to the brain; however, there was no direct evidence that this was true. In contrast, we explored the possibility that the succinylcholine effect on the brain was explained by the afferentation theory of cerebral arousal, which predicts that agents or maneuvers that stimulate muscle stretch receptors will tend to stimulate the brain. Our research in tracheally intubated, lightly anesthetized dogs discovered that IV succinylcholine (which does not cross the blood-brain barrier) produced a doubling of cerebral blood flow that lasted for 30 min and corresponded to activation of the electroencephalogram and increases in intracranial pressure. Later, in our Classic Paper, we were able to assess simultaneously cerebral physiology and afferent nerve traffic emanating from muscle stretch receptors (primarily muscle spindles). We affirmed that the cerebral arousal response to succinylcholine was indeed driven by muscle afferent traffic and was independent of fasciculations or increases in intrathoracic or central venous pressures. Later research in complementary models demonstrated that endogenous movement (e.g., coughing, hiccups) produced a cerebral response very similar to IV succinylcholine, apparently as a result of the same muscle afferent mechanisms, independent of intrathoracic and central venous pressures. Thus, the importance of afferentation theory as a driver of the cerebral state of arousal and cerebral physiology during anesthesia was affirmed., (Copyright © 2023, the American Society of Anesthesiologists. All Rights Reserved.)

Aims: Patients with sympathetic excess are those most likely to benefit from novel interventions targeting the autonomic nervous system. To inform such personalized therapy, we identified determinants of augmented muscle sympathetic nerve activity (MSNA) in heart failure, versus healthy controls., Methods and Results: We compared data acquired in 177 conventionally-treated, stable non-diabetic patients in sinus rhythm, aged 18-79 years (149 males; 28 females; left ventricular ejection fraction [LVEF] 25 ± 11% [mean ± standard deviation]; range 5-60%), and, concurrently, under similar conditions, in 658 healthy, normotensive volunteers (398 males; aged 18-81 years). In heart failure, MSNA ranged between 7 and 90 bursts·min -1 , proportionate to heart rate (p < 0.0001) and body mass index (BMI) (p = 0.03), but was unrelated to age, blood pressure, or drug therapy. Mean MSNA, adjusted for age, sex, BMI, and heart rate, was greater in heart failure (+14.2 bursts·min -1 ; 95% confidence interval [CI] 12.1-16.3; p < 0.0001), but lower in women (-5.0 bursts·min -1 ; 95% CI 3.4-6.6; p < 0.0001). With spline modeling, LVEF accounted for 9.8% of MSNA variance; MSNA related inversely to LVEF below an inflection point of ∼21% (p < 0.006), but not above. Burst incidence was greater in ischaemic than dilated cardiomyopathy (p = 0.01), and patients with sleep apnoea (p = 0.03). Burst frequency correlated inversely with stroke volume (p < 0.001), cardiac output (p < 0.001), and peak oxygen consumption (p = 0.002), and directly with norepinephrine (p < 0.0001) and peripheral resistance (p < 0.001)., Conclusion: Burst frequency and incidence exceeded normative values in only ∼53% and ∼33% of patients. Such diversity encourages selective deployment of sympatho-modulatory therapies. Clinical characteristics can highlight individuals who may benefit from future personalized interventions targeting pathological sympathetic activation., (© 2022 European Society of Cardiology.)

Background: We conducted meta-analyses to identify relationships between obstructive sleep apnea (OSA) severity, muscle sympathetic nerve activity (MSNA), and blood pressure (BP). We quantified the effect of OSA treatment on MSNA., Methods: Structured searches of electronic databases were performed until June 2021. All observational designs (except reviews) were included: population (individuals with OSA); exposures (OSA diagnosis and direct measures of MSNA); comparator (individuals without OSA or different severity of OSA); outcomes (MSNA, BP, and heart rate)., Results: Fifty-six studies (N=1872) were included. MSNA burst frequency was higher in OSA (27 studies; n=542) versus controls (n=488; mean differences [MDs], +15.95 bursts/min [95% CI, 12.6-17.6 bursts/min]; I 2 =86%). As was burst incidence (20 studies; n=357 OSA, n=312 Controls; MD, +22.23 bursts/100 hbs [95% CI, 18.49-25.97 bursts/100 hbs]; I 2 =67%). Meta-regressions indicated relationships between MSNA and OSA severity (burst frequency, R 2 =0.489 ; P <0.001; burst incidence, R 2 =0.573 ; P <0.001). MSNA burst frequency was related to systolic pressure (R 2 =0.308; P =0.016). OSA treatment with continuous positive airway pressure reduced MSNA burst frequency (MD, 11.91 bursts/min [95% CI, 9.36-14.47 bursts/min] I 2 =15%) and systolic (n=49; MD, 10.3 mm Hg [95% CI, 3.5-17.2 mm Hg]; I 2 =42%) and diastolic (MD, 6.9 mm Hg [95% CI, 2.3-11.6 mm Hg]; I 2 =37%) BP., Conclusions: MSNA is higher in individuals with OSA and related to severity. This sympathoexcitation is also related to BP in patients with OSA. Treatment effectively reduces MSNA and BP, but limited data prevents an assessment of the link between these reductions. These data are clinically important for understanding cardiovascular disease risk in patients with OSA., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: CRD42021285159.

Botulinum neurotoxins (BoNTs) are paralytic agents used to treat a variety of conditions in jaw muscles. Although their effect is considered temporary, there are reports of persistent functional changes. Using rabbits that received BoNT injection in one masseter muscle, the recovery of neuromuscular connection was investigated using nerve stimulation to evoke an electromyographic (EMG) response, and the recovery of muscle fibers was investigated using histological morphometry and bromodeoxyuridine (BrdU) immunohistochemistry. One month after treatment, evoked EMG was greatly reduced in both amplitude and duration, indicating that little reinnervation had taken place. Muscle fibers were atrophied and collagenous tissue was increased. Three months after treatment, evoked EMG duration was normal, indicating that at least some neuromuscular junctions were functional. Histologically, some muscle fibers were hypertrophied, some were still atrophied, and some appeared to have died. Fibrosis was still apparent amid slight increases in dividing cells and regenerating fibers. The histological effects of BoNT were evident although attenuated at a distance of about 1 cm from the injection level, but no regional differences could be discerned for the evoked EMGs. In conclusion, there were persistent muscular deficits seen 3 months after BoNT treatment that may have been caused by the failure of some affected muscle fibers to become reinnervated., (© 2021 American Association for Anatomy.)

Objective . Proprioception is the sense of one's position, orientation, and movement in space, and it is of fundamental importance for motor control. When proprioception is impaired or absent, motor execution becomes error-prone, leading to poorly coordinated movements. The kinaesthetic illusion, which creates perceptions of limb movement in humans through non-invasively applying vibrations to muscles or tendons, provides an avenue for studying and restoring the sense of joint movement (kinaesthesia). This technique, however, leaves ambiguity between proprioceptive percepts that arise from muscles versus those that arise from skin receptors. Here we propose the concept of a stimulation system to activate kinaesthesia through the untethered application of localized vibration through implanted magnets. Approach . In this proof-of-concept study, we use two simplified one-DoF systems to show the feasibility of eliciting muscle-sensory responses in an animal model across multiple frequencies, including those that activate the kinaesthetic illusion (70-115 Hz). Furthermore, we generalized the concept by developing a five-DoF prototype system capable of generating directional, frequency-selective vibrations with desired displacement profiles. Main results. In-vivo tests with the one-DoF systems demonstrated the feasibility to elicit muscle sensory neural responses in the median nerve of an animal model. Instead, in-vitro tests with the five-DoF prototype demonstrated high accuracy in producing directional and frequency selective vibrations along different magnet axes. Significance . These results provide evidence for a new technique that interacts with the native neuro-muscular anatomy to study proprioception and eventually pave the way towards the development of advanced limb prostheses or assistive devices for the sensory impaired., (Creative Commons Attribution license.)

Decoding the molecular mechanisms underlying axon guidance is key to precise understanding of how complex neural circuits form during neural development. Although substantial progress has been made over the last three decades in identifying numerous axon guidance molecules and their functional roles, little is known about how these guidance molecules collaborate to steer growth cones to their correct targets. Recent studies in Drosophila point to the importance of the combinatorial action of guidance molecules, and further show that selective fasciculation and defasciculation at specific choice points serve as a fundamental strategy for motor axon guidance. Here, I discuss how attractive and repulsive guidance cues cooperate to ensure the recognition of specific choice points that are inextricably linked to selective fasciculation and defasciculation, and correct pathfinding decision-making.

The decline of neuronal synapses is an established feature of ageing accompanied by the diminishment of neuronal function, and in the motor system at least, a reduction of behavioural capacity. Here, we have investigated Drosophila motor neuron synaptic terminals during ageing. We observed cumulative fragmentation of presynaptic structures accompanied by diminishment of both evoked and miniature neurotransmission occurring in tandem with reduced motor ability. Through discrete manipulation of each neurotransmission modality, we find that miniature but not evoked neurotransmission is required to maintain presynaptic architecture and that increasing miniature events can both preserve synaptic structures and prolong motor ability during ageing. Our results establish that miniature neurotransmission, formerly viewed as an epiphenomenon, is necessary for the long-term stability of synaptic connections., (© 2021. The Author(s).)

Successful execution of behavior requires coordinated activity and communication between multiple cell types. Studies using the relatively simple neural circuits of invertebrates have helped to uncover how conserved molecular and cellular signaling events shape animal behavior. To understand the mechanisms underlying neural circuit activity and behavior, we have been studying a simple circuit that drives egg-laying behavior in the nematode worm Caenorhabditis elegans Here we show that the sex-specific, ventral C (VC) motor neurons are important for vulval muscle contractility and egg laying in response to serotonin. Ca 2+ imaging experiments show the VCs are active during times of vulval muscle contraction and vulval opening, and optogenetic stimulation of the VCs promotes vulval muscle Ca 2+ activity. Blocking VC neurotransmission inhibits egg laying in response to serotonin and increases the failure rate of egg-laying attempts, indicating that VC signaling facilitates full vulval muscle contraction and opening of the vulva for efficient egg laying. We also find the VCs are mechanically activated in response to vulval opening. Optogenetic stimulation of the vulval muscles is sufficient to drive VC Ca 2+ activity and requires muscle contractility, showing the presynaptic VCs and the postsynaptic vulval muscles can mutually excite each other. Together, our results demonstrate that the VC neurons facilitate efficient execution of egg-laying behavior by coordinating postsynaptic muscle contractility in response to serotonin and mechanosensory feedback. SIGNIFICANCE STATEMENT Many animal motor behaviors are modulated by the neurotransmitters, serotonin and ACh. Such motor circuits also respond to mechanosensory feedback, but how neurotransmitters and mechanoreceptors work together to coordinate behavior is not well understood. We address these questions using the egg-laying circuit in Caenorhabditis elegans where we can manipulate presynaptic neuron and postsynaptic muscle activity in behaving animals while recording circuit responses through Ca 2+ imaging. We find that the cholinergic VC motoneurons are important for proper vulval muscle contractility and egg laying in response to serotonin. Muscle contraction also activates the VCs, forming a positive feedback loop that promotes full contraction for egg release. In all, mechanosensory feedback provides a parallel form of modulation that shapes circuit responses to neurotransmitters., (Copyright © 2021 the authors.)

Throughout the nervous system, the convergence of two or more presynaptic inputs on a target cell is commonly observed. The question we ask here is to what extent converging inputs influence each other's structural and functional synaptic plasticity. In complex circuits, isolating individual inputs is difficult because postsynaptic cells can receive thousands of inputs. An ideal model to address this question is the Drosophila larval neuromuscular junction (NMJ) where each postsynaptic muscle cell receives inputs from two glutamatergic types of motor neurons (MNs), known as 1b and 1s MNs. Notably, each muscle is unique and receives input from a different combination of 1b and 1s MNs; we surveyed multiple muscles for this reason. Here, we identified a cell-specific promoter that allows ablation of 1s MNs postinnervation and measured structural and functional responses of convergent 1b NMJs using microscopy and electrophysiology. For all muscles examined in both sexes, ablation of 1s MNs resulted in NMJ expansion and increased spontaneous neurotransmitter release at corresponding 1b NMJs. This demonstrates that 1b NMJs can compensate for the loss of convergent 1s MNs. However, only a subset of 1b NMJs showed compensatory evoked neurotransmission, suggesting target-specific plasticity. Silencing 1s MNs led to similar plasticity at 1b NMJs, suggesting that evoked neurotransmission from 1s MNs contributes to 1b synaptic plasticity. Finally, we genetically blocked 1s innervation in male larvae and robust 1b synaptic plasticity was eliminated, raising the possibility that 1s NMJ formation is required to set up a reference for subsequent synaptic perturbations. SIGNIFICANCE STATEMENT In complex neural circuits, multiple convergent inputs contribute to the activity of the target cell, but whether synaptic plasticity exists among these inputs has not been thoroughly explored. In this study, we examined synaptic plasticity in the structurally and functionally tractable Drosophila larval neuromuscular system. In this convergent circuit, each muscle is innervated by a unique pair of motor neurons. Removal of one neuron after innervation causes the adjacent neuron to increase neuromuscular junction outgrowth and functional output. However, this is not a general feature as each motor neuron differentially compensates. Further, robust compensation requires initial coinnervation by both neurons. Understanding how neurons respond to perturbations in adjacent neurons will provide insight into nervous system plasticity in both healthy and disease states., (Copyright © 2021 the authors.)

Thoracic radiculopathy is a rare cause of thoracic-abdominal or abdominal pain in subjects with poorly controlled diabetes. We present a case of a young woman with type I diabetes and a severe abdominal pain in both lower quadrants. An extensive diagnostic gastroenterological and gynaecological workup did not disclose abnormalities. Electromyography revealed an initial polyneuropathy and significant neurogenic abnormalities in the T10-T12 paravertebral muscles. Following the hypothesis that the radiculopathy-related abdominal pain might have an immuno-mediated pathogenesis, the patient underwent a complex trial of immunotherapy, which was accompanied by a sustained improvement over months to full recovery. This report would support the hypothesis that immune-mediated mechanisms are still active even months after onset of symptoms., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

How do descending inputs from the brain control leg motor circuits to change how an animal walks? Conceptually, descending neurons are thought to function either as command-type neurons, in which a single type of descending neuron exerts a high-level control to elicit a coordinated change in motor output, or through a population coding mechanism, whereby a group of neurons, each with local effects, act in combination to elicit a global motor response. The Drosophila Moonwalker Descending Neurons (MDNs), which alter leg motor circuit dynamics so that the fly walks backwards, exemplify the command-type mechanism. Here, we identify several dozen MDN target neurons within the leg motor circuits, and show that two of them mediate distinct and highly-specific changes in leg muscle activity during backward walking: LBL40 neurons provide the hindleg power stroke during stance phase; LUL130 neurons lift the legs at the end of stance to initiate swing. Through these two effector neurons, MDN directly controls both the stance and swing phases of the backward stepping cycle. These findings suggest that command-type descending neurons can also operate through the distributed control of local motor circuits.

The sonographic appearance of soft tissue can be altered by trauma and positional change with torsional stress. This creates challenges for ultrasonographic interpretation, because most descriptive literature and standard instructional references are displayed in anatomically neutral or other conventional positions. Knowledge of anatomic alteration and changes in sonographic appearance with torsional stress is essential for accurately assessing soft tissue abnormalities in conditions of spasticity, traumatic and post-surgical changes, and other conditions that distort musculoskeletal relationships. A systematic scanning approach to these alterations is needed for accurate diagnostic interpretation, optimizing electrode placement for electrodiagnostic techniques, effective needle placement for therapeutic ultrasound-guided procedures, and even planning for restorative surgery. This review describes expected positional changes of normal structures with torsional alteration, as well as sonographic recognition of scars, burns, hematomas, fat layer fracture, Morel-Lavallee lesions, abscesses, foreign bodies, myotendinous lesions, muscle injury and denervation, and traumatic peripheral nerve injury., (© 2020 Wiley Periodicals LLC.)

Background: Targeted muscle reinnervation (TMR) has been shown to decrease or prevent neuropathic pain, including phantom and residual limb pain, after extremity amputation. Currently, a paucity of data and lack of anatomical description exists regarding TMR in the setting of hemipelvectomy and/or hip disarticulations. We elaborate on the technique of TMR, illustrated through cadaveric and clinical correlates., Methods: Cadaveric dissections of multiple transpelvic exposures were performed. The major mixed motor and sensory nerve branches were identified, dissected, and tagged. Amputated peripheral nerves were transferred to identified, labeled target motor nerves via direct end-to-end nerve coaptations per traditional TMR technique. A retrospective review was completed by our multi-institutional teams to include examples of clinical correlates for TMR performed in the setting of hemipelvectomies and hip disarticulations., Results: A total of 12 TMR hemipelvectomy/hip disarticulation cases were performed over a 2 to 3-year period (2018-2020). Of these 12 cases, 9 were oncologic in nature, 2 were secondary to traumatic injury, and 1 was a failed limb salvage in the setting of chronic refractory osteomyelitis of the femoral shaft., Conclusions: This manuscript outlines the technical considerations for TMR in the setting of hemipelvectomy and hip disarticulation with supporting clinical case correlates., (© 2020 Wiley Periodicals LLC.)

Within mammalian brain circuits, activity-dependent synaptic adaptations, such as synaptic scaling, stabilize neuronal activity in the face of perturbations. Stability afforded through synaptic scaling involves uniform scaling of quantal amplitudes across all synaptic inputs formed on neurons, as well as on the postsynaptic side. It remains unclear whether activity-dependent uniform scaling also operates within peripheral circuits. We tested for such scaling in a Drosophila larval neuromuscular circuit, where the muscle receives synaptic inputs from different motoneurons. We used motoneuron-specific genetic manipulations to increase the activity of only one motoneuron and recordings of postsynaptic currents from inputs formed by the different motoneurons. We discovered an adaptation which caused uniform downscaling of evoked neurotransmitter release across all inputs through decreases in release probabilities. This "presynaptic downscaling" maintained the relative differences in neurotransmitter release across all inputs around a homeostatic set point, caused a compensatory decrease in synaptic drive to the muscle affording robust and stable muscle activity, and was induced within hours. Presynaptic downscaling was associated with an activity-dependent increase in Drosophila vesicular glutamate transporter expression. Activity-dependent uniform scaling can therefore manifest also on the presynaptic side to produce robust and stable circuit outputs. Within brain circuits, uniform downscaling on the postsynaptic side is implicated in sleep- and memory-related processes. Our results suggest that evaluation of such processes might be broadened to include uniform downscaling on the presynaptic side. SIGNIFICANCE STATEMENT To date, compensatory adaptations which stabilise target cell activity through activity-dependent global scaling have been observed only within central circuits, and on the postsynaptic side. Considering that maintenance of stable activity is imperative for the robust function of the nervous system as a whole, we tested whether activity-dependent global scaling could also manifest within peripheral circuits. We uncovered a compensatory adaptation which causes global scaling within a peripheral circuit and on the presynaptic side through uniform downscaling of evoked neurotransmitter release. Unlike in central circuits, uniform scaling maintains functionality over a wide, rather than a narrow, operational range, affording robust and stable activity. Activity-dependent global scaling therefore operates on both the presynaptic and postsynaptic sides to maintain target cell activity., (Copyright © 2020 the authors.)

Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing motor neuron degenerative disease that is without effective treatment. The receptor for advanced glycation end products (RAGE) is a major component of the innate immune system that has been implicated in ALS pathogenesis. However, the contribution of RAGE signalling to the neuroinflammation that underlies ALS neurodegeneration remains unknown. The present study therefore generated SOD1 G93A mice lacking RAGE and compared them with SOD1 G93A transgenic ALS mice in respect to disease progression (i.e. body weight, survival and muscle strength), neuroinflammation and denervation markers in the spinal cord and tibialis anterior muscle. We found that complete absence of RAGE signalling exerted a protective effect on SOD1 G93A pathology, slowing disease progression and significantly extending survival by ~ 3 weeks and improving motor function (rotarod and grip strength). This was associated with reduced microgliosis, cytokines, innate immune factors (complement, TLRs, inflammasomes), and oxidative stress in the spinal cord, and a reduction of denervation markers in the tibialis anterior muscle. We also documented that RAGE mRNA expression was significantly increased in the spinal cord and muscles of preclinical SOD1 and TDP43 models of ALS, supporting a widespread involvement for RAGE in ALS pathology. In summary, our results indicate that RAGE signalling drives neuroinflammation and contributes to neurodegeneration in ALS and highlights RAGE as a potential immune therapeutic target for ALS.

Background: Peripheral nerve defects (PND) often cause lifelong physical disability, and the available treatment options are often not satisfactory. PND are usually bridged with an autologous nerve transplant or a nerve guidance conduit (NGC), when coaptation as preferred technique is not possible. The aim of this experimental study was to determine the effectiveness of a novel NGC for regeneration in the treatment of PND., Materials and Methods: A conduit made of gelatin with an innovative interior structure was tested for the repair of a 6-mm gap versus direct microsurgical suture repair without gap., Results: We found that bridging the defect with this conduit was as effective as direct microsurgical coaptation without a defect., Conclusions: This nerve conduit, effective in bridging neural defects, appears as an alternative to autologous nerve grafts, avoiding the problems related to nerve graft harvesting, host-donor differences in diameter, mismatches in number and pattern of fascicles, cross-sectional shape and area, and morbidity of the donor area.

Rhesus macaques represent an important species for translational and pre-clinical research studies across a multitude of disease and injury models, including aging. Ketamine anesthesia is used in humans and non-human primates but may be associated with adverse effects, including neuromuscular reactions. The effects of aging on ketamine adverse effects is not well characterized. Urodynamic recordings and electromyography (EMG) studies were performed in aged (>20 years old) and adult (3.9-14.9 years old) female rhesus macaques under an equal and light plane of sedation by constant rate infusion (CRI) of ketamine. A total of 4 of 41 adult subjects (9.7%) showed clinical signs of ketamine-induced abnormal neuromuscular reactivity, whereas a larger portion of 14 of 26 aged subjects showed similar ketamine-induced neuromuscular reactivity (53.8%; P< 0.001). The ketamine CRI rate was 19.8±0.9 mg/kg/h in adults and lower in aged subjects at 16.5±1.4 mg/kg/h (P<0.05). The ketamine CRI rate was negatively correlated with age (r = -0.30, P<0.05, n = 64). The incidence of ketamine reactivity or CRI rate was not different between aged pre-and post-menopausal females. EMG recordings during neuromuscular reactivity showed coordinated activation of multiple muscles, suggesting a central nervous system (CNS) mechanism for ketamine-associated neuromuscular reactivity. The incidence of ketamine-induced neuromuscular reactivity is age related but not affected by the estrous cycle in female rhesus macaques. A coordinated activation of multiple muscles, innervated by different peripheral nerves, suggests that ketamine-induced neuromuscular reactivity originates in the CNS., Competing Interests: The authors have declared that no competing interests exist.

Objective - Conflicting theoretical models exist regarding the mechanism related to the ability of the Jendrassik maneuver to reinforce reflex parameters. Our objective was to investigate if vigorous handgrip would induce changes in recurrent inhibition of soleus motoneurons. Method - Soleus H reflex was evoked by stimulating the tibial nerve at rest and during bilateral vigorous handgrip, alternating single (H1) and paired stimulation (H2). At paired stimulation we used interstimulus intervals of 10, 15, 20 and 25 ms and supramaximal test stimulus. H1- and H2-wave amplitudes were expressed as percentage of maximal M-wave amplitude. Conditioned H2 wave maximal (H2max) and minimal (H2) amplitudes evoked at rest and expressed as a percentage of the unconditioned H1max amplitude were compared with the corresponding values obtained during handgrip by means of paired Student test and Bonferroni correction. Subjects - At the study participated 28 healthy volunteers. Results - The H1max/Mmax × 100 values obtained during handgrip (37.5±10.1) were significantly higher than those obtained at rest (27.1±7.4). The H2max/H1max × 100-va-lues obtained at paired stimulation were significantly higher during handgrip than at rest, while no significant diffe-rence was found between the H2/H1max × 100-values obtained during handgrip and at rest respectively. Discussion - The H2max/H1max is determined by both the excitability of the motoneurons and the recurrent inhibition elicited by the conditioning stimulus, while H2/H1max indicates only the level of recurrent inhibition. According to our results the Renshaw cells retain their inhibitory effect on the soleus alpha motoneurons during remote muscle contraction. Conclusion - Soleus H reflex enhancement during Jendrassik maneuver is not due to decrease of recurrent inhibition.

Heart failure is a rapidly growing epidemic in developed countries. It has been well documented that heart failure is associated with abnormal neurohumoral activation. The autonomic regulation is characterized by decreased parasympathetic and elevated sympathetic activity. While the cardiovagal activity could be easily assessed by various heart rate variability parameters, markers of the sympathetic activity are not readily available. Percutaneous insertion of microelectrodes in a peripheral nerve allows recording of the muscle sympathetic vasomotor nerve activity (MSNA). MSNA shows good correlation with the cardiac sympathetic activity, and also with the levels of circulating catecholamines. Besides determination of the baseline sympathetic activity, rapid sympathetic responses to various stimuli can be also described by changes of MSNA. Elevated MSNA has been documented in several diseases, including hypertension, obesity, myocardial ischemia and renal failure. In heart failure, the elevated MSNA is well correlated to the clinical severity of the patient's conditions, and serves as a prognostic marker of mortality. In our paper, we give a short account of the history of MSNA studies, describe its physiological background and clinical relevance with special regard to heart failure. Orv Hetil. 2020; 161(29): 1190-1199.

Ion channels are present at specific levels within subcellular compartments of excitable cells. The regulation of ion channel trafficking and targeting is an effective way to control cell excitability. The BK channel is a calcium-activated potassium channel that serves as a negative feedback mechanism at presynaptic axon terminals and sites of muscle excitation. The C. elegans BK channel ortholog, SLO-1, requires an endoplasmic reticulum (ER) membrane protein for efficient anterograde transport to these locations. Here, we found that, in the absence of this ER membrane protein, SLO-1 channels that are seemingly normally folded and expressed at physiological levels undergo SEL-11/HRD1-mediated ER-associated degradation (ERAD). This SLO-1 degradation is also indirectly regulated by a SKN-1A/NRF1-mediated transcriptional mechanism that controls proteasome levels. Therefore, our data indicate that SLO-1 channel density is regulated by the competitive balance between the efficiency of ER trafficking machinery and the capacity of ERAD., Competing Interests: The authors have declared that no competing interests exist.

Acute pain is a common complication after injury of a peripheral nerve but the underlying mechanism is obscure. We established a model of acute neuropathic pain via pulling a pre-implanted suture loop to transect a peripheral nerve in awake rats. The tibial (both muscular and cutaneous), gastrocnemius-soleus (muscular only), and sural nerves (cutaneous only) were each transected. Transection of the tibial and gastrocnemius-soleus nerves, but not the sural nerve immediately evoked spontaneous pain and mechanical allodynia in the skin territories innervated by the adjacent intact nerves. Evans blue extravasation and cutaneous temperature of the intact skin territory were also significantly increased. In vivo electrophysiological recordings revealed that injury of a muscular nerve induced mechanical hypersensitivity and spontaneous activity in the nociceptive C-neurons in adjacent intact nerves. Our results indicate that injury of a muscular nerve, but not a cutaneous nerve, drives acute neuropathic pain.

Genetic variations in TMEM106B, coding for a lysosomal membrane protein, affect frontotemporal lobar degeneration (FTLD) in GRN- (coding for progranulin) and C9orf72-expansion carriers and might play a role in aging. To determine the physiological function of TMEM106B, we generated TMEM106B-deficient mice. These mice develop proximal axonal swellings caused by drastically enlarged LAMP1-positive vacuoles, increased retrograde axonal transport of lysosomes, and accumulation of lipofuscin and autophagosomes. Giant vacuoles specifically accumulate at the distal end and within the axon initial segment, but not in peripheral nerves or at axon terminals, resulting in an impaired facial-nerve-dependent motor performance. These data implicate TMEM106B in mediating the axonal transport of LAMP1-positive organelles in motoneurons and axonal sorting at the initial segment. Our data provide mechanistic insight into how TMEM106B affects lysosomal proteolysis and degradative capacity in neurons., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Despites several decades of studies on the neuromuscular system, the relationship between muscle stem cells and motor neurons remains elusive. Using the Drosophila model, we provide evidence that adult muscle precursors (AMPs), the Drosophila muscle stem cells, interact with the motor axons during embryogenesis. AMPs not only hold the capacity to attract the navigating intersegmental (ISN) and segmental a (SNa) nerve branches, but are also mandatory to the innervation of muscles in the lateral field. This so-far-ignored AMP role involves their filopodia-based interactions with nerve growth cones. In parallel, we report the previously undetected expression of the guidance molecule-encoding genes sidestep and side IV in AMPs. Altogether, our data support the view that Drosophila muscle stem cells represent spatial landmarks for navigating motor neurons and reveal that their positioning is crucial for the muscles innervation in the lateral region. Furthermore, AMPs and motor axons are interdependent, as the genetic ablation of SNa leads to a specific loss of SNa-associated lateral AMPs., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

The labial palps of bivalves are thought to be involved in suspension feeding. However, the function of their muscular movements and neural regulation are still unclear. In semi-intact preparations of Mytilus , in which one valve was removed, suspended particles were removed from the labial palps following two kinds of compound movements: torsional and rotational. Both of these compound movements are therefore thought to function in rejection during feeding. These movements were observed in reduced preparations of isolated labial palps with intact cerebral ganglia, and were maintained even after removal of the cerebral ganglia, suggesting that they are generated by the peripheral neural network. Stimulation of the anterior pallial nerve elicited tetanic contraction of the labial palp, followed by secondary responses, including torsional movement. Secondary responses were dramatically reduced by a high concentration of divalent cations, in which polysynaptic pathways were inhibited. Hence, the cerebral ganglia may play an excitatory role within the peripheral neural network and the labial palp musculature via the anterior pallial nerve. Administration of serotonin induced repetitive muscular movements, whereas dopamine did not induce muscular movements. Serotonin-induced muscular movements were not elicited under a high concentration of divalent cation condition. In histochemical experiments, both the serotonergic and dopaminergic neural processes and cell body-like structures were widely observed inside the labial palp, the anterior pallial nerve, and the cerebral ganglia. Serotonin may thus contribute to activation of polysynaptic peripheral pathways, which are involved in regulating compound movements.

Growing evidence shows that alterations occurring at early developmental stages contribute to symptoms manifested in adulthood in the setting of neurodegenerative diseases. Here, we studied the molecular mechanisms causing giant axonal neuropathy (GAN), a severe neurodegenerative disease due to loss-of-function of the gigaxonin-E3 ligase. We showed that gigaxonin governs Sonic Hedgehog (Shh) induction, the developmental pathway patterning the dorso-ventral axis of the neural tube and muscles, by controlling the degradation of the Shh-bound Patched receptor. Similar to Shh inhibition, repression of gigaxonin in zebrafish impaired motor neuron specification and somitogenesis and abolished neuromuscular junction formation and locomotion. Shh signaling was impaired in gigaxonin-null zebrafish and was corrected by both pharmacological activation of the Shh pathway and human gigaxonin, pointing to an evolutionary-conserved mechanism regulating Shh signaling. Gigaxonin-dependent inhibition of Shh activation was also demonstrated in primary fibroblasts from patients with GAN and in a Shh activity reporter line depleted in gigaxonin. Our findings establish gigaxonin as a key E3 ligase that positively controls the initiation of Shh transduction, and reveal the causal role of Shh dysfunction in motor deficits, thus highlighting the developmental origin of GAN.

Deciphering the mechanisms that govern skeletal muscle plasticity is essential to understand its pathophysiological processes, including age-related sarcopenia. The voltage-gated calcium channel CaV1.1 has a central role in excitation-contraction coupling (ECC), raising the possibility that it may also initiate the adaptive response to changes during muscle activity. Here, we revealed the existence of a gene transcription switch of the CaV1.1 β subunit (CaVβ1) that is dependent on the innervation state of the muscle in mice. In a mouse model of sciatic denervation, we showed increased expression of an embryonic isoform of the subunit that we called CaVβ1E. CaVβ1E boosts downstream growth differentiation factor 5 (GDF5) signaling to counteract muscle loss after denervation in mice. We further reported that aged mouse muscle expressed lower quantity of CaVβ1E compared with young muscle, displaying an altered GDF5-dependent response to denervation. Conversely, CaVβ1E overexpression improved mass wasting in aging muscle in mice by increasing GDF5 expression. We also identified the human CaVβ1E analogous and show a correlation between CaVβ1E expression in human muscles and age-related muscle mass decline. These results suggest that strategies targeting CaVβ1E or GDF5 might be effective in reducing muscle mass loss in aging., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

A common pathological hallmark of amyotrophic lateral sclerosis (ALS) and the related neurodegenerative disorder frontotemporal dementia, is the cellular mislocalization of transactive response DNA-binding protein 43 kDa (TDP-43). Additionally, multiple mutations in the TARDBP gene (encoding TDP-43) are associated with familial forms of ALS. While the exact role for TDP-43 in the onset and progression of ALS remains unclear, the identification of factors that can prevent aberrant TDP-43 localization and function could be clinically beneficial. Previously, we discovered that the oxidation resistance 1 (Oxr1) protein could alleviate cellular mislocalization phenotypes associated with TDP-43 mutations, and that over-expression of Oxr1 was able to delay neuromuscular abnormalities in the hSOD1G93A ALS mouse model. Here, to determine whether Oxr1 can protect against TDP-43-associated phenotypes in vitro and in vivo, we used the same genetic approach in a newly described transgenic mouse expressing the human TDP-43 locus harbouring an ALS disease mutation (TDP-43M337V). We show in primary motor neurons from TDP-43M337V mice that genetically-driven Oxr1 over-expression significantly alleviates cytoplasmic mislocalization of mutant TDP-43. We also further quantified newly-identified, late-onset neuromuscular phenotypes of this mutant line, and demonstrate that neuronal Oxr1 over-expression causes a significant reduction in muscle denervation and neuromuscular junction degeneration in homozygous mutants in parallel with improved motor function and a reduction in neuroinflammation. Together these data support the application of Oxr1 as a viable and safe modifier of TDP-43-associated ALS phenotypes., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Whole-organism phenotypic assays are central to the assessment of neuromuscular function and health in model organisms such as the nematode C. elegans. In this study, we report a new assay format for engaging C. elegans in burrowing that enables rapid assessment of nematode neuromuscular health. In contrast to agar environments that pose specific drawbacks for characterization of C. elegans burrowing ability, here we use the optically transparent and biocompatible Pluronic F-127 gel that transitions from liquid to gel at room temperature, enabling convenient and safe handling of animals. The burrowing assay methodology involves loading animals at the bottom of well plates, casting a liquid-phase of Pluronic on top that solidifies via a modest temperature upshift, enticing animals to reach the surface via chemotaxis to food, and quantifying the relative success animals have in reaching the chemoattractant. We study the influence of Pluronic concentration, gel height and chemoattractant choice to optimize assay performance. To demonstrate the simplicity of the assay workflow and versatility, we show its novel application in multiple areas including (i) evaluating muscle mutants with defects in dense bodies and/or M-lines (pfn-3, atn-1, uig-1, dyc-1, zyx-1, unc-95 and tln-1), (ii) tuning assay conditions to reveal changes in the mutant gei-8, (iii) sorting of fast burrowers in a genetically-uniform wild-type population for later quantitation of their distinct muscle gene expression, and (iv) testing proteotoxic animal models of Huntington and Parkinson's disease. Results from our studies show that stimulating animals to navigate in a dense environment that offers mechanical resistance to three-dimensional locomotion challenges the neuromuscular system in a manner distinct from standard crawling and thrashing assays. Our simple and high throughput burrowing assay can provide insight into molecular mechanisms for maintenance of neuromuscular health and facilitate screening for therapeutic targets.

Background and Objectives: Sympathetic neural activation occurs in congestive heart failure (CHF). However, the small sample size of the microneurographic studies, heterogeneity of the patients examined, presence of comorbidities as well as confounders (including treatment) represented major weaknesses not allowing to identify the major features of the phoenomenon, particularly in mild CHF. This meta-analysis evaluated 2530 heart failure (CHF) patients recruited in 106 microneurographic studies. It was based on muscle sympathetic nerve activity (MSNA) quantification in CHF of different clinical severity, but data from less widely addressed conditions, such as ischemic vs. idiopathic, were also considered., Methods: Assessment was extended to the relationships of MSNA with venous plasma norepinephrine, heart rate (HR) and echocardiographic parameters of cardiac morphology [left ventricular (LV) end-diastolic diameter] and function (LV ejection fraction) as well., Results: MSNA was significantly greater (1.9 times, P < 0.001) in CHF patients as compared with healthy controls, a progressive significant increase being observed from New York Heart Association classes I-IV in unadjusted and adjusted analyses. MSNA was significantly greater in both untreated and treated CHF (P < 0.001 for both), related to left ventricular (LV) end-diastolic diameter and to a lesser extent to LV ejection fraction (r = 0.24 and -0.05, P < 0.001 and <0.01, respectively), and closely associated with HR (r = 0.66, P < 0.001) and plasma norepinephrine (r = 0.68, P < 0.001)., Conclusion: CHF is characterized by sympathetic overactivity which mirrors the degree of LV dysfunction independently of the stage of CHF, its cause and presence of confounders or pharmacological treatment. plasma norepinephrine and HR represent potentially valuable surrogate markers of sympathetic activation in the clinical setting.

Development of the next generation of bio- and nano-electronics is inseparably connected to the innovative concept of emulation and reproduction of biological sensorimotor systems and artificial neurobotics. Here, we report for the first time principally new artificial bioinspired optoelectronic sensorimotor system for the controlable immitation of opto-genetically engineered neurons in the biological motor system. The device is based on inorganic optical synapse (In-doped TiO 2 nanofilm) assembled into a liquid metal (galinstan) actuator. The optoelectronic synapse generates polarised excitatory and inhibitory postsynaptic potentials to trigger the liquid metal droplet to vibrate and then mimic the expansion and contraction of biological fibre muscle. The low-energy consumption and precise modulation of electrical and mechanical outputs are the distinguished characteristics of fabricated sensorimotor system. This work is the underlying significant step towards the development of next generation of low-energy the internet of things for bioinspired neurorobotic and bioelectronic system.

In the pathophysiology and progression of pelvic organ prolapse (POP), it has been demonstrated that there is a reorganisation of the muscularis propria of the anterior vaginal wall due to a phenotypic smooth muscle cell to myofibroblast switch. An abnormal deposition of collagen type III seems to be influenced by the involvement of advanced glycation end-products. The aim of the present study was to evaluate the hypothesis that this connective tissue remodelling could also be associated with neurovascular alterations of the muscularis in women with POP compared with control patients. We examined 30 women with POP and 10 control patients treated for uterine fibromatosis. Immunohistochemical analysis, using glial fibrillary acidic protein, S-100 protein, receptor tyrosine kinase, neurofilament and α-smooth muscle actin antibodies, was performed. S-100, receptor tyrosine kinase and neurofilament were also evaluated using Western blot analysis. We observed a decrease in all neurovascular-tested markers in nerve bundles, ganglia and interstitial cells of Cajal from POP samples as compared with controls. Even if the processes responsible for these morphological alterations are still not known, it is conceivable that collagen III deposition in the anterior vaginal wall affects not only the architecture of the muscle layer but could also modify the intramuscular neurovascularisation and account for an alteration of the neuromuscular plasticity of the layer., (© 2019 The Authors. Journal of Anatomy published by John Wiley & Sons Ltd on behalf of Anatomical Society.)

Pinnatoxins (PnTXs) are emerging neurotoxins that were discovered about 30 years ago. They are solely produced by the marine dinoflagellate Vulcanodinium rugosum , and may be transferred into the food chain, as they have been found in various marine invertebrates, including bivalves. No human intoxication has been reported to date although acute toxicity was induced by PnTxs in rodents. LD 50 values have been estimated for the different PnTXs through the oral route. At sublethal doses, all symptoms are reversible, and no neurological sequelae are visible. These symptoms are consistent with impairment of central and peripheral cholinergic network functions. In fact, PnTXs are high-affinity competitive antagonists of nicotinic acetylcholine receptors (nAChRs). Moreover, their lethal effects are consistent with the inhibition of muscle nAChRs, inducing respiratory distress and paralysis. Human intoxication by ingestion of PnTXs could result in various symptoms observed in episodes of poisoning with natural nAChR antagonists. This review updates the available data on PnTX toxicity with a focus on their mode of action on cholinergic networks and suggests the effects that could be extrapolated on human physiology.

Circadian rhythms are ~24-hour cycles of physiology and behavior that are synchronized to environmental cycles, such as the light-dark cycle. During the 20th century, most research focused on establishing the fundamental properties of circadian rhythms and discovering circadian pacemakers that were believed to reside in the nervous system of animals. During this time, studies that suggested the existence of circadian oscillators in peripheral organs in mammals were largely dismissed. The discovery of a single-locus circadian pacemaker in the nervous system of several animals affirmed the single-oscillator model of the circadian system. However, the discovery of the genes that constituted the molecular timekeeping system provided the tools for demonstrating the existence of bona fide circadian oscillators in nearly every peripheral tissue in animals, including rodents, in the late 1990s and early 2000s. These studies led to our current understanding that the circadian system in animals is a hierarchical multi-oscillatory network, composed of master pacemaker(s) in the brain and oscillators in peripheral organs. Further studies showed that altering the temporal relationship between these oscillators by simulating jet-lag and metabolic challenges in rodents caused adverse physiological outcomes. Herein we review the studies that led to our current understanding of the function and pathology of the hierarchical multi-oscillator circadian system.

Animal locomotion requires spatiotemporally coordinated contraction of muscles throughout the body. Here, we investigate how contractions of antagonistic groups of muscles are intersegmentally coordinated during bidirectional crawling of Drosophila larvae. We identify two pairs of higher-order premotor excitatory interneurons present in each abdominal neuromere that intersegmentally provide feedback to the adjacent neuromere during motor propagation. The two feedback neuron pairs are differentially active during either forward or backward locomotion but commonly target a group of premotor interneurons that together provide excitatory inputs to transverse muscles and inhibitory inputs to the antagonistic longitudinal muscles. Inhibition of either feedback neuron pair compromises contraction of transverse muscles in a direction-specific manner. Our results suggest that the intersegmental feedback neurons coordinate contraction of synergistic muscles by acting as delay circuits representing the phase lag between segments. The identified circuit architecture also shows how bidirectional motor networks could be economically embedded in the nervous system.

Median and Ulnar nerve palsy is a devastating condition that compromise hand function. A procedure of tendon transfer may be helpful to restore the movements by linking palsy muscles to other muscles able to contract. Scientific discoveries and technological innovations have profoundly changed this kind of surgery; studies on sarcomeres, for example, changed the concept of tensioning. To date we know that muscle strength and its contraction capacity depends on many factors (not only tensioning) such as sarcomeres length, cellular cytoskeleton and extracellular matrix composition: all of these factors interact together and in a ways not still fully understood, determining the complex concept of "movement." Technology made possible the production of smaller and more complex prostheses so to open new frontiers for modulation of the tendon length during grasping. These devices, currently studied on computer models, on cadaver or on animals, behaved great impetus to research but are still not suitable for implantation in humans. Challenges are still numerous: for example obtain more biocompatible implantable device, find new surgical approach, new ways to obtain better results for this kind of patients.

Functional outcomes following nerve repair remain suboptimal. Scarring at the repair site is a major impediment to regeneration. A biomaterial scaffold applied around the coaptation site that decreases inflammation holds great potential in reducing scarring, enhancing axonal growth, and improving functional recovery. In this study, we evaluated the effect of a macroporous nanofiber wrap, comprised of nonwoven electrospun poly-ε-caprolactone (PCL), in improving axonal regeneration in a rat sciatic nerve cut and direct repair model. Controls consisted of conventional epineurial repair. We also evaluated our wrap against the commercially available AxoGuard wrap. At five weeks following repair, the nanofiber wrap group showed a significantly decreased intraneural macrophage invasion and collagen deposition at the repair site. This was associated with increased expression of the anti-inflammatory cytokine (IL-10), decreased expression of the pro-inflammatory cytokine (TNF-α), and a decrease in the M1:M2 macrophage phenotype ratio. These findings suggest that this nanofiber wrap, with its unique macroporosity, is modulating the inflammatory response at the repair site by polarizing macrophages towards a pro-regenerative M2 phenotype. Concomitantly, a higher number of regenerated axons was noted. At sixteen weeks, the nanofiber wrap resulted in enhanced functional recovery as demonstrated by electrophysiology, neuromuscular re-innervation, and muscle histology. When compared to the AxoGuard wrap, the nanofiber wrap showed similar inflammation at the repair site and similar nerve morphometric findings, but there was a trend towards a lower overall number of macrophages invading the wrap wall. These results demonstrate favorable outcomes of the macroporous nanofiber wrap in promoting neuroregeneration and functional recovery following nerve repair. STATEMENT OF SIGNIFICANCE: Electrospun nanofiber scaffolds, with specific fiber and pore sizes, were shown to modulate the immune response and create a regenerative environment. In this paper, we present a macroporous nanofiber wrap, made of poly-ε-caprolactone, to be applied at the coaptation site in primary nerve repair. We show that it regulates the inflammatory response at the repair site and decreases scarring/fibrosis. This results in enhanced axonal regeneration, allowing a higher number of axons to cross the suture line and reach the target muscle in a timely fashion. Functional outcomes are thus improved., (Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

The hypoglossal or twelfth cranial nerve is the motor nerve to the extrinsic and intrinsic muscles of the tongue, and the superior root of the ansa cervicalis and the thyrohyoid and geniohyoid branches are delivered through the nerve. This study investigated the muscular branches of the hypoglossal nerve to clarify their spatial relationships with the muscles of the tongue and the neighboring structures. The muscles and the nerve were gross anatomically examined in 42 cadavers. The superior root and the thyrohyoid branch left the nerve near the occipital and lingual arteries, respectively. The extrinsic muscles consisted of some components, and the geniohyoid branch and the lingual branches arose on the hyoglossus. The ascending lingual branches formed a plexus on the anterior part of the hyoglossus and were divided into the proximal and distal groups. They supplied the two parts of the hyoglossus, the three bundles of the styloglossus and the superior and inferior longitudinal muscles and communicated with the lingual nerve. The descending lingual branches supplied the inferior part of the genioglossus, and the terminal branches gave intramuscular twigs to its main part and the transverse and vertical muscles. The findings indicated that the branching pattern of the hypoglossal nerve is characterized by the positional relationships to the components of the extrinsic muscles. The hyoid bone can be an effective marker to identify the branches and affected position if it was used in combination with the morphology of the extrinsic muscles, and the knowledge of their variations is also beneficial. Anat Rec, 302:558-567, 2019. © 2018 Wiley Periodicals, Inc., (© 2018 Wiley Periodicals, Inc.)

Jackhammer esophagus (JE) is a hypercontractile disorder, the pathogenesis of which is incompletely understood. Multiple rapid swallows (MRS) and rapid drink challenge (RDC) are complementary tests used during high-resolution manometry (HRM) that evaluate inhibitory and excitatory neuromuscular function and latent obstruction, respectively. Our aim was to evaluate esophageal pathophysiology using MRS and RDC in 83 JE patients (28 men; median age: 63 yr; IQR: 54-70 yr). Twenty-one healthy subjects (11 men; median age: 28 yr; range: 26-30 yr) were used as a control group. All patients underwent solid-state HRM with ten 5-ml single swallows (SS) and one to three 10-ml MRS; 34 patients also underwent RDC. Data are shown as median (interquartile range). Abnormal motor inhibition was noted during at least one MRS test in 48% of JE patients compared with 29% of controls ( P = 0.29). Mean distal contractile integral (DCI) after MRS was significantly lower than after SS [6,028 (3,678-9,267) mmHg·cm·s vs. 7,514 (6,238-9,197) mmHg·cm·s, P = 0.02], as was highest DCI ( P < 0.0001). Consequently, 66% of JE patients had no contraction reserve. At least one variable of obstruction during RDC (performed in 34 patients) was outside the normal range in 25 (74%) of JE patients. Both highest DCI after SS and pressure gradient across the esophagogastric junction (EGJ) during RDC were higher in patients with dysphagia versus those without ( P = 0.04 and 0.01, respectively). Our data suggest altered neural control in JE patients with heterogeneity in inhibitory function. Furthermore, some patients had latent EGJ obstruction during RDC, which correlated with the presence of dysphagia. NEW & NOTEWORTHY Presence of abnormal inhibition was observed during multiple rapid swallows (MRS) in some but not all patients with jackhammer esophagus (JE). Unlike healthy subjects, JE patients were more strongly stimulated after single swallows than after MRS. An obstructive pattern was frequently observed during rapid drink challenge (RDC) and was related to presence of dysphagia. MRS and RDC during high-resolution manometry are useful to show individual pathophysiological patterns in JE and may guide optimal therapeutic strategies.

The aim of the study was to verify whether neuromuscular magnetic stimulation (NMMS) improves muscle function in spinal-onset amyotrophic lateral sclerosis (ALS) patients. Twenty-two ALS patients were randomized in two groups to receive, daily for two weeks, NMMS in right or left arm (referred to as real-NMMS, rNMMS), and sham NMMS (sNMMS) in the opposite arm. All the patients underwent a median nerve conduction (compound muscle action potential, CMAP) study and a clinical examination that included a handgrip strength test and an evaluation of upper limb muscle strength by means of the Medical Research Council Muscle Scale (MRC). Muscle biopsy was then performed bilaterally on the flexor carpi radialis muscle to monitor morpho-functional parameters and molecular changes. Patients and physicians who performed examinations were blinded to the side of real intervention. The primary outcome was the change in the muscle strength in upper arms. The secondary outcomes were the change from baseline in the CMAP amplitudes, in the nicotinic ACh currents, in the expression levels of a selected panel of genes involved in muscle growth and atrophy, and in histomorphometric parameters of ALS muscle fibers. The Repeated Measures (RM) ANOVA with a Greenhouse-Geisser correction (sphericity not assumed) showed a significant effect [F(3, 63) = 5.907, p < 0.01] of rNMMS on MRC scale at the flexor carpi radialis muscle, thus demonstrating that the rNMMS significantly improves muscle strength in flexor muscles in the forearm. Secondary outcomes showed that the improvement observed in rNMMS-treated muscles was associated to counteracting muscle atrophy, down-modulating the proteolysis, and increasing the efficacy of nicotinic ACh receptors (AChRs). We did not observe any significant difference in pre- and post-stimulation CMAP amplitudes, evoked by median nerve stimulation. This suggests that the improvement in muscle strength observed in the stimulated arm is unlikely related to reinnervation. The real and sham treatments were well tolerated without evident side effects. Although promising, this is a proof of concept study, without an immediate clinical translation, that requires further clinical validation.