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Muscle spindles have unique anatomical characteristics that can be directly affected by the surrounding tissues under physiological and pathological conditions. Understanding their spatial distribution and density in different muscles is imperative to unravel the complexity of motor function. In the present study, the distribution and number/density of muscle spindles in human and animal muscles were reviewed. We identified 56 articles focusing on muscle spindle distribution; 13 articles focused on human muscles and 43 focused on animal muscles. The results demonstrate that spindles are located at the nerve entry points and along distributed vessels and they relate to the intramuscular connective tissue. Muscles' deep layers and middle segments are the main topographic distribution areas. Eleven articles on humans and thirty-three articles on animals (totaling forty-four articles) focusing on muscle spindle quantity and density were identified. Hand and head muscles, such as the pronator teres/medial pterygoid muscle/masseter/flexor digitorum, were most commonly studied in the human studies. For animals, whole-body musculature was studied. The present study summarized the spindle quantity in 77 human and 189 animal muscles. We identified well-studied muscles and any as-yet unfound data. The current data fail to clarify the relationship between quantity/density and muscle characteristics. The intricate distribution of the muscle spindles and their density and quantity throughout the body present some unique patterns or correlations, according to the current data. However, it remains unclear whether muscles with fine motor control have more muscle spindles since the study standards are inconsistent and data on numerous muscles are missing. This study provides a comprehensive and exhaustive approach for clinicians and researchers to determine muscle spindle status.

Neuromuscular control of bionic arms has constantly improved over the past years, however, restoration of sensation remains elusive. Previous approaches to reestablish sensory feedback include tactile, electrical, and peripheral nerve stimulation, however, they cannot recreate natural, intuitive sensations. Here, we establish an experimental biological sensorimotor interface and demonstrate its potential use in neuroprosthetics. We transfer a mixed nerve to a skeletal muscle combined with glabrous dermal skin transplantation, thus forming a bi-directional communication unit in a rat model. Morphological analyses indicate reinnervation of the skin, mechanoreceptors, NMJs, and muscle spindles. Furthermore, sequential retrograde labeling reveals specific sensory reinnervation at the level of the dorsal root ganglia. Electrophysiological recordings show reproducible afferent signals upon tactile stimulation and tendon manipulation. The results demonstrate the possibility of surgically creating an interface for both decoding efferent motor control, as well as encoding afferent tactile and proprioceptive feedback, and may indicate the way forward regarding clinical translation of biological communication pathways for neuroprosthetic applications., (© 2024. The Author(s).)

The goals of this review are to improve understanding of the aetiology of chronic muscle pain and identify new targets for treatments. Muscle pain is usually associated with trigger points in syndromes such as fibromyalgia and myofascial syndrome, and with small spots associated with spontaneous electrical activity that seems to emanate from fibers inside muscle spindles in EMG studies. These observations, added to the reports that large-diameter primary afferents, such as those innervating muscle spindles, become hyperexcitable and develop spontaneous ectopic firing in conditions leading to neuropathic pain, suggest that changes in excitability of these afferents might make an important contribution to the development of pathological pain. Here, we review evidence that the muscle spindle afferents (MSAs) of the jaw-closing muscles become hyperexcitable in a model of chronic orofacial myalgia. In these afferents, as in other large-diameter primary afferents in dorsal root ganglia, firing emerges from fast membrane potential oscillations that are supported by a persistent sodium current (I NaP ) mediated by Na + channels containing the α-subunit Na V 1.6. The current flowing through Na V 1.6 channels increases when the extracellular Ca 2+ concentration decreases, and studies have shown that I NaP -driven firing is increased by S100β, an astrocytic protein that chelates Ca 2+ when released in the extracellular space. We review evidence of how astrocytes, which are known to be activated in pain conditions, might, through their regulation of extracellular Ca 2+ , contribute to the generation of ectopic firing in MSAs. To explain how ectopic firing in MSAs might cause pain, we review evidence supporting the hypothesis that cross-talk between proprioceptive and nociceptive pathways might occur in the periphery, within the spindle capsule., (© 2023 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

By translating mechanical forces into molecular signals, proprioceptive neurons provide the CNS with information on muscle length and tension, which is necessary to control posture and movement. However, the identities of the molecular players that mediate proprioceptive sensing are largely unknown. Here, we confirm the expression of the mechanosensitive ion channel ASIC2 in proprioceptive sensory neurons. By combining in vivo proprioception-related functional tests with ex vivo electrophysiological analyses of muscle spindles, we showed that mice lacking Asic2 display impairments in muscle spindle responses to stretch and motor coordination tasks. Finally, analysis of skeletons of Asic2 loss-of-function mice revealed a specific effect on spinal alignment. Overall, we identify ASIC2 as a key component in proprioceptive sensing and a regulator of spine alignment., (© 2023 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Our objective was to evaluate an ex vivo muscle-nerve preparation used to study mechanosensory signalling by low threshold mechanosensory receptors (LTMRs). Specifically, we aimed to assess how well the ex vivo preparation represents in vivo firing behaviours of the three major LTMR subtypes of muscle primary sensory afferents, namely type Ia and II muscle spindle (MS) afferents and type Ib tendon organ afferents. Using published procedures for ex vivo study of LTMRs in mouse hindlimb muscles, we replicated earlier reports on afferent firing in response to conventional stretch paradigms applied to non-contracting, that is passive, muscle. Relative to in vivo studies, stretch-evoked firing for confirmed MS afferents in the ex vivo preparation was markedly reduced in firing rate and deficient in encoding dynamic features of muscle stretch. These deficiencies precluded conventional means of discriminating type Ia and II afferents. Muscle afferents, including confirmed Ib afferents were often indistinguishable based on their similar firing responses to the same physiologically relevant stretch paradigms. These observations raise uncertainty about conclusions drawn from earlier ex vivo studies that either attribute findings to specific afferent types or suggest an absence of treatment effects on dynamic firing. However, we found that replacing the recording solution with bicarbonate buffer resulted in afferent firing rates and profiles more like those seen in vivo. Improving representation of the distinctive sensory encoding properties in ex vivo muscle-nerve preparations will promote accuracy in assigning molecular markers and mechanisms to heterogeneous types of muscle mechanosensory neurons., (© 2023 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Hereditary sensory and autonomic neuropathy type III (HSAN III), also known as familial dysautonomia or Riley-Day syndrome, results from an autosomal recessive genetic mutation that causes a selective loss of specific sensory neurones, leading to greatly elevated pain and temperature thresholds, poor proprioception, marked ataxia and disturbances in blood pressure control. Stretch reflexes are absent throughout the body, which can be explained by the absence of functional muscle spindle afferents - assessed by intraneural microelectrodes inserted into peripheral nerves in the upper and lower limbs. This also explains the greatly compromised proprioception at the knee joint, as assessed by passive joint-angle matching. Moreover, there is a tight correlation between loss of proprioceptive acuity at the knee and the severity of gait impairment. Surprisingly, proprioception is normal at the elbow, suggesting that participants are relying more on sensory cues from the overlying skin; microelectrode recordings have shown that myelinated tactile afferents in the upper and lower limbs appear to be normal. Nevertheless, the lack of muscle spindles does affect sensorimotor control in the upper limb: in addition to poor performance in the finger-to-nose test, manual performance in the Purdue pegboard task is much worse than in age-matched healthy controls. Unlike those rare individuals with large-fibre sensory neuropathy, in which both muscle spindle and cutaneous afferents are absent, those with HSAN III present as a means of assessing sensorimotor control following the selective loss of muscle spindle afferents., (© 2023 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

This paper is in two parts: 'There', which is a review of some of the major advances in the study of spindle structure and function during the past 50 years, serving as an introduction to the symposium entitled 'Mechanotransduction, Muscle Spindles and Proprioception' held in Munich in July 2022; and 'And Back Again', presenting new quantitative morphological results on the equatorial nuclei of intrafusal muscle fibres and of the primary sensory ending in relationship to passive stretch of the spindle., (© 2023 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Muscle spindles encode mechanosensory information by mechanisms that remain only partially understood. Their complexity is expressed in mounting evidence of various molecular mechanisms that play essential roles in muscle mechanics, mechanotransduction and intrinsic modulation of muscle spindle firing behaviour. Biophysical modelling provides a tractable approach to achieve more comprehensive mechanistic understanding of such complex systems that would be difficult/impossible by more traditional, reductionist means. Our objective here was to construct the first integrative biophysical model of muscle spindle firing. We leveraged current knowledge of muscle spindle neuroanatomy and in vivo electrophysiology to develop and validate a biophysical model that reproduces key in vivo muscle spindle encoding characteristics. Crucially, to our knowledge, this is the first computational model of mammalian muscle spindle that integrates the asymmetric distribution of known voltage-gated ion channels (VGCs) with neuronal architecture to generate realistic firing profiles, both of which seem likely to be of great biophysical importance. Results predict that particular features of neuronal architecture regulate specific characteristics of Ia encoding. Computational simulations also predict that the asymmetric distribution and ratios of VGCs is a complementary and, in some instances, orthogonal means to regulate Ia encoding. These results generate testable hypotheses and highlight the integral role of peripheral neuronal structure and ion channel composition and distribution in somatosensory signalling., (© 2023 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Muscle spindles relay vital mechanosensory information for movement and posture, but muscle spindle feedback is coupled to skeletal motion by a compliant tendon. Little is known about the effects of tendon compliance on muscle spindle feedback during movement, and the complex firing of muscle spindles makes these effects difficult to predict. Our goal was to investigate changes in muscle spindle firing using added series elastic elements (SEEs) to mimic a more compliant tendon, and to characterize the accompanying changes in firing with respect to muscle-tendon unit (MTU) and muscle fascicle displacements (recorded via sonomicrometry). Sinusoidal, ramp-and-hold and triangular stretches were analysed to examine potential changes in muscle spindle instantaneous firing rates (IFRs) in locomotor- and perturbation-like stretches as well as serial history dependence. Added SEEs effectively reduced overall MTU stiffness and generally reduced muscle spindle firing rates, but the effect differed across stretch types. During sinusoidal stretches, peak and mean firing rates were not reduced and IFR was best-correlated with fascicle velocity. During ramp stretches, SEEs reduced the initial burst, dynamic and static responses of the spindle. Notably, IFR was negatively related to fascicle displacement during the hold phase. During triangular stretches, SEEs reduced the mean IFR during the first and second stretches, affecting the serial history dependence of mean IFR. Overall, these results demonstrate that tendon compliance may attenuate muscle spindle feedback during movement, but these changes cannot be fully explained by reduced muscle fascicle length or velocity, or MTU force., (© 2023 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

We recently showed that within an intact muscle compartment, changing the length of one muscle affects the firing behaviour of muscle spindles located within a neighbouring muscle. The conditions tested, however, involved muscle lengths and relative positions that were beyond physiological ranges. The aim of the present study was to investigate the effects of simulated knee movements on the firing behaviour of muscle spindles located within rat soleus (SO) muscle. Firing from single muscle spindle afferents in SO was measured intra-axonally for different lengths (static) and during lengthening (dynamic) of the lateral gastrocnemius and plantaris muscles. Also, the location of the spindle within the muscle was assessed. Changing the length of synergistic ankle plantar flexors (simulating different static knee positions, between 45 and 130°) affected the force threshold, but not the length threshold, of SO muscle spindles. The effects on type II afferents were substantially (four times) higher than those on type IA afferents. Triangular stretch-shortening of synergistic muscles (simulating dynamic knee joint rotations of 15°) caused sudden changes in the firing rate of SO type IA and II afferents. Lengthening decreased and shortening increased the firing rate, independent of spindle location. This supports our prediction that the major point of application of forces exerted by connections between adjacent muscles is at the distal end of SO. We conclude that muscle spindles provide the CNS with information about the condition of adjacent joints that the muscle does not span., (© 2023 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Computational models can be critical to linking complex properties of muscle spindle organs to the sensory information that they encode during behaviours such as postural sway and locomotion where few muscle spindle recordings exist. Here, we augment a biophysical muscle spindle model to predict the muscle spindle sensory signal. Muscle spindles comprise several intrafusal muscle fibres with varied myosin expression and are innervated by sensory neurons that fire during muscle stretch. We demonstrate how cross-bridge dynamics from thick and thin filament interactions affect the sensory receptor potential at the spike initiating region. Equivalent to the Ia afferent's instantaneous firing rate, the receptor potential is modelled as a linear sum of the force and rate change of force (yank) of a dynamic bag1 fibre and the force of a static bag2/chain fibre. We show the importance of inter-filament interactions in (i) generating large changes in force at stretch onset that drive initial bursts and (ii) faster recovery of bag fibre force and receptor potential following a shortening. We show how myosin attachment and detachment rates qualitatively alter the receptor potential. Finally, we show the effect of faster recovery of receptor potential on cyclic stretch-shorten cycles. Specifically, the model predicts history-dependence in muscle spindle receptor potentials as a function of inter-stretch interval (ISI), pre-stretch amplitude and the amplitude of sinusoidal stretches. This model provides a computational platform for predicting muscle spindle response in behaviourally relevant stretches and can link myosin expression seen in healthy and diseased intrafusal muscle fibres to muscle spindle function., (© 2023 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Effort perception is widely acknowledged to originate from central processes within the brain, mediated by the integration of an efference copy of motor commands in sensory areas. However, in this topical review, we aim to challenge this perspective by presenting evidence from neural mechanisms and empirical studies that suggest that reafferent signals from muscle spindles also play a significant role in effort perception. It is now imperative for future research (a) to investigate the precise mechanisms underlying the interactions between the efference copy and reafferent spindle signals in the generation of effort perception, and (b) to explore the potential for altering spindle sensitivity to affect perceived effort during ecological physical exercise and, subsequently, influence physical activity behaviours., (© 2023 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Biological motor control is versatile, efficient, and depends on proprioceptive feedback. Muscles are flexible and undergo continuous changes, requiring distributed adaptive control mechanisms that continuously account for the body's state. The canonical role of proprioception is representing the body state. We hypothesize that the proprioceptive system could also be critical for high-level tasks such as action recognition. To test this theory, we pursued a task-driven modeling approach, which allowed us to isolate the study of proprioception. We generated a large synthetic dataset of human arm trajectories tracing characters of the Latin alphabet in 3D space, together with muscle activities obtained from a musculoskeletal model and model-based muscle spindle activity. Next, we compared two classes of tasks: trajectory decoding and action recognition, which allowed us to train hierarchical models to decode either the position and velocity of the end-effector of one's posture or the character (action) identity from the spindle firing patterns. We found that artificial neural networks could robustly solve both tasks, and the networks' units show tuning properties similar to neurons in the primate somatosensory cortex and the brainstem. Remarkably, we found uniformly distributed directional selective units only with the action-recognition-trained models and not the trajectory-decoding-trained models. This suggests that proprioceptive encoding is additionally associated with higher-level functions such as action recognition and therefore provides new, experimentally testable hypotheses of how proprioception aids in adaptive motor control., Competing Interests: KS, PM, CM, MB, AM No competing interests declared, MM Reviewing editor, eLife, (© 2023, Sandbrink, Mamidanna et al.)

Across the human body, skeletal muscles have a broad range of biomechanical roles that employ complex proprioceptive control strategies to successfully execute a desired movement. This information is derived from peripherally located sensory apparatus, the muscle spindle and Golgi tendon organs. The abundance of these sensory organs, particularly muscle spindles, is known to differ considerably across individual muscles. Here we present a comprehensive data set of 119 muscles across the human body including architectural properties (muscle fibre length, mass, pennation angle and physiological cross-sectional area) and statistically test their relationships with absolute spindle number and relative spindle abundance (the residual value of the linear regression of the log-transformed spindle number and muscle mass). These data highlight a significant positive relationship between muscle spindle number and fibre length, emphasising the importance of fibre length as an input into the central nervous system. However, there appears to be no relationship between muscles architecturally optimised to function as displacement specialists and their provision of muscle spindles. Additionally, while there appears to be regional differences in muscle spindle abundance, independent of muscle mass and fibre length, our data provide no support for the hypothesis that muscle spindle abundance is related to anatomical specialisation., (© 2023. The Author(s).)

The proprioceptive system is essential for the control of coordinated movement, posture, and skeletal integrity. The sense of proprioception is produced in the brain using peripheral sensory input from receptors such as the muscle spindle, which detects changes in the length of skeletal muscles. Despite its importance, the molecular composition of the muscle spindle is largely unknown. In this study, we generated comprehensive transcriptomic and proteomic datasets of the entire muscle spindle isolated from the murine deep masseter muscle. We then associated differentially expressed genes with the various tissues composing the spindle using bioinformatic analysis. Immunostaining verified these predictions, thus establishing new markers for the different spindle tissues. Utilizing these markers, we identified the differentiation stages the spindle capsule cells undergo during development. Together, these findings provide comprehensive molecular characterization of the intact spindle as well as new tools to study its development and function in health and disease., Competing Interests: BB, LH, SK, RA, BD, DL, MK, GB, RB, EZ No competing interests declared, (© 2023, Bornstein, Heinemann-Yerushalmi et al.)

Animals move across a wide range of surface conditions in real-world environments to acquire resources and avoid predation. To effectively navigate a variety of surfaces, animals rely on several mechanisms including intrinsic mechanical responses, spinal-level central pattern generators, and neural commands that require sensory feedback. Muscle spindle Ia afferents play a critical role in providing sensory feedback and informing motor control strategies across legged vertebrate locomotion, which is apparent in cases where this sensory input is compromised. Here, we tested the hypothesis that spindle Ia afferents from hindlimb muscles are important for coordinating forelimb landing behavior in the cane toad. We performed bilateral sciatic nerve reinnervations to ablate the stretch reflex from distal hindlimb muscles while allowing for motor neuron recovery. We found that toads significantly delayed the onset and reduced the activation duration of their elbow extensor muscle following spindle Ia afferent ablation in the hindlimbs. However, reinnervated toads achieved similar elbow extension at touchdown to that of their pre-surgery state. Our results suggest that while toads likely tuned the activation timing of forelimb muscles in response to losing Ia afferent sensation from the hindlimbs they were likely able to employ compensatory strategies that allowed them to continue landing effectively with reduced sensory information during take-off. These findings indicate muscle spindle Ia afferents may contribute to tuning complex movements involving multiple limbs., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)

Muscle spindles, one of the two main classes of proprioceptors together with Golgi tendon organs, are sensory structures that keep the central nervous system updated about the position and movement of body parts. Although they were discovered more than 150 years ago, their function during movement is not yet fully understood. Here, we summarize the morphology and known functions of muscle spindles, with a particular focus on locomotion. Although certain properties such as the sensitivity to dynamic and static muscle stretch are long known, recent advances in molecular biology have allowed the characterization of the molecular mechanisms for signal transduction in muscle spindles. Building upon classic literature showing that a lack of sensory feedback is deleterious to locomotion, we bring to the discussion more recent findings that support a pivotal role of muscle spindles in maintaining murine and human locomotor robustness, defined as the ability to cope with perturbations. Yet, more research is needed to expand the existing mechanistic understanding of how muscle spindles contribute to the production of robust, functional locomotion in real world settings. Future investigations should focus on combining different animal models to identify, in health and disease, those peripheral, spinal and brain proprioceptive structures involved in the fine tuning of motor control when locomotion happens in challenging conditions., (© 2022 The Authors. The Journal of Physiology © 2022 The Physiological Society.)

Robust locomotion relies on information from proprioceptors: sensory organs that communicate the position of body parts to the spinal cord and brain. Proprioceptive circuits in the spinal cord are known to coarsely regulate locomotion in the presence of perturbations. Yet, the regulatory importance of the brain in maintaining robust locomotion remains less clear. Here, through mouse genetic studies and in vivo electrophysiology, we examined the role of the brain in integrating proprioceptive information during perturbed locomotion. The systemic removal of proprioceptors left the mice in a constantly perturbed state, similar to that observed during mechanically perturbed locomotion in wild-type mice and characterised by longer and less accurate synergistic activation patterns. By contrast, after surgically interrupting the ascending proprioceptive projection to the brain through the dorsal column of the spinal cord, wild-type mice showed normal walking behaviour, yet lost the ability to respond to external perturbations. Our findings provide direct evidence of a pivotal role for ascending proprioceptive information in achieving robust, safe locomotion. KEY POINTS: Whether brain integration of proprioceptive feedback is crucial for coping with perturbed locomotion is not clear. We showed a crucial role of the brain for responding to external perturbations and ensure robust locomotion. We used mouse genetics to remove proprioceptors and a spinal lesion model to interrupt the flow of proprioceptive information to the brain through the dorsal column in wild-type animals. Using a custom-built treadmill, we administered sudden and random mechanical perturbations to mice during walking. External perturbations affected locomotion in wild-type mice similar to the absence of proprioceptors in genetically modified mice. Proprioceptive feedback from muscle spindles and Golgi tendon organs contributed to locomotor robustness. Wild-type mice lost the ability to respond to external perturbations after interruption of the ascending proprioceptive projection to the brainstem., (© 2022 The Authors. The Journal of Physiology © 2022 The Physiological Society.)

Muscle spindles are encapsulated sensory organs found in most of our muscles. Prevalent models of sensorimotor control assume the role of spindles is to reliably encode limb posture and movement. Here, I argue that the traditional view of spindles is outdated. Spindle organs can be tuned by spinal γ motor neurons that receive top-down and peripheral input, including from cutaneous afferents. A new model is presented, viewing γ motor activity as an intermediate coordinate transformation that allows multimodal information to converge on spindles, creating flexible coordinate representations at the level of the peripheral nervous system. That is, I propose that spindles play a unique overarching role in the nervous system: that of a peripheral signal-processing device that flexibly facilitates sensorimotor performance, according to task characteristics. This role is compatible with previous findings and supported by recent studies with naturalistically active humans. Such studies have so far shown that spindle tuning enables the independent preparatory control of reflex muscle stiffness, the selective extraction of information during implicit motor adaptation, and for segmental stretch reflexes to operate in joint space. Incorporation of advanced signal-processing at the periphery may well prove a critical step in the evolution of sensorimotor control theories., Competing Interests: MD No competing interests declared, (© 2022, Dimitriou.)

Muscle spindle abundance is highly variable within and across species, but we currently lack any clear picture of the mechanistic causes or consequences of this variation. Previous use of spindle abundance as a correlate for muscle function implies a mechanical underpinning to this variation, but these ideas have not been tested. Herein, we use integrated medical imaging and subject-specific musculoskeletal models to investigate the relationship between spindle abundance, muscle architecture and in vivo muscle behaviour in the human locomotor system. These analyses indicate that muscle spindle number is tightly correlated with muscle fascicle length, absolute fascicle length change, velocity of fibre lengthening and active muscle forces during walking. Novel correlations between functional indices and spindle abundance are also recovered, where muscles with a high abundance predominantly function as springs, compared to those with a lower abundance mostly functioning as brakes during walking. These data demonstrate that muscle fibre length, lengthening velocity and fibre force are key physiological signals to the central nervous system and its modulation of locomotion, and that muscle spindle abundance may be tightly correlated to how a muscle generates work. These insights may be combined with neuromechanics and robotic studies of motor control to help further tease apart the functional drivers of muscle spindle composition.

In needle electromyography, there are two spontaneous waveforms, miniature end plate potentials and "end plate spikes", appearing usually together. Miniature end plate potentials are local, non-propagating postsynaptic waves, caused by spontaneous exocytosis of acetylcholine in the neuromuscular junction. The prevailing hypothesis states that "end plate spikes" are propagated postsynaptic action potentials of muscle fibers, caused by presynaptic irritation of the motor nerve or nerve terminal. Using several small concentric needle electrodes in parallel with the muscle fibers, most "end plate spikes" are strictly local or propagating for 2-4 mm. At the end plate zone, there are miniature end plate potentials without "end plate spikes". Local "end plate spikes" are junctional potentials of intrafusal gamma neuromuscular junctions of the nuclear bag fibers, and propagated "end plate spikes" are potentials of nuclear chain muscle fibers of muscle spindles. Miniature end plate potentials without "end plate spikes" at the end plate zone derive from alpha neuromuscular junctions. These findings contrast with the prevailing hypothesis. The history of observations and different hypotheses of the origin of end plate spikes are described., (© 2022. The Author(s).)

Hand proprioception, the sense of the posture and movements of the wrist and digits, is critical to dexterous manual behavior and to stereognosis, the ability to sense the three-dimensional structure of objects held in the hand. To better understand this sensory modality and its role in hand function, we sought to characterize the acuity with which the postures and movements of finger joints are sensed. To this end, we measured the ability of human subjects to discriminate changes in posture and speed around the three joints of the index finger. In these experiments, we isolated the sensory component by imposing the postures on an otherwise still hand, to complement other studies in which subjects made judgments on actively achieved postures. We found that subjects could reliably sense 12-16% changes in joint angle and 18-32% changes in joint speed. Furthermore, the acuity for posture and speed was comparable across the three joints of the finger. Finally, task performance was unaffected by the presence of a vibratory stimulus, calling into question the role of cutaneous cues in hand proprioception. NEW & NOTEWORTHY Manual dexterity and stereognosis are supported by two exquisite sensory systems, namely touch and proprioception. Here, we measure the sensitivity of hand proprioception and show that humans can sense the posture and movements of the fingers with great accuracy. We also show that application of a skin vibration does not impair sensitivity, suggesting that proprioceptive acuity relies primarily on receptors in the muscles (and possibly tendons) rather than the skin.

Joint torque feedback is a new and promising means of kinesthetic feedback imposed by a wearable device. The torque feedback provides the wearer temporal and spatial information during a motion task. Nevertheless, little research has been conducted on quantifying the psychophysical parameters of how well humans can perceive external torques under various joint conditions. This study aims to investigate the just noticeable difference (JND) perceptual ability of the elbow joint to joint torques. The paper focuses on the ability of two primary joint proprioceptors, the Golgi-tendon organ (GTO) and muscle spindle (MS), to detect elbow torques, since touch and pressure sensors were masked. We studied 14 subjects while the arm was isometrically contracted (static condition) and was moving at a constant speed (dynamic condition). In total there were 10 joint conditions investigated, which varied the direction of the arm's movement and the preload direction as well as torque direction. The JND torques under static conditions ranged from 0.097 Nm with no preload to 0.197 Nm with a preload of 1.28 Nm. The maximum dynamic JND torques were 0.799 Nm and 0.428 Nm, when the arm was flexing and extending at 213 degrees per second, respectively., (© 2021. The Author(s).)

New Findings: What is the topic of this review? We describe the structure and function of secondary sensory endings of muscle spindles, their reflex action and role in motor control and proprioception. What advances does it highlight? In most mammalian skeletal muscles, secondary endings of spindles are more or much more numerous than primary endings but are much less well studied. By focusing on secondary endings in this review, we aim to redress the balance, draw attention to what is not known and stimulate future research., Abstract: Kinaesthesia and the control of bodily movement rely heavily on the sensory input from muscle spindles. Hundreds of these sensory structures are embedded in mammalian muscles. Each spindle has one or more sensory endings and its own complement of small muscle fibres that are activated by the CNS via fusimotor neurons, providing efferent control of sensory responses. Exactly how the CNS wields this influence remains the subject of much fascination and debate. There are two types of sensory endings, primary and secondary, with differing development, morphology, distribution and responsiveness. Spindle primary endings have received more attention than secondaries, although the latter usually outnumber them. This review focuses on the secondary endings. Their location within the spindle, their response properties, the projection of their afferents within the CNS and their reflex actions all suggest that secondaries have certain separate roles from the primaries in proprioception and motor control. Specifically, spindle secondaries seem more adapted than primaries to signalling slow and maintained changes in the relative position of bodily segments, thereby contributing to position sense, postural control and static limb positioning. By highlighting, in this way, the roles of secondary endings, a final aim of the review is to broaden understanding of muscle spindles more generally and of the important contributions they make to both sensory and motor mechanisms., (© 2021 The Authors. Experimental Physiology © 2021 The Physiological Society.)

Perception of limb position and motion combines sensory information from spindles in muscles that span one joint (monoarticulars) and two joints (biarticulars). This anatomical organization should create interactions in estimating limb position. We developed two models, one with only monoarticulars and one with both monoarticulars and biarticulars, to explore how biarticulars influence estimates of arm position in hand ( x , y ) and joint ( shoulder, elbow ) coordinates. In hand coordinates, both models predicted larger medial-lateral than proximal-distal errors, although the model with both muscle groups predicted that biarticulars would reduce this bias. In contrast, the two models made significantly different predictions in joint coordinates. The model with only monoarticulars predicted that errors would be uniformly distributed because estimates of angles at each joint would be independent. In contrast, the model that included biarticulars predicted that errors would be coupled between the two joints, resulting in smaller errors for combinations of flexion or extension at both joints and larger errors for combinations of flexion at one joint and extension at the other joint. We also carried out two experiments to examine errors made by human subjects during an arm position matching task in which a robot passively moved one arm to different positions and the subjects moved their other arm to mirror-match each position. Errors in hand coordinates were similar to those predicted by both models. Critically, however, errors in joint coordinates were only similar to those predicted by the model with monoarticulars and biarticulars. These results highlight how biarticulars influence perceptual estimates of limb position by helping to minimize medial-lateral errors. NEW & NOTEWORTHY It is unclear how sensory information from muscle spindles located within muscles spanning multiple joints influences perception of body position and motion. We address this issue by comparing errors in estimating limb position made by human subjects with predicted errors made by two musculoskeletal models, one with only monoarticulars and one with both monoarticulars and biarticulars. We provide evidence that biarticulars produce coupling of errors between joints, which help to reduce errors.

Gastric electrical stimulation (GES) is used clinically to promote proximal GI emptying and motility. In acute experiments, we measured duodenal motor responses elicited by GES applied at 141 randomly chosen electrode sites on the stomach serosal surface. Overnight-fasted (H 2 O available) anesthetized male rats ( n = 81) received intermittent biphasic GES for 5 min (20-s-on/40-s-off cycles; I = 0.3 mA; pw = 0.2 ms; 10 Hz). A strain gauge on the serosal surface of the proximal duodenum of each animal was used to evaluate baseline motor activity and the effect of GES. Using ratios of time blocks compared with a 15-min prestimulation baseline, we evaluated the effects of the 5-min stimulation on concurrent activity, on the 10 min immediately after the stimulation, and on the 15-min period beginning with the onset of stimulation. We mapped the magnitude of the duodenal response (three different motility indices) elicited from the 141 stomach sites. Post hoc electrode site maps associated with duodenal responses suggested three zones similar to the classic regions of forestomach, corpus, and antrum. Maximal excitatory duodenal motor responses were elicited from forestomach sites, whereas inhibitory responses occurred with stimulation of the corpus. Moderate excitatory duodenal responses occurred with stimulation of the antrum. Complex, weak inhibitory/excitatory responses were produced by stimulation at boundaries between stomach regions. Patterns of GES efficacies coincided with distributions of previously mapped vagal afferents, suggesting that excitation of the duodenum is strongest when GES electrodes are situated over stomach concentrations of vagal intramuscular arrays, putative stretch receptors in the muscle wall.

Despite decades of research, we lack a mechanistic framework capable of predicting how movement-related signals are transformed into the diversity of muscle spindle afferent firing patterns observed experimentally, particularly in naturalistic behaviors. Here, a biophysical model demonstrates that well-known firing characteristics of mammalian muscle spindle Ia afferents - including movement history dependence, and nonlinear scaling with muscle stretch velocity - emerge from first principles of muscle contractile mechanics. Further, mechanical interactions of the muscle spindle with muscle-tendon dynamics reveal how motor commands to the muscle (alpha drive) versus muscle spindle (gamma drive) can cause highly variable and complex activity during active muscle contraction and muscle stretch that defy simple explanation. Depending on the neuromechanical conditions, the muscle spindle model output appears to 'encode' aspects of muscle force, yank, length, stiffness, velocity, and/or acceleration, providing an extendable, multiscale, biophysical framework for understanding and predicting proprioceptive sensory signals in health and disease., Competing Interests: KB, KC, BH, PN, SH, TC, LT No competing interests declared, (© 2020, Blum et al.)

The sensorimotor integration during unconstrained reaching movements in the presence of variable environmental forces remains poorly understood. The objective of this study was to quantify how much the primary afferent activity of muscle spindles can contribute to shaping muscle coactivation patterns during reaching movements with complex dynamics. To achieve this objective, we designed a virtual reality task that guided healthy human participants through a set of planar reaching movements with controlled kinematic and dynamic conditions that were accompanied by variable muscle co-contraction. Next, we approximated the Ia afferent activity using a phenomenological model of the muscle spindle and muscle lengths derived from a musculoskeletal model. The parameters of the spindle model were altered systematically to evaluate the effect of fusimotor drive on the shape of the temporal profile of afferent activity during movement. The experimental and simulated data were analyzed with hierarchical clustering. We found that the pattern of co-activation of agonistic and antagonistic muscles changed based on whether passive forces in each movement played assistive or resistive roles in limb dynamics. The reaching task with assistive limb dynamics was associated with the most muscle co-contraction. In contrast, the simulated Ia afferent profiles were not changing between tasks and they were largely reciprocal with homonymous muscle activity. Simulated physiological changes to the fusimotor drive were not sufficient to reproduce muscle co-contraction. These results largely rule out the static set and α-γ coactivation as the main types of fusimotor drive that transform the monosynaptic Ia afferent feedback into task-dependent co-contraction of antagonistic muscles. We speculate that another type of nonlinear transformation of Ia afferent signals that is independent of signals modulating the activity of α motoneurons is required for Ia afferent-based co-contraction. This transformation could either be applied through a complex nonlinear profile of fusimotor drive that is not yet experimentally observed or through presynaptic inhibition.

New Findings: What is the central question of this study? Are there age-related differences in corticospinal responses whilst passively changing muscle length? What is the main finding and its importance? In contrast to young, older adults exhibited no modulation of corticospinal excitability in tibialis anterior during passive ankle movement. These data show impaired sensorimotor response in older adults during length changes of tibialis anterior, thus contributing to our understanding of age-related changes in sensorimotor control., Abstract: Corticospinal responses have been shown to increase and decrease with passive muscle shortening and lengthening, respectively, as a result of changes in muscle spindle afferent feedback. The ageing sensory system is accompanied by a number of alterations that might influence the processing and integration of sensory information. Consequently, corticospinal excitability might be modulated differently whilst changing muscle length. In 10 older adults (66 ± 4 years), corticospinal responses (MEP/M max ) were evoked in a static position, and during passive shortening and lengthening of soleus (SOL) and tibialis anterior (TA), and these data were compared to the re-analysed data pool of 18 younger adults (25 ± 4 years) published previously. Resting motor threshold was greater in SOL compared to TA (P < 0.001), but did not differ between young and older (P = 0.405). No differences were observed in MEP/M max between the static position, passive shortening or lengthening in SOL (young: all 0.02 ± 0.01; older: 0.05 ± 0.04, 0.03 ± 0.02 and 0.04 ± 0.01, respectively; P = 0.298), and responses were not dependent on age (P = 0.090). Conversely, corticospinal responses in TA were modulated differently between the age groups (P = 0.002), with greater MEP/M max during passive shortening (0.22 ± 0.12) compared to passive lengthening (0.13 ± 0.10) and static position (0.10 ± 0.05) in young (P < 0.001), but unchanged in older adults (0.19 ± 0.11, 0.22 ± 0.11 and 0.18 ± 0.07, respectively; P ≥ 0.867). The present experiment shows that length-dependent changes in corticospinal excitability in TA of the young are not evident in older adults. This suggests impaired sensorimotor response during muscle length changes in older age that might only be present in ankle flexors, but not extensors., (© 2019 The Authors. Experimental Physiology © 2019 The Physiological Society.)

Key Points: Golgi tendon organ feedback has been evaluated most frequently using electrical stimulation of peripheral nerves, which is not a physiological or selective stimulus for Golgi tendon organs. Golgi tendon organs are most responsive to active muscle contractions. This study provides evidence that muscle stimulation evoked twitches - a physiological stimulus for Golgi tendon organs - induces intermuscular effects most likely due to mechanical activation of Golgi tendon organ feedback and not direct activation of sensory axons. The results demonstrate that twitch contractions are a feasible non-invasive approach that can be used to advance understanding of the functional role of Golgi tendon organ feedback., Abstract: Force feedback from Golgi tendon organs (GTOs) has widespread intermuscular projections mediated by interneurons that share inputs from muscle spindles, among others. Because current methods to study GTO circuitry (nerve stimulation or muscle stretch) also activate muscle spindle afferents, the selective role of GTOs remains uncertain. Here, we tested the hypothesis that intramuscular stimulation evoked twitch contractions could be used to naturally bias activation of GTOs and thus evaluate their intermuscular effects in decerebrate cats. This was achieved by comparing the effects of twitch contractions and stretches as donor inputs onto the motor output of recipient muscles. Donor-recipient pairs evaluated included those already known in the cat to receive donor excitatory muscle spindle feedback only, inhibitory GTO feedback only, and both excitatory spindle and inhibitory GTO effects. Muscle stretch, but not twitch contractions, evoked excitation onto recipient muscles with muscle spindle afferent inputs only. Both donor muscle stretch and twitch contractions inhibited a recipient muscle with GTO projections only. In a recipient muscle that receives both muscle spindle and GTO projections, donor muscle stretch evoked both excitatory and inhibitory effects, whereas twitch contractions evoked inhibitory effects only. These data support the hypothesis that muscle stimulation evoked contractions can induce intermuscular effects most consistent with mechanical GTO receptor activation and not direct activation of sensory axons. We propose this approach can be used to evaluate GTO circuitry more selectively than muscle stretch or nerve stimulation and can be adapted to study GTO feedback non-invasively in freely moving cats and humans., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)

Muscle spindles are integral to proprioception and their behavior is of particular interest for the design of somatosensory neuroprostheses. Prior knowledge about human muscle spindles has been limited to microneurography recordings in peripheral nerves using joint movements that do not disrupt the electrode. Recent studies demonstrate a new methodology for studying the afferent encoding of proprioception during freestanding, providing important information for neural engineering and the broader scientific community (Knellwolf TP, Burton AR, Hammam E, Macefield VG. J Neurophysiol 120: 953-959, 2018; Knellwolf TP, Burton AR, Hammam E, Macefield VG. J Neurophysiol 121: 74-84, 2019; Macefield VG, Knellwolf TP. J Neurophysiol 120: 452-467, 2018).

Stretches of relaxed cat and rat muscle elicit similar history-dependent muscle spindle Ia firing rates that resemble history-dependent forces seen in single activated muscle fibers ( Nichols and Cope, 2004). Owing to thixotropy, whole musculotendon forces and muscle spindle firing rates are history dependent during stretch of relaxed cat muscle, where both muscle force and muscle spindle firing rates are elevated in the first stretch in a series of stretch-shorten cycles ( Blum et al., 2017). By contrast, rat musculotendon exhibits only mild thixotropy, such that the measured forces when stretched cannot explain history-dependent muscle spindle firing rates in the same way ( Haftel et al., 2004). We hypothesized that history-dependent muscle spindle firing rates elicited in stretch of relaxed rat muscle mirror history-dependent muscle fiber forces, which are masked at the level of whole musculotendon force by extracellular tissue force. We removed estimated extracellular tissue force contributions from recorded musculotendon force using an exponentially elastic tissue model. We then showed that the remaining estimated muscle fiber force resembles history-dependent muscle spindle firing rates recorded simultaneously. These forces also resemble history-dependent forces recorded in stretch of single activated fibers that are attributed to muscle cross-bridge mechanisms ( Campbell and Moss, 2000). Our results suggest that history-dependent muscle spindle firing in both rats and cats arise from history-dependent forces owing to thixotropy in muscle fibers., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)

In addition to being a prerequisite for many activities of daily living, the ability to maintain steady upright standing is a relevant model to study sensorimotor integrative function. Upright standing requires managing multimodal sensory inputs to produce finely tuned motor output that can be adjusted to accommodate changes in standing conditions and environment. The sensory information used for postural control mainly arises from the vestibular system of the inner ear, vision, and proprioception. Proprioception (sense of body position and movement) encompasses signals from mechanoreceptors (proprioceptors) located in muscles, tendons, and joint capsules. There is general agreement that proprioception signals from leg muscles provide the primary source of information for postural control. This is because of their exquisite sensitivity to detect body sway during unperturbed upright standing that mainly results from variations in leg muscle length induced by rotations around the ankle joint. However, aging is associated with alterations of muscle spindles and their neural pathways, which induce a decrease in the sensitivity, acuity, and integration of the proprioceptive signal. These alterations promote changes in postural control that reduce its efficiency and thereby may have deleterious consequences for the functional independence of an individual. This narrative review provides an overview of how aging alters the proprioceptive signal from the legs and presents compelling evidence that these changes modify the neural control of upright standing.

It is well known that muscle spindles have a monosynaptic, excitatory connection with α-motoneurons. However, the influence of muscle spindles on human motor unit behavior during maximal efforts remains untested. It has also been shown that muscle spindle function, as assessed by peripheral reflexes, can be systematically manipulated with muscle vibration. Therefore, the purpose of this study was to analyze the effects of brief and prolonged vibration on maximal motor unit firing properties. A crossover design was used, in which each of the 24 participants performed one to three maximal knee extensions under three separate conditions: 1 ) control, 2 ) brief vibration that was applied during the contraction, and 3 ) after prolonged vibration that was applied for ~20 min before the contraction. Multichannel EMG was recorded from the vastus lateralis during each contraction and was decomposed into its constituent motor unit action potential trains. Surprisingly, an approximate 9% reduction in maximal voluntary strength was observed not only after prolonged vibration but also during brief vibration. In addition, both vibration conditions had a large, significant effect on firing rates (a decrease in the rates) and a small to moderate, nonsignificant effect on recruitment thresholds (a small increase in the thresholds). Therefore, vibration had a detrimental influence on both maximal voluntary strength and motor unit firing properties, which we propose is due to altered function of the stretch reflex pathway. NEW & NOTEWORTHY We used vibration to alter muscle spindle function and examined the vibration's influence on maximal motor unit properties. We discovered that vibration had a detrimental influence on motor unit behavior and motor output by decreasing motor unit firing rates, increasing recruitment thresholds, which led to decreased maximal strength. We believe that understanding the role of muscle spindles during maximal contractions provides a deeper insight into motor control and sensorimotor integration.

Key Points: Locomotion on land and in water requires the coordination of a great number of muscle activations and joint movements. Constant feedback about the position of own body parts in relation to the surrounding environment and the body itself (proprioception) is required to maintain stability and avoid failure. The central nervous system may follow a modular type of organization by controlling muscles in orchestrated groups (muscle synergies) rather than individually. We used this concept on genetically modified mice lacking muscle spindles, one of the two main classes of proprioceptors. We provide evidence that proprioceptive feedback is required by the central nervous system to accurately tune the modular organization of locomotion., Abstract: For exploiting terrestrial and aquatic locomotion, vertebrates must build their locomotor patterns based on an enormous amount of variables. The great number of muscles and joints, together with the constant need for sensory feedback information (e.g. proprioception), make the task of controlling movement a problem with overabundant degrees of freedom. It is widely accepted that the central nervous system may simplify the creation and control of movement by generating activation patterns common to muscle groups, rather than specific to individual muscles. These activation patterns, called muscle synergies, describe the modular organization of movement. We extracted synergies through electromyography from the hind limb muscle activities of wild-type and genetically modified mice lacking sensory feedback from muscle spindles. Muscle spindle-deficient mice underwent a modification of the temporal structure (motor primitives) of muscle synergies that resulted in diminished functionality during walking. In addition, both the temporal and spatial (motor modules) components of synergies were severely affected when external perturbations were introduced or when animals were immersed in water. These findings show that sensory feedback from group Ia/II muscle spindles regulates motor function in normal and perturbed walking. Moreover, when group Ib Golgi tendon organ feedback is lacking due to enhanced buoyancy, the modular organization of swimming is almost completely compromised., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)

Proprioceptive feedback from Group Ia/II muscle spindle afferents and Group Ib Golgi tendon afferents is critical for the normal execution of most motor tasks, yet how these distinct proprioceptor subtypes emerge during development remains poorly understood. Using molecular genetic approaches in mice of either sex, we identified 24 transcripts that have not previously been associated with a proprioceptor identity. Combinatorial expression analyses of these markers reveal at least three molecularly distinct proprioceptor subtypes. In addition, we find that 12 of these transcripts are expressed well after proprioceptors innervate their respective sensory receptors, and expression of three of these markers, including the heart development molecule Heg1 , is significantly reduced in mice that lack muscle spindles. These data reveal Heg1 as a putative marker for proprioceptive muscle spindle afferents. Moreover, they suggest that the phenotypic specialization of functionally distinct proprioceptor subtypes depends, in part, on extrinsic sensory receptor organ-derived signals. SIGNIFICANCE STATEMENT Sensory feedback from muscle spindle (MS) and Golgi tendon organ (GTO) sensory end organs is critical for normal motor control, but how distinct MS and GTO afferent sensory neurons emerge during development remains poorly understood. Using (bulk) transcriptome analysis of genetically identified proprioceptors, this work reveals molecular markers for distinct proprioceptor subsets, including some that appear selectively expressed in MS afferents. Detailed analysis of the expression of these transcripts provides evidence that MS/GTO afferent subtype phenotypes may, at least in part, emerge through extrinsic, sensory end organ-derived signals., (Copyright © 2019 the authors.)

Studies on anesthetized animals have revealed that nociceptors can excite fusimotor neurons and thereby change the sensitivity of muscle spindles to stretch; such nociceptive reflexes have been suggested to underlie the mechanisms that lead to chronic musculoskeletal pain syndromes. However, the validity of the "vicious cycle" hypothesis in humans has yielded results contrasting with those found in animals. Given that spindle firing rates are much lower in humans than in animals, it is possible that some of the discrepancies between human experimental data and those obtained in animals could be explained by differences in background fusimotor drive when the leg muscles are relaxed. We examined the effects of tonic muscle pain during voluntary contractions of the ankle dorsiflexors. Unitary recordings were obtained from 10 fusimotor-driven muscle spindle afferents (6 primary, 4 secondary) supplying the ankle dorsiflexors via a microelectrode inserted percutaneously into the common peroneal nerve. A series of 1-min weak contractions was performed at rest and during 1 h of muscle pain induced by intramuscular infusion of 5% hypertonic saline into the tibialis anterior muscle. We did not observe any statistically significant increases in muscle spindle firing rates of six afferents followed during tonic muscle pain, although discharge variability increased slightly. Furthermore, a participant's capacity to maintain a constant level of force, while relying on proprioceptive feedback in the absence of visual feedback, was not compromised during pain. We conclude that nociceptive inputs from contracting muscle do not excite fusimotor neurons during voluntary isometric contractions in humans. NEW & NOTEWORTHY Data obtained in the cat have shown that muscle pain causes a marked increase in the firing of muscle spindles, attributed to a nociceptor-driven fusimotor reflex. However, our studies of muscle spindles in relaxed leg muscles failed to find any effect on spindle discharge. Here we showed that experimental muscle pain failed to increase the firing of muscle spindle afferents during weak voluntary contractions, when fusimotor drive sufficient to increase their firing is present.

Key Points: Acetylcholine receptors are aggregated in the central regions of intrafusal muscle fibres. Single unit muscle spindle afferent responses from isolated mouse extensor digitorum longus muscle were recorded in the absence of fusimotor input to ramp and hold stretches as well as to sinusoidal vibrations in the presence and absence of the acetylcholine receptor blockers d-tubocurarine and α-bungarotoxin. Proprioceptive afferent responses to both types of stretch were enhanced in the presence of either blocker. Blocking acetylcholine uptake and vesicular acetylcholine release by hemicholinium-3 also enhanced stretch-evoked responses. These results represent the first evidence that acetylcholine receptors negatively modulate muscle spindle responses to stretch. The data support the hypothesis that the sensory nerve terminal is able to release vesicles to fine-tune proprioceptive afferent sensitivity., Abstract: Muscle spindles are complex stretch-sensitive mechanoreceptors. They consist of specialized skeletal muscle fibres, called intrafusal fibres, which are innervated in the central (equatorial) region by afferent sensory axons and in both polar regions by efferent γ-motoneurons. Previously it was shown that acetylcholine receptors (AChR) are concentrated in the equatorial region at the contact site between the sensory neuron and the intrafusal muscle fibre. To address the function of these AChRs, single unit sensory afferents were recorded from an isolated mouse extensor digitorum longus muscle in the absence of γ-motoneuron activity. Specifically, we investigated the responses of individual sensory neurons to ramp-and-hold stretches and sinusoidal vibrations before and after the addition of the competitive and non-competitive AChR blockers d-tubocurarine and α-bungarotoxin, respectively. The presence of either drug did not affect the resting action potential discharge frequency. However, the action potential frequencies in response to stretch were increased. In particular, frequencies of the dynamic peak and dynamic index to ramp-and-hold stretches were significantly higher in the presence of either drug. Treatment of muscle spindle afferents with the high-affinity choline transporter antagonist hemicholinium-3 similarly increased muscle spindle afferent firing frequencies during stretch. Moreover, the firing rate during sinusoidal vibration stimuli at low amplitudes was higher in the presence of α-bungarotoxin compared to control spindles also indicating an increased sensitivity to stretch. Collectively these data suggest a modulation of the muscle spindle afferent response to stretch by AChRs in the central region of intrafusal fibres possibly fine-tuning muscle spindle sensitivity., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)

We recently developed an approach for recording from muscle spindles in the intrinsic muscles of the foot in freestanding humans by inserting a tungsten microelectrode into the posterior tibial nerve behind the medial malleolus of the ankle. Here we characterize the behavior of muscle spindles in the small muscles of the foot in 1) seated subjects with the leg horizontal and the foot naturally plantarflexed and 2) standing subjects. In the first study, recordings were made from 26 muscle spindle afferents located within flexor digiti minimi brevis ( n = 4), abductor digiti minimi ( n = 3), quadratus plantae ( n = 3), plantar interossei ( n = 4), flexor digitorum brevis ( n = 3), dorsal interossei ( n = 2), and lumbricals ( n = 2), with one each supplying abductor hallucis, adductor hallucis, and flexor hallucis brevis. The identity of another two muscle afferents was unknown. The majority of the units were silent at rest, only seven (27%) being spontaneously active. Because of the anatomic constraints of the foot, some spindles supplying muscles acting on the toes responded to movements of one or more digits. In the second study, 12 muscle spindle afferents were examined during standing. The ongoing discharge of eight spindle afferents covaried with changes in the center of pressure during postural sway. We conclude that the majority of spindle endings in the small muscles of the foot are silent at rest, which may allow them to encode changes in conformation of the foot when it is loaded during standing. Moreover, these muscle spindle afferents can provide useful proprioceptive information during standing and postural sway. NEW & NOTEWORTHY We have characterized the firing properties of muscle spindles in the intrinsic muscles of the human foot for the first time. The majority of the spindle endings are silent in seated subjects, and most fire tonically during standing, their discharge covarying with center of pressure during postural sway. We conclude that spindle endings in the intrinsic muscles of the foot provide useful proprioceptive information during free standing.

Terrestrial animals increase their walking speed by increasing the activity of the extensor muscles. However, the mechanism underlying how this speed-dependent amplitude modulation is achieved remains obscure. Previous studies have shown that group Ib afferent feedback from Golgi tendon organs that signal force is one of the major regulators of the strength of muscle activity during walking in cats and humans. In contrast, the contribution of group Ia/II afferent feedback from muscle spindle stretch receptors that signal angular displacement of leg joints is unclear. Some studies indicate that group II afferent feedback may be important for amplitude regulation in humans, but the role of muscle spindle feedback in regulation of muscle activity strength in quadrupedal animals is very poorly understood. To examine the role of feedback from muscle spindles, we combined in vivo electrophysiology and motion analysis with mouse genetics and gene delivery with adeno-associated virus. We provide evidence that proprioceptive sensory feedback from muscle spindles is important for the regulation of the muscle activity strength and speed-dependent amplitude modulation. Furthermore, our data suggest that feedback from the muscle spindles of the ankle extensor muscles, the triceps surae, is the main source for this mechanism. In contrast, muscle spindle feedback from the knee extensor muscles, the quadriceps femoris, has no influence on speed-dependent amplitude modulation. We provide evidence that proprioceptive feedback from ankle extensor muscles is critical for regulating muscle activity strength as gait speed increases. NEW & NOTEWORTHY Animals upregulate the activity of extensor muscles to increase their walking speed, but the mechanism behind this is not known. We show that this speed-dependent amplitude modulation requires proprioceptive sensory feedback from muscle spindles of ankle extensor muscle. In the absence of muscle spindle feedback, animals cannot walk at higher speeds as they can when muscle spindle feedback is present.

Muscle spindles and Golgi tendon organs (GTOs) are two types of sensory receptors that respond to changes in length or tension of skeletal muscles. These mechanosensors have long been known to participate in both proprioception and stretch reflex. Here, we present recent findings implicating these organs in maintenance of spine alignment as well as in realignment of fractured bones. These discoveries have been made in several mouse lines lacking functional mechanosensors in part or completely. In both studies, the absence of functional spindles and GTOs produced a more severe phenotype than that of spindles alone. Interestingly, the spinal curve phenotype, which appeared during peripubertal development, bears resemblance to the human condition adolescent idiopathic scoliosis. This similarity may contribute to the study of the disease by offering both an animal model and a clue as to its aetiology. Moreover, it raises the possibility that impaired proprioceptive signalling may be involved in the aetiology of other conditions. Overall, these new findings expand considerably the scope of involvement of proprioception in musculoskeletal development and function.This article is part of the Theo Murphy meeting issue 'Mechanics of development'., (© 2018 The Author(s).)

Reference frame transformations (RFTs) are crucial components of sensorimotor transformations in the brain. Stochasticity in RFTs has been suggested to add noise to the transformed signal due to variability in transformation parameter estimates (e.g., angle) as well as the stochastic nature of computations in spiking networks of neurons. Here, we varied the RFT angle together with the associated variability and evaluated the behavioral impact in a reaching task that required variability-dependent visual-proprioceptive multisensory integration. Crucially, reaches were performed with the head either straight or rolled 30° to either shoulder, and we also applied neck loads of 0 or 1.8 kg (left or right) in a 3 × 3 design, resulting in different combinations of estimated head roll angle magnitude and variance required in RFTs. A novel three-dimensional stochastic model of multisensory integration across reference frames was fitted to the data and captured our main behavioral findings: 1) neck load biased head angle estimation across all head roll orientations, resulting in systematic shifts in reach errors; 2) increased neck muscle tone led to increased reach variability due to signal-dependent noise; and 3) both head roll and neck load created larger angular errors in reaches to visual targets away from the body compared with reaches toward the body. These results show that noise in muscle spindles and stochasticity in general have a tangible effect on RFTs underlying reach planning. Since RFTs are omnipresent in the brain, our results could have implications for processes as diverse as motor control, decision making, posture/balance control, and perception. NEW & NOTEWORTHY We show that increasing neck muscle tone systematically biases reach movements. A novel three-dimensional multisensory integration across reference frames model captures the data well and provides evidence that the brain must have online knowledge of full-body geometry together with the associated variability to plan reach movements accurately.

The posterior tibial nerve, located behind the medial malleolus of the ankle, supplies the intrinsic muscles of the foot and most of the skin of the sole. We describe a novel approach for recording from this nerve via a percutaneously inserted tungsten microelectrode and provide examples of recordings from presumed muscle spindle endings recorded in freely standing human subjects. The fact that the angular excursions of the ankle joint are small as the foot is loaded during the transition from the seated position to standing means that one can obtain stable recordings of neural traffic in unloaded, loaded, and freely standing conditions. We conclude that this novel approach will allow studies that will increase our understanding of the roles of muscle and cutaneous afferents in the foot in the control of upright posture. NEW & NOTEWORTHY We have performed the first microneurographic studies from the posterior tibial nerve at the ankle. Stability of the recording site allows one to record from muscle spindles in the intrinsic muscles of the foot as well as from cutaneous mechanoreceptors in the sole of the foot during the transition from seated to standing. This novel approach opens up new opportunities for studying the roles of muscle and cutaneous afferents in the foot in the control of upright stance.

Inflammation is known to alter nervous system function, but its effect on muscle spindle afferent mechanosensation and sensory integration in the spinal cord has not been well studied. We tested the hypothesis that systemic inflammation induced by an intraperitoneal injection of the endotoxin lipopolysaccharide (LPS; 7.5 × 10 5 endotoxin units/kg 18 h before experiment) would alter muscle spindle afferent mechanosensation and spinal cord excitability to Group Ia input in male and female adult C57Bl/6 mice. LPS injection caused a systemic immune response, evidenced by decreased white blood cell, monocyte, and lymphocyte concentrations in the blood, increased blood granulocyte concentration, and body weight loss. The immune response in both sexes was qualitatively similar. We used an in vitro muscle-nerve preparation to assay muscle spindle afferent response to stretch and vibration. LPS injection did not significantly change the response to stretch or vibration, with the exception of small decreases in the ability to entrain to high-frequency vibration in male mice. Similarly, LPS injection did not alter spinal cord excitability to Group Ia muscle spindle afferent input as measured by the Hoffman's reflex test in anesthetized mice (100 mg/kg ketamine, 10 mg/kg xylazine). Specifically, there were no changes in M or H wave latencies nor in the percentage of motor neurons excited by electrical afferent stimulation (H max /M max ). Overall, we found no major alterations in muscle proprioceptor function or sensory integration following exposure to LPS at a dose and time course that causes changes in nociceptor function and central processing., (© 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Muscle spindles are ubiquitous encapsulated mechanoreceptors found in most mammalian muscles. There are two types of endings, primary and secondary, and both are sensitive to changes in muscle length and velocity, with the primary endings having a greater dynamic sensitivity. Unlike other mechanoreceptors in the somatosensory system, muscle spindles are unique in possessing motor innervation, via γ-motoneurons (fusimotor neurons), that control their sensitivity to stretch. Much of what we know about human muscles spindles comes from studying the behavior of their afferents via intraneural microelectrodes (microneurography) inserted into accessible peripheral nerves. We review the functional properties of human muscle spindles, comparing and contrasting with what we know about the functions of muscle spindles studied in experimental animals. As in the cat, many human muscle spindles possess a background discharge that is related to the degree of muscle stretch, but mean firing rates are much lower (~10 Hz). They can faithfully encode changes in muscle fascicle length in passive conditions, but higher level extraction of information is required by the central nervous system to measure changes in muscle length during muscle contraction. Moreover, although there is some evidence supporting independent control of human muscle spindles via fusimotor neurons, any effects are modest compared with the clearly independent control of fusimotor neurons observed in the cat.

Populations with obesity are more likely to fall and exhibit balance instability. The reason for this is likely multifactorial, but there is some evidence that sensory function is impaired during obesity. We tested the hypothesis that muscle proprioceptor function is compromised in a mouse model of diet induced obesity. An in vitro muscle-nerve preparation was used to record muscle spindle afferent responses to physiological stretch and sinusoidal vibration. We compared the responses of C57/Bl6 male and female mice on a control diet (10% kcal fat) with those eating a high fat diet (HFD; 60% kcal fat) for 10 weeks (final age 14-15 weeks old). Following HFD feeding, adult mice of both sexes exhibited decreased muscle spindle afferent responses to muscle movement. Muscle spindle afferent firing rates during the plateau phase of stretch were significantly lower in both male and female HFD animals as were two measures of dynamic sensitivity (dynamic peak and dynamic index). Muscle spindle afferents in male mice on a HFD were also significantly less likely to entrain to vibration. Due to the importance of muscle spindle afferents to proprioception and motor control, decreased muscle spindle afferent responsiveness may contribute to balance instability during obesity.

Recordings of alpha motoneuron discharges from branches of the intercostal and abdominal nerves in anesthetized cats were analyzed for modulation during the cardiac cycle. Cardiac modulation was assessed by the construction of cross-correlation histograms between the R-wave of the ECG and the largest amplitude efferent spikes. In all but two recordings (which were believed to have either no or few alpha spikes), the histograms showed relatively short duration peaks and/or troughs (widths at half amplitude 4-50 ms) at lags of 10-150 ms. These observations were deduced to result from activity in oligosynaptic pathways, probably from muscle spindle afferents, whose discharges are known to be synchronized to the cardiac pulse. The results suggest that onward transmission of the cardiac signal from thoracic muscle afferents (and possibly from other dynamically sensitive afferents) to other parts of the central nervous system is highly likely and that therefore these afferents could contribute to cardiac interoception. NEW & NOTEWORTHY It has been recognized since 1933 that muscle spindles respond to the cardiac pulse, but it is unknown whether this cardiac signal is transmitted to other levels in the nervous system. Here we show that a cardiac signal, likely arising from muscle spindles, is present in the efferent activities of thoracic and abdominal muscle nerves, suggesting probable onward transmission of this signal to higher levels and therefore that muscle spindles could contribute to cardiac interoception.

A method is described that, for the first time, allows instantaneous estimation of the Ia fiber input to human soleus motoneurons following electrical stimulation of the tibial nerve. The basis of the method is to determine the thresholds of the most and least excitable 1a fibers to electrical stimulation, and to treat the intervening thresholds as having a normal distribution about the mean; the validity of this approach is discussed. It was found that, for the same Ia fiber input, the percentage of soleus motoneurons contributing to the H (Hoffmann)-reflex differed considerably among subjects; when the results were pooled, however, there was an approximately linear relationship between Ia input and motoneuron output. Weak extension of the great toe diminished the soleus motoneuron reflex discharge in all but 2 of 16 subjects; the results for weak ankle plantarflexion were less consistent, but overall, there was a reduction in soleus motoneuron output also. The methodology should provide new insights into disorders of movement and tone, especially as it permits estimates of motoneuron depolarization to be made. NEW & NOTEWORTHY Assuming a normal distribution of Ia fiber thresholds to electrical stimulation and using the H-reflex, we determined for the first time an Ia input-α-motoneuron output relationship for the human soleus muscle. The relationship varies greatly among subjects but, overall, is approximately linear. Minimal contraction of a toe muscle alters the relationship dramatically, probably due to presynaptic inhibition of Ia fibers. Drawing on the literature, we can calculate changes in α-motoneuron membrane potential.

Involuntary force variability below 15 Hz arises from, and is influenced by, many factors including descending neural drive, proprioceptive feedback, and mechanical properties of muscles and tendons. However, their potential interactions that give rise to the well-structured spectrum of involuntary force variability are not well understood due to a lack of experimental techniques. Here, we investigated the generation, modulation, and interactions among different sources of force variability using a physiologically-grounded closed-loop simulation of an afferented muscle model. The closed-loop simulation included a musculotendon model, muscle spindle, Golgi tendon organ (GTO), and a tracking controller which enabled target-guided force tracking. We demonstrate that closed-loop control of an afferented musculotendon suffices to replicate and explain surprisingly many cardinal features of involuntary force variability. Specifically, we present 1) a potential origin of low-frequency force variability associated with co-modulation of motor unit firing rates (i.e.,'common drive'), 2) an in-depth characterization of how proprioceptive feedback pathways suffice to generate 5-12 Hz physiological tremor, and 3) evidence that modulation of those feedback pathways (i.e., presynaptic inhibition of Ia and Ib afferents, and spindle sensitivity via fusimotor drive) influence the full spectrum of force variability. These results highlight the previously underestimated importance of closed-loop neuromechanical interactions in explaining involuntary force variability during voluntary 'isometric' force control. Furthermore, these results provide the basis for a unifying theory that relates spinal circuitry to various manifestations of altered involuntary force variability in fatigue, aging and neurological disease.