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Signals from sensory receptors in muscles and skin enter the central nervous system ( CNS), where they contribute to kinaesthesia and the generation of motor commands. Many lines of evidence indicate that sensory input from skin receptors, muscle spindles and Golgi tendon organs play the predominant role in this regard. Yet in spite of over 100 years of research on this topic, some quite fundamental questions remain unresolved. How does the CNS choose to use the ability to control muscle spindle sensitivity during voluntary movements? Do spinal reflexes contribute usefully to load compensation, given that the feedback gain must be quite low to avoid instability? To what extent do signals from skin stretch receptors contribute? This article provides a brief review of various theories, past and present, that address these questions. To what extent has the knowledge gained resulted in clinical applications? Muscles paralyzed as a result of spinal cord injury or stroke can be activated by electrical stimulation delivered by neuroprostheses. In practice, at most two or three sensors can be deployed on the human body, providing only a small fraction of the information supplied by the tens of thousands of sensory receptors in animals. Most of the neuroprostheses developed so far do not provide continuous feedback control. Instead, they switch from one state to another when signals from their one or two sensors meet pre-set thresholds (finite state control). The inherent springiness of electrically activated muscle provides a crucial form of feedback control that helps smooth the resulting movements. In spite of the dissimilarities, parallels can be found between feedback control in neuroprostheses and in animals and this can provide surprising insights in both directions. [ABSTRACT FROM AUTHOR]

I present a brief review of current understanding of the innervation of the mammalian muscle spindle, from a personal historical perspective. The review begins with comparative studies on the numbers of spindle afferents and considers how their relative abundance may best be assessed. This is followed by an examination of the distribution and some functional properties of the motor innervation. The primary ending is the subject of the final section, in particular, I look at what can be learned from serial sectioning and volumetric reconstruction, and present new results on a model and simulations concerning sensory terminal deformation during stretch. [ABSTRACT FROM AUTHOR]

The first descriptions of muscle spindles with intrafusal fibres containing striated myofibrils and nervous elements were given approximately 150 years ago. It took, however, another 100 years to establish the presence of two types of intrafusal muscle fibres: nuclear bag and nuclear chain fibres. The present paper highlights primarily the contribution of Robert Banks in fibre typing of intrafusal fibres: the confirmation of the principle of two types of nuclear bag fibres in mammalian spindles and the variation in occurrence of a dense M-band along the fibres. Furthermore, this paper summarizes how studies from the Umeå University group (Laboratory of Muscle Biology in the Department of Integrative Medical Biology) on fibre typing and the structure and composition of M-bands have contributed to the current understanding of muscle spindle complexity in adult humans as well as to muscle spindle development and effects of ageing. The variable molecular composition of the intrafusal sarcomeres with respect to myosin heavy chains and M-band proteins gives new perspectives on the role of the intrafusal myofibrils as stretch-activated sensors influencing tension/stiffness and signalling to nuclei. [ABSTRACT FROM AUTHOR]

In this mini-review I have proposed that there are two kinds of position sense, one a sense of the position of one part of the body relative to another, the other a sense of the location in space of our body and its limbs. A common method used to measure position sense is to ask subjects to match with one arm the position adopted by the other. Here all of the evidence points to muscle spindles as the major proprioceptors, with cutaneous receptors acting as proprioceptors providing a supporting role. Other senses such as vision do not play a major role. The sense of localisation in space measured by pointing to the arm, rather than matching its position, I propose, is not served by proprioceptors but by exteroceptors, vision, touch and hearing. Here the afferent input is relayed to sensory areas of the brain, to address the postural schema, a cortical map of the body and limbs, specifying its size and shape. It is here that spatial location is computed. This novel interpretation of position sense as two separate entities has the advantage of proposing new, future experiments and if it is supported by the findings, it will represent an important step forward in our understanding of the central processing of spatial information. [ABSTRACT FROM AUTHOR]

Mammals may exhibit different forms of locomotion even within a species. A particular form of locomotion (e.g. walk, run, bound) appears to be selected by supraspinal commands, but the precise pattern, i.e. phasing of limbs and muscles, is generated within the spinal cord by so-called central pattern generators. Peripheral sense organs, particularly the muscle spindle, play a crucial role in modulating the central pattern generator output. In turn, the feedback from muscle spindles is itself modulated by static and dynamic fusimotor (gamma) neurons. The activity of muscle spindle afferents and fusimotor neurons during locomotion in the cat is reviewed here. There is evidence for some alpha-gamma co-activation during locomotion involving static gamma motoneurons. However, both static and dynamic gamma motoneurons show patterns of modulation that are distinct from alpha motoneuron activity. It has been proposed that static gamma activity may drive muscle spindle secondary endings to signal the intended movement to the central nervous system. Dynamic gamma motoneuron drive appears to prime muscle spindle primary endings to signal transitions in phase of the locomotor cycle. These findings come largely from reduced animal preparations (decerebrate) and require confirmation in freely moving intact animals. [ABSTRACT FROM AUTHOR]

The article discuses the anatomical description of the fine structure of muscle spindles. Topics discussed include histological distinction between bag and chain intrafusal muscle fibres, mechano-electric signal transduction to transmit information to the central nervous system (VNS) and afferent axons branch within the spindle. It also mentions the importance of the spinal cord as it filters the sensory messages decodes the brain's descending command in pattern of motoneuronal firing.

The health of primary sensory afferents supplying muscle has to be a first consideration in assessing deficits in proprioception and related motor functions. Here we discuss the role of a particular proprioceptor, the IA muscle spindle proprioceptor in causing movement disorders in response to either regeneration of a sectioned peripheral nerve or damage from neurotoxic chemotherapy. For each condition, there is a single preferred and widely repeated explanation for disability of movements associated with proprioceptive function. We present a mix of published and preliminary findings from our laboratory, largely from in vivo electrophysiological study of treated rats to demonstrate newly discovered IA afferent defects that seem likely to make important contributions to movement disorders. First, we argue that reconnection of regenerated IA afferents with inappropriate targets, although often repeated as the reason for lost stretch-reflex contraction, is not a complete explanation. We present evidence that despite successful recovery of stretch-evoked sensory signaling, peripherally regenerated IA afferents retract synapses made with motoneurons in the spinal cord. Second, we point to evidence that movement disability suffered by human subjects months after discontinuation of oxaliplatin (OX) chemotherapy for some is not accompanied by peripheral neuropathy, which is the acknowledged primary cause of disability. Our studies of OX-treated rats suggest a novel additional explanation in showing the loss of sustained repetitive firing of IA afferents during static muscle stretch. Newly extended investigation reproduces this effect in normal rats with drugs that block Na+ channels apparently involved in encoding static IA afferent firing. Overall, these findings highlight multiplicity in IA afferent deficits that must be taken into account in understanding proprioceptive disability, and that present new avenues and possible advantages for developing effective treatment. Extending the study of IA afferent deficits yielded the additional benefit of elucidating normal processes in IA afferent mechanosensory function. [ABSTRACT FROM AUTHOR]

This article summarises progress to date over an exciting and very enjoyable first 15 years of collaboration with Bob Banks. Our collaboration began when I contacted him with (to me) an unexpected observation that a dye used to mark recycling synaptic vesicle membrane at efferent terminals also labelled muscle spindle afferent terminals. This observation led to the re-discovery of a system of small clear vesicles present in all vertebrate primary mechanosensory nerve terminals. These synaptic-like vesicles ( SLVs) have been, and continue to be, the major focus of our work. This article describes our characterisation of the properties and functional significance of these SLVs, combining our complementary skills: Bob's technical expertise and encyclopaedic knowledge of mechanosensation with my experience of synaptic vesicles and the development of the styryl pyridinium dyes, of which the most widely used is FM1-43. On the way we have found that SLVs seem to be part of a constitutive glutamate secretory system necessary to maintain the stretch-sensitivity of spindle endings. The glutamate activates a highly unusual glutamate receptor linked to phospholipase D activation, which we have termed the PLD- mGluR. It has a totally distinct pharmacology first described in the hippocampus nearly 20 years ago but, like the SLVs that were first described over 50 years ago, has since been little researched. Yet, our evidence and literature searches suggest this glutamate/ SLV/ PLD- mGluR system is a ubiquitous feature of mechanosensory endings and, at least for spindles, is essential for maintaining mechanosensory function. This article summarises how this system integrates with the classical model of mechanosensitive channels in spindles and other mechanosensory nerve terminals, including hair follicle afferents and baroreceptors controlling blood pressure. Finally, in this time when there is an imperative to show translational relevance, I describe how this fascinating system might actually be a useful therapeutic drug target for clinical conditions such as hypertension and muscle spasticity. This has been a fascinating 15-year journey in collaboration with Bob who, as well as having an astute scientific mind, is also a great enthusiast, motivator and friend. I hope this exciting and enjoyable journey will continue well into the future. [ABSTRACT FROM AUTHOR]

Mechanotransduction by proprioceptive sensory organs is poorly understood. Evidence was recently shown that muscle spindle and hair follicle primary afferents (lanceolates) constantly release glutamate from synaptic-like vesicles ( SLVs) within the terminals. The secreted glutamate activates a highly unusual metabotropic glutamate receptor ( mGluR) to modulate the firing rate (spindles) and SLV recycling (lanceolates). This receptor has yet to be isolated and sequenced. To further investigate this receptor's pharmacology, ligands selective for classical mGluRs have been recently characterised for their ability to alter stretch-evoked spindle firing and SLV endocytosis in these different endings. Here, it is described how the results of these screens facilitated the development of novel compounds to be used in the process of isolating and sequencing of this non-canonical mGluR. This study shows how the compounds were tested for their ability to alter stretch-evoked afferent firing in muscle spindles and SLV endocytosis in the lanceolate endings of hair follicles to ensure they maintained their ability to bind to the receptor. For the development of novel compounds, kainate was chosen as the parent ligand due to its potency and ease of chemical modification. Novel kainate derivatives were then synthesised and tested to find potent analogues suitable for 'click-chemistry', an established technique for relatively quick, cheap, stereospecific and high-yield chemical modifications (Angewandte Chemie (International ed. in English), 40, 2001, pp2004). Of the novel kainate analogues developed, unfortunately ZCZ49 and ZCZ50 lost the ability to produce a significant change in spindle stretch-evoked firing. However, ZCZ90 was as potent as kainate, increasing firing by a similar margin at 1 μ m ( n = 8; P < 0.001). The addition of either a biotin or a fluorescein side group to ZCZ90, using the click-chemistry technique, did not affect the potency and hence these compounds will be used in further studies of the receptor. As well as the development of these compounds, the study found not only many similarities, but also some key differences between the two types of primary mechanosensory endings investigated. These differences must be taken into account in further study. However, they also present an intriguing opportunity for these receptors to be targeted selectively to modulate ending sensitivity as treatments for muscle spasm in multiple sclerosis and spinal cord injury, and possibly even baroreceptor firing to treat hypertension. [ABSTRACT FROM AUTHOR]

Information forwarded by individual muscle spindles is modulated by the dynamic and static gamma motoneurons in a differentiated way, depending on the coupling between the fusimotor neurons and the various intrafusal muscle fibres. Further modulation of this information at the level of spinal neurons is also differentiated because connections between individual muscle spindles and their spinal target cells are quite variable. This review illustrates this variability with respect to the spinal trajectory of muscle spindle primary afferents and the distribution of their synaptic contacts on motoneurons and other spinal neurons. It also discusses some of the consequences of this variability for the processing of information from proprioceptors. [ABSTRACT FROM AUTHOR]

Much attention has been given to mammalian muscle spindles and their role in stretch-mediated muscle proprioception. Recent studies, particularly, have sought to determine the molecular mediators of stretch-evoked mechanotransduction, which these endings rely upon for functionality. Nonetheless, much about these endings remains unknown. Opportunities may be presented from consideration of extensive parallel research in stretch receptor mechanisms in arthropods. Such systems may provide a useful source of additional data and powerful tools for dissecting the complex systems of stretch transduction apparatus. At the least, such systems provide tractable exemplars of how organisms solve the problem of converting stretch stimuli to electrical output. Potentially, they may even provide molecular mechanisms and candidate molecular mediators of direct relevance to mammalian muscle spindles. Here we provide a brief overview of research on arthropod stretch receptors. [ABSTRACT FROM AUTHOR]

In the present study, muscle pain was induced experimentally in healthy subjects by administrating hypertonic saline injections into the tibialis anterior (TA) muscle. We first aimed at comparing the analgesic effects of mechanical vibration applied to either cutaneous or muscle receptors of the TA or to both types simultaneously. Secondly, pain alleviation was compared in subjects in whom muscle tendon vibration evoked kinesthetic illusions of the ankle joint. Muscle tendon vibration, which primarily activated muscle receptors, reduced pain intensity by 30% ( p <0.01). In addition, tangential skin vibration reduced pain intensity by 33% ( p <0.01), primarily by activating cutaneous receptors. Concurrently stimulating both sensory channels induced stronger analgesic effects (−51%, p <0.01), as shown by the lower levels of electrodermal activity. The strongest analgesic effects of the vibration-induced muscle inputs occurred when illusory movements were perceived (−38%, p =0.01). The results suggest that both cutaneous and muscle sensory feedback reduce muscle pain, most likely via segmental and supraspinal processes. Further clinical trials are needed to investigate these new methods of muscle pain relief. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction: Muscle spindles are crucial for neuronal regulation of striated muscles, but their presence and involvement in the superficial perineal muscles is not known. Methods: Bulbospongiosus and ischiocavernosus muscle specimens were obtained from 31 human cadavers. Serial sections were stained with hematoxylin and eosin, Sirius red, antibodies against Podocalyxin, myosin heavy chain isoforms (MyHC-slow tonic, S46; MyHC-2a/2x, A4.74), and neurofilament for the purpose of muscle spindle screening, counting, and characterization. Results: A low but consistent number of spindles were detected in both muscles. The muscles contained few intrafusal fibers, but otherwise showed normal spindle morphology. The extrafusal fibers of both muscles were small in diameter. Conclusions: The presence of muscle spindles in bulbospongiosus and ischiocavernosus muscles supports physiological models of pelvic floor regulation and may provide a basis for further clinical observations regarding sexual function and micturition. The small number of muscle spindles points to a minor level of proprioceptive regulation. Muscle Nerve 52: 55-62, 2015 [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the presence of sympathetic innervation in human muscle spindles, using antibodies against neuropeptide Y ( NPY), NPY receptors and tyrosine hydroxylase ( TH). A total of 232 muscle spindles were immunohistochemically examined. NPY and NPY receptors were found on the intrafusal fibers, on the blood vessels supplying muscle spindles and on free nerve endings in the periaxial space. TH-immunoreactivity was present mainly in the spindle nerve and vessel. This is, to our knowledge, the first morphological study concerning the sympathetic innervation of the human muscle spindles. The results provide anatomical evidence for direct sympathetic innervation of the intrafusal fibers and show that sympathetic innervation is not restricted to the blood vessels supplying spindles. Knowledge about direct sympathetic innervation of the muscle spindle might expand our understanding of motor and proprioceptive dysfunction under stress conditions, for example, chronic muscle pain syndromes. [ABSTRACT FROM AUTHOR]

Skeletal muscle satellite cells (SCs) are Pax7+ myogenic stem cells that reside between the basal lamina and the plasmalemma of the myofiber. In mature muscles, SCs are typically quiescent, but can be activated in response to muscle injury. Depending on the magnitude of tissue trauma, SCs may divide minimally to repair subtle damage within individual myofibers or produce a larger progeny pool that forms new myofibers in cases of overt muscle injury. SC transition through proliferation, differentiation and renewal is governed by the molecular blueprint of the cells as well as by the extracellular milieu at the SC niche. In particular, the role of the fibroblast growth factor (FGF) family in regulating SCs during growth and aging is well recognized. Of the several FGFs shown to affect SCs, FGF1, FGF2, and FGF6 proteins have been documented in adult skeletal muscle. These prototypic paracrine FGFs transmit their mitogenic effect through the FGFRs, which are transmembrane tyrosine kinase receptors. Using the mouse model, we show here that of the four Fgfr genes, only Fgfr1 and Fgfr4 are expressed at relatively high levels in quiescent SCs and their proliferating progeny. To further investigate the role of FGFR1 in adult myogenesis, we have employed a genetic (Cre/loxP) approach for myogenic-specific (MyoDCre-driven) ablation of Fgfr1. Neither muscle histology nor muscle regeneration following cardiotoxin-induced injury were overtly affected in Fgfr1-ablated mice. This suggests that FGFR1 is not obligatory for SC performance in this acute muscle trauma model, where compensatory growth factor/cytokine regulatory cascades may exist. However, the SC mitogenic response to FGF2 is drastically repressed in isolated myofibers prepared from Fgfr1-ablated mice. Collectively, our study indicates that FGFR1 is important for FGF-mediated proliferation of SCs and its mitogenic role is not compensated by FGFR4 that is also highly expressed in SCs. [ABSTRACT FROM AUTHOR]

Muscle spindles from the hind limb muscles of adult Ryr1 I4895T/wt (IT/+) mice exhibit severe structural abnormalities. Up to 85% of the spindles are separated from skeletal muscle fascicles by a thick layer of connective tissue. Many intrafusal fibers exhibit degeneration, with Z-line streaming, compaction and collapse of myofibrillar bundles, mitochondrial clumping, nuclear shrinkage and pyknosis. The lesions resemble cores observed in the extrafusal myofibers of this animal model and of core myopathy patients. Spindle abnormalities precede those in extrafusal fibers, indicating that they are a primary pathological feature in this murine Ryr1- related core myopathy. Muscle spindle involvement, if confirmed for human core myopathy patients, would provide an explanation for an array of devastating clinical features characteristic of these diseases and provide novel insights into the pathology of RYR1 -related myopathies. [ABSTRACT FROM AUTHOR]

The primary sensory neurons supplying muscle spindles of jaw-closing muscles are unique in that they have their somata in the mesencephalic trigeminal nucleus ( MTN) in the brainstem, thereby receiving various synaptic inputs. MTN neurons display bursting upon activation of glutamatergic synaptic inputs while they faithfully relay respective impulses arising from peripheral sensory organs. The persistent sodium current ( INaP) is reported to be responsible for both the generation of bursts and the relay of impulses. We addressed how INaP is controlled either to trigger bursts or to relay respective impulses as single spikes in MTN neurons. Protein kinase C ( PKC) activation enhanced INaP only at low voltages. Spike generation was facilitated by PKC activation at membrane potentials more depolarized than the resting potential. By injection of a ramp current pulse, a burst of spikes was triggered from a depolarized membrane potential whereas its instantaneous spike frequency remained almost constant despite the ramp increases in the current intensity beyond the threshold. A puff application of glutamate preceding the ramp pulse lowered the threshold for evoking bursts by ramp pulses while chelerythrine abolished such effects of glutamate. Dihydroxyphenylglycine, an agonist of mGluR1/5, also caused similar effects, and increased both the frequency and impedance of membrane resonance. Immunohistochemistry revealed that glutamatergic synapses are made onto the stem axons, and that mGluR1/5 and Nav1.6 are co-localized in the stem axon. Taken together, glutamatergic synaptic inputs onto the stem axon may be able to switch the relaying to the bursting mode. [ABSTRACT FROM AUTHOR]

We previously demonstrated that accurate regulation of isometric contraction (IC) of jaw-closing muscles to counteract the ramp load applied to the jaw in the jaw-opening direction is achieved through the calibration between the two sensations arising from muscle spindles (MSs) and periodontal mechanoreceptors (PMRs). However, it remains unclear whether this calibration mechanism accurately works at any jaw positions, i.e., any vertical dimensions of occlusion (VDO). In the present study, we examined the effects of altering VDO on the IC of the masseter muscles in complete dentulous and edentulous subjects. At a VDO higher than the original VDO (O-VDO), the root mean square (RMS) of masseter EMG activity increased more steeply with a load increase, resulting in an over-counteraction. The regression coefficient of the load-RMS relationship significantly increased as the VDO was increased, suggesting that the overestimation became more pronounced with the VDO increases. Consistently also in the edentulous subjects, at a higher VDO than the O-VDO, a steeper increase in the RMS emerged with a delay in response to the same ramp load whereas a similar steeper increase was seen surprisingly even at a lower VDO. Thus, the edentulous subjects displayed a delayed overestimation of the ramp load presumably due to less and slowly sensitive mucous membrane mechanoreceptor (MMR) in alveolar ridge compared with the PMR. Taken together, the accurate calibration between the two sensations arising from MSs and PMRs/MMRs can be done only at the O-VDO, suggesting that the O-VDO is the best calibration point for performing accurate IC. NEW & NOTEWORTHY Since 1934, the vertical dimension of occlusion (VDO) in edentulous individuals has been anatomically determined mostly by referring to the resting jaw position. However, such a static method is not always accurate. Considering the dynamic nature of clenching/mastication, it is desirable to determine VDO dynamically. We demonstrate that VDO can be accurately determined by measuring masseter EMG during the voluntary isometric contraction of jaw-closing muscles exerted against the ramp load in the jaw-opening direction.

Over the past 30 years, Botulinum toxin (BoNT) has emerged as an effective and safe therapeutic tool for a number of neurological conditions, including dystonia. To date, the exact mechanism of action of BoNT in dystonia is not fully understood. Although it is well known that BoNT mainly acts on the neuromuscular junction, a growing body of evidence suggests that the therapeutic effect of BoNT in dystonia may also depend on its ability to modulate peripheral sensory feedback from muscle spindles. Animal models also suggest a retrograde and anterograde BoNT transportation from the site of injection to central nervous system structures. In humans, however, BoNT central effects seem to depend on the modulation of afferent input rather than on BoNT transportation. In this chapter, we aimed to report and discuss research evidence providing information on the possible mechanisms of action of BoNT in relation to treatment of dystonia., (Copyright © 2023. Published by Elsevier Inc.)

The goal of this study is to assess how reflexes and intrinsic properties contribute to low-back stabilization and modulate with conditions. Upper body sway was evoked by anterior-posterior platform translations, while subjects were seated with a restrained pelvis and free upper body. Kinematic analysis of trunk translations and rotations illustrated that a fixed rotation point between the vertebrae L4 and L5 adequately captures lumbar bending up to 5 Hz. To investigate the motor control modulation, the conditions varied in vision (eyes open or closed), task instruction ( Balance naturally or Resist perturbations by minimizing low-back motions), and perturbation bandwidth (from 0.2 up to 1, 3 or 10 Hz). Frequency response functions and physiological modeling parameters showed substantial modulation between all conditions. The eyes-open condition led to trunk-in-space behavior with additional long-latency visual feedback and decreased proprioceptive feedback. The task instruction to resist led to trunk-on-pelvis stabilization behavior, which was achieved by higher co-contraction levels and increased reflexive velocity feedback. Perturbations below the low-back natural frequency (~1 Hz) led to trunk-on-pelvis stabilization behavior, mainly attributed to increased intrinsic damping. This indicates that bandwidth effects should not be ignored and that experiments with high-bandwidth perturbations do not fully represent the intrinsic and reflexive behavior during most (low-bandwidth) daily life activities. The neck stabilized the head orientation effectively (head rotation amplitudes 2 % of trunk), but did not effectively stabilize the head in space (global head translations exceeded trunk translations by 20 %). This indicates that low-back motor control is involved in head-in-space stabilization and could explain the low-back motor control modulations due to vision. [ABSTRACT FROM AUTHOR]

Context: Proprioception is essential to motor control and joint stability during daily and sport activities. Recent studies demonstrated that athletes have better joint position sense (JPS) when compared with controls matched for age, suggesting that physical training could have an effect on proprioception. Objective: To evaluate the result of an 8-week strengthtraining program on shoulder JPS and to verify whether using training intensities that are the same or divergent for the shoulder's dynamic-stabilizer muscles promote different effects on JPS. Design: Randomized controlled clinical trial. Setting: We evaluated JPS in a research laboratory and conducted training in a gymnasium. Patients or Other Participants: A total of 90 men, right handed and asymptomatic, with no history of any type of injury or shoulder instability. Intervention(s): For 8 weeks, the participants performed the strength-training program 3 sessions per week. We used 4 exercises (bench press, lat pull down, shoulder press, and seated row), with 2 sets each. Main Outcome Measure(s): We measured shoulder JPS acuity by calculating the absolute error. Results: We found an interaction between group and time. To examine the interaction, we conducted two 1-way analyses of variance comparing groups at each time. The groups did not differ at pretraining; however, a difference among groups was noted posttraining. Conclusions: Strength training using exercises at the same intensity produced an improvement in JPS compared with exercises of varying intensity, suggesting that the former resulted in improvements in the sensitivity of muscle spindles and, hence, better neuromuscular control in the shoulder. [ABSTRACT FROM AUTHOR]

The sensory and motor control of human extraocular muscles (EOMs) have been subjected to considerable speculation in ophthalmic literature, often related to infranuclear structures such as the unique complement of muscle fibres and their associated sensory organs. The intrafusal fibres do not resemble their somatic counterparts and their peculiar morphology has raised questions about their proprioceptive capacity. No Golgi tendon organs have so far been observed and the myotendinous nerve endings, previously assumed to convey sensory information, have recently been argued to merely represent constituents of the efferent innervation serving the multiply innervated muscles fibres. These observations raise questions about the overall capacity to monitor the activity created by the generous efferent nerve supply observed in these muscles. Furthermore, the argued independent activity of muscular layers and compartments suggest that the required feedback must be highly structured and more specific than previously assumed. Yet, uncertainty about the source of such information remains. The purpose of this paper is to provide a short review of neuromuscular properties of human extraocular muscles. Their functional implications and the most reputable sources of proprioception will also be discussed. The promoted views are based on pertinent literature and previous research undertaken by the authors. [ABSTRACT FROM AUTHOR]

Is there any difference between matching the position of the hands by asking the subjects to move them to the same spatial location or to mirror-symmetric locations with respect to the body midline? If the motion of the hands were planned in the extrinsic space, the mirror-symmetric task would imply an additional challenge, because we would need to flip the coordinates of the target on the other side of theworkspace. Conversely, if the planning were done in intrinsic coordinates, in order to move both hands to the same spot in the workspace,we should compute different joint angles for each arm. Even if both representations were available to the subjects, the two tasks might lead to different results, providing some cue on the organization of the "body schema". In order to answer such questions, the middle fingertip of the non-dominant hand of a population of healthy subjects was passively moved by a manipulandum to 20 different target locations. Subjects matched these positions with the middle fingertip of their dominant hand. For most subjects, the matching accuracy was higher in the extrinsic modality both in terms of systematic error and variability, even for the target locations in which the configuration of the arms was the same for both modalities.This suggests that the matching performance of the subjects could be determined not only by proprioceptive information but also by the cognitive representation of the task: expressing the goal as reaching for the physical location of the hand in space is apparently more effective than requiring to match the proprioceptive representation of joint angles. [ABSTRACT FROM AUTHOR]

The focus of this review is on the principal sensory ending of the mammalian muscle spindle, known as the primary ending. The process of mechanosensory transduction in the primary ending is examined under five headings: (i) action potential responses to defined mechanical stimuli-representing the ending's input-output properties; (ii) the receptor potential-including the currents giving rise to it; (iii) sensory-terminal deformation-measurable changes in the shape of the primary-ending terminals correlated with intrafusal sarcomere length, and what may cause them; (iv) putative stretch-sensitive channels-pharmacological and immunocytochemical clues to their identity; and (v) synaptic-like vesicles-the physiology and pharmacology of an intrinsic glutamatergic system in the primary and other mechanosensory endings, with some thoughts on the possible role of the system. Thus, the review highlights spindle stretch-evoked output is the product of multi-ionic receptor currents plus complex and sophisticated regulatory gain controls, both positive and negative in nature, as befits its status as the most complex sensory organ after the special senses. [ABSTRACT FROM AUTHOR]

Intrafusal fibers of muscle spindles are innervated in the central region by afferent sensory axons and at both polar regions by efferent γ-motoneurons. We previously demonstrated that both neuron-muscle contact sites contain cholinergic synapse-like specialisation, including aggregates of the nicotinic acetylcholine receptor ( AChR). In this study we tested the hypothesis that agrin and its receptor complex (consisting of LRP4 and the tyrosine kinase Mu SK) are involved in the aggregation of AChRs in muscle spindles, similar to their role at the neuromuscular junction. We show that agrin, Mu SK and LRP4 are concentrated at the contact site between the intrafusal fibers and the sensory- and γ-motoneuron, respectively, and that they are expressed in the cell bodies of proprioceptive neurons in dorsal root ganglia. Moreover, agrin and LRP4, but not Mu SK, are expressed in γ-motoneuron cell bodies in the ventral horn of the spinal cord. In agrin- and in Mu SK-deficient mice, AChR aggregates are absent from the polar regions. In contrast, the subcellular concentration of AChRs in the central region where the sensory neuron contacts the intrafusal muscle fiber is apparently unaffected. Skeletal muscle-specific expression of miniagrin in agrin−/− mice in vivo is sufficient to restore the formation of γ-motoneuron endplates. These results show that agrin and Mu SK are major determinants during the formation of γ-motoneuron endplates but appear dispensable for the aggregation of AChRs at the central region. Our results therefore suggest different molecular mechanisms for AChR clustering within two domains of intrafusal fibers. [ABSTRACT FROM AUTHOR]

Objective: The aims of this study were to determine whether the application of vibration on a postural lower limb muscle altered the sensorimotor control of its joint as measured by isometric force production parameters and to compare present findings with previous work conducted on trunk muscle. Methods: Twenty healthy adults were asked to reproduce submaximal isometric plantar flexion under 3 different conditions: no vibration and vibration frequencies of 30 and 80 Hz on the soleus muscle. Time to peak torque, variable error, as well as constant error and absolute error in peak torque were calculated and compared across conditions. Results: Under vibration, participants were significantly less accurate in the force reproduction task, as they mainly undershot the target torque. Applying an 80-Hz vibration resulted in a significantly higher negative constant error than lower-frequency vibration (30 Hz) or no-vibration condition. Decreases in isometric force production accuracy under vibration influence were also observed in a previous study conducted on trunk muscle. However, no difference in constant error was found between 30- and 80-Hz vibration conditions. Conclusion: The results suggest that acute soleus muscle vibration interferes with plantar flexion torque generation by distorting proprioceptive information, leading to decreases in accuracy of a force reproduction task. Similar results in an isometric trunk extension force reproduction task were found with vibration applied on erector spinae muscle. However, high-frequency vibration applied on soleus muscle elicited higher force reproduction errors than low-frequency stimulation. [ABSTRACT FROM AUTHOR]

The lack of multi-scale empirical measurements (e.g., recording simultaneously from neurons, muscles, whole body, etc.) complicates understanding of sensorimotor function in humans. This is particularly true for the understanding of development during childhood, which requires evaluation of measurements over many years. We have developed a synthetic platform for emulating multi-scale activity of the vertebrate sensorimotor system. Our design benefits from Very Large Scale Integrated-circuit (VLSI) technology to provide considerable scalability and high-speed, as much as 365× faster than real-time. An essential component of our design is the proprioceptive sensor, or muscle spindle. Here we demonstrate an accurate and extremely fast emulation of a muscle spindle and its spiking afferents, which are computationally expensive but fundamental for reflex functions. We implemented a well-known rate-based model of the spindle (Mileusnic et al., 2006) and a simplified spiking sensory neuron model using the Izhikevich approximation to the Hodgkin–Huxley model. The resulting behavior of our afferent sensory system is qualitatively compatible with classic cat soleus recording (Crowe and Matthews, 1964b; Matthews, 1964, 1972). Our results suggest that this simplified structure of the spindle and afferent neuron is sufficient to produce physiologically-realistic behavior. The VLSI technology allows us to accelerate this behavior beyond 365× real-time. Our goal is to use this testbed for predicting years of disease progression with only a few days of emulation. This is the first hardware emulation of the spindle afferent system, and it may have application not only for emulation of human health and disease, but also for the construction of compliant neuromorphic robotic systems. [ABSTRACT FROM AUTHOR]

When a muscle relaxes after a contraction, cross-bridges between actin and myosin in sarcomeres detach, but about 1 % spontaneously form new, non-force-generating attachments. These bridges give muscle its thixotropic property. They remain in place for long periods if the muscle is left undisturbed and give the muscle a passive stiffness in response to a stretch. They are detached by stretch, but reform at the new length. If the muscle is then shortened, the presence of these bridges prevents muscle fibres from shortening and they fall slack. So, resting muscle can be in one of two states, where it presents in response to a stretch with a high stiffness, if no slack is present, or with a compliant response in the presence of slack. Intrafusal fibres of muscle spindles show thixotropic behaviour. For spindles, after a conditioning contraction, they are left stretch sensitive, with a high level of background discharge. Alternatively, if after the contraction the muscle is shortened, intrafusal fibres fall slack, leaving spindles with a low level of background activity and insensitivity to stretch. Muscle spindles are receptors involved in the senses of human limb position and movement. The technique of muscle conditioning can be used to help understand the contribution of muscle spindles to these senses and how the brain interprets signals arising in spindles. When, in a two-arm position-matching task, elbow muscles of the two arms are deliberately conditioned in opposite ways, the blindfolded subject makes large position errors of which they are unaware. The evidence suggests that the brain is concerned with the difference signal coming from the antagonists acting at the elbow and with the overall difference in signal from the two arms. Another way of measuring position sense is to use a single arm and indicate its perceived position with a pointer. Here, there is no access to a signal from the other limb, and position sense relies on referral to a central map of the body, the postural schema. [ABSTRACT FROM AUTHOR]

Muscle spindles are commonly considered as stretch receptors encoding movement, but the functional consequence of their efferent control has remained unclear. The " α - γ coactivation" hypothesis states that activity in a muscle is positively related to the output of its spindle afferents. However, in addition to the above, possible reciprocal inhibition of spindle controllers entails a negative relationship between contractile activity in one muscle and spindle afferent output from its antagonist. By recording spindle afferent responses from alert humans using microneurography, I show that spindle output does reflect antagonistic muscle balance. Specifically, regardless of identical kinematic profiles across active finger movements, stretch of the loaded antagonist muscle (i.e., extensor) was accompanied by increased afferent firing rates from this muscle compared with the baseline case of no constant external load. In contrast, spindle firing rates from the stretching antagonist were lowest when the agonist muscle powering movement (i.e., flexor) acted against an additional resistive load. Stepwise regressions confirmed that instantaneous velocity, extensor, and flexor muscle activity had a significant effect on spindle afferent responses, with flexor activity having a negative effect. Therefore, the results indicate that, as consequence of their efferent control, spindle sensitivity (gain) to muscle stretch reflects the balance of activity between antagonistic muscles rather than only the activity of the spindle-bearing muscle. [ABSTRACT FROM AUTHOR]

Muscle spindles are complex stretch-sensitive mechanoreceptors. They consist of specialized skeletal muscle fibers, called intrafusal fibers, which are innervated in the central (equatorial) region by afferent sensory axons and in both polar regions by efferent γ-motoneurons. We show that AChRs are concentrated at the γ-motoneuron endplate as well as in the equatorial region where they colocalize with the sensory nerve ending. In addition to the AChRs, the contact site between sensory nerve ending and intrafusal muscle fiber contains a high concentration of choline acetyltransferase, vesicular acetylcholine transporter and the AChR-associated protein rapsyn. Moreover, bassoon, a component of the presynaptic cytomatrix involved in synaptic vesicle exocytosis, is present in γ-motoneuron endplates but also in the sensory nerve terminal. Finally, we demonstrate that during postnatal development of the γ-motoneuron endplate, the AChR subunit stoichiometry changes from the γ-subunit-containing fetal AChRs to the ε-subunit-containing adult AChRs, similar and approximately in parallel to the postnatal subunit maturation at the neuromuscular junction. In contrast, despite the onset of ε-subunit expression during postnatal development the γ-subunit remains detectable in the equatorial region by subunit-specific antibodies as well as by analysis of muscle spindles from mice with genetically-labeled AChR γ-subunits. These results demonstrate an unusual maturation of the AChR subunit composition at the annulospiral endings and suggest that in addition to the recently described glutamatergic secretory system, the sensory nerve terminals are also specialized for cholinergic synaptic transmission, synaptic vesicle storage and exocytosis. [ABSTRACT FROM AUTHOR]

Processes underlying mechanotransduction and its regulation are poorly understood. Inhibitors of Ca2+-activated K+ channels cause a dramatic increase in afferent output from stretched muscle spindles. We used immunocytochemistry to test for the presence and location of small conductance Ca2+-activated K+ channels (SK1-3) in primary endings of muscle spindles and lanceolate endings of hair follicles in the rat. Tissue sections were double immunolabelled with antibodies to one of the SK channel isoforms and to either synaptophysin (SYN, as a marker of synaptic like vesicles (SLV), present in many mechanosensitive endings) or S100 (a Ca2+-binding protein present in glial cells). SK channel immunoreactivity was also compared to immunolabelling for the Na+ ion channel ASIC2, previously reported in both spindle primary and lanceolate endings. SK1 was not detected in sensory terminals of either muscle spindles or lanceolate endings. SK2 was found in the terminals of both muscle spindles and lanceolate endings, where it colocalised with the SLV marker SYN (spindles and lanceolates) and the satellite glial cell (SGC) marker S100 (lanceolates). SK3 was not detected in muscle spindles; by contrast it was present in hair follicle endings, expressed predominantly in SGCs but perhaps also in the SGC: terminal interface, as judged by colocalisation statistical analysis of SYN and S100 immunoreactivity. The possibility that all three isoforms might be expressed in pre-terminal axons, especially at heminodes, cannot be ruled out. Differential distribution of SK channels is likely to be important in their function of responding to changes in intracellular [Ca2+] thereby modulating mechanosensory transduction by regulating the excitability of the sensory terminals. In particular, the presence of SK2 throughout the sensory terminals of both kinds of mechanoreceptor indicates an important role for an outward Ca2+-activated K+ current in the formation of the receptor potential in both types of ending. [ABSTRACT FROM AUTHOR]

ABSTRACT Although proprioceptive impairments are reported in knee osteoarthritis (OA), there has been little investigation of the underlying causes. Muscle spindles make an important contribution to proprioception. This study investigated whether function of quadriceps, triceps surae, and tibialis anterior muscle spindles is altered in individuals with knee OA. Thirty individuals with knee OA (17 females, 66 ± 7 [mean ± SD] years) and 30 healthy asymptomatic controls (17 females, 65 ± 8 years) stood comfortably and blindfolded on a force plate. Mechanical vibration (60 Hz) was applied bilaterally over the quadriceps, triceps surae, or tibialis anterior muscles for the middle 15 s (Vibration) of a 45 s trial (preceded and followed by 15 s Baseline and Recovery periods). Two trials were recorded for each muscle site. Mean anterior-posterior displacement of centre of pressure was analysed. Although there were no differences between groups for trials with vibration applied to the quandriceps or tibialis anterior, participants with knee OA were initially perturbed more by triceps surae vibration and accommodated less to repeated exposure than controls. This indicates that people with knee OA have less potential to detect or compensate for disturbed input to triceps surae, possibly due to an inability to compensate using muscles spindles in the quadriceps muscle. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:989-996, 2014. [ABSTRACT FROM AUTHOR]

Background Compartmentalized responses in motor unit ( MU) activity of the short head ( SH) and long head ( LH) of the biceps brachii are observed following forearm position change. Differential muscle spindle afferent distribution has been proposed as a potential mechanism underlying this behaviour. Tendon vibration is an effective, non-invasive method of increasing muscle spindle afferent activity of a target muscle group offering a paradigm in which this hypothesis may be investigated further. Aim To determine the effect of tendon vibration on MU recruitment and discharge rates of the SH and LH, muscle activity of the elbow flexors and triceps brachii, intermuscular coherence among the SH, LH, brachioradialis and triceps brachii and force steadiness in young males and females during isometric elbow flexion. Methods Intramuscular electromyography ( EMG) of the SH and LH, and surface EMG of the elbow flexors were recorded pre- and post-vibration during low-force isometric contractions. Motor unit recruitment thresholds, MU discharge rates and MU discharge variability; surface EMG amplitude, intermuscular coherence and force steadiness were determined pre- and post-vibration. Results Differential changes in all MU properties, EMG amplitude and intermuscular coherence were observed among elbow flexors. Although MU properties exhibited differential changes, they accounted for little variance in isometric force steadiness. However, intermuscular EMG coherence among all muscles investigated was reduced post-vibration. Conclusion Uncoupling of common oscillatory input as a result of differential muscle spindle afferent inputs to elbow flexors may be responsible for the reduction in force steadiness following tendon vibration and a forearm position change. [ABSTRACT FROM AUTHOR]

Abstract: Hereditary sensory and autonomic neuropathy type III (HSAN III, Riley–Day syndrome, Familial Dysautomia) is characterised by elevated thermal thresholds and an indifference to pain. Using microelectrode recordings we recently showed that these patients possess no functional stretch-sensitive mechanoreceptors in their muscles (muscle spindles), a feature that may explain their lack of stretch reflexes and ataxic gait, yet patients have apparently normal low-threshold cutaneous mechanoreceptors. The density of C-fibres in the skin is markedly reduced in patients with HSAN III, but it is not known whether the C-tactile afferents, a distinct type of low-threshold C fibre present in hairy skin that is sensitive to gentle stroking and has been implicated in the coding of pleasant touch are specifically affected in HSAN III patients. We addressed the relationship between C-tactile afferent function and pleasant touch perception in 15 patients with HSAN III and 15 age-matched control subjects. A soft make-up brush was used to apply stroking stimuli to the forearm and lateral aspect of the leg at five velocities: 0.3, 1, 3, 10 and 30cm/s. As demonstrated previously, the control subjects rated the slowest and highest velocities as less pleasant than those applied at 1–10cm/s, which fits with the optimal velocities for exciting C-tactile afferents. Conversely, for the patients, ratings of pleasantness did not fit the profile for C-tactile afferents. Patients either rated the higher velocities as more pleasant than the slow velocities, with the slowest velocities being rated unpleasant, or rated all velocities equally pleasant. We interpret this to reflect absent or reduced C-tactile afferent density in the skin of patients with HSAN III, who are likely using tactile cues (i.e. myelinated afferents) to rate pleasantness of stroking or are attributing pleasantness to this type of stimulus irrespective of velocity. [Copyright &y& Elsevier]

There is some evidence that signals coming from both arms are used to determine the perceived position and movement of one arm. We examined whether the sense of position and movement of one (reference) arm is altered by increases in muscle spindle signals in the other (indicator) arm in blindfolded participants ( n = 26). To increase muscle spindle discharge, we applied 70-80 Hz muscle vibration to the elbow flexors of the indicator arm. In a first experiment, proprioceptive illusions in the vibrated reference arm in a forearm position-matching task were compared between conditions in which the indicator arm elbow flexors were vibrated or not vibrated. We found that the vibration illusion of arm extension induced by vibration of reference arm elbow flexors was reduced in the presence of vibration of the indicator elbow flexors. In a second experiment, participants were asked to describe their perception of the illusion of forearm extension movements of the reference arm evoked by vibration of reference arm elbow flexors in response to on/off and off/on transitions of vibration of non-reference arm elbow flexors. When vibration of non-reference arm elbow flexors was turned on, they reported a sensation of slowing down of the illusion of the reference arm. When it was turned off, they reported a sensation of speeding up. To conclude, the present study shows that both the sense of limb position and the sense of limb movement of one arm are dependent to some extent on spindle signals coming from the other arm. [ABSTRACT FROM AUTHOR]