Muscle Spindles Research Articles

The association between muscle architecture and muscle spindle abundance

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.

Intrafusal-fiber LRP4 for muscle spindle formation and maintenance in adult and aged animals

Proprioception is sensed by muscle spindles for precise locomotion and body posture. Unlike the neuromuscular junction (NMJ) for muscle contraction which has been well studied, mechanisms of spindle formation are not well understood. Here we show that sensory nerve terminals are disrupted by the mutation of Lrp4, a gene required for NMJ formation; inducible knockout of Lrp4 in adult mice impairs sensory synapses and movement coordination, suggesting that LRP4 is required for spindle formation and maintenance. LRP4 is critical to the expression of Egr3 during development; in adult mice, it interacts in trans with APP and APLP2 on sensory terminals. Finally, spindle sensory endings and function are impaired in aged mice, deficits that could be diminished by LRP4 expression. These observations uncovered LRP4 as an unexpected regulator of muscle spindle formation and maintenance in adult and aged animals and shed light on potential pathological mechanisms of abnormal muscle proprioception.

Molecular characterization of the intact mouse muscle spindle using a multi-omics approach.

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.

Assistive Loading Promotes Goal-Directed Tuning of Stretch Reflex Gains.

Voluntary movements are prepared before they are executed. Preparatory activity has been observed across the CNS and recently documented in first-order neurons of the human PNS (i.e., in muscle spindles). Changes seen in sensory organs suggest that independent modulation of stretch reflex gains may represent an important component of movement preparation. The aim of the current study was to further investigate the preparatory modulation of short-latency stretch reflex responses (SLRs) and long-latency stretch reflex responses (LLRs) of the dominant upper limb of human subjects. Specifically, we investigated how different target parameters (target distance and direction) affect the preparatory tuning of stretch reflex gains in the context of goal-directed reaching, and whether any such tuning depends on preparation duration and the direction of background loads. We found that target distance produced only small variations in reflex gains. In contrast, both SLR and LLR gains were strongly modulated as a function of target direction, in a manner that facilitated the upcoming voluntary movement. This goal-directed tuning of SLR and LLR gains was present or enhanced when the preparatory delay was sufficiently long (>250 ms) and the homonymous muscle was unloaded [i.e., when a background load was first applied in the direction of homonymous muscle action (assistive loading)]. The results extend further support for a relatively slow-evolving process in reach preparation that functions to modulate reflexive muscle stiffness, likely via the independent control of fusimotor neurons. Such control can augment voluntary goal-directed movement and is triggered or enhanced when the homonymous muscle is unloaded.

Hindlimb muscle spindles inform preparatory forelimb coordination prior to landing in toads.

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.

Excessive mechanotransduction in sensory neurons causes joint contractures.

Distal arthrogryposis (DA) is a collection of rare disorders that are characterized by congenital joint contractures. Most DA mutations are in muscle- and joint-related genes, and the anatomical defects originate cell-autonomously within the musculoskeletal system. However, gain-of-function mutations in PIEZO2, a principal mechanosensor in somatosensation, cause DA subtype 5 (DA5) through unknown mechanisms. We show that expression of a gain-of-function PIEZO2 mutation in proprioceptive sensory neurons that mainly innervate muscle spindles and tendons is sufficient to induce DA5-like phenotypes in mice. Overactive PIEZO2 causes anatomical defects through increased activity within the peripheral nervous system during postnatal development. Furthermore, botulinum toxin (Botox) and a dietary fatty acid that modulates PIEZO2 activity reduce DA5-like deficits. This reveals a role for somatosensory neurons: Excessive mechanosensation within these neurons disrupts musculoskeletal development.

There and back again: 50 years of wandering through terra incognita fusorum.

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.

Modulation of Cerebral Function by Muscle Afferent Activity, with Reference to Intravenous Succinylcholine.

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

Upper Limb Function but Not Proprioception is Impaired in Essential Tremor: A Between-Groups Study and Causal Mediation Analysis.

Essential tremor (ET) is characterized by abnormal oscillatory muscle activity and cerebellar involvement, factors that can lead to proprioceptive deficits, especially in active tasks. The present study aimed to quantify the severity of proprioceptive deficits in people with ET and estimate how these contribute to functional impairments. Upper limb sensory, proprioceptive and motor function was assessed inindividuals with ET (n = 20) and healthy individuals (n = 22). To measure proprioceptive ability, participants discriminated the width of grasped objects and the weight of objects liftedwith the wrist extensors. Causal mediation analysis was used to estimate the extentthat impairments in upper limb function in ET was mediated by proprioceptive ability. Participants with ET had impaired upper limb function in all outcomes, and had greater postural and kinetic tremor. There were no differences between groups in proprioceptive discrimination of width (between-group mean difference [95% CI]: 0.32 mm [-0.23 to 0.87 mm]) or weight (-1.12 g [-7.31 to 5.07 g]). Causal mediation analysis showed the effect of ET on upper limb function was not mediated by proprioceptive ability. Upper limb function but not proprioception was impaired in ET. The effect of ET on motor function was not mediated by proprioception. These results indicate that the central nervous system of people with ET is able to accommodate mild to moderate tremor in active proprioceptive tasks that rely primarily on afferent signals from muscle spindles.

How does botulinum toxin really work?

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.

Motor rehabilitation of aphasic stroke patient: the possibility of Rood's approach.

Motor rehabilitation of aphasic stroke patient: the possibility of Rood's approach.

Muscle spindles and their role in maintaining robust locomotion.

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 150years 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.

Revisiting the use of Hoffmann reflex in motor control research on humans.

Research in movement science aims at unravelling mechanisms and designing methods for restoring and maximizing human functional capacity, and many techniques provide access to neural adjustments (acute changes) or long-term adaptations (chronic changes) underlying changes in movement capabilities. First described by Paul Hoffmann over a century ago, when an electrical stimulus is applied to a peripheral nerve, this causes action potentials in afferent axons, primarily the Ia afferents of the muscle spindles, which recruit homonymous motor neurons, thereby causing an electromyographic response known as the Hoffmann (H) reflex. This technique is a valuable tool in the study of the neuromuscular function in humans and has provided relevant information in the neural control of movement. The large use of the H reflex in motor control research on humans relies in part to its relative simplicity. However, such simplicity masks subtleties that require rigorous experimental protocols and careful data interpretation. After highlighting basic properties and methodological aspects that should be considered for the correct use of the H-reflex technique, this brief narrative review discusses the purpose of the H reflex and emphasizes its use as a tool to assess the effectiveness of Ia afferents in discharging motor neurones. The review also aims to reconsider the link between H-reflex modulation and Ia presynaptic inhibition, the use of the H-reflex technique in motor control studies, and the effects of ageing. These aspects are summarized as recommendations for the use of the H reflex in motor control research on humans.

Texture recognition based on multi-sensory integration of proprioceptive and tactile signals

The sense of touch plays a fundamental role in enabling us to interact with our surrounding environment. Indeed, the presence of tactile feedback in prostheses greatly assists amputees in doing daily tasks. In this line, the present study proposes an integration of artificial tactile and proprioception receptors for texture discrimination under varying scanning speeds. Here, we fabricated a soft biomimetic fingertip including an 8 × 8 array tactile sensor and a piezoelectric sensor to mimic Merkel, Meissner, and Pacinian mechanoreceptors in glabrous skin, respectively. A hydro-elastomer sensor was fabricated as an artificial proprioception sensor (muscle spindles) to assess the instantaneous speed of the biomimetic fingertip. In this study, we investigated the concept of the complex receptive field of RA-I and SA-I afferents for naturalistic textures. Next, to evaluate the synergy between the mechanoreceptors and muscle spindle afferents, ten naturalistic textures were manipulated by a soft biomimetic fingertip at six different speeds. The sensors’ outputs were converted into neuromorphic spike trains to mimic the firing pattern of biological mechanoreceptors. These spike responses are then analyzed using machine learning classifiers and neural coding paradigms to explore the multi-sensory integration in real experiments. This synergy between muscle spindle and mechanoreceptors in the proposed neuromorphic system represents a generalized texture discrimination scheme and interestingly irrespective of the scanning speed.

Intranuclear inclusions in muscle biopsy can differentiate oculopharyngodistal myopathy and oculopharyngeal muscular dystrophy

Oculopharyngodistal myopathy (OPDM) and oculopharyngeal muscular dystrophy (OPMD) are similar and even believed to be indistinguishable in terms of their myopathological features. To address the diagnostic gap, we evaluated the muscle biopsy samples for p62 expression by immunohistochemistry and compared the occurrence and the frequency of intranuclear inclusions among the individuals with OPDM (harboring CGG repeat expansion in LRP12 (n = 19), GIPC1 (n = 6), or NOTCH2NLC (n = 7)), OPMD (n = 15), and other rimmed vacuolar myopathies. We found that myonuclei with p62-positive intra-nuclear inclusions (myo-INIs) were significantly more frequent in OPMD (11.9 ± 1.1%, range 5.9–18.6%) than in OPDM and other rimmed vacuolar myopathies (RVMs) (0.9–1.5% on average, range 0.0–2.8%, p < 0.0001). In contrast, INIs in non-muscle cells such as blood vessels, peripheral nerve bundles, and muscle spindles (non-muscle-INIs) were present in OPDM, but absent in OPMD. These results indicate that OPMD can be differentiated from OPDM and other RVMs by the frequent presence of myo-INIs; and in OPDM, the presence of non-muscle-INIs in muscle pathology should be a diagnostic hallmark.

Revising the stretch reflex threshold method to measure stretch hyperreflexia in cerebral palsy.

Hyper-resistance is an increased resistance to passive muscle stretch, a common feature in neurological disorders. Stretch hyperreflexia, an exaggerated stretch reflex response, is the neural velocity-dependent component of hyper-resistance, and has been quantitatively measured using the stretch reflex threshold (i.e., joint angle at the stretch reflex electromyographic onset). In this study, we introduce a correction in how the stretch reflex threshold is calculated, by accounting for the stretch reflex latency (i.e., time between the stretch reflex onset at the muscle spindles and its appearance in the electromyographic signal). Furthermore, we evaluated how this correction affects the stretch reflex threshold in children and young adults with spastic cerebral palsy. A motor-driven ankle dynamometer induced passive ankle dorsiflexions at four incremental velocities in 13 children with cerebral palsy (mean age: 13.5years, eight males). The stretch reflex threshold for soleus and medial gastrocnemius muscles was calculated as 1) the joint angle corresponding to the stretch reflex electromyographic onset (i.e., original method); and as 2) the joint angle corresponding to the electromyographic onset minus the individual Hoffmann-reflex latency (i.e., latency corrected method). The group linear regression slopes between stretch velocity and stretch reflex threshold differed in both muscles between methods (p < 0.05). While the original stretch reflex threshold was velocity dependent in both muscles (p < 0.05), the latency correction rendered it velocity independent. Thus, the effects of latency correction on the stretch reflex threshold are substantial, especially at higher stretch velocities, and should be considered in future studies.

Smart Pneumatic Artificial Muscle Using a Bend Sensor like a Human Muscle with a Muscle Spindle.

Shortage of labor and increased work of young people are causing problems in terms of care and welfare of a growing proportion of elderly people. This is a looming social problem because people of advanced ages are increasing. Necessary in the fields of care and welfare, pneumatic artificial muscles in actuators of robots are being examined. Pneumatic artificial muscles have a high output per unit of weight, and they are soft, similarly to human muscles. However, in previous research of robots using pneumatic artificial muscles, rigid sensors were often installed at joints and other locations due to the robots' structures. Therefore, we developed a smart actuator that integrates a bending sensor that functions as a human muscle spindle; it can be externally attached to the pneumatic artificial muscle. This paper reports a smart artificial muscle actuator that can sense contraction, which can be applied to developed self-monitoring and robot posture control.

The brain integrates proprioceptive information to ensure robust locomotion.

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.

Associations between Deformation of the Thoracolumbar Fascia and Activation of the Erector Spinae and Multifidus Muscle in Patients with Acute Low Back Pain and Healthy Controls: A Matched Pair Case-Control Study.

The thoracolumbar fascia (TLF) is thought to play a role in the development of LBP, but it is not yet clear which factor of TLF changes is a cause and which is an effect. Therefore, some studies used the cross-correlation function (CCR) to reveal time-dependent relationships between biomechanical and neuromotor factors. Ten patients with acute low back pain (aLBP) were matched to healthy controls. Simultaneous recording of surface electromyography (sEMG) of the erector spinae and multifidus muscle (ESM) and dynamic ultrasound (US) images of TLF deformation were performed during trunk extension. CCR functions and Granger causality (GC) were used to describe the relationship between the two measures. CCR time lags were significant higher in the aLBP group (p = 0.04). GC showed a direct effect of TLF deformation on ESM activation only in the aLBP group (p &lt; 0.03). The results suggest that in aLBP, ESM activity is significantly affected by TLF, whereas this relationship is completely random in healthy subjects studied with CCR and GC comparisons of dynamic US imaging and sEMG data signals. Fascia-related disturbances in neuromotor control, particularly due to altered muscle spindle functions, are suspected as a possible mechanism behind this.

Surgical quadriceps lengthening can reduce quadriceps spasticity in chronic stroke patients. A case-control study.

BackgroundMuscle overactivity is one of the positive signs of upper motor neuron lesions. In these patients, the loss of muscle length and extensibility resulting from soft tissue rearrangement has been suggested as a contributing cause of muscle overactivity in response to stretching.ObjectiveTo assess the effects of surgical lengthening of the quadriceps femoris (QF) muscle-tendon unit by aponeurectomy on muscle spasticity.MethodsThis is a case-control study on chronic stroke patients with hemiparesis that have undergone lower limb functional surgery over a 8-year period. CASEs underwent corrective surgery for both the foot and knee deviations, inclusive of a QF aponeurectomy. Controls (CTRLs) underwent corrective surgery for foot deviations only. QF spasticity was assessed with the Modified Tardieu Scale (MTS) before and 1 month after surgery. The Wilcoxon test was used to assess MTS variations over time and the Mann–Whitney test was used to verify the presence of group differences at the 1 month mark.ResultsNinety-three patients were included: 57 cases (30F, 1–34 years from lesion) and 36 controls (12F, 1–35 years from lesion). Before surgery, both CASEs and CTRLs had similar MTS scores (median MTS = 3) and functional characteristics. One month after surgery, QF spasticity was significantly lower in the CASEs compared to CTRLs (p = 0.033) due to a significant reduction of the median MTS score from 3 to 0 in the CASE group (p < 0.001) and no variations in the CTRL group (p = 0.468). About half of the cases attained clinically significant MTS reductions and complete symptom relief even many years from the stroke.ConclusionsFunctional surgery inclusive of QF aponeurectomy can be effective in reducing or suppressing spasticity in chronic stroke patients. This is possibly a result of the reduction in neuromuscular spindle activation due to a decrease in muscle shortening, passive tension, and stiffness.