A new "spin" on recovery after spinal cord injury.

Functional recovery can occur after incomplete spinal cord injury. Takeoka et al. now report that such recovery relies on muscle spindle feedback that is necessary for neuronal circuit remodeling, suggesting novel targets to restore motor functions following spinal cord injuries.

Muscle spindle feedback directs locomotor recovery and circuit reorganization after spinal cord injury.

Spinal cord injuries alter motor function by disconnecting neural circuits above and below the lesion, rendering sensory inputs a primary source of direct external drive to neuronal networks caudal to the injury. Here, we studied mice lacking functional muscle spindle feedback to determine the role of this sensory channel in gait control and locomotor recovery after spinal cord injury. High-resolution kinematic analysis of intact mutant mice revealed proficient execution in basic locomotor tasks but poor performance in a precision task. After injury, wild-type mice spontaneously recovered basic locomotor function, whereas mice with deficient muscle spindle feedback failed to regain control over the hindlimb on the lesioned side. Virus-mediated tracing demonstrated that mutant mice exhibit defective rearrangements of descending circuits projecting to deprived spinal segments during recovery. Our findings reveal an essential role for muscle spindle feedback in directing basic locomotor recovery and facilitating circuit reorganization after spinal cord injury.

Localisation of the centre of the highest region of muscle spindle abundance of anterior forearm muscles.

The centre of the highest region of muscle spindle abundance (CHRMSA) in the intramuscular nerve-dense region has been suggested as the optimal target location for injecting botulinum toxin A to block muscle spasms. The anterior forearm muscles have a high incidence of spasticity. However, the CHRMSA in the intramuscular nerve-dense region of the forearm anterior muscle group has not been defined. This study aimed to accurately define the body surface position and the depth of CHRMSA in an intramuscular nerve-dense region of the anterior forearm muscles. Twenty-four adult cadavers (57.7 ± 11.5 years) were included in this study. The curved line close to the skin connecting the medial and lateral epicondyles of the humerus was designated as the horizontal reference line (H line), and the line connecting the medial epicondyle of the humerus and the ulnar styloid was defined as the longitudinal reference line (L line). Modified Sihler's staining, haematoxylin-eosin staining and computed tomography scanning were employed to determine the projection points (P and P') of the CHRMSAs on the anterior and posterior surfaces of the forearm. The positions (PH and PL) of point P projected onto the H and L lines, and the depth of each CHRMSA, were determined using the Syngo system. The PH of the CHRMSA of the ulnar head of pronator teres, humeral head of pronator teres, flexor carpi radialis, palmaris longus, flexor carpi ulnaris, ulnar part of flexor digitorum superficialis, radial part of flexor digitorum superficialis, flexor pollicis longus, ulnar part of flexor digitorum profundus, radial portion of flexor digitorum profundus and pronator quadratus muscles were located at 42.48%, 45.52%, 41.20%, 19.70%, 7.77%, 25.65%, 47.42%, 53.47%, 12.28%, 38.41% and 51.68% of the H line, respectively; the PL were located at 18.38%, 12.54%, 28.83%, 13.43%, 17.65%, 32.76%, 57.32%, 64.12%, 20.05%, 45.94% and 88.71% of the L line, respectively; the puncture depths were located at 21.92%, 27.25%, 23.76%, 18.04%, 15.49%, 31.36%, 26.59%, 41.28%, 38.72%, 45.14% and 53.58% of the PP' line, respectively. The percentage values are the means of individual values. We recommend that the body surface puncture position and depth of the CHRMSA are the preferred locations for the intramuscular injection of botulinum toxin A to block anterior forearm muscle spasms.

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.

Biophysical model of muscle spindle encoding.

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.

Sensorimotor control in the congenital absence of functional muscle spindles.

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.

Attenuation of muscle spindle firing with artificially increased series compliance during stretch of relaxed muscle.

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.

Mechanosensory encoding in ex vivo muscle-nerve preparations.

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.

Intrafusal cross-bridge dynamics shape history-dependent muscle spindle responses to stretch.

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.

Knee movements cause changes in the firing behaviour of muscle spindles located within the mono-articular ankle extensor soleus in the rat.

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.

Hyperexcitability of muscle spindle afferents in jaw-closing muscles in experimental myalgia: Evidence for large primary afferents involvement in chronic pain.

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 (INaP ) mediated by Na+ channels containing the α-subunit NaV 1.6. The current flowing through NaV 1.6 channels increases when the extracellular Ca2+ concentration decreases, and studies have shown that INaP -driven firing is increased by S100ß, an astrocytic protein that chelates Ca2+ 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 Ca2+ , 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.

Proprioceptors in extraocular muscles.

Proprioception is the sense that lets us perceive the location, movement and action of the body parts. The proprioceptive apparatus includes specialized sense organs (proprioceptors) which are embedded in the skeletal muscles. The eyeballs are moved by six pairs of eye muscles and binocular vision depends on fine-tuned coordination of the optical axes of both eyes. Although experimental studies indicate that the brain has access to eye position information, both classical proprioceptors (muscle spindles and Golgi tendon organ) are absent in the extraocular muscles of most mammalian species. This paradox of monitoring extraocular muscle activity in the absence of typical proprioceptors seemed to be resolved when a particular nerve specialization (the palisade ending) was detected in the extraocular muscles of mammals. In fact, for decades there was consensus that palisade endings were sensory structures that provide eye position information. The sensory function was called into question when recent studies revealed the molecular phenotype and the origin of palisade endings. Today we are faced with the fact that palisade endings exhibit sensory as well as motor features. This review aims to evaluate the literature on extraocular muscle proprioceptors and palisade endings and to reconsider current knowledge of their structure and function.

The mechanosensitive ion channel ASIC2 mediates both proprioceptive sensing and spinal alignment.

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.

The effects of periodic and noisy tendon vibration on a kinesthetic targeting task.

Tendon vibration is used extensively to assess the role of peripheral mechanoreceptors in motor control, specifically, the muscle spindles. Periodic tendon vibration is known to activate muscle spindles and induce a kinesthetic illusion that the vibrated muscle is longer than it actually is. Noisy tendon vibration has been used to assess the frequency characteristics of proprioceptive reflex pathways during standing; however, it is unknown if it induces the same kinesthetic illusions as periodic vibration. The purpose of the current study was to assess the effects of both periodic and noisy tendon vibration in a kinesthetic targeting task. Participants (N = 15) made wrist extension movements to a series of visual targets without vision of the limb, while their wrist flexors were either vibrated with periodic vibration (20, 40, 60, 80, and 100 Hz), or with noisy vibration which consisted of filtered white noise with power between ~ 20 and 100 Hz. Overall, our results indicate that both periodic and noisy vibration can induce robust targeting errors during a wrist targeting task. Specifically, the vibration resulted in an undershooting error when moving to the target. The findings from this study have important implications for the use of noisy tendon vibration to assess proprioceptive reflex pathways and should be considered when designing future studies using noisy vibration.

Quantity and Distribution of Muscle Spindles in Animal and Human Muscles.

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.

What if muscle spindles were also involved in the sense of effort?

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.

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 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.

The mechanism for regulating the isometric contraction of masseter muscles is involved in determining the vertical dimension of occlusion.

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.

Distribution and length of muscle spindles and their 3D visualisation in the medial gastrocnemius of male and female rats.

The spatial distribution of the medial gastrocnemius muscle spindles of 10 male and 10 female rats was analysed under a light microscope, and for the first time, visualised using a 3D model of the muscle. Serial cross-sections of the medial gastrocnemius muscles were separated into 10 divisions along with the proximo-distal axis. The muscle spindles of the rat medial gastrocnemius were predominantly distributed on the proximo-medial divisions of the muscle. There were no sex-related differences in the distribution of the studied receptors. A single division contained an average of 2.71 receptors for animals of both sexes. Moreover, the calculated lengths of male and female rat muscle spindles were comparable, and average lengths did not significantly differ (3.30 ± 1.47 mm for male and 3.26 ± 1.32 mm for female rats). Therefore, the present results fill gaps in recent observations concerning similarities in muscle spindle numbers between male and female animals, despite significant differences in muscle mass and size.

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.