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Despite decades of research, we lack a mechanistic framework capable of predicting how movement-related signals are transformed into the diversity of muscle spindle afferent firing patterns observed experimentally, particularly in naturalistic behaviors. Here, a biophysical model demonstrates that well-known firing characteristics of mammalian muscle spindle Ia afferents – including movement history dependence, and nonlinear scaling with muscle stretch velocity – emerge from first principles of muscle contractile mechanics. Further, mechanical interactions of the muscle spindle with muscle-tendon dynamics reveal how motor commands to the muscle (alpha drive) versus muscle spindle (gamma drive) can cause highly variable and complex activity during active muscle contraction and muscle stretch that defy simple explanation. Depending on the neuromechanical conditions, the muscle spindle model output appears to ‘encode’ aspects of muscle force, yank, length, stiffness, velocity, and/or acceleration, providing an extendable, multiscale, biophysical framework for understanding and predicting proprioceptive sensory signals in health and disease.

The axon initial segment (AIS) responsible for action potential initiation is a dynamic structure that varies and changes together with neuronal excitability. Like other neuron types, alpha motoneurons in the mammalian spinal cord express heterogeneity and plasticity in AIS geometry, including length (AIS l ) and distance from soma (AIS d ). The present study aimed to establish the relationship of AIS geometry with a measure of intrinsic excitability, rheobase current, that varies by 20-fold or more among normal motoneurons. We began by determining whether AIS length or distance differed for motoneurons in motor pools that exhibit different activity profiles. Motoneurons sampled from the medial gastrocnemius (MG) motor pool exhibited values for average AIS d that were significantly greater than that for motoneurons from the soleus (SOL) motor pool, which is more readily recruited in low-level activities. Next, we tested whether AIS d covaried with intrinsic excitability of individual motoneurons. In anesthetized rats, we measured rheobase current intracellularly from MG motoneurons in vivo before labeling them for immunohistochemical study of AIS structure. For 16 motoneurons sampled from the MG motor pool, this combinatory approach revealed that AIS d , but not AIS l , was significantly related to rheobase, as AIS tended to be located further from the soma on motoneurons that were less excitable. Although a causal relation with excitability seems unlikely, AIS d falls among a constellation of properties related to the recruitability of motor units and their parent motoneurons.

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. What is the central question of the study? How does the neuronal architecture and asymmetric distribution of voltage‐gated channels influence mechanosensory encoding by muscle spindle afferents? What is the main finding and its importance? The results predict that neuronal architecture and the distribution and ratios of voltage‐gated ion channels are a complementary and, in some instances, orthogonal means to regulate Ia encoding. The importance of these findings highlights the integral role of peripheral neuronal structure and ion channel expression in mechanosensory signalling. Generally, our computational approach offers an integrative means to generate testable hypotheses and prioritize targets for future mechanistic studies.

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. What is the central question of the study? Little is known about the effects of tendon compliance on muscle spindle function: does increasing the series compliance of the muscle–tendon unit reduce Ia afferent responses to stretch? And what is the relationship between muscle spindle firing rates and muscle fascicle biomechanics? What is the main finding and its importance? Muscle spindle firing was generally attenuated with added series compliance, with the exception of firing rates during sinusoidal stretches. Overall, the changes depended upon stretch profiles, and could not be fully explained by muscle fascicle length or velocity, or muscle–tendon unit force.

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. What is the central question of this study? How well have studies using ex vivo  muscle‐ nerve preparations represented in vivo features of sensory encoding by low threshold mechanoreceptors in muscle? What is the main finding and its importance? We find experimental adjustments to the ex vivo approach that improve representation of mechanosensory encoding observed in vivo. These adjustments will enhance accuracy in the search for molecular identity and encoding mechanisms of heterogeneous muscle mechanosensory neurons.

Purpose Arthroplasty registries gained increasing importance to the re-certification of orthopaedic implants according to the European Union (EU) Medical Device Regulation (MDR) adopted in 2017. Until recently, several European countries only had regional arthroplasty registries. Whether regional registries deliver data quality comparable with national registries remained unclear. Therefore, the purpose of this study was to validate the Austrian Tyrolean Hip Arthroplasty Registry (THAR) and to evaluate if this regional registry showed adequate adherence, completeness and correctness when compared with well-established national registries. Methods A consecutive series of 1100 primary total hip arthroplasties were identified from our institution’s medical database. Patients were interviewed by phone and completed questionnaires after a mean follow-up period of 8.05 years and were asked if they had had revision surgeries. The data were compared to the corresponding dataset from the THAR. Results Adherence was 97.91% for primary total hip arthroplasty. Clinical follow-up identified 10 missing cases, resulting in adherence of 81.48% for revisions. Completeness of patient-reported outcome measurements was 78.55% before surgery and 84.45% 1 year after surgery. Correctness was 99.7% for demographic data, 99.54% for implant specifications, and 99.35% for mode of fixation. Conclusion The data of this study showed that regional arthroplasty registries can deliver data quality comparable with well-established national registries. The main reason for unrecorded revision cases and wrongly recoded implants was human error. Further digitalization with more automatic data submission may have the potential to reduce these failure rates in the future. Overall, the THAR represents a valid data source for re-certification of medical implants according to the EU’s MDR.

Neuropathy and myopathy can cause weakness during critical illness. To determine whether reduced excitability of peripheral nerves, rather than degeneration, is the mechanism underlying acute neuropathy in critically ill patients, we prospectively followed patients during the acute phase of critical illness and early recovery and assessed nerve conduction. During the period of early recovery from critical illness, patients recovered from neuropathy within days. This rapidly reversible neuropathy has not to our knowledge been previously described in critically ill patients and may be a novel type of neuropathy. In vivo intracellular recordings from dorsal root axons in septic rats revealed reduced action potential amplitude, demonstrating that reduced excitability of nerve was the mechanism underlying neuropathy. When action potentials were triggered by hyperpolarizing pulses, their amplitudes largely recovered, indicating that inactivation of sodium channels was an important contributor to reduced excitability. There was no depolarization of axon resting potential in septic rats, which ruled out a contribution of resting potential to the increased inactivation of sodium channels. Our data suggest that a hyperpolarized shift in the voltage dependence of sodium channel inactivation causes increased sodium inactivation and reduced excitability. Acquired sodium channelopathy may be the mechanism underlying acute neuropathy in critically ill patients.

The ability to recover purposeful movement soon after debilitating neuromuscular injury is essential to animal survival. Various neural and mechanical mechanisms exist to preserve whole-limb kinematics despite exhibiting long-term deficits of individual joints following peripheral nerve injury. However, it is unclear whether functionally relevant whole-limb movement is acutely conserved following injury. Therefore, the objective of this longitudinal study of the injury response from four individual cats was to test the hypothesis that whole-limb length is conserved following localized nerve injury of ankle extensors in cats with intact nervous systems. The primary finding of our study was that whole-limb kinematics during walking was not immediately preserved following peripheral nerve injuries that paralyzed subsets of ankle extensor muscles. Instead, whole-limb kinematics recovered gradually over multiple weeks, despite having the mechanical capacity of injury-spared muscles across all joints to achieve immediate functional recovery. The time taken to achieve complete recovery of whole-limb kinematics is consistent with an underlying process that relies on neuromuscular adaptation. Importantly, the gradual recovery of ankle joint kinematics remained incomplete, discontinuing once whole-limb kinematics had fully recovered. These findings support the hypothesis that a whole-limb representation of healthy limb function guides a locomotor compensation strategy after neuromuscular injury that arrests progressive changes in the joint kinematics once whole-limb kinematics is regained.

Cancer survivors rank sensorimotor disability among the most distressing, long-term consequences of chemotherapy. Disorders in gait, balance, and skilled movements are commonly assigned to chemotoxic damage of peripheral sensory neurons without consideration of the deterministic role played by the neural circuits that translate sensory information into movement. This oversight precludes sufficient, mechanistic understanding and contributes to the absence of effective treatment for reversing chemotherapy-induced disability. We rectified this omission through the use of a combination of electrophysiology, behavior, and modeling to study the operation of a spinal sensorimotor circuit in vivo in a rat model of chronic, oxaliplatin (chemotherapy)–induced neuropathy (cOIN). Key sequential events were studied in the encoding of propriosensory information and its circuit translation into the synaptic potentials produced in motoneurons. In cOIN rats, multiple classes of propriosensory neurons expressed defective firing that reduced accurate sensory representation of muscle mechanical responses to stretch. Accuracy degraded further in the translation of propriosensory signals into synaptic potentials as a result of defective mechanisms residing inside the spinal cord. These sequential, peripheral, and central defects compounded to drive the sensorimotor circuit into a functional collapse that was consequential in predicting the significant errors in propriosensory-guided movement behaviors demonstrated here in our rat model and reported for people with cOIN. We conclude that sensorimotor disability induced by cancer treatment emerges from the joint expression of independent defects occurring in both peripheral and central elements of sensorimotor circuits.

Purpose To determine whether the preoperative degree of degeneration of the patellofemoral joint really affects the outcome of total knee arthroplasty (TKA) surgery without patella resurfacing and thus to establish a parameter that might serve as a guiding factor to decide whether or not to perform retropatellar resurfacing. It was hypothesized that patients with preoperative mild patellofemoral osteoarthritis (Iwano Stages 0–2) would significantly differ from patients with preoperative severe patellofemoral osteoarthritis (Iwano Stages 3–4) in terms of patient-reported outcome (Hypothesis 1) and revision rates/survival (Hypothesis 2) after TKA without patella resurfacing. Methods Application of a retrospective–comparative design on the basis of Arthroplasty Registry data that included patients with primary TKA without patella resurfacing. Patients were allocated to the following groups based on preoperative radiographic stage of patellofemoral joint degeneration: (a) mild patellofemoral osteoarthritis (Iwano Stage ≤ 2) and (b) severe patellofemoral osteoarthritis (Iwano Stages 3–4). The Western Ontario and MacMaster Universities Osteoarthritis Index (WOMAC) score was assessed preoperative and 1 year postoperative (0: best, 100 worst). In addition, implant survival was calculated from the Arthroplasty Registry data. Results In 1209 primary TKA without patella resurfacing, postoperative WOMAC total and WOMAC subscores did not differ significantly between groups, but potentially suffered from type 2 error. Three-year survival was 97.4% and 92.5% in patients with preoperative mild and severe patellofemoral osteoarthritis, respectively ( p  = 0.002). Five-year survival was 95.8% vs. 91.4% ( p  = 0.033) and 10-year survival was 93.3% vs. 88.6% ( p  = 0.033), respectively. Conclusions From the study findings, it is concluded that patients with preoperative severe patellofemoral osteoarthritis have significantly higher risks for reoperation than do those with preoperative mild patellofemoral osteoarthritis—when treated with TKA without patella resurfacing. Hence, it is recommended that patella resurfacing be applied in patients with severe Iwano Stage 3 or 4 patellofemoral osteoarthritis during TKA. Level of evidence III, Retrospective comparative.