Task-driven neural network models predict neural dynamics of proprioception.

Proprioception tells the brain the state of the body based on distributed sensory neurons. Yet, the principles that govern proprioceptive processing are poorly understood. Here, we employ a task-driven modeling approach to investigate the neural code of proprioceptive neurons in cuneate nucleus (CN) and somatosensory cortex area 2 (S1). We simulated muscle spindle signals through musculoskeletal modeling and generated a large-scale movement repertoire to train neural networks based on 16 hypotheses, each representing different computational goals. We found that the emerging, task-optimized internal representations generalize from synthetic data to predict neural dynamics in CN and S1 of primates. Computational tasks that aim to predict the limb position and velocity were the best at predicting the neural activity in both areas. Since task optimization develops representations that better predict neural activity during active than passive movements, we postulate that neural activity in the CN and S1 is top-down modulated during goal-directed movements.

The Form and Function of PIEZO2.

Mechanosensation is the ability to detect dynamic mechanical stimuli (e.g., pressure, stretch, and shear stress) and is essential for a wide variety of processes, including our sense of touch on the skin. How touch is detected and transduced at the molecular level has proved to be one of the great mysteries of sensory biology. A major breakthrough occurred in 2010 with the discovery of a family of mechanically gated ion channels that were coined PIEZOs. The last 10 years of investigation have provided a wealth of information about the functional roles and mechanisms of these molecules. Here we focus on PIEZO2, one of the two PIEZO proteins found in humans and other mammals. We review how work at the molecular, cellular, and systems levels over the past decade has transformed our understanding of touch and led to unexpected insights into other types of mechanosensation beyond the skin.

Motor neurons generate pose-targeted movements via proprioceptive sculpting.

Motor neurons are the final common pathway1 through which the brain controls movement of the body, forming the basic elements from which all movement is composed. Yet how a single motor neuron contributes to control during natural movement remains unclear. Here we anatomically and functionally characterize the individual roles of the motor neurons that control head movement in the fly, Drosophila melanogaster. Counterintuitively, we find that activity in a single motor neuron rotates the head in different directions, depending on the starting posture of the head, such that the head converges towards a pose determined by the identity of the stimulated motor neuron. A feedback model predicts that this convergent behaviour results from motor neuron drive interacting with proprioceptive feedback. We identify and genetically2 suppress a single class of proprioceptive neuron3 that changes the motor neuron-induced convergence as predicted by the feedback model. These data suggest a framework for how the brain controls movements: instead of directly generating movement in a given direction by activating a fixed set of motor neurons, the brain controls movements by adding bias to a continuing proprioceptive-motor loop.

Making sense of proprioception.

Proprioception - the sense of body position in space - is intimately linked to motor control. Here, we briefly review the current knowledge of the proprioceptive system and how advances in the genetic characterisation of proprioceptive sensory neurons in mice promise to dissect its role in health and disease.

Proprioception: A New Era Set in Motion by Emerging Genetic and Bionic Strategies?

The generation of an internal body model and its continuous update is essential in sensorimotor control. Although known to rely on proprioceptive sensory feedback, the underlying mechanism that transforms this sensory feedback into a dynamic body percept remains poorly understood. However, advances in the development of genetic tools for proprioceptive circuit elements, including the sensory receptors, are beginning to offer new and unprecedented leverage to dissect the central pathways responsible for proprioceptive encoding. Simultaneously, new data derived through emerging bionic neural machine-interface technologies reveal clues regarding the relative importance of kinesthetic sensory feedback and insights into the functional proprioceptive substrates that underlie natural motor behaviors.

The neural mechanisms of manual dexterity.

The hand endows us with unparalleled precision and versatility in our interactions with objects, from mundane activities such as grasping to extraordinary ones such as virtuoso pianism. The complex anatomy of the human hand combined with expansive and specialized neuronal control circuits allows a wide range of precise manual behaviours. To support these behaviours, an exquisite sensory apparatus, spanning the modalities of touch and proprioception, conveys detailed and timely information about our interactions with objects and about the objects themselves. The study of manual dexterity provides a unique lens into the sensorimotor mechanisms that endow the nervous system with the ability to flexibly generate complex behaviour.

How we perceive the width of grasped objects: Insights into the central processes that govern proprioceptive judgements.

Low-level proprioceptive judgements involve a single frame of reference, whereas high-level proprioceptive judgements are made across different frames of reference. The present study systematically compared low-level (grasp → $\rightarrow$ grasp) and high-level (vision → $\rightarrow$ grasp, grasp → $\rightarrow$ vision) proprioceptive tasks, and quantified the consistency of grasp → $\rightarrow$ vision and possible reciprocal nature of related high-level proprioceptive tasks. Experiment 1 (n = 30) compared performance across vision → $\rightarrow$ grasp, a grasp → $\rightarrow$ vision and a grasp → $\rightarrow$ grasp tasks. Experiment 2 (n = 30) compared performance on the grasp → $\rightarrow$ vision task between hands and over time. Participants were accurate (mean absolute error 0.27 cm [0.20 to 0.34]; mean [95% CI]) and precise ( R 2 $R^2$ = 0.95 [0.93 to 0.96]) for grasp → $\rightarrow$ grasp judgements, with a strong correlation between outcomes (r = -0.85 [-0.93 to -0.70]). Accuracy and precision decreased in the two high-level tasks ( R 2 $R^2$ = 0.86 and 0.89; mean absolute error = 1.34 and 1.41 cm), with most participants overestimating perceived width for the vision → $\rightarrow$ grasp task and underestimating it for grasp → $\rightarrow$ vision task. There was minimal correlation between accuracy and precision for these two tasks. Converging evidence indicated performance was largely reciprocal (inverse) between the vision → $\rightarrow$ grasp and grasp → $\rightarrow$ vision tasks. Performance on the grasp → $\rightarrow$ vision task was consistent between dominant and non-dominant hands, and across repeated sessions a day or week apart. Overall, there are fundamental differences between low- and high-level proprioceptive judgements that reflect fundamental differences in the cortical processes that underpin these perceptions. Moreover, the central transformations that govern high-level proprioceptive judgements of grasp are personalised, stable and reciprocal for reciprocal tasks. KEY POINTS: Low-level proprioceptive judgements involve a single frame of reference (e.g. indicating the width of a grasped object by selecting from a series of objects of different width), whereas high-level proprioceptive judgements are made across different frames of reference (e.g. indicating the width of a grasped object by selecting from a series of visible lines of different length). We highlight fundamental differences in the precision and accuracy of low- and high-level proprioceptive judgements. We provide converging evidence that the neural transformations between frames of reference that govern high-level proprioceptive judgements of grasp are personalised, stable and reciprocal for reciprocal tasks. This stability is likely key to precise judgements and accurate predictions in high-level proprioception.

Volitional muscle activation intensifies neuronal processing of proprioceptive afference in the primary sensorimotor cortex: an EEG study.

Proprioception refers to the ability to perceive the position and movement of body segments in space. The cortical aspects of the proprioceptive afference from the body can be investigated using corticokinematic coherence (CKC). CKC accurately quantifies the degree of coupling between cortical activity and limb kinematics, especially if precise proprioceptive stimulation of evoked movements is used. However, there is no evidence on how volitional muscle activation during proprioceptive stimulation affects CKC strength. Twenty-five healthy volunteers (28.8 ± 7 yr, 11 females) participated in the experiment, which included electroencephalographic (EEG), electromyographic (EMG), and kinematic recordings. Ankle-joint rotations (2-Hz) were elicited through a movement actuator in two conditions: passive condition with relaxed ankle and active condition with constant 5-Nm plantar flexion exerted during the stimulation. In total, 6 min of data were recorded per condition. CKC strength was defined as the maximum coherence value among all the EEG channels at the 2-Hz movement frequency for each condition separately. Both conditions resulted in significant CKC peaking at the Cz electrode over the foot area of the primary sensorimotor (SM1) cortex. Stronger CKC was found for the active (0.13 ± 0.14) than the passive (0.03 ± 0.04) condition (P < 0.01). The results indicated that volitional activation of the muscles intensifies the neuronal proprioceptive processing in the SM1 cortex. This finding could be explained both by peripheral sensitization of the ankle joint proprioceptors and central modulation of the neuronal proprioceptive processing at the spinal and cortical levels.NEW & NOTEWORTHY The current study is the first to investigate the effect of volitional muscle activation on CKC-based assessment of cortical proprioception of the ankle joint. Results show that the motor efference intensifies the neuronal processing of proprioceptive afference of the ankle joint. This is a significant finding as it may extend the use of CKC method during active tasks to further evaluate the motor efference-proprioceptive afference relationship and the related adaptations to exercise, rehabilitation, and disease.

The precision of signals encoding active self-movement.

Everyday actions like moving the head, walking around, and grasping objects are typically self-controlled. This presents a problem when studying the signals encoding such actions because active self-movement is difficult to control experimentally. Available techniques demand repeatable trials, but each action is unique, making it difficult to measure fundamental properties like psychophysical thresholds. We present a novel paradigm that recovers both precision and bias of self-movement signals with minimal constraint on the participant. The paradigm relies on linking image motion to previous self-movement, and two experimental phases to extract the signal encoding the latter. The paradigm takes care of a hidden source of external noise not previously accounted for in techniques that link display motion to self-movement in real time (e.g., virtual reality). We use head rotations as an example of self-movement, and show that the precision of the signals encoding head movement depends on whether they are being used to judge visual motion or auditory motion. We find that perceived motion is slowed during head movement in both cases. The "nonimage" signals encoding active head rotation (motor commands, proprioception, and vestibular cues) are therefore biased toward lower speeds and/or displacements. In a second experiment, we trained participants to rotate their heads at different rates and found that the imprecision of the head rotation signal rises proportionally with head speed (Weber's law). We discuss the findings in terms of the different motion cues used by vision and hearing, and the implications they have for Bayesian models of motion perception.NEW & NOTEWORTHY We present a psychophysical technique for measuring the precision of signals encoding active self-movements. Using head movements, we show that 1) precision is greater when active head rotation is performed using visual comparison stimuli versus auditory; 2) precision decreases with head speed (Weber's law); 3) perceived speed is lower during head rotation. The findings may reflect the steps needed to convert different cues into common units, and challenge standard Bayesian models of motion perception.

Multisensory perception depends on the reliability of the type of judgment.

The brain engages the processes of multisensory integration and recalibration to deal with discrepant multisensory signals. These processes consider the reliability of each sensory input, with the more reliable modality receiving the stronger weight. Sensory reliability is typically assessed via the variability of participants' judgments, yet these can be shaped by factors both external and internal to the nervous system. For example, motor noise and participant's dexterity with the specific response method contribute to judgment variability, and different response methods applied to the same stimuli can result in different estimates of sensory reliabilities. Here we ask how such variations in reliability induced by variations in the response method affect multisensory integration and sensory recalibration, as well as motor adaptation, in a visuomotor paradigm. Participants performed center-out hand movements and were asked to judge the position of the hand or rotated visual feedback at the movement end points. We manipulated the variability, and thus the reliability, of repeated judgments by asking participants to respond using either a visual or a proprioceptive matching procedure. We find that the relative weights of visual and proprioceptive signals, and thus the asymmetry of multisensory integration and recalibration, depend on the reliability modulated by the judgment method. Motor adaptation, in contrast, was insensitive to this manipulation. Hence, the outcome of multisensory binding is shaped by the noise introduced by sensorimotor processing, in line with perception and action being intertwined.NEW & NOTEWORTHY Our brain tends to combine multisensory signals based on their respective reliability. This reliability depends on sensory noise in the environment, noise in the nervous system, and, as we show here, variability induced by the specific judgment procedure.

Minimal impact of chronic proprioceptive loss on implicit sensorimotor adaptation and perceived movement outcome.

Implicit sensorimotor adaptation keeps our movements well calibrated amid changes in the body and environment. We have recently postulated that implicit adaptation is driven by a perceptual error: the difference between the desired and perceived movement outcome. According to this perceptual realignment model, implicit adaptation ceases when the perceived movement outcome-a multimodal percept determined by a prior belief conveying the intended action, the motor command, and feedback from proprioception and vision-is aligned with the desired movement outcome. Here, we examined the role of proprioception in implicit motor adaptation and perceived movement outcome by examining individuals who experience deafferentation (i.e., individuals with impaired proprioception and touch). We used a modified visuomotor rotation task designed to isolate implicit adaptation and probe perceived movement outcomes throughout the experiment. Surprisingly, both implicit adaptation and perceived movement outcome were minimally impacted by chronic deafferentation, posing a challenge to the perceptual realignment model of implicit adaptation.NEW & NOTEWORTHY We tested six individuals with chronic somatosensory deafferentation on a novel task that isolates implicit sensorimotor adaptation and probes perceived movement outcome. Strikingly, both implicit motor adaptation and perceptual movement outcome were not significantly impacted by chronic deafferentation, posing a challenge for theoretical models of adaptation that involve proprioception.

Velocity dependence of sensory reweighting in human balance control.

The relative contributions of proprioceptive, vestibular, and visual sensory cues to balance control change depending on their availability and reliability. This sensory reweighting is classically supported by nonlinear sway responses to increasing visual surround and/or surface tilt amplitudes. However, recent evidence indicates that visual cues are reweighted based on visual tilt velocity rather than tilt amplitude. Therefore, we designed a study to specifically test the hypothesized velocity dependence of reweighting while expanding on earlier findings for visual reweighting by testing proprioceptive reweighting for standing balance on a tilting surface. Twenty healthy young adults stood with their eyes closed on a toes-up/-down tilting platform. We designed four pseudorandom tilt sequences with either a slow (S) or a fast (F) tilt velocity and different peak-to-peak amplitudes. We used model-based interpretations of measured sway characteristics to estimate the proprioceptive sensory weight (Wprop) within each trial. In addition, root-mean-square values of measured body center of mass sway amplitude (RMS) and velocity (RMSv) were calculated for each tilt sequence. Wprop, RMS, and RMSv values varied depending on the stimulus velocity, exhibiting large effects (all Cohen's d >1.10). In contrast, we observed no significant differences across stimulus amplitudes for Wprop (Cohen's d: 0.02-0.16) and, compared with the differences in velocity, there were much smaller changes in RMS and RMSv values (Cohen's d: 0.05-0.91). These results confirmed the hypothesized velocity, rather than amplitude, dependence of sensory reweighting.NEW & NOTEWORTHY This novel study examined the velocity dependence of sensory reweighting for human balance control using support surface tilt stimuli with independently varied amplitude and velocity. Estimates of the proprioceptive contribution to standing balance, derived from model-based interpretations of sway characteristics, showed greater sensitivity to changes in surface tilt velocity than surface tilt amplitude. These results support a velocity-based mechanism underlying sensory reweighting for human balance control.

Imprecise perception of hand position during early motor adaptation.

Localizing one's body parts is important for movement control and motor learning. Recent studies have shown that the precision with which people localize their hand places constraints on motor adaptation. Although these studies have assumed that hand localization remains equally precise across learning, we show that precision decreases rapidly during early motor learning. In three experiments, healthy young participants (n = 92) repeatedly adapted to a 45° visuomotor rotation for a cycle of two to four reaches, followed by a cycle of two to four reaches with veridical feedback. Participants either used an aiming strategy that fully compensated for the rotation (experiment 1), or always aimed directly at the target, so that adaptation was implicit (experiment 2). We omitted visual feedback for the last reach of each cycle, after which participants localized their unseen hand. We observed an increase in the variability of angular localization errors when subjects used a strategy to counter the visuomotor rotation (experiment 1). This decrease in precision was less pronounced in the absence of reaiming (experiment 2), and when subjects knew that they would have to localize their hand on the upcoming trial, and could thus focus on hand position (experiment 3). We propose that strategic reaiming decreases the precision of perceived hand position, possibly due to attention to vision rather than proprioception. We discuss how these dynamics in precision during early motor learning could impact on motor control and shape the interplay between implicit and strategy-based motor adaptation.NEW & NOTEWORTHY Recent studies indicate that the precision with which people localize their hand limits implicit visuomotor learning. We found that localization precision is not static, but decreases early during learning. This decrease is pronounced when people apply a reaiming strategy to compensate for a visuomotor perturbation and is partly resistant to allocation of attention to the hand. We propose that these dynamics in position sense during learning may influence how implicit and strategy-based motor adaption interact.

Effects of rTMS to primary motor cortex and cerebellum on balance control in healthy adults.

Both the primary motor cortex (M1) and the cerebellum are crucial for postural stability and deemed as potential targets for non-invasive brain stimulation (NIBS) to enhance balance performance. However, the optimal target remains unknown. The purpose of this study was to compare the role of M1 and the cerebellum in modulating balance performance in young healthy adults using facilitatory 5 Hz repetitive transcranial magnetic stimulation (rTMS). Twenty-one healthy young adults (mean age = 27.95 ± 1.15 years) received a single session of 5 Hz rTMS on M1 and the cerebellum in a cross-over order with a 7-day washout period between the two sessions. Three balance assessments were performed on the Biodex Balance system SD: Limits of Stability (LOS), modified Clinical Test of Sensory Interaction on Balance (mCTSIB), and Balance Error Scoring System (BESS). No significant effect of rTMS was found on the LOS. The effect of rTMS on the mCTSIB was mediated by stimulation target, proprioception, and vision (p = .003, ηp 2 = 0.37). Cerebellar rTMS improved the mCTSIB sway index under eyes closed-foam surface condition (p = .02), whereas M1 rTMS did not result in improvement on the mCTSIB. The effect of rTMS on the BESS was mediated by stimulation target, posture, and proprioception (p = .049, ηp 2 = 0.14). Cerebellar rTMS enhanced reactive balance performance during most sensory deprived conditions.

Resting state functional connectivity associated with impaired proprioception post-stroke.

Deficits in proprioception, the knowledge of limb position and movement in the absence of vision, occur in ~50% of all strokes; however, our lack of knowledge of the neurological mechanisms of these deficits diminishes the effectiveness of rehabilitation and prolongs recovery. We performed resting-state functional magnetic resonance imaging (fMRI) on stroke patients to determine functional brain networks that exhibited changes in connectivity in association with proprioception deficits determined by a Kinarm robotic exoskeleton assessment. Thirty stroke participants were assessed for proprioceptive impairments using a Kinarm robot and underwent resting-state fMRI at 1 month post-stroke. Age-matched healthy control (n = 30) fMRI data were also examined and compared to stroke data in terms of the functional connectivity of brain regions associated with proprioception. Stroke patients exhibited reduced connectivity of the supplementary motor area and the supramarginal gyrus, relative to controls. Functional connectivity of these regions plus primary somatosensory cortex and parietal opercular area was significantly associated with proprioceptive function. The parietal lobe of the lesioned hemisphere is a significant node for proprioception after stroke. Assessment of functional connectivity of this region after stroke may assist with prognostication of recovery. This study also provides potential targets for therapeutic neurostimulation to aid in stroke recovery.

Texture congruence modulates perceptual bias but not sensitivity to visuotactile stimulation during the rubber hand illusion.

The sense of body ownership is the feeling that one's body belongs to oneself. To study body ownership, researchers use bodily illusions, such as the rubber hand illusion (RHI), which involves experiencing a visible rubber hand as part of one's body when the rubber hand is stroked simultaneously with the hidden real hand. The RHI is based on a combination of vision, touch, and proprioceptive information following the principles of multisensory integration. It has been posited that texture incongruence between rubber hand and real hand weakens the RHI, but the underlying mechanisms remain poorly understood. To investigate this, we recently developed a novel psychophysical RHI paradigm. Based on fitting psychometric functions, we discovered the RHI resulted in shifts in the point of subjective equality when the rubber hand and the real hand were stroked with matching materials. We analysed these datasets further by using signal detection theory analysis, which distinguishes between the participants' sensitivity to visuotactile stimulation and the associated perceptual bias. We found that texture incongruence influences the RHI's perceptual bias but not its sensitivity to visuotactile stimulation. We observed that the texture congruence bias effect was the strongest in shorter visuotactile asynchronies (50-100 ms) and weaker in longer asynchronies (200 ms). These results suggest texture-related perceptual bias is most prominent when the illusion's sensitivity is at its lowest. Our findings shed light on the intricate interactions between top-down and bottom-up processes in body ownership, the links between body ownership and multisensory integration, and the impact of texture congruence on the RHI.

Active self-touch restores bodily proprioceptive spatial awareness following disruption by 'rubber hand illusion'.

Bodily self-awareness relies on a constant integration of visual, tactile, proprioceptive, and motor signals. In the 'rubber hand illusion' (RHI), conflicting visuo-tactile stimuli lead to changes in self-awareness. It remains unclear whether other, somatic signals could compensate for the alterations in self-awareness caused by visual information about the body. Here, we used the RHI in combination with robot-mediated self-touch to systematically investigate the role of tactile, proprioceptive and motor signals in maintaining and restoring bodily self-awareness. Participants moved the handle of a leader robot with their right hand and simultaneously received corresponding tactile feedback on their left hand from a follower robot. This self-touch stimulation was performed either before or after the induction of a classical RHI. Across three experiments, active self-touch delivered after-but not before-the RHI, significantly reduced the proprioceptive drift caused by RHI, supporting a restorative role of active self-touch on bodily self-awareness. The effect was not present during involuntary self-touch. Unimodal control conditions confirmed that both tactile and motor components of self-touch were necessary to restore bodily self-awareness. We hypothesize that active self-touch transiently boosts the precision of proprioceptive representation of the touched body part, thus counteracting the visual capture effects that underlie the RHI.

Role of proprioceptors in chronic musculoskeletal pain.

Proprioceptors are non-nociceptive low-threshold mechanoreceptors. However, recent studies have shown that proprioceptors are acid-sensitive and express a variety of proton-sensing ion channels and receptors. Accordingly, although proprioceptors are commonly known as mechanosensing neurons that monitor muscle contraction status and body position, they may have a role in the development of pain associated with tissue acidosis. In clinical practice, proprioception training is beneficial for pain relief. Here we summarize the current evidence to sketch a different role of proprioceptors in 'non-nociceptive pain' with a focus on their acid-sensing properties.

Genetic exploration of roles of acid-sensing ion channel subtypes in neurosensory mechanotransduction including proprioception.

Although acid-sensing ion channels (ASICs) are proton-gated ion channels responsible for sensing tissue acidosis, accumulating evidence has shown that ASICs are also involved in neurosensory mechanotransduction. However, in contrast to Piezo ion channels, evidence of ASICs as mechanically gated ion channels has not been found using conventional mechanoclamp approaches. Instead, ASICs are involved in the tether model of mechanotransduction, with the channels gated via tethering elements of extracellular matrix and intracellular cytoskeletons. Methods using substrate deformation-driven neurite stretch and micropipette-guided ultrasound were developed to reveal the roles of ASIC3 and ASIC1a, respectively. Here we summarize the evidence supporting the roles of ASICs in neurosensory mechanotransduction in knockout mouse models of ASIC subtypes and provide insight to further probe their roles in proprioception.

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.