Erroneous Compensation for Long-Latency Feedback Delays as Origin of Essential Tremor.

Essential tremor (ET), a movement disorder characterized by involuntary oscillations of the limbs during movement, remains to date not well understood. It has been recently suggested that the tremor originates from impaired delay compensation, affecting movement representation and online control. Here we tested this hypothesis directly with 24 ET patients (14 female; 10 male) and 28 neurologically intact (NI) human volunteers (17 female; 11 male) in an upper limb postural perturbation task. After maintaining their hand in a visual target, participants experienced perturbations of unpredictable direction and magnitude and were instructed to counter the perturbation and steer their hand back to the starting position. In comparison with NI volunteers, ET patients' early muscular responses (short and long-latency responses, 20-50 and 50-100 ms, respectively) were preserved or even slightly increased. However, they exhibited perturbation-dependent deficits when stopping and stabilizing their hand in the final target supporting the hypothesis that the tremor was generated by the feedback controller. We show in a computational model that errors in delay compensation accumulating over time produced the same small increase in initial feedback response followed by oscillations that scaled with the perturbation magnitude as observed in ET population. Our experimental results therefore validate the computational hypothesis that inaccurate delay compensation in long-latency pathways could be the origin of the tremor.

Continuous evaluation of cost-to-go for flexible reaching control and online decisions.

Humans consider the parameters linked to movement goal during reaching to adjust their control strategy online. Indeed, rapid changes in target structure or disturbances interfering with their initial plan elicit rapid changes in behavior. Here, we hypothesize that these changes could result from the continuous use of a decision variable combining motor and cognitive components. We combine an optimal feedback controller with a real-time evaluation of the expected cost-to-go, which considers target- and movement-related costs, in a common theoretical framework. This model reproduces human behaviors in presence of changes in the target structure occurring during movement and of online decisions to flexibly change target following external perturbations. It also predicts that the time taken to decide to select a novel goal after a perturbation depends on the amplitude of the disturbance and on the rewards of the different options, which is a direct result of the continuous monitoring of the cost-to-go. We show that this result was present in our previously collected dataset. Together our developments point towards a continuous evaluation of the cost-to-go during reaching to update control online and make efficient decisions about movement goal.

Impairments of saccadic and reaching adaptation in essential tremor are linked to movement execution.

Essential tremor (ET) is a neurological disorder characterized by involuntary oscillations of the limbs. Previous studies have hypothesized that ET is a cerebellar disorder and reported impairments in motor adaptation. However, recent advances have highlighted that motor adaptation involves several components linked to anticipation and control, all dependent on cerebellum. We studied the contribution of both components in adaptation to better understand the adaptation impairments observed in ET from a behavioral perspective. To address this question, we investigated behavioral markers of adaptation in ET patients (n = 20) and age-matched neurologically intact volunteers (n = 20) in saccadic and upper limb adaptation tasks, probing compensation for target jumps and for velocity-dependent force fields, respectively. We found that both groups adapted their movements to the novel contexts; however, ET patients adapted to a lesser extent compared with neurologically intact volunteers. Importantly, components of the movement linked to anticipation were preserved in the ET group, whereas components linked to movement execution appeared responsible for the adaptation deficit in this group. Altogether, our results suggest that execution deficits may be a specific functional consequence of the alteration of neural pathways associated with ET.NEW & NOTEWORTHY We tested essential tremor patients' adaptation abilities in classical tasks including saccadic adaptation to target jumps and reaching adaptation to force field disturbances. Patients' adaptation was present but impaired in both tasks. Interestingly, the deficits were mainly present during movement execution, whereas the anticipatory components of movements were similar to neurologically intact volunteers. These findings reinforce the hypothesis of a cerebellar origin for essential tremor and detail the motor adaptation impairments previously found in this disorder.

Separability of Human Motor Memories during reaching adaptation with force cues.

Judging by the breadth of our motor repertoire during daily activities, it is clear that learning different tasks is a hallmark of the human motor system. However, for reaching adaptation to different force fields, the conditions under which this is possible in laboratory settings have remained a challenging question. Previous work has shown that independent movement representations or goals enabled dual adaptation. Considering the importance of force feedback during limb control, here we hypothesised that independent cues delivered by means of background loads could support simultaneous adaptation to various velocity-dependent force fields, for identical kinematic plan and movement goal. We demonstrate in a series of experiments that indeed healthy adults can adapt to opposite force fields, independently of the direction of the background force cue. However, when the cue and force field were in the same direction but differed by heir magnitude, the formation of different motor representations was still observed but the associated mechanism was subject to increased interference. Finally, we highlight that this paradigm allows dissociating trial-by-trial adaptation from online feedback adaptation, as these two mechanisms are associated with different time scales that can be identified reliably and reproduced in a computational model.

Effects of overground gait training assisted by a wearable exoskeleton in patients with Parkinson's disease.

BACKGROUND: In the recent past, wearable devices have been used for gait rehabilitation in patients with Parkinson's disease. The objective of this paper is to analyze the outcome of a wearable hip orthosis whose assistance adapts in real time to the patient's gait kinematics via adaptive oscillators. In particular, this study focuses on a metric characterizing natural gait variability, i.e., the level of long-range autocorrelations (LRA) in series of stride durations. METHODS: Eight patients with Parkinson's disease (Hoehn and Yahr stages 1[Formula: see text]2.5) performed overground gait training three times per week for four consecutive weeks, assisted by a wearable hip orthosis. Gait was assessed based on performance metrics such as the hip range of motion, speed, stride length and duration, and the level of LRA in inter-stride time series assessed using the Adaptive Fractal Analysis. These metrics were measured before, directly after, and 1 month after training. RESULTS: After training, patients increased their hip range of motion, their gait speed and stride length, and decreased their stride duration. These improvements were maintained 1 month after training. Regarding long-range autocorrelations, the population's behavior was standardized towards a metric closer to the one of healthy individuals after training, but with no retention after 1 month. CONCLUSION: This study showed that an overground gait training with adaptive robotic assistance has the potential to improve key gait metrics that are typically affected by Parkinson's disease and that lead to higher prevalence of fall. TRIAL REGISTRATION: ClinicalTrials.gov Identifer NCT04314973. Registered on 11 April 2020.

Integration of proprioceptive and visual feedback during online control of reaching.

Visual and proprioceptive feedback both contribute to perceptual decisions, but it remains unknown how these feedback signals are integrated together or consider factors such as delays and variance during online control. We investigated this question by having participants reach to a target with randomly applied mechanical and/or visual disturbances. We observed that the presence of visual feedback during a mechanical disturbance did not increase the size of the muscle response significantly but did decrease variance, consistent with a dynamic Bayesian integration model. In a control experiment, we verified that vision had a potent influence when mechanical and visual disturbances were both present but opposite in sign. These results highlight a complex process for multisensory integration, where visual feedback has a relatively modest influence when the limb is mechanically disturbed, but a substantial influence when visual feedback becomes misaligned with the limb.NEW & NOTEWORTHY Visual feedback is more accurate, but proprioceptive feedback is faster. How should you integrate these sources of feedback to guide limb movement? As predicted by dynamic Bayesian models, the size of the muscle response to a mechanical disturbance was essentially the same whether visual feedback was present or not. Only under artificial conditions, such as when shifting the position of a cursor representing hand position, can one observe a muscle response from visual feedback.

Online modification of goal-directed control in human reaching movements.

Humans are able to perform very sophisticated reaching movements in a myriad of contexts based on flexible control strategies influenced by the task goal and environmental constraints such as obstacles. However, it remains unknown whether these control strategies can be adjusted online. The objective of this study was to determine whether the factors that determine control strategies during planning also modify the execution of an ongoing movement following sudden changes in task demand. More precisely, we investigated whether, and at which latency, feedback responses to perturbation loads followed the change in the structure of the goal target or environment. We changed the target width (square or rectangle) to alter the task redundancy, or the presence of obstacles to induce different constraints on the reach path, and assessed based on surface electromyography (EMG) recordings when the change in visual display altered the feedback response to mechanical perturbations. Task-related EMG responses were detected within 150 ms of a change in target shape. Considering visuomotor delays of ∼ 100 ms, these results suggest that it takes 50 ms to change control policy within a trial. An additional 30-ms delay was observed when the change in context involved sudden appearance or disappearance of obstacles. Overall, our results demonstrate that the control policy within a reaching movement is not static: contextual factors that influence movement planning also influence movement execution at surprisingly short latencies. Moreover, the additional 30 ms associated with obstacles suggests that these two types of changes may be mediated via distinct processes.NEW & NOTEWORTHY The present work demonstrates that the control strategies used to perform reaching movements are adjusted online when the structure of the target or the presence of obstacles are altered during movements. Thus, the properties of goal-directed reaching control are not simply selected during the planning stage of a movement prior to execution. Rather, they are dynamically and rapidly adjusted online, within ∼150 ms, according to changes in environment.

Interjoint coupling of position sense reflects sensory contributions of biarticular muscles.

Perception of limb position and motion combines sensory information from spindles in muscles that span one joint (monoarticulars) and two joints (biarticulars). This anatomical organization should create interactions in estimating limb position. We developed two models, one with only monoarticulars and one with both monoarticulars and biarticulars, to explore how biarticulars influence estimates of arm position in hand (x, y) and joint (shoulder, elbow) coordinates. In hand coordinates, both models predicted larger medial-lateral than proximal-distal errors, although the model with both muscle groups predicted that biarticulars would reduce this bias. In contrast, the two models made significantly different predictions in joint coordinates. The model with only monoarticulars predicted that errors would be uniformly distributed because estimates of angles at each joint would be independent. In contrast, the model that included biarticulars predicted that errors would be coupled between the two joints, resulting in smaller errors for combinations of flexion or extension at both joints and larger errors for combinations of flexion at one joint and extension at the other joint. We also carried out two experiments to examine errors made by human subjects during an arm position matching task in which a robot passively moved one arm to different positions and the subjects moved their other arm to mirror-match each position. Errors in hand coordinates were similar to those predicted by both models. Critically, however, errors in joint coordinates were only similar to those predicted by the model with monoarticulars and biarticulars. These results highlight how biarticulars influence perceptual estimates of limb position by helping to minimize medial-lateral errors.NEW & NOTEWORTHY It is unclear how sensory information from muscle spindles located within muscles spanning multiple joints influences perception of body position and motion. We address this issue by comparing errors in estimating limb position made by human subjects with predicted errors made by two musculoskeletal models, one with only monoarticulars and one with both monoarticulars and biarticulars. We provide evidence that biarticulars produce coupling of errors between joints, which help to reduce errors.

Effects of pupillary light and darkness reflex on the generation of pro- And anti-saccades.

Saccades are often directed toward a stimulus that provides useful information for observers to navigate the visual world. The quality of visual signals of a stimulus is influenced by global luminance, and the pupil constricts or dilates after a luminance increase or decrease, respectively, to optimize visual signals for further information processing. Although luminance level changes regularly in the real environment, saccades are mostly studied in the luminance-unchanged setup. Whether pupillary responses triggered by global luminance changes modulate saccadic behavior are yet to be explored. Through varying background luminance level in an interleaved pro- and anti-saccade paradigm, we investigated the modulation of pupillary luminance responses on the generation of reflexive and voluntary saccades. Subjects were instructed to either automatically look at the peripheral stimulus (pro-saccade) or to suppress the automatic response and voluntarily look in the opposite direction from the stimulus (anti-saccade). Level of background luminance was increased (light), decreased (dark), or unchanged (control) during the instructed fixation period. Saccade reaction time distributions of correct pro- and anti-saccades in the light and dark conditions were differed significantly from those in the control condition. Moreover, the luminance condition modulated saccade kinematics, showing reduced performances in the light condition than in the control condition, particularly in pro-saccades. Modeling results further suggested that both pupil diameter and pupil size derivative significantly modulated saccade behavior, though effect sizes were small and mainly mediated by intersubject differences. Together, our results demonstrated the influence of pupillary luminance responses on the generation of pro- and anti-saccades.

Robust Control in Human Reaching Movements: A Model-Free Strategy to Compensate for Unpredictable Disturbances.

Current models of motor learning suggest that multiple timescales support adaptation to changes in visual or mechanical properties of the environment. These models capture patterns of learning and memory across a broad range of tasks, yet do not consider the possibility that rapid changes in behavior may occur without adaptation. Such changes in behavior may be desirable when facing transient disturbances, or when unpredictable changes in visual or mechanical properties of the task make it difficult to form an accurate model of the perturbation. Whether humans can modulate control strategies without an accurate model of the perturbation remains unknown. Here we frame this question in the context of robust control (H∞-control), a control strategy that specifically considers unpredictable disturbances by increasing initial movement speed and feedback gains. Correspondingly, we demonstrate in two human reaching experiments including males and females that the occurrence of a single unpredictable disturbance led to an increase in movement speed and in the gain of rapid feedback responses to mechanical disturbances on subsequent movements. This strategy reduced perturbation-related motion regardless of the direction of the perturbation. Furthermore, we found that changes in the control strategy were associated with co-contraction, which amplified the gain of muscle responses to both lengthening and shortening perturbations. These results have important implications for studies on motor adaptation because they highlight that trial-by-trial changes in limb motion also reflected changes in control strategies dissociable from error-based adaptation.SIGNIFICANCE STATEMENT Humans and animals use internal representations of movement dynamics to anticipate the impact of predictable disturbances. However, we are often confronted with transient or unpredictable disturbances, and it remains unknown whether and how the nervous system handles these disturbances over fast time scales. Here we hypothesized that humans can modulate their control strategy to make reaching movements less sensitive to perturbations. We tested this hypothesis in the framework of robust control, and found changes in movement speed and feedback gains consistent with the model predictions. These changes impacted participants' behavior on a trial-by-trial basis. We conclude that compensation for disturbances over fast time scales involves a robust control strategy, which potentially plays a key role in motor planning and execution.

Correlations Between Primary Motor Cortex Activity with Recent Past and Future Limb Motion During Unperturbed Reaching.

Many studies highlight that human movements are highly successful yet display a surprising amount of variability from trial to trial. There is a consistent pattern of variability throughout movement: initial motor errors are corrected by the end of movement, suggesting the presence of a powerful online control process. Here, we analyze the trial-by-trial variability of goal-directed reaching in nonhuman primates (five male Rhesus monkeys) and demonstrate that they display a similar pattern of variability during reaching, including a strong negative correlation between initial and late hand motion. We then demonstrate that trial-to-trial neural variability of primary motor cortex (M1) is positively correlated with variability of future hand motion (τ = ∼160 ms) during reaching. Furthermore, the variability of M1 activity is also correlated with variability of past hand motion (τ = ∼90 ms), but in the opposite polarity (i.e., negative correlation). Partial correlation analysis demonstrated that M1 activity independently reflects the variability of both past and future hand motions. These findings provide support for the hypothesis that M1 activity is involved in online feedback control of motor actions.SIGNIFICANCE STATEMENT Previous studies highlight that primary motor cortex (M1) rapidly responds to either visual or mechanical disturbances, suggesting its involvement in online feedback control. However, these studies required external disturbances to the motor system and it is not clear whether a similar feedback process addresses internal noise/errors generated by the motor system itself. Here, we introduce a novel analysis that evaluates how variations in the activity of M1 neurons covary with variations in hand motion on a trial-to-trial basis. The analyses demonstrate that M1 activity is correlated with hand motion in both the near future and the recent past, but with opposite polarity. These results suggest that M1 is involved in online feedback motor control to address errors/noise within the motor system.

Long-latency reflexes for inter-effector coordination reflect a continuous state feedback controller.

Successful performance in many everyday tasks requires compensating unexpected mechanical disturbance to our limbs and body. The long-latency reflex plays an important role in this process because it is the fastest response to integrate sensory information across several effectors, like when linking the elbow and shoulder or the arm and body. Despite the dozens of studies on inter-effector long-latency reflexes, there has not been a comprehensive treatment of how these reveal the basic control organization that sets constraints on any candidate model of neural feedback control such as optimal feedback control. We considered three contrasting ways that controllers can be organized: multiple independent controllers vs. a multiple-input multiple-output (MIMO) controller, a continuous feedback controller vs. an intermittent feedback controller, and a direct MIMO controller vs. a state feedback controller. Following a primer on control theory and review of the relevant evidence, we conclude that continuous state feedback control best describes the organization of inter-effector coordination by the long-latency reflex.

Optimal use of limb mechanics distributes control during bimanual tasks.

Bimanual tasks involve the coordination of both arms, which often offers redundancy in the ways a task can be completed. The distribution of control across limbs is often considered from the perspective of handedness. In this context, although there are differences across dominant and nondominant arms during reaching control ( Sainburg 2002 ), previous studies have shown that the brain tends to favor the dominant arm when performing bimanual tasks ( Salimpour and Shadmehr 2014 ). However, biomechanical factors known to influence planning and control in unimanual tasks may also generate limb asymmetries in force generation, but their influence on bimanual control has remained unexplored. We investigated this issue in a series of experiments in which participants were instructed to generate a 20-N force with both arms, with or without perturbation of the target force during the trial. We modeled the task in the framework of optimal feedback control of a two-link model with six human-like muscles groups. The biomechanical model predicted a differential contribution of each arm dependent on the orientation of the target force and joint configuration that was quantitatively matched by the participants' behavior, regardless of handedness. Responses to visual perturbations were strongly influenced by the perturbation direction, such that online corrections also reflected an optimal use of limb biomechanics. These results show that the nervous system takes biomechanical constraints into account when optimizing the distribution of forces generated across limbs during both movement planning and feedback control of a bimanual task. NEW & NOTEWORTHY Here, we studied a bimanual force production task to examine the effects of biomechanical constraints on the distribution of control across limbs. Our findings show that the central nervous system optimizes the distribution of force across the two arms according to the joint configuration of the upper limbs. We further show that the underlying mechanisms influence both movement planning and online corrective responses to sudden changes in the target force.

Dynamic Multisensory Integration: Somatosensory Speed Trumps Visual Accuracy during Feedback Control.

UNLABELLED: Recent advances in movement neuroscience have consistently highlighted that the nervous system performs sophisticated feedback control over very short time scales (<100 ms for upper limb). These observations raise the important question of how the nervous system processes multiple sources of sensory feedback in such short time intervals, given that temporal delays across sensory systems such as vision and proprioception differ by tens of milliseconds. Here we show that during feedback control, healthy humans use dynamic estimates of hand motion that rely almost exclusively on limb afferent feedback even when visual information about limb motion is available. We demonstrate that such reliance on the fastest sensory signal during movement is compatible with dynamic Bayesian estimation. These results suggest that the nervous system considers not only sensory variances but also temporal delays to perform optimal multisensory integration and feedback control in real-time. SIGNIFICANCE STATEMENT: Numerous studies have demonstrated that the nervous system combines redundant sensory signals according to their reliability. Although very powerful, this model does not consider how temporal delays may impact sensory reliability, which is an important issue for feedback control because different sensory systems are affected by different temporal delays. Here we show that the brain considers not only sensory variability but also temporal delays when integrating vision and proprioception following mechanical perturbations applied to the upper limb. Compatible with dynamic Bayesian estimation, our results unravel the importance of proprioception for feedback control as a consequence of the shorter temporal delays associated with this sensory modality.

Rapid online selection between multiple motor plans.

Recent theories of voluntary control predict that multiple motor strategies can be precomputed and expressed throughout movement. We examined online decisional processing in humans by asking them to make reaching movements with obstacles located just to the sides of a direct path between start and end targets. On random trials, the limb was perturbed with one of four mechanical loads that varied in direction and amplitude. Notably, we observed two different strategies when we applied a perturbation (left medium-sized) that deviated the participants' hand directly toward an obstacle. In some trials, subjects directed their hand between the obstacles and in other trials to the left of the obstacles. Importantly, changes in the muscle stretch response between these two strategies were observed in <60 ms after perturbation, during the R2 long-latency epoch (~45-75 ms). As predicted, the selected strategy depended on the estimated position of the limb when it was perturbed. In our second experiment, we presented either one or three potential goal targets. Movements initially directed to the closest target could be quickly redirected to other potential targets after a perturbation. Differences in muscle stretch responses for redirected movements were observed ~75 ms after perturbation during the R3 long-latency epoch (~75-105 ms). The results show that decisional processes are rapidly implemented during movement execution. In addition, our data suggest a hierarchical process with corrective responses on "how" to attain a behavioral goal expressed during the R2 epoch and responses on "what" goal to attain during the R3 epoch.

Beyond muscles stiffness: importance of state-estimation to account for very fast motor corrections.

Feedback delays are a major challenge for any controlled process, and yet we are able to easily control limb movements with speed and grace. A popular hypothesis suggests that the brain largely mitigates the impact of feedback delays (∼50 ms) by regulating the limb intrinsic visco-elastic properties (or impedance) with muscle co-contraction, which generates forces proportional to changes in joint angle and velocity with zero delay. Although attractive, this hypothesis is often based on estimates of limb impedance that include neural feedback, and therefore describe the entire motor system. In addition, this approach does not systematically take into account that muscles exhibit high intrinsic impedance only for small perturbations (short-range impedance). As a consequence, it remains unclear how the nervous system handles large perturbations, as well as disturbances encountered during movement when short-range impedance cannot contribute. We address this issue by comparing feedback responses to load pulses applied to the elbow of human subjects with theoretical simulations. After validating the model parameters, we show that the ability of humans to generate fast and accurate corrective movements is compatible with a control strategy based on state estimation. We also highlight the merits of delay-uncompensated robust control, which can mitigate the impact of internal model errors, but at the cost of slowing feedback corrections. We speculate that the puzzling observation of presynaptic inhibition of peripheral afferents in the spinal cord at movement onset helps to counter the destabilizing transition from high muscle impedance during posture to low muscle impedance during movement.

Fast feedback control involves two independent processes utilizing knowledge of limb dynamics.

Corrective muscle responses occurring 50-100 ms after a mechanical perturbation are tailored to the mechanical features of the limb and its environment. For example, the evoked response by the shoulder's extensor muscle counters an imposed shoulder torque, rather than local shoulder motion, by integrating motion information from the shoulder and elbow appropriate for their dynamic interaction. Previous studies suggest that arm muscle activity within this epoch, alternately termed the R2/3 response, or long-latency reflex, reflects the summed result of two distinct components: an activity-dependent component which scales with the background muscle activity, and a task-dependent component which scales with the required vigor of the behavioral task. Here we examine how the knowledge of limb dynamics expressed during the shoulder muscle's R2/3 epoch is related to these two functional components. Subjects countered torque steps applied to their shoulder and/or elbow under different conditions of background torque and target size to recruit the activity-dependent and task-dependent component in varying degrees. Experiment 1 involved four torque perturbations, two levels of background torques and two target sizes; this design revealed that both background torque and target size impacted the shoulder's R2/3 activity, indicative of knowledge of limb dynamics. Experiment 2 involved two perturbation torques, five levels of background torque and two target sizes; this design demonstrated that the two factors had an independent impact on the R2/3 activity indicative of knowledge of limb dynamics. We conclude that a sophisticated feature of upper limb feedback control reflects the summation of two processes having a common capability.

Priors engaged in long-latency responses to mechanical perturbations suggest a rapid update in state estimation.

In every motor task, our brain must handle external forces acting on the body. For example, riding a bike on cobblestones or skating on irregular surface requires us to appropriately respond to external perturbations. In these situations, motor predictions cannot help anticipate the motion of the body induced by external factors, and direct use of delayed sensory feedback will tend to generate instability. Here, we show that to solve this problem the motor system uses a rapid sensory prediction to correct the estimated state of the limb. We used a postural task with mechanical perturbations to address whether sensory predictions were engaged in upper-limb corrective movements. Subjects altered their initial motor response in ∼60 ms, depending on the expected perturbation profile, suggesting the use of an internal model, or prior, in this corrective process. Further, we found trial-to-trial changes in corrective responses indicating a rapid update of these perturbation priors. We used a computational model based on Kalman filtering to show that the response modulation was compatible with a rapid correction of the estimated state engaged in the feedback response. Such a process may allow us to handle external disturbances encountered in virtually every physical activity, which is likely an important feature of skilled motor behaviour.

Fast grip force adaptation to friction relies on localized fingerpad strains.

During object manipulation, humans adjust the grip force to friction, such that slippery objects are squeezed more firmly than sticky ones. This essential mechanism to keep a stable grasp relies on feedback from tactile afferents innervating the fingertips, that are sensitive to local skin strains. To test if this feedback originates from the skin-object interface, we asked participants to perform a grip-lift task with an instrumented object able to monitor skin strains at the contact through transparent plates of different frictions. We observed that, following an unbeknown change in plate across trials, participants adapted their grip force to friction. After switching from high to low friction, we found a significant increase in strain inside the contact arising ~100 ms before the modulation of grip force, suggesting that differences in strain patterns before lift-off are used by the nervous system to quickly adjust the force to the frictional properties of manipulated objects.