Shanie A L Jayasinghe

Fabrice R Sarlegna

Robert A Scheidt

Robert L Sainburg

Somatosensory deafferentation reveals lateralization of proprioception-based feedforward processes for controlling posture and movement

Keywords: internal model, dynamic dominance, sensory neuropathy, trajectory control

Proprioception provides crucial information necessary for determining limb position and movement and plausibly also for updating internal models that might underlie the control of movement and posture. Seminal studies of upper-limb movements in individuals living with chronic, large-fiber deafferentation have provided evidence for the role of proprioceptive information in the hypothetical formation and maintenance of internal models to produce accurate motor commands. Vision also contributes to sensorimotor functions but cannot fully compensate for proprioceptive deficits. More recent work has shown that posture and movement control processes are lateralized in the brain, and that proprioception plays a fundamental role in coordinating the contributions of these processes to the control of goal-directed actions. In fact, the behavior of each limb in a deafferented individual resembles the action of a controller in isolation. Proprioception thus provides state estimates necessary for the nervous system to efficiently coordinate multiple motor control processes.

Introduction

Proprioception, a term coined by Sir Charles Sherrington in 1906 [START_REF] Sherrington | Integrative action of the nervous system[END_REF] refers to information about position and movement derived from muscular, tendon and articular sensors. Later research emphasized the specific role of muscle spindles and Golgi tendon organs by demonstrating that joint position sense remains largely intact after complete joint replacement surgeries [START_REF] Barrack | Effect of articular disease and total knee arthroplasty on knee joint-position sense[END_REF], a finding consistent with experimental demonstrations that joint receptors do not provide information in the midrange of the joint [START_REF] Clark | Slowly adapting receptors in cat knee joint: Can they signal joint angle?[END_REF]. Thus, joint receptors cannot provide continuous information about segment configuration and movement. Rare cases of large fiber sensory neuropathy (LFSN) have shown that a massive yet specific loss of the large afferent fibers that innervate Golgi tendon organs (Ib) and muscle spindles (Ia & II) result in profound loss of position and movement sensation, regardless of intact small fibers that innervate joint articular tissues and skin. The fact that the most energetically costly sensory neurons (with large fibers) in the mammalian system innervate these sensors, and that muscle spindles are found in all skeletal muscles in the primate system, suggests an important role of proprioception in adaptive behavior.

Seminal research on these sensors, their innervation and central projections has elucidated the important roles of spinal circuits, including both homogenous and heterogenous reflexes, in modulating mechanical behavior of the muscles in response to perturbations [START_REF] Nichols | Improvement in linearity and regulation of stiffness that results from actions of stretch reflex[END_REF][START_REF] Huyghues-Despointes | Intrinsic Properties and Reflex Compensation in Reinnervated Triceps Surae Muscles of the Cat: Effect of Activation Level[END_REF][START_REF] De Haan | Somatosensation in the Brain: A Theoretical Reevaluation and a New Model[END_REF]. Research in human deafferentation has introduced the important role of proprioception in feedforward mechanisms to update the internal model of limb dynamics, which is largely mediated by supraspinal centers, including the cerebellum [START_REF] Therrien | The cerebellum as a movement sensor[END_REF], and regions of the cerebral cortex [START_REF] De Haan | Somatosensation in the Brain: A Theoretical Reevaluation and a New Model[END_REF][START_REF] Ohashi | Somatosensory cortical excitability changes precede those in motor cortex during human motor learning[END_REF]. In this review, we elucidate the importance of proprioception in feedforward mechanisms that specify upper limb reaching trajectories and final limb positions, drawing largely on evidence from experimental studies in deafferented individuals with LFSN.

The role of proprioception in updating internal models for the feedforward control of movement

Sensory information is used for both feedforward and feedback motor control processes.

Feedforward processes refer to the modification of system output using anticipated results in order to modify descending commands before the onset of the impending movement.

Feedback processes compare state estimates derived from sensory signals to predicted sensory states, using the difference as an error signal to generate corrections. When the feedback loop is rapid and gains are optimized, feedback can lead to stability of responses, such as the linearization of the rapid and incremental stretch response by stiffness regulation [START_REF] Nichols | Improvement in linearity and regulation of stiffness that results from actions of stretch reflex[END_REF]. However, errors requiring large proportional gains without an appropriate derivative gain, and invoking loops of longer latency can lead to destabilizing responses. Feedforward mechanisms provide the ability to anticipate system responses to future output and, thus, allow for stability of behavior when predictions are fairly accurate. It should be stressed that feedforward mechanisms can be used to modulate feedback systems, allowing robustness in the face of inaccurate predictions due to environmental variations, prediction errors, and/or neural noise (see [START_REF] Scott | Optimal feedback control and the neural basis of volitional motor control[END_REF][START_REF] Crevecoeur | Robust control in human reaching movements: a model-free strategy to compensate for unpredictable disturbances[END_REF][START_REF] Keyser | Task-dependent responses to muscle vibration during reaching[END_REF][START_REF] Franklin | Rapid visuomotor feedback gains are tuned to the task dynamics[END_REF] for recent articles on optimal feedback control and gain modulation).

The term 'internal model' has been widely studied through behavioral and neurophysiological research in the field of neuroscience [START_REF] Kawato | Internal models for motor control and trajectory planning[END_REF][START_REF] Vandevoorde | Internal model recalibration does not deteriorate with age while motor adaptation does[END_REF]. Here we refer to an internal model as a neural process that allows prediction of motor actions and their consequences. The internal model is continuously updated by sensory information, and the predicted movement features vary depending on task goals and costs [START_REF] Heald | Increasing muscle co-contraction speeds up internal model acquisition during dynamic motor learning[END_REF]. For instance, when kinematic and kinetic variables, such as smoothness and work, are critical costs for a task, the internal model makes predictions to optimize each variable. While researchers can model this process through forward and inverse dynamic equations, we expect that the biological system has less explicit solutions to predict the effects of impending dynamic events. Cognitive models of the body, referred to as body schema, are also a type of internal model that appears to be dependent on proprioceptive information [START_REF] Cole | Living without touch and peripheral information about body position and movement: Studies with deafferented subjects. In The body and the self[END_REF][START_REF] Martel | Somatosensory-guided tool use modifies arm representation for action[END_REF]. In fact, Sacks has reported cases in which individuals who have lost proprioception can view their deafferented limbs as foreign and even pernicious [START_REF] Sacks | The man who mistook his wife for a hat and other clinical tales[END_REF].

Studies in deafferented individuals have exhibited the critical roles played by proprioception, and vision, in rapid online control of movement as well as in the development, maintenance and modification of internal models. There is evidence that visual and proprioceptive information contribute differently for control of trajectory vs. final position of reaching, with proprioception deemed sufficient to recover movement direction after a perturbation, and early vision of hand position considered necessary to correct initial direction errors [START_REF] Scheidt | Interaction of visual and proprioceptive feedback during adaptation of human reaching movements[END_REF][START_REF] Shabbott | On-line corrections for visuomotor errors[END_REF]. Vision can provide information of limb configuration, which may explain why deafferented individuals can adapt to a novel force field when provided with visual information about hand position, and update their internal model of limb dynamics using vision alone [START_REF] Sarlegna | Force-field adaptation without proprioception: can vision be used to model limb dynamics?[END_REF][START_REF] Lefumat | Generalization of force-field adaptation in proprioceptively-deafferented subjects[END_REF][START_REF] Miall | Proprioceptive loss and the perception, control and learning of arm movements in humans: evidence from sensory neuronopathy[END_REF]. In fact, a study with three deafferented individuals showed that vision of the limb, either prior to or during a reaching movement, was necessary to update the internal models for trajectory control [START_REF] Ghez | Impairments of reaching movements in patients without proprioception. II. Effects of visual information on accuracy[END_REF]. The absence of vision degrades accuracy of the model, resulting in high movement variability and drift.

While visual information also contributes to movement control, it does not suffice to maintain accuracy of the presumptive internal model that accounts for limb dynamics in specification of movement trajectories. Deafferented individuals make movements under visual guidance that are abnormal, even years after the proprioceptive loss [START_REF] Miall | Proprioceptive loss and the perception, control and learning of arm movements in humans: evidence from sensory neuronopathy[END_REF][START_REF] Cuadra | Case Studies in Neuroscience: The central and somatosensory contributions to finger interdependence and coordination: lessons from a study of a "deafferented person[END_REF][START_REF] Miall | Loss of haptic feedback impairs control of hand posture: a study in chronically deafferented individuals when grasping and lifting objects[END_REF], reflecting poor coordination of intersegmental dynamics [START_REF] Sainburg | Loss of proprioception produces deficits in interjoint coordination[END_REF][START_REF] Sainburg | Control of limb dynamics in normal subjects and patients without proprioception[END_REF]. A seminal study examining unconstrained multi joint movements in two deafferented individuals revealed their inability to accurately and sharply reverse movements of the arm when instructed to produce out-and-back goal-directed slicing motions of the hand [START_REF] Sainburg | Loss of proprioception produces deficits in interjoint coordination[END_REF]. The slicing motions required precise coordination of movement between shoulder and elbow joints, and were well achieved in neurologically intact controls; however, the deafferented individuals produced curved hand paths, rather than sharp movement reversals even when vision of the limb was provided during movement. This resulted from an inability to account for the intersegmental interaction torques produced at one joint by motion of the other joints. A follow-up study [START_REF] Sainburg | Control of limb dynamics in normal subjects and patients without proprioception[END_REF] demonstrated that these reversal errors varied with the amplitude of such interaction torques. Participants made out-and-back movements along different directions and varying distances from the start position that required the same amount of elbow excursion but different amounts of shoulder excursion. While control participants made linear movements with direction-dependent changes in interaction torques, deafferented individuals produced errors at movement reversal that did not adapt to direction-dependent changes in interaction torques, resulting in inter-joint coordination deficits (Figure 1). Because intersegmental interactions are transient and large in amplitude, interjoint coordination depends on feedforward mechanisms that shape motor output signals in accord with impending variations in movement direction and speed. This series of studies demonstrated the importance of proprioception in tuning the parameters used to predict and compensate for the effects of limb inertial dynamics on rapid arm movements. It is likely that feedforward and feedback processes share a model-based process that accounts for limb dynamics [START_REF] Maeda | Feedforward and feedback control share an internal model of the arm's dynamics[END_REF], and that proprioception provides the foundation necessary for coordinating posture and movement.

Figure 1. Loss of interjoint coordination in the absence of proprioception. A)

Representative hand paths from a control participant and a deafferented patient when completing an out-andback tracing movement in 6 different directions. B) Correlation between peak elbow joint acceleration and peak interaction torque during movement reversal for all 6 directions in two controls and deafferented patients. C) Histograms of the range of interjoint coupling intervals (time between elbow and shoulder reversals) for controls and deafferented patients. Adapted from [START_REF] Sainburg | Control of limb dynamics in normal subjects and patients without proprioception[END_REF].

Proprioception-mediated differential feedforward control of movement and posture

The coordination of the left and right arms in primates is most often asymmetric in ways suggesting that feedforward and/or feedback control are lateralized. The dynamic dominance hypothesis suggests a differentiation of the control of limb dynamics: in right-hand dominant individuals, the dominant left hemisphere specializes in the feedforward control of trajectory dynamics and the nondominant right hemisphere specifies the feedforward and feedback control of limb impedance about final equilibrium positions [START_REF] Sainburg | Evidence for a dynamic-dominance hypothesis of handedness[END_REF]. We conducted a recent study on a deafferented individual (GL), which revealed that proprioception does indeed play a critical role in both of these control mechanisms [START_REF] Jayasinghe | The neural foundations of handedness: Insights from a rare case of deafferentation[END_REF]. GL and a group of neurologically intact controls performed point-to-point reaching movements using each hand while the arm was supported on an air sled that eliminated the mechanical effects of gravity and friction. In the absence of vision of hand position, GL exhibited deficits in trajectory and final position stabilization that differed between the left and right hand, and which differed markedly from movements made by control participants (Figure 2 A,B). GL's nondominant left hand produced large initial direction errors as well as oscillations at the target. Her dominant right hand produced less initial direction errors, but exhibited large drifts away from the target at the end of movement (Figure 2 C,D).

Computer simulations explained these findings as reflecting a temporal discoordination between separate and poorly tuned trajectory and impedance controllers. Previously, a serial hybrid model of movement explained differences in movement behavior between the left and right hands as resulting from differences in when control of the arm switches from predominantly trajectory control to predominantly impedance control [START_REF] Yadav | Handedness can be explained by a serial hybrid control scheme[END_REF]. Experimental findings in GL and computer simulations are consistent with the idea that the switch time from trajectory to impedance control occurs earlier for the nondominant left hand than for the dominant right hand [START_REF] Jayasinghe | The neural foundations of handedness: Insights from a rare case of deafferentation[END_REF], thus, suggesting an unequal contribution of each controller to each limb. Therefore, in the absence of online peripheral information, the limb that receives less direct input from a controller (i.e., the ipsilateral controller) would be especially impaired in the performance aspect for which the ipsilateral controller is specialized. The trajectories shown in Figure 2B

Limitations and future directions

The studies reviewed here mostly focus on reaching as a paradigm for studying human motor control, in healthy and deafferented individuals. The deafferented patients have a specific, well-characterized proprioceptive loss; however, the experimental findings reflect the effects of both complete proprioceptive loss as well as the re-adaptation of motor skills to their chronic condition. While reaching is an important component of functional motor performance, many other actions are critical to adaptive behavior in humans, including but not limited to locomotor behaviors, object manipulation, catching and throwing behaviors, and coordination between whole body and limb movements for activities of daily living. The focus of the reviewed papers on reaching behaviors is an early step in understanding the role of proprioception in motor control and lateralization, which was driven by many decades of foundational research in motor control and biomechanics. Selecting a given paradigm is likely to influence the view of motor lateralization, which must be treated as a dynamic process where the contribution of each hemisphere to movement control is driven by the skill level and attentional focus of the performer [START_REF] Serrien | Dynamics of hemispheric specialization and integration in the context of motor control[END_REF], the type and complexity of the task, and the relative importance of the various goals and costs of the task [START_REF] Yadav | Limb dominance results from asymmetries in predictive and impedance control mechanisms[END_REF]. The tasks employed to study the contributions of sensory information to motor control are likely to expand as our understanding of the basic principles of the sensory contributions to motor control advance. This should translate to innovations for restoring proprioceptive signals (see [START_REF] Risi | Supplemental vibrotactile feedback of real-time limb position enhances precision of goal-directed reaching[END_REF][START_REF] Andersen | From thought to action: The brain-machine interface in posterior parietal cortex[END_REF]) in amputees and individuals with neurological disorders [START_REF] Mochizuki | Movement kinematics and proprioception in post-stroke spasticity: assessment using the Kinarm robotic exoskeleton[END_REF].

  illustrate this point clearly. Taken together, this line of research emphasizes the importance of proprioception in feedforward control processes used for coordination of movement trajectories and for stabilizing accurate final limb postures.

Figure 2 .

 2 Figure 2. Deafferentation reveals differential feedforward control of arm movement and posture. Participants performed reaching movements to a target (blue) placed in one of three directions from an initial start position (green). Vision of hand path was removed upon leaving the start position. Left and right hand paths and tangential velocity profiles are shown for A) a representative control individual and B) a deafferented individual. Scale bars next to the left hand trajectories represent 2 cm hand movement. C) Mean initial direction error and D) mean error at movement's end is displayed for each hand of 5 control participants and the deafferented individual. Error bars in control data represent 1 standard deviation from the mean. Mean values for each control participant are plotted as purple squares (left hand) or yellow triangles (right hand). p < 0.001 (*). Reprinted from [31].

Acknowledgements

This work was supported by the National Institutes of Health [grant R01HD059783 awarded to R.L.S.] and the National Center for Scientific Research-France (PICS grant awarded to F.R.S.).