Biology subjects

Krakauer, J. W.

Publications and source records attributed to Krakauer, J. W..

At least 19 recordsLinked to original sources

bioRxiv2026

Cervical spinal cord stimulation disrupts proprioception yet improves voluntary arm reaching

Whether proprioception is necessary for upper-limb motor control has been debated for decades. Classic studies in deafferented animals and humans suggested that proprioception may be dispensable for rapid, goal-directed movements. However, chronic sensory loss conflates the absence of proprioceptive input with years of compensatory adaptation. As a result, the field has lacked a strong causal test of proprioceptions contribution to motor control. Here, we leveraged a clinical trial of cervical spinal cord stimulation (SCS) in individuals with chronic post-stroke hemiparesis to study if electrical stimulation of sensory afferents causally perturbs proprioception and affects arm reaching. We found that turning SCS ON causally impaired proprioceptive perception and postural stabilization in response to force perturbations, and enhanced adaptation to visual errors during implicit learning. Yet visually and non-visually rapid, goal-directed reaching improved in smoothness, straightness and spatial accuracy. These findings provide strong causal evidence that proprioception is not required for rapid, goal-directed action, helping resolve a decades-long debate regarding its necessity for effective movement.

bioengineering↗

bioRxiv2026

Novel tool use does not depend on mechanical reasoning: evidence from apraxia

A hallmark of human intelligence is the ability to use tools. Yet the cognitive processes supporting this ability remain debated. One contemporary view holds that mechanical reasoning is central for tool use, especially in the case of tools with which we have no prior experience. However, previous support for the role of mechanical reasoning often relies on circular logic, wherein poor performance on novel tool-use tasks is taken as evidence that impaired mechanical reasoning causes tool-use deficits in limb apraxia. To address this limitation, we independently assessed mechanical reasoning and novel tool use in separate tasks in individuals with limb apraxia, and compared their performance to individuals without apraxia. We also examined whether these two abilities are similarly associated with other cognitive abilities including motor imagery, mental rotation of non-body objects, general reasoning, and spatial working memory. Finally, we explored brain-behavior relationships using support vector regression lesion-symptom mapping. Our behavioral and imaging data together showed that mechanical reasoning does not underlie novel tool-use deficits in apraxia. Graphical analysis further revealed that novel tool use and mechanical reasoning loaded onto distinct latent clusters: novel tool use was strongly associated with other praxis abilities yet separable from cognitive abilities that require reasoning and mental simulation, whereas mechanical reasoning was primarily linked to other high-level reasoning abilities but not tool use. These findings challenge the notion that mechanical reasoning is central to tool-use ability, and instead suggest that tool use is more likely to be an intuitive or automatic process.

neuroscience↗

bioRxiv2026

Extent of damage to descending output from cortex rather than to specific cortical regions drives the emergence of flexor synergy in non-human primates

Obligate flexor synergies are a defining feature of the hemiparetic phenotype following stroke in humans. Although these intrusive synergies can diminish over time, recovery may plateau, leaving some individuals with movements permanently constrained to synergies. Despite their clinical significance, the neural mechanisms underlying the emergence and persistence of abnormal synergies remain poorly understood. To investigate this mechanistically, three macaque monkeys were trained on a reach and grasp task prior to receiving one of three unilateral lesion types: 1) a focal sensorimotor cortical lesion, 2) a combined sensorimotor cortical and magnocellular red nucleus (RNm) lesion, or 3) a lesion of the internal capsule. Upper limb three-dimensional kinematics and EMG cross correlation were used to measure the intrusion of synergies during in synergy vs out of synergy reaching. A combined RNm and cortical lesion produced weakness but no flexor synergy. A similar-sized cortical lesion generated mild synergies which substantially recovered. By contrast, a large internal capsule lesion produced severe, persistent flexor synergy. Collectively, these findings suggest that the emergence of abnormal synergies is determined by the extent of corticofugal disruption, and their persistence depends on the ability of surviving supraspinal motor pathways to regain selective control over muscle contractions.

neuroscience↗

bioRxiv2026

The changing contributions of weakness and the flexor synergy to post-stroke arm function over time: A kinematic re-examination of Twitchell

In 1951, the neurologist Thomas Twitchell published a seminal paper in Brain describing the time-course of recovery from hemiplegia after stroke in 25 participants from hospitalization to when they reached what he deemed steady state. His main emphasis was on the evolution of voluntary movements at the shoulder, elbow and hand, first within an obligatory flexor synergy, and then independently out-of-synergy. We thought that 75 years later, an update using modern motion capture technology should be attempted as it would allow for finer granularity in the characterization of the time courses of both functional recovery and of the flexor synergy, and then relate them to each other, to weakness and to well-established clinical scales. To this end, we used marker-less 3D kinematics to assess task performance and intrusion of synergies in thirty-three stroke participants longitudinally, from the early sub-acute stage (1 - 8 weeks post-stroke) to the chronic stage (24 - 64 weeks post-stroke). Participants performed an out-of-flexor synergy (shoulder flexion and elbow extension) reaching task. We assessed the time course of recovery of obligatory intrusion of pathological synergies based on measures derived from the angular velocity profiles of the shoulder and the elbow joints. Task-related kinematic measures were obtained and compared to sixteen healthy controls. Grip strength, Motor impairment (FMA), and function (ARAT) scores were also collected. Task kinematics were different from controls in the early, late sub-acute, and chronic stages, but showed gradual recovery over time. Weakness in the hand remained impaired at all time points. Flexor-synergy intrusion was maximal in the early sub-acute stage and then began to subside. Regression analysis with functional kinematic and clinical (FMA, ARAT) measures indicated that flexor-synergy intrusion was a significant predictor in the early and late sub-acute stages, but not in the chronic stage, while weakness remained a significant predictor at all stages of recovery. To better address the relationship between synergies, weakness, and function, we analyzed the more severe cases (ARAT<21) separately. In the sub-acute stage, most of them (11/13) suffered from intrusion of synergies, whereas in the chronic phase, only a minority (2/8) did. Weakness seemed to be the main contributor to poor outcome in the chronic phase. We conclude that weakness and synergy intrusion evolve separately from the subacute to the chronic phase, perhaps more so when neurorehabilitation is given at a dose higher than standard of care.

neuroscience↗

bioRxiv2025

Arm dominance emerges through asymmetric practice of complex trajectory shapes inherent to tool-use

Limb dominance is a human behavioral characteristic with many cultural, practical, scientific and clinical implications. Yet why the dominant limb performs better across a range of motor skill-requiring tasks remains unanswered. Is it because of an intrinsic hemispheric advantage or instead is it the result of life-long practice with the dominant side? We tested these alternatives using two tasks. The first was 3D reaching with either an inertial challenge or the need to use a stick-like tool. The second required participants to write with their dominant and non-dominant elbows. We applied a novel geometric analysis to quantify movement-trajectory shape. We show that (1) tool-use unmasks markedly inferior control in the non-dominant arm, and this is because tools impose the need to generate unfamiliarly shaped movement trajectories; and (2) there is no general dominant limb motor control advantage, only task-specific experience or practice. These results reframe dominance as predominantly about learned control of tool kinematics rather than baseline asymmetry in control of limb dynamics.

neuroscience↗

bioRxiv2025

Kinematic Dissection of Arm Paresis after Focal New M1, Old M1 and Red Nucleus Lesions in Non-Human Primates

Cortical and subcortical lesions to the motor system, as often occur with stroke, typically lead to transitions through a stereotyped upper limb recovery sequence. After initial weakness and loss of dexterity, spasticity and fixed muscle coactivation patterns (synergies) appear. Early work suggested that different features arise from distinct primary motor cortex (M1) subdivisions. Here we investigated this with modern methods, using ischemic lesions of various cortical areas and electrocoagulation lesions of magnocellular red nucleus (RNm) in rhesus monkeys. Nine animals were trained on a reach and grasp task; hand kinematics were assessed with markerless tracking. The proportion of damaged cortical layer V cells in each cortical area was quantified, and corresponding kinematic effects evaluated. Reaching speed showed greater and more persistent reductions with larger lesions to the posterior part of M1 on the gyrus (Posterior Old M1 in Stricks terminology). Initial increases in trajectory variability were more consistent with greater damage within the central sulcus (New M1); these partially recovered. Lesions involving Anterior Old M1 (Area 4s in Hines terminology) had no additive negative effects. An extensive cortical lesion, which combined New and Old M1 with pre-motor and somatosensory cortex damage did not produce a worse or more persistent deficit than lesions limited to M1, suggesting that loss of arm control arose mainly from damage to descending pathways rather than cortico-cortical interactions. Lesions of RNm led to long-lasting slowing of reach, but no increase in variability. Subsequent cortical lesions to Old M1 led to more severe effects, and worse recovery, than without the preceding RNm lesion. This suggests an important neural compensatory role for the rubrospinal tract following cortical damage in monkey, which is not available in humans where the rubrospinal tract is vestigial. None of the lesions investigated led to overt abnormal synergies. The results are consistent with known differences in descending connections from each area: New M1 has fast cortico-motoneuronal output, known to be important for fine motor control (here assessed by trajectory variability); Old M1 has cortico-reticular connections able to activate the reticulospinal tract, important for generating the high forces needed for fast movements.

neuroscience↗

bioRxiv2025

A spinal origin for the obligate flexor synergy in the non-human primate: Implications for control of reaching

Stroke survivors frequently develop the flexor synergy, an obligate co-contraction of shoulder abductors and elbow flexors; the neural substrate has proven elusive. Here we trained healthy monkeys to generate isometric elbow and shoulder torques to move an on-screen cursor, and recorded neuron firing from motor cortical areas and the reticular formation. In all regions we found cells correlated with activity around a single joint. Neurons coding co-contractions showed a bias towards combinations orthogonal to the post-stroke flexor synergy, e.g. shoulder abduction with elbow extension. Threshold microstimulation in the spinal cord but not in either motor cortex or the reticular formation generated coactivation aligned to the flexor synergy. We suggest the evolution of prehension required descending systems either to control or bypass locomotion-dedicated spinal circuits. Loss of descending input after stroke constrains the upper limb to spinal synergies best suited to primitive locomotor functions.

neuroscience↗

bioRxiv2023

Continuous motor skills as flexible control policies: a video game study

Many motor skills consist of continuous sequential actions, such as a tennis serve. It is currently unclear how these surprisingly understudied behaviors are learned, with the leading hypothesis being that sequences of single actions become "chunked" into larger single executable units. Under this hypothesis, continuous sequential actions should become more task-specific and less generalizable with practice. To test this, we developed a video game that requires participants to hold a tablet with both hands and steer a virtual car (the "ant car") along a curving track. We tested participants ability to generalize their skill to a probe track that required a different sequence of turns. Across days of practice, task success increased, and movement variability decreased. On the probe track, movement quality at the level of kinematics fully generalized but performance at the level of task success showed a consistent decrement. To address this apparent paradox, we empirically derived the control policy participants used at their maximal skill level on the training track. Notably, this policy was fully transferred to the probe track, but there were more instances of momentary deviations from it (lapses), which explains the worse performance despite equivalent skill. We conclude that continuous motor skills are acquired through learning of a flexible control policy that maps states onto actions and not through chunking or automatizing of a specific sequence of actions.

neuroscience↗

bioRxiv2023

Loss of finger control complexity and intrusion of flexor biases are dissociable in finger individuation impairment after stroke

The ability to control each finger independently is an essential component of human hand dexterity. A common observation of hand function impairment after stroke is the loss of this finger individuation ability, often referred to as enslavement, i.e., the unwanted coactivation of non-intended fingers in individuated finger movements. In the previous literature, this impairment has been attributed to several factors, such as the loss of corticospinal drive, an intrusion of flexor synergy due to upregulations of the subcortical pathways, and/or biomechanical constraints. These factors may or may not be mutually exclusive and are often difficult to tease apart. It has also been suggested, based on a prevailing impression, that the intrusion of flexor synergy appears to be an exaggerated pattern of the involuntary coactivations of task-irrelevant fingers seen in a healthy hand, often referred to as a flexor bias. Most previous studies, however, were based on assessments of enslavement in a single dimension (i.e., finger flexion/extension) that coincide with the flexor bias, making it difficult to tease apart the other aforementioned factors. Here, we set out to closely examine the nature of individuated finger control and finger coactivation patterns in all dimensions. Using a novel measurement device and a 3D finger-individuation paradigm, we aim to tease apart the contributions of lower biomechanical, subcortical constraints, and top-down cortical control to these patterns in both healthy and stroke hands. For the first time, we assessed all five fingers full capacity for individuation. Our results show that these patterns in the healthy and paretic hands present distinctly different shapes and magnitudes that are not influenced by biomechanical constraints. Those in the healthy hand presented larger angular distances that were dependent on top-down task goals, whereas those in the paretic hand presented larger Euclidean distances that arise from two dissociable factors: a loss of complexity in finger control and the dominance of an intrusion of flexor bias. These results suggest that finger individuation impairment after stroke is due to two dissociable factors: the loss of finger control complexity present in the healthy hand reflecting a top-down neural control strategy and an intrusion of flexor bias likely due to an upregulation of subcortical pathways. Our device and paradigm are demonstrated to be a promising tool to assess all aspects of the dexterous capacity of the hand.

neuroscience↗

bioRxiv2022

Independence and interaction between the control of moving and holding still in post-stroke arm paresis

Moving and holding-still (holding) have been posited to be under separate control regimes for both eye and arm movements. The paretic arm after stroke exhibits different abnormalities during rest vs. movement, providing an opportunity to ask whether control of these behaviors is independently affected in stroke. Here, we quantified resting postural abnormalities in stroke patients by measuring their biases in force production as they held their hand still in various locations in a planar workspace, and then assessed the influence of these resting force biases on reaching in the same workspace. We found that patients had marked resting force biases at each location, even when the arm was supported. However, these biases did not transfer to arm-supported planar reaching movements: not during initial acceleration, not in response to mid-trajectory perturbations, and not during deceleration to a stop. Rather, the abnormal resting forces only appeared to switch on after a movement had fully stopped. These findings suggest that moving and holding are functionally separable modes of control. At the same time, we found that the resting biases mirrored characteristics of abnormal synergies during movement: they markedly decreased when arm support was provided; they were higher in more distant positions that require breaking out of flexion; and they scaled with the Fugl-Meyer score for the upper extremity (a measure of intrusion of abnormal synergies during active movement). These three shared features suggest a common mechanism for resting biases and abnormal synergies, which appears to be a contradiction given the functional separation of moving and holding observed in the same patients. To resolve this paradox, we propose a conceptual model that predicts a breakdown in the functional separation between reaching and holding when patients move in the absence of weight support. This conceptual model posits that synergies are the behavioral manifestation of a spillover of posture into movement. Mapping these functional systems onto anatomical and physiological details of lesioned substrate after stroke may provide implementation-level insight into how normal arm motor control is assembled.

neuroscience↗

bioRxiv2021

Black-box testing in motor sequence learning

During learning of novel motor sequences, practice leads to the consolidation of hierarchical structures, namely motor chunks, facilitating the accurate execution of sequences at increasing speeds. Recent studies show that such hierarchical structures are largely represented upstream of the primary motor cortex in the motor network, suggesting their function to be more related to the encoding, storage, and retrieval of sequences rather than their sole execution. We isolated different components of motor skill acquisition related to the consolidation of spatiotemporal features and followed their evolution over training. We found that optimal motor skill acquisition relies on the storage of the spatial features of the sequence in memory, followed by the optimization of its execution and increased execution speeds (i.e., a shift in the speed-accuracy trade-off) early in training, supporting the model proposed by Hikosaka in 1999. Contrasting the dynamics of these components during ageing, we identified less-than-optimal mechanisms in older adults explaining the observed differences in performance. We applied noninvasive brain stimulation in an attempt to support the aging brain to compensate for these deficits. The present study found that anodal direct current stimulation applied over the motor cortex restored the mechanisms involved in the consolidation of spatial features, without directly affecting the speed of execution of the sequence. This led older adults to sharply improve their accuracy, resulting in an earlier yet gradual emergence of motor chunks. The results suggest the early storage of the sequence in memory, largely independent of motor practice, is crucial for an optimal motor acquisition and retrieval of this motor behavior. Nevertheless, the consolidation of optimal temporal patterns, detected as motor chunks at a behavioral level, is not a direct consequence of storing the sequence elements, but rather of motor practice.

neuroscience↗

bioRxiv2021

The proportional recovery rule redux: Arguments for its biological and predictive relevance

The proportional recovery rule (PRR) posits that most stroke survivors can expect to reduce a fixed proportion of their motor impairment. As a statistical model, the PRR explicitly relates change scores to baseline values - an approach that has the potential to introduce artifacts and flawed conclusions. We describe approaches that can assess associations between baseline and changes from baseline while avoiding artifacts due either to mathematical coupling or regression to the mean due to measurement error. We also describe methods that can compare different biological models of recovery. Across several real datasets, we find evidence for non-artifactual associations between baseline and change, and support for the PRR compared to alternative models. We conclude that the PRR remains a biologically-relevant model of recovery, and also introduce a statistical perspective that can be used to assess future models.

neuroscience↗

bioRxiv2020

Competition between parallel sensorimotor learning systems

Sensorimotor adaptation benefits from learning in two parallel systems: one that has access to explicit knowledge, and another that relies on implicit, unconscious correction. However, it is unclear how these systems interact: does enhancing one systems contributions, for example through instruction, impair the other, or do they learn independently? Here we illustrate that certain contexts can lead to competition between implicit and explicit learning. In some cases, each system is responsive to a task-related visual error. This shared error appears to create competition between these systems, such that when the explicit system increases its response, errors are siphoned away from the implicit system, thus reducing its learning. This model suggests that explicit strategy can mask changes in implicit error sensitivity related to savings and interference. Other contexts suggest that the implicit system can respond to multiple error sources. When these error sources conflict, a second type of competition occurs. Thus, the data show that during sensorimotor adaptation, behavior is shaped by competition between parallel learning systems.

neuroscience↗

bioRxiv2020

Implicit adaptation is driven by direct policy updates rather than forward-model-based learning

The human motor system can rapidly adapt its motor output in response to errors. The prevailing theory of this process posits that the motor system adapts an internal forward model that predicts the consequences of outgoing motor commands, and that this forward model is then used to guide selection of motor output. However, although there is clear evidence for the existence of adaptive forward models to help track the state of the body, there is no real evidence that such models influence the selection of motor output. A possible alternative to the forward-model-based theory of adaptation is that motor output could be directly adjusted by movement errors ("direct policy learning"), in parallel with but independent of any updates to a predictive forward model. Here, we show evidence for this latter theory based on the properties of implicit adaptation under mirror-reversed visual feedback. We show that implicit adaptation still occurs under this extreme perturbation but acts in an inappropriate direction, following a pattern consistent with direct policy learning but not forward-model-based learning. We suggest that the forward-model-based theory of adaptation needs to be re-examined and that direct policy learning is a more plausible mechanism of implicit adaptation.

neuroscience↗

bioRxiv2019

No evidence for motor recovery-related cortical reorganization after stroke using resting-state fMRI

Cortical reorganization has been suggested as mechanism for recovery after stroke. It has been proposed that a form of cortical reorganization (changes in functional connectivity between brain areas) can be assessed with resting-state fMRI. Here we report the largest longitudinal data-set in terms of overall sessions in 19 patients with subcortical stroke and 11 controls. Patients were imaged up to 5 times over one year. We found no evidence for post-stroke cortical reorganization despite substantial behavioral recovery. These results could be construed as questioning the value of resting-state imaging. Here we argue instead that they are consistent with other emerging reasons to challenge the idea of motor recovery-related cortical reorganization post-stroke when conceived as changes in connectivity between cortical areas.

neuroscience↗

bioRxiv2019

Holding the arm still through subcortical mathematical integration of cortical commands

A period of holding still follows every movement. It has been assumed that for the arm, moving and holding are functionally independent: movement is via an adaptive, feedback-dependent controller that generates commands to transport the arm, while holding is via setting of reflexes that produce a postural field at movement endpoint. This assumption predicts that commands that move the arm should not affect the postural field at movement termination. Surprisingly, we found that as the reach commands changed, so did the ensuing postural field. The postural commands depended on mathematical integration of the reach commands. Following damage to the corticospinal tract, despite severe reach impairments, the holding system faithfully integrated the imperfect reach commands on a trial-by-trial basis. Together, these findings suggest that holding the arm still is accomplished via a separate, likely subcortical structure that acts as a mathematical integrator of the commands generated by the cortical reach controller.

neuroscience↗

bioRxiv2018

Can patients with cerebellar disease switch learning mechanisms to reduce their adaptation deficits?

Systematic perturbations in motor adaptation tasks are primarily countered by learning from sensory-prediction errors, with secondary contributions from other learning processes. Despite the availability of these additional processes, particularly the use of explicit re-aiming to counteract observed target errors, patients with cerebellar degeneration are surprisingly unable to compensate for their sensory-prediction-error deficits by spontaneously switching to another learning mechanism. We hypothesized that if the nature of the task was changed - by allowing vision of the hand, which eliminates sensory-prediction errors - patients could be induced to preferentially adopt aiming strategies to solve visuomotor rotations. To test this, we first developed a novel visuomotor rotation paradigm that provides participants with vision of their hand in addition to the cursor, effectively setting the sensory-prediction-error signal to zero. We demonstrated in younger healthy controls that this promotes a switch to strategic re-aiming based on target errors. We then showed that with vision of the hand, patients with spinocerebellar ataxia could also switch to an aiming strategy in response to visuomotor rotations, performing similarly to age-matched participants (older controls). Moreover, patients could retrieve their learned aiming solution after vision of the hand was removed, and retain it for at least one year. Both patients and older controls, however, exhibited impaired overall adaptation performance compared to younger healthy controls (age, 18-33), likely due to age-related reductions in spatial and working memory. Moreover, patients failed to generalize, i.e., they were unable to adopt analogous aiming strategies in response to novel rotations, nor could they further improve their performance without vision of the hand. Hence, there appears to be an inescapable obligatory dependence on sensory-prediction-error-based learning - even when this system is impaired in patients with cerebellar degeneration. The persistence of sensory-prediction-error-based learning effectively suppresses a switch to target-error-based learning, which perhaps explains the unexpectedly poor performance by patients with spinocerebellar ataxia in visuomotor adaptation tasks.

neuroscience↗

bioRxiv2018

Movement imitation depends on an abstract trajectory representation in dorsal premotor cortex

Humans are particularly good at copying novel and meaningless gestures. The mechanistic and anatomical basis for this specialized imitation ability remains largely unknown. One idea is that imitation occurs by matching body configurations. Here we propose an alternative route to imitation that depends on a body-independent representation of the trajectory path of the end-effector. We studied a group of patients with strokes in the left frontoparietal cortices. We found that they were equally impaired at imitating movement trajectories using the ipsilesional limb (i.e., the non-paretic side) that were cued either by an actor using their whole arm or just by a cursor, suggesting that body configuration is not always critical for imitation and that a representation of abstract trajectory shape may suffice. In addition, imitation ability was uncorrelated to the ability to identify the trajectory shape, suggesting a dissociation between producing trajectory shapes and perceiving their paths. Finally, a lesion-symptom mapping analysis found that imitation deficits were associated with lesions in left dorsal premotor but not parietal cortex. Together, these findings suggest a novel body-independent route to imitation that relies on the ability to plan abstract movement trajectories within dorsal premotor cortex.\n\nSignificance StatementThe ability to imitate is critical for rapidly learning to produce new gestures and actions, but how the brain translates observed movements into motor commands is poorly understood. Examining the ability of patients with strokes affecting the left hemisphere revealed that meaningless gestures can be imitated by succinctly representing only the motion of the hand in space, rather than the posture of the entire arm. Moreover, performance deficits correlated with lesions in dorsal premotor cortex, an area not previously associated with impaired imitation of arm postures. These findings thus describe a novel route to imitation that may also be impaired in some patients with apraxia.

neuroscience↗