Grand Challenges at the Interface of Engineering and Medicine.

Over the past two decades Biomedical Engineering has emerged as a major discipline that bridges societal needs of human health care with the development of novel technologies. Every medical institution is now equipped at varying degrees of sophistication with the ability to monitor human health in both non-invasive and invasive modes. The multiple scales at which human physiology can be interrogated provide a profound perspective on health and disease. We are at the nexus of creating "avatars" (herein defined as an extension of "digital twins") of human patho/physiology to serve as paradigms for interrogation and potential intervention. Motivated by the emergence of these new capabilities, the IEEE Engineering in Medicine and Biology Society, the Departments of Biomedical Engineering at Johns Hopkins University and Bioengineering at University of California at San Diego sponsored an interdisciplinary workshop to define the grand challenges that face biomedical engineering and the mechanisms to address these challenges. The Workshop identified five grand challenges with cross-cutting themes and provided a roadmap for new technologies, identified new training needs, and defined the types of interdisciplinary teams needed for addressing these challenges. The themes presented in this paper include: 1) accumedicine through creation of avatars of cells, tissues, organs and whole human; 2) development of smart and responsive devices for human function augmentation; 3) exocortical technologies to understand brain function and treat neuropathologies; 4) the development of approaches to harness the human immune system for health and wellness; and 5) new strategies to engineer genomes and cells.

External Rotation Strength After TSA in Osteoarthritic Shoulders with Eccentric Deformity Is Not Impacted by Posterior Rotator Cuff Deficiency.

Background: Patients with persistent glenohumeral osteoarthritis symptoms despite nonoperative management may pursue anatomic total shoulder arthroplasty (TSA). TSA revision rates are higher in patients with preoperative eccentric (asymmetric posterior erosion) compared with concentric (symmetric) glenoid deformity. If posterior rotator cuff deficiency demonstrated preoperatively in patients with eccentric deformity persists after TSA, it may manifest as relative weakness in external compared with internal rotation secondary to deficient activity of the shoulder external rotator muscles. Persistent posterior rotator cuff deficiency is hypothesized to contribute to TSA failures. However, it remains unknown whether rotational strength is impaired after TSA in patients with eccentric deformity. Our goal was to determine if patients with eccentric deformity exhibit relative external rotation weakness that may be explained by posterior rotator cuff deficiency after TSA. Methods: Patients who were >1 year after TSA for primary glenohumeral osteoarthritis and had had preoperative eccentric or concentric deformity were prospectively recruited. Torque was measured and electromyography was performed during maximal isometric contractions in 26 three-dimensional direction combinations. Relative strength in opposing directions (strength balance) and muscle activity of 6 shoulder rotators were compared between groups. Results: The internal (+) and external (-) rotation component of strength balance did not differ in patients with eccentric (mean internal-external rotation component of strength balance: -7.6% ± 7.4%) compared with concentric deformity (-10.3% ± 6.8%) (mean difference: 2.7% [95% confidence interval (CI), -1.3% to 6.7%]; p = 0.59), suggesting no relative external rotation weakness. Infraspinatus activity was reduced in patients with eccentric (43.9% ± 10.4% of maximum voluntary contraction [MVC]) compared with concentric (51.3% ± 10.4% of MVC) deformity (mean difference: -7.4% [95% CI, -13.4% to -1.4%] of MVC; p = 0.04). Conclusions: A relative external rotation strength deficit following TSA was not found, despite evidence of reduced infraspinatus activity, in the eccentric-deformity group. Reduced infraspinatus activity suggests that posterior rotator cuff deficiencies may persist following TSA in patients with eccentric deformities. Longitudinal study is necessary to evaluate muscle imbalance as a contributor to higher TSA failure rates. Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

The Simultaneous Model-Based Estimation of Joint, Muscle, and Tendon Stiffness is Highly Sensitive to the Tendon Force-Strain Relationship.

OBJECTIVE: Accurate estimation of stiffness across anatomical levels (i.e., joint, muscle, and tendon) in vivo has long been a challenge in biomechanics. Recent advances in electromyography (EMG)-driven musculoskeletal modeling have allowed the non-invasive estimation of stiffness during dynamic joint rotations. Nevertheless, validation has been limited to the joint level due to a lack of simultaneous in vivo experimental measurements of muscle and tendon stiffness. METHODS: With a focus on the triceps surae, we employed a novel perturbation-based experimental technique informed by dynamometry and ultrasonography to derive reference stiffness at the joint, muscle, and tendon levels simultaneously. Here, we propose a new EMG-driven model-based approach that does not require external joint perturbation, nor ultrasonography, to estimate multi-level stiffness. We present a novel set of closed-form equations that enables the person-specific tuning of musculoskeletal parameters dictating biological stiffness, including passive force-length relationships in modeled muscles and tendons. RESULTS: Calibrated EMG-driven musculoskeletal models estimated the reference data with average normalized root-mean-square error ≈ 20%. Moreover, only when calibrated tendons were approximately four times more compliant than typically modeled, our approach could estimate multi-level reference stiffness. CONCLUSION: EMG-driven musculoskeletal models can be calibrated on a larger set of reference data to provide more realistic values for the biomechanical variables across multiple anatomical levels. Moreover, the tendon models that are typically used in musculoskeletal modeling are too stiff. SIGNIFICANCE: Calibrated musculoskeletal models informed by experimental measurements give access to an augmented range of biomechanical variables that might not be easily measured with sensors alone.

At matched loads, aging does not alter ankle, muscle, or tendon stiffness.

Older adults have difficulty maintaining balance when faced with postural disturbances, a task that is influenced by the stiffness of the triceps surae and Achilles tendon. Age-related changes in Achilles tendon stiffness have been reported at matched levels of effort, but measures typically have not been made at matched loads, which is important due to age-dependent changes in strength. Moreover, age-dependent changes in muscle stiffness have yet to be tested. Here, we investigate how age alters muscle and tendon stiffness and their influence on ankle stiffness. We hypothesized that age-related changes in muscle and tendon contribute to reduced ankle stiffness in older adults and evaluated this hypothesis when either load or effort were matched. We used B-mode ultrasound with joint-level perturbations to quantify ankle, muscle, and tendon stiffness across a range of loads and efforts in seventeen healthy younger and older adults. At matched loads, there was no significant difference in ankle, muscle, or tendon stiffness between groups (all p>0.13). However, at matched effort, older adults exhibited a significant decrease in ankle (27%; p=0.008), muscle (37%; p=0.02), and tendon stiffness (22%; p=0.03) at 30% of maximum effort. This is consistent with our finding that older adults were 36% weaker than younger adults in plantarflexion (p=0.004). Together these results indicate that, at the loads tested in this study, there are no age-dependent changes in the mechanical properties of muscle or tendon, only differences in strength that result in altered ankle, muscle, and tendon stiffness at matched levels of effort.

Cancer survivors post-chemotherapy exhibit unimpaired short-latency stretch reflexes in the proximal upper extremity.

Oxaliplatin (OX) chemotherapy can lead to long-term sensorimotor impairments in cancer survivors. The impairments are often thought to be caused by OX-induced progressive degeneration of sensory afferents known as length-dependent dying-back sensory neuropathy. However, recent preclinical work has identified functional defects in the encoding of muscle proprioceptors and in motoneuron firing. These functional defects in the proprioceptive sensorimotor circuitry could readily impair muscle stretch reflexes, a fundamental building block of motor coordination. Given that muscle proprioceptors are distributed throughout skeletal muscle, defects in stretch reflexes could be widespread, including in the proximal region where dying-back sensory neuropathy is less prominent. All previous investigations on chemotherapy-related reflex changes focused on distal joints, leading to results that could be influenced by dying-back sensory neuropathy rather than more specific changes to sensorimotor circuitry. Our study extends this earlier work by quantifying stretch reflexes in the shoulder muscles in 16 cancer survivors and 16 healthy controls. Conduction studies of the sensory nerves in hand were completed to detect distal sensory neuropathy. We found no significant differences in the short-latency stretch reflexes (amplitude and latency) of the shoulder muscles between cancer survivors and healthy controls, contrasting with the expected differences based on the preclinical work. Our results may be linked to differences between the human and preclinical testing paradigms including, among many possibilities, differences in the tested limb or species. Determining the source of these differences will be important for developing a complete picture of how OX chemotherapy contributes to long-term sensorimotor impairments.NEW & NOTEWORTHY Our results showed that cancer survivors after oxaliplatin (OX) treatment exhibited stretch reflexes that were comparable with age-matched healthy individuals in the proximal upper limb. The lack of OX effect might be linked to differences between the clinical and preclinical testing paradigms. These findings refine our expectations derived from the preclinical study and guide future assessments of OX effects that may have been insensitive to our measurement techniques.

Haptic Human-Human Interaction During an Ankle Tracking Task: Effects of Virtual Connection Stiffness.

While treating sensorimotor impairments, a therapist may provide physical assistance by guiding their patient's limb to teach a desired movement. In this scenario, a key aspect is the compliance of the interaction, as the therapist can provide subtle cues or impose a movement as demonstration. One approach to studying these interactions involves haptically connecting two individuals through robotic interfaces. Upper-limb studies have shown that pairs of connected individuals estimate one another's goals during tracking tasks by exchanging haptic information, resulting in improved performance dependent on the ability of one's partner and the stiffness of the virtual connection. In this study, our goal was to investigate whether these findings generalize to the lower limb during an ankle tracking task. Pairs of healthy participants (i.e., dyads) independently tracked target trajectories with and without connections rendered between two ankle robots. We tested the effects of connection stiffness as well as visual noise to manipulate the correlation of tracking errors between partners. In our analysis, we compared changes in task performance across conditions while tracking with and without the connection. We found that tracking improvements while connected increased with connection stiffness, favoring the worse partner in the dyad during hard connections. We modeled the interaction as three springs in series, considering the stiffness of the connection and each partners' ankle, to show that improvements were likely due to a cancellation of random tracking errors between partners. These results suggest a simplified mechanism of improvements compared to what has been reported during upper-limb dyadic tracking.

A motor plan is accessible for voluntary initiation and involuntary triggering at similar short latencies.

Movement goals are an essential component of motor planning, altering voluntary and involuntary motor actions. While there have been many studies of motor planning, it is unclear if motor goals influence voluntary and involuntary movements at similar latencies. The objectives of this study were to determine how long it takes to prepare a motor action and to compare this time for voluntary and involuntary movements. We hypothesized a prepared motor action would influence voluntarily and involuntarily initiated movements at the same latency. We trained subjects to reach with a forced reaction time paradigm and used a startling acoustic stimulus (SAS) to trigger involuntary initiation of the same reaches. The time available to prepare was controlled by varying when one of four reach targets was presented. Reach direction was used to evaluate accuracy. We quantified the time between target presentation and the cue or trigger for movement initiation. We found that reaches were accurately initiated when the target was presented 48 ms before the SAS and 162 ms before the cue to voluntarily initiate movement. While the SAS precisely controlled the latency of movement onset, voluntary reach onset was more variable. We, therefore, quantified the time between target presentation and movement onset and found no significant difference in the time required to plan reaches initiated voluntarily or involuntarily (∆ = 8 ms, p = 0.2). These results demonstrate that the time required to plan accurate reaches is similar regardless of if they are initiated voluntarily or triggered involuntarily. This finding may inform the understanding of neural pathways governing storage and access of motor plans.

Non-linear properties of the Achilles tendon determine ankle impedance over a broad range of activations in humans.

Regulating ankle mechanics is essential for controlled interactions with the environment and rejecting unexpected disturbances. Ankle mechanics can be quantified by impedance, the dynamic relationship between an imposed displacement and the torque generated in response. Ankle impedance in the sagittal plane depends strongly on the triceps surae and Achilles tendon, but their relative contributions remain unknown. It is commonly assumed that ankle impedance is controlled by changing muscle activation and, thereby, muscle impedance, but this ignores that tendon impedance also changes with activation-induced loading. Thus, we sought to determine the relative contributions from the triceps surae and Achilles tendon during conditions relevant to postural control. We used a novel technique that combines B-mode ultrasound imaging with joint-level perturbations to quantify ankle, muscle and tendon impedance simultaneously across activation levels from 0% to 30% of maximum voluntary contraction. We found that muscle and tendon stiffness, the static component of impedance, increased with voluntary plantarflexion contractions, but that muscle stiffness exceeded tendon stiffness at very low loads (21±7 N). Above these loads, corresponding to 1.3% of maximal strength for an average participant in our study, ankle stiffness was determined predominately by Achilles tendon stiffness. At approximately 20% MVC for an average participant, ankle stiffness was 4 times more sensitive to changes in tendon stiffness than to changes in muscle stiffness. We provide the first empirical evidence demonstrating that the nervous system, through changes in muscle activations, leverages the non-linear properties of the Achilles tendon to increase ankle stiffness during postural conditions.

Optimism persists when walking in unpredictable environments.

Humans continuously modulate their control strategies during walking based on their ability to anticipate disturbances. However, how people adapt and use motor plans to create stable walking in unpredictable environments is not well understood. Our purpose was to investigate how people adapt motor plans when walking in a novel and unpredictable environment. We evaluated the whole-body center of mass (COM) trajectory of participants as they performed repetitions of a discrete goal-directed walking task during which a laterally-directed force field was applied to the COM. The force field was proportional in magnitude to forward walking velocity and randomly directed towards either the right or left each trial. We hypothesized that people would adapt a control strategy to reduce the COM lateral deviations created by the unpredictable force field. In support of our hypothesis, we found that with practice the magnitude of COM lateral deviation was reduced by 28% (force field left) and 44% (force field right). Participants adapted two distinct unilateral strategies, implemented regardless of if the force field was applied to the right or to the left, that collectively created a bilateral resistance to the unpredictable force field. These strategies included an anticipatory postural adjustment to resist against forces applied to the left, and a more lateral first step to resist against forces applied to the right. In addition, during catch trials when the force field was unexpectedly removed, participants exhibited trajectories similar to baseline trials. These findings were consistent with an impedance control strategy that provides a robust resistance to unpredictable perturbations. However, we also found evidence that participants made predictive adaptations in response to their immediate experience that persisted for three trials. Due to the unpredictable nature of the force field, this predictive strategy would sometimes result in greater lateral deviations when the prediction was incorrect. The presence of these competing control strategies may have long term benefits by allowing the nervous system to identify the best overall control strategy to use in a novel environment.

Axial stress determines the velocity of shear wave propagation in passive but not active muscles in vivo.

Ultrasound shear wave elastography can be used to characterize mechanical properties of unstressed tissue by measuring shear wave velocity (SWV), which increases with increasing tissue stiffness. Measurements of SWV have often been assumed to be directly related to the stiffness of muscle. Some have also used measures of SWV to estimate stress, since muscle stiffness and stress covary during active contractions, but few have considered the direct influence of muscle stress on SWV. Rather, it is often assumed that stress alters the material properties of muscle, and in turn, shear wave propagation. The objective of this study was to determine how well the theoretical dependency of SWV on stress can account for measured changes of SWV in passive and active muscles. Data were collected from six isoflurane-anesthetized cats; three soleus muscles and three medial gastrocnemius muscles. Muscle stress and stiffness were measured directly along with SWV. Measurements were made across a range of passively and actively generated stresses, obtained by varying muscle length and activation, which was controlled by stimulating the sciatic nerve. Our results show that SWV depends primarily on the stress in a passively stretched muscle. In contrast, the SWV in active muscle is higher than would be predicted by considering only stress, presumably due to activation-dependent changes in muscle stiffness. Our results demonstrate that while SWV is sensitive to changes in muscle stress and activation, there is not a unique relationship between SWV and either of these quantities when considered in isolation.NEW & NOTEWORTHY Ultrasound shear wave elastography may be an inexpensive way to measure muscle stress in passive muscle. Here, using a cat model we directly measured shear wave velocity (SWV), muscle stress, and muscle stiffness. Our results show that SWV depends primarily on the stress in a passively stretched muscle. In contrast, the SWV in active muscle is higher than would be predicted by considering only stress, presumably due to activation-dependent changes in muscle stiffness.

Effect of Dyadic Haptic Collaboration on Ankle Motor Learning and Task Performance.

Optimizing skill acquisition during novel motor tasks and regaining lost motor functions have been the interest of many researchers over the past few decades. One approach shown to accelerate motor learning involves haptically coupling two individuals through robotic interfaces. Studies have shown that an individual's solo performance during upper-limb tracking tasks may improve after haptically-coupled training with a partner. In this study, our goal was to investigate whether these findings can be translated to lower-limb motor tasks, more specifically, during an ankle position tracking task. Using one-degree-of-freedom ankle movements, pairs of participants (i.e., dyads) tracked target trajectories independently. Participants alternated between tracking trials with and without haptic coupling, achieved by rendering a virtual spring between two ankle rehabilitation robots. In our analysis, we compared changes in task performance across trials while training with and without haptic coupling. The tracking performance of both individuals (i.e., dyadic task performance) improved during haptic coupling, which was likely due to averaging of random errors of the dyadic pair during tracking. However, we found that dyadic haptic coupling did not lead to faster individual learning for the tracking task. These results suggest that haptic coupling between unimpaired individuals may not be an effective method of training ankle movements during a simple, one-degree-of-freedom task.

Short-latency stretch reflexes depend on the balance of activity in agonist and antagonist muscles during ballistic elbow movements.

The spinal stretch reflex is a fundamental building block of motor function, with a sensitivity that varies continuously during movement and when changing between movement and posture. Many have investigated task-dependent reflex sensitivity, but few have provided simple, quantitative analyses of the relationship between the volitional control and stretch reflex sensitivity throughout tasks that require coordinated activity of several muscles. Here, we develop such an analysis and use it to test the hypothesis that modulation of reflex sensitivity during movement can be explained by the balance of activity within agonist and antagonist muscles better than by activity only in the muscle homonymous with the reflex. Subjects completed hundreds of flexion and extension movements as small, pseudorandom perturbations of elbow angle were applied to obtain estimates of stretch reflex amplitude throughout the movement. A subset of subjects performed a postural control task with muscle activities matched to those during movement. We found that reflex modulation during movement can be described by background activity in antagonist muscles about the elbow much better than by activity only in the muscle homonymous to the reflex (P < 0.001). Agonist muscle activity enhanced reflex sensitivity, whereas antagonist activity suppressed it. Surprisingly, the magnitude of these effects was similar, suggesting a balance of control between agonists and antagonists very different from the dominance of sensitivity to homonymous activity during posture. This balance is due to a large decrease in sensitivity to homonymous muscle activity during movement rather than substantial changes in the influence of antagonistic muscle activity.NEW & NOTEWORTHY This study examined the sensitivity of the stretch reflexes elicited in elbow muscles to the background activity in these same muscles during movement and postural tasks. We found a heightened reciprocal control of reflex sensitivity during movement that was not present during maintenance of posture. These results help explain previous discrepancies in reflex sensitivity measured during movement and posture and provide a simple model for assessing their contributions to muscle activity in both tasks.

Stretch reflex gain scaling at the shoulder varies with synergistic muscle activity.

The unique anatomy of the shoulder allows for expansive mobility but also sometimes precarious stability. It has long been suggested that stretch-sensitive reflexes contribute to maintaining joint stability through feedback control, but little is known about how stretch-sensitive reflexes are coordinated between the muscles of the shoulder. The purpose of this study was to investigate the coordination of stretch reflexes in shoulder muscles elicited by rotations of the glenohumeral joint. We hypothesized that stretch reflexes are sensitive to not only a given muscle's background activity but also the aggregate activity of all muscles crossing the shoulder based on the different groupings of muscles required to actuate the shoulder in three rotational degrees of freedom. We examined the relationship between a muscle's background activity and its reflex response in eight shoulder muscles by applying rotational perturbations while participants produced voluntary isometric torques. We found that this relationship, defined as gain scaling, differed at both short and long latencies based on the direction of voluntary torque generated by the participant. Therefore, gain scaling differed based on the aggregate of muscles that were active, not just the background activity in the muscle within which the reflex was measured. Across all muscles, the consideration of torque-dependent gain scaling improved model fits (ΔR2) by 0.17 ± 0.12. Modulation was most evident when volitional torques and perturbation directions were aligned along the same measurement axis, suggesting a functional role in resisting perturbations among synergists while maintaining task performance.NEW & NOTEWORTHY Careful coordination of muscles crossing the shoulder is needed to maintain the delicate balance between the joint's mobility and stability. We provide experimental evidence that stretch reflexes within shoulder muscles are modulated based on the aggregate activity of muscles crossing the joint, not just the activity of the muscle in which the reflex is elicited. Our results reflect coordination through neural coupling that may help maintain shoulder stability during encounters with environmental perturbations.

Frontal plane ankle stiffness increases with axial load independent of muscle activity.

Ankle sprains are the most common musculoskeletal injury, typically resulting from excessive inversion of the ankle. One way to prevent excessive inversion and maintain ankle stability is to generate a stiffness that is sufficient to resist externally imposed rotations. Frontal-plane ankle stiffness increases as participants place more weight on their ankle, but whether this effect is due to muscle activation or axial loading of the ankle is unknown. Identifying whether and to what extent axial loading affects ankle stiffness is important in understanding what role the passive mechanics of the ankle joint play in maintaining its stability. The objective of this study was to determine the effect of passive axial load on frontal-plane ankle stiffness. We had subjects seated in a chair as an axial load was applied to the ankle ranging from 10% to 50% body weight. Small rotational perturbations were applied to the ankle in the frontal plane to estimate stiffness. We found a significant, linear, 3-fold increase in ankle stiffness with axial load from the range of 0% body weight to 50% body weight. This increase could not be due to muscle activity as we observed no significant axial-load-dependent change in any of the recorded muscle activations. These results demonstrate that axial loading is a significant contributor to maintaining frontal-plane ankle stability, and that disruptions to the mechanism mediating this sensitivity of stiffness to axial loading may result in pathological cases of ankle instability.

No Strength Differences Despite Greater Posterior Rotator Cuff Intramuscular Fat in Patients With Eccentric Glenohumeral Osteoarthritis.

BACKGROUND: When nonoperative measures do not alleviate the symptoms of glenohumeral osteoarthritis (OA), patients with advanced OA primarily are treated with anatomic total shoulder arthroplasty (TSA). It is unknown why TSAs performed in patients with eccentric (asymmetric glenoid wear) compared with concentric (symmetric glenoid wear) deformities exhibit higher failure rates, despite surgical advances. Persistent disruption of the posterior-to-anterior rotator cuff (RC) force couple resulting from posterior RC intramuscular degeneration in patients with eccentric deformities could impair external rotation strength and may contribute to eventual TSA failure. Pain and intramuscular fat within the RC muscles may impact external rotation strength measures and are important to consider. QUESTIONS/PURPOSES: (1) Is there relative shoulder external rotation weakness in patients with eccentric compared with concentric deformities? (2) Is there higher resting or torque-dependent pain in patients with eccentric compared with concentric deformities? (3) Do patients with eccentric deformities have higher posterior-to-anterior RC intramuscular fat percent ratios than patients with concentric deformities? METHODS: From February 2020 to November 2021, 65% (52 of 80) of patients with OA met study eligibility criteria. Of these, 63% (33 of 52) of patients enrolled and provided informed consent. From a convenience sample of 21 older adults with no history of shoulder pain, 20 met eligibility criteria as control participants. Of the convenience sample, 18 patients enrolled and provided informed consent. In total for this prospective, cross-sectional study, across patients with OA and control participants, 50% (51 of 101) of participants were enrolled and allocated into the eccentric (n = 16), concentric (n = 17), and control groups (n = 18). A 3-degree-of-freedom load cell was used to sensitively quantify strength in all three dimensions surrounding the shoulder. Participants performed maximal isometric contractions in 26 1-, 2-, and 3-degree-of-freedom direction combinations involving adduction/abduction, internal/external rotation, and/or flexion/extension. To test for relative external rotation weakness, we quantified relative strength in opposing directions (three-dimensional [3D] strength balance) along the X (+adduction/-abduction), Y (+internal/-external rotation), and Z (+flexion/-extension) axes and compared across the three groups. Patients with OA rated their shoulder pain (numerical rating 0-10) before testing at rest (resting pain; response to "How bad is your pain today?") and with each maximal contraction (torque-dependent pain; numerical rating 0-10). Resting and torque-dependent pain were compared between patients with eccentric and concentric deformities to determine if pain was higher in the eccentric group. The RC cross-sectional areas and intramuscular fat percentages were quantified on Dixon-sequence MRIs by a single observer who performed manual segmentation using previously validated methods. Ratios of posterior-to-anterior RC fat percent (infraspinatus + teres minor fat percent/subscapularis fat percent) were computed and compared between the OA groups. RESULTS: There was no relative external rotation weakness in patients with eccentric deformities (Y component of 3D strength balance, mean ± SD: -4.7% ± 5.1%) compared with patients with concentric deformities (-0.05% ± 4.5%, mean difference -4.7% [95% CI -7.5% to -1.9%]; p = 0.05). However, there was more variability in 3D strength balance in the eccentric group (95% CI volume, % 3 : 893) compared with the concentric group (95% CI volume, % 3 : 579). In patients with eccentric compared with concentric deformities, there was no difference in median (IQR) resting pain (1.0 [3.0] versus 2.0 [2.3], mean rank difference 4.5 [95% CI -6.6 to 16]; p = 0.61) or torque-dependent pain (0.70 [3.0] versus 0.58 [1.5], mean rank difference 2.6 [95% CI -8.8 to 14]; p = 0.86). In the subset of 18 of 33 patients with OA who underwent MRI, seven patients with eccentric deformities demonstrated a higher posterior-to-anterior RC fat percent ratio than the 11 patients with concentric deformities (1.2 [0.8] versus 0.70 [0.3], mean rank difference 6.4 [95% CI 1.4 to 11.5]; p = 0.01). CONCLUSION: Patients with eccentric deformities demonstrated higher variability in strength compared with patients with concentric deformities. This increased variability suggests patients with potential subtypes of eccentric wear patterns (posterior-superior, posterior-central, and posterior-inferior) may compensate differently for underlying anatomic changes by adopting unique kinematic or muscle activation patterns. CLINICAL RELEVANCE: Our findings highlight the importance of careful clinical evaluation of patients presenting with eccentric deformities because some may exhibit potentially detrimental strength deficits. Recognition of such strength deficits may allow for targeted rehabilitation. Future work should explore the relationship between strength in patients with specific subtypes of eccentric wear patterns and potential forms of kinematic or muscular compensation to determine whether these factors play a role in TSA failures in patients with eccentric deformities.

Simultaneous Quantification of Ankle, Muscle, and Tendon Impedance in Humans.

OBJECTIVE: Regulating the impedance of our joints is essential for the effective control of posture and movement. The impedance of a joint is governed mainly by the mechanical properties of the muscle-tendon units spanning it. Many studies have quantified the net impedance of joints but not the specific contributions from the muscles and tendons. The inability to quantify both muscle and tendon impedance limits the ability to determine the causes underlying altered movement control associated with aging, neuromuscular injury, and other conditions that have different effects on muscle and tendon properties. Therefore, we developed a technique to quantify joint, muscle, and tendon impedance simultaneously and evaluated this technique at the human ankle. METHODS: We used a single degree of freedom actuator to deliver pseudorandom rotations to the ankle while measuring the corresponding torques. We simultaneously measured the displacement of the medial gastrocnemius muscle-tendon junction with B-mode ultrasound. From these experimental measurements, we were able to estimate ankle, muscle, and tendon impedance using non-parametric system identification. RESULTS: We validated our estimates by comparing them to previously reported measurements of muscle and tendon stiffness, the position-dependent component of impedance, to demonstrate that our technique generates reliable estimates of these properties. CONCLUSION: Our approach can be used to clarify the respective contributions from the muscle and tendon to the net mechanics of a joint. SIGNIFICANCE: This is a critical step forward in the ultimate goal of understanding how muscles and tendons govern ankle impedance during posture and movement.

Leveraging Joint Mechanics Simplifies the Neural Control of Movement.

Behaviors we perform each day, such as manipulating an object or walking, require precise control of the interaction forces between our bodies and the environment. These forces are generated by muscle contractions, specified by the nervous system, and by joint mechanics, determined by the intrinsic properties of the musculoskeletal system. Depending on behavioral goals, joint mechanics might simplify or complicate control of movement by the nervous system. Whether humans can exploit joint mechanics to simplify neural control remains unclear. Here we evaluated if leveraging joint mechanics simplifies neural control by comparing performance in three tasks that required subjects to generate specified torques about the ankle during imposed sinusoidal movements; only one task required torques that could be generated by leveraging the intrinsic mechanics of the joint. The complexity of the neural control was assessed by subjects' perceived difficulty and the resultant task performance. We developed a novel approach that used continuous estimates of ankle impedance, a quantitative description of the joint mechanics, and measures of muscle activity to determine the mechanical and neural contributions to the net ankle torque generated in each task. We found that the torque resulting from changes in neural control was reduced when ankle impedance was consistent with the task being performed. Subjects perceived this task to be easier than those that were not consistent with the impedance of the ankle and were able to perform it with the highest level of consistency across repeated trials. These results demonstrate that leveraging the mechanical properties of a joint can simplify task completion and improve performance.

Cancer survivors post-chemotherapy exhibit unique proprioceptive deficits in proximal limbs.

BACKGROUND: Oxaliplatin (OX) chemotherapy for colorectal cancer is associated with adverse neurotoxic effects that can contribute to long-term sensorimotor impairments in cancer survivors. It is often thought that the sensorimotor impairments are dominated by OX-induced dying-back sensory neuropathy that primarily affects the distal regions of the limb. Recent preclinical studies have identified encoding dysfunction of muscle proprioceptors as an alternative mechanism. Unlike the dying-back sensory neuropathy affecting distal limbs, dysfunction of muscle proprioceptors could have more widespread effects. Most investigations of chemotherapy-induced sensorimotor impairments have considered only the effects of distal changes in sensory processing; none have evaluated proximal changes or their influence on function. Our study fills this gap by evaluating the functional use of proprioception in the shoulder and elbow joints of cancer survivors post OX chemotherapy. We implemented three multidirectional sensorimotor tasks: force matching, target reaching, and postural stability tasks to evaluate various aspects of proprioception and their use. Force and kinematic data of the sensorimotor tasks were collected in 13 cancer survivors treated with OX and 13 age-matched healthy controls. RESULTS: Cancer survivors exhibited less accuracy and precision than an age-matched control group when they had to rely only on proprioceptive information to match force, even for forces that required only torques about the shoulder. There were also small differences in the ability to maintain arm posture but no significant differences in reaching. The force deficits in cancer survivors were significantly correlated with self-reported motor dysfunction. CONCLUSIONS: These results suggest that cancer survivors post OX chemotherapy exhibit proximal proprioceptive deficits, and that the deficits in producing accurate and precise forces are larger than those for producing unloaded movements. Current clinical assessments of chemotherapy-related sensorimotor dysfunction are largely limited to distal symptoms. Our study suggests that we also need to consider changes in proximal function. Force matching tasks similar to those used here could provide a clinically meaningful approach to quantifying OX-related movement dysfunction during and after chemotherapy.

Experimentally quantifying the feasible torque space of the human shoulder.

Daily tasks rely on our ability to generate multi-dimensional shoulder torques. When function is limited, strength assessments are used to identify impairments and guide treatment. However, these assessments are often one-dimensional and limited in their sensitivity to diagnose shoulder pathology. To address these limitations, we have proposed novel metrics to quantify shoulder torque capacity in all directions. To quantify the feasible torque space of the shoulder, we measured maximal volitional shoulder torques in 32 unique directions and fit an ellipsoid model to these data. This ellipsoid model was used to quantify overall strength magnitude, strength balance, and the directions in which participants were strongest and weakest. We used these metrics to characterize three-dimensional shoulder strength in healthy adults and demonstrated their repeatability across days. Finally, using musculoskeletal simulations, we showed that our proposed metrics can distinguish between changes in muscle strength associated with aging or rotator cuff tears and quantified the influence of altered experimental conditions on this diagnostic capacity. Our results demonstrate that the proposed metrics can robustly quantify the feasible torque space of the shoulder and may provide a clinically useful description of the functional capacity of the shoulder in health and disease.

Estimating the dimensionality of the manifold underlying multi-electrode neural recordings.

It is generally accepted that the number of neurons in a given brain area far exceeds the number of neurons needed to carry any specific function controlled by that area. For example, motor areas of the human brain contain tens of millions of neurons that control the activation of tens or at most hundreds of muscles. This massive redundancy implies the covariation of many neurons, which constrains the population activity to a low-dimensional manifold within the space of all possible patterns of neural activity. To gain a conceptual understanding of the complexity of the neural activity within a manifold, it is useful to estimate its dimensionality, which quantifies the number of degrees of freedom required to describe the observed population activity without significant information loss. While there are many algorithms for dimensionality estimation, we do not know which are well suited for analyzing neural activity. The objective of this study was to evaluate the efficacy of several representative algorithms for estimating the dimensionality of linearly and nonlinearly embedded data. We generated synthetic neural recordings with known intrinsic dimensionality and used them to test the algorithms' accuracy and robustness. We emulated some of the important challenges associated with experimental data by adding noise, altering the nature of the embedding of the low-dimensional manifold within the high-dimensional recordings, varying the dimensionality of the manifold, and limiting the amount of available data. We demonstrated that linear algorithms overestimate the dimensionality of nonlinear, noise-free data. In cases of high noise, most algorithms overestimated the dimensionality. We thus developed a denoising algorithm based on deep learning, the "Joint Autoencoder", which significantly improved subsequent dimensionality estimation. Critically, we found that all algorithms failed when the intrinsic dimensionality was high (above 20) or when the amount of data used for estimation was low. Based on the challenges we observed, we formulated a pipeline for estimating the dimensionality of experimental neural data.