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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.

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.

Abstract 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.

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.

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.

Abstract 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.

Abstract Chemotherapy agents used in the standard treatments for many types of cancer are neurotoxic and can lead to lasting sensory and motor symptoms that compromise day-to-day movement functions in cancer survivors. To date, the details of movement disorders associated with chemotherapy are known largely through self-reported symptoms and functional limitations. There are few quantitative studies of specific movement deficits, limiting our understanding of dysfunction, as well as effective assessments and interventions. The aim of this narrative review is to consolidate the current understanding of sensorimotor disabilities based on quantitative measures in cancer survivors who received chemotherapy. We performed literature searches on PubMed and found 32 relevant movement studies. We categorized these studies into three themes based on the movement deficits investigated: (1) balance and postural control; (2) gait function; (3) upper limb function. This literature suggests that cancer survivors have increased postural sway, more conservative gait patterns, and suboptimal hand function compared to healthy individuals. More studies are needed that use objective measures of sensorimotor function to better characterize movement disabilities and investigate the underlying causes, as required for developing targeted assessments and interventions. By updating our understanding of movement impairments in this population, we identify significant gaps in knowledge that will help guide the direction of future research.

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.

Muscle activation helps stabilize the glenohumeral joint and prevent dislocations, which are more common at the shoulder than at any other human joint. Feedforward control of shoulder muscles is important for protecting the glenohumeral joint from harm caused by anticipated external perturbations. However, dislocations are frequently caused by unexpected perturbations for which feedback control is essential. Stretch-evoked reflexes elicited by translations of the glenohumeral joint may therefore be an important mechanism for maintaining joint integrity, yet little is known about them. Specifically, reflexes elicited by glenohumeral translations have only been studied under passive conditions, and there have been no investigations of how responses are coordinated across the functional groupings of muscles found at the shoulder. Our objective was to characterize stretch-evoked reflexes elicited by translations of the glenohumeral joint while shoulder muscles are active. We aimed to determine how these responses differ between the rotator cuff muscles, which are essential for maintaining glenohumeral stability, and the primary shoulder movers, which are essential for the large mobility of this joint. We evoked reflexes using anterior and posterior translations of the humeral head while participants produced voluntary isometric torque in six directions spanning the three rotational degrees-of-freedom about the shoulder. Electromyograms were used to measure the stretch-evoked reflexes elicited in nine shoulder muscles. We found that reflex amplitudes were larger in the rotator cuff muscles than in the primary shoulder movers, in part due to increased background activation during torque generation but more so due to an increased scaling of reflex responses with background activation. The reflexes we observed likely arose from the diversity of proprioceptors within the muscles and in the passive structures surrounding the shoulder. The large reflexes observed in the rotator cuff muscles suggest that feedback control of the rotator cuff augments the feedforward control that serves to compress the humeral head into the glenoid. This coordination may serve to stabilize the shoulder rapidly when preparing for and responding to unexpected disturbances.

Prosthetic devices need to be controlled by their users, typically using physiological signals. People tend to look at objects before reaching for them and we have shown that combining eye movements with other continuous physiological signal sources enhances control. This approach suffers when subjects also look at non-targets, a problem we addressed with a probabilistic mixture over targets where subject gaze information is used to identify target candidates. However, this approach would be ineffective if a user wanted to move towards targets that have not been foveated. Here we evaluated how the accuracy of prior target information influenced decoding accuracy, as the availability of neural control signals was varied. We also considered a mixture model where we assumed that the target may be foveated or, alternatively, that the target may not be foveated. We tested the accuracy of the models at decoding natural reaching data, and also in a closed-loop robot-assisted reaching task. The mixture model worked well in the face of high target uncertainty. Furthermore, errors due to inaccurate target information were reduced by including a generic model that relied on neural signals only.

One theory for how humans control movement is that muscles are activated in weighted groups or synergies. Studies have shown that electromyography (EMG) from a variety of tasks can be described by a low-dimensional space thought to reflect synergies. These studies use algorithms, such as nonnegative matrix factorization, to identify synergies from EMG. Due to experimental constraints, EMG can rarely be taken from all muscles involved in a task. However, it is unclear if the choice of muscles included in the analysis impacts estimated synergies. The aim of our study was to evaluate the impact of the number and choice of muscles on synergy analyses. We used a musculoskeletal model to calculate muscle activations required to perform an isometric upper-extremity task. Synergies calculated from the activations from the musculoskeletal model were similar to a prior experimental study. To evaluate the impact of the number of muscles included in the analysis, we randomly selected subsets of between 5 and 29 muscles and compared the similarity of the synergies calculated from each subset to a master set of synergies calculated from all muscles. We determined that the structure of synergies is dependent upon the number and choice of muscles included in the analysis. When five muscles were included in the analysis, the similarity of the synergies to the master set was only 0.57 ± 0.54; however, the similarity improved to over 0.8 with more than ten muscles. We identified two methods, selecting dominant muscles from the master set or selecting muscles with the largest maximum isometric force, which significantly improved similarity to the master set and can help guide future experimental design. Analyses that included a small subset of muscles also over-estimated the variance accounted for (VAF) by the synergies compared to an analysis with all muscles. Thus, researchers should use caution using VAF to evaluate synergies when EMG is measured from a small subset of muscles.

The human motor system is highly redundant, having more kinematic degrees of freedom than necessary to complete a given task. Understanding how kinematic redundancies are utilized in different tasks remains a fundamental question in motor control. One possibility is that they can be used to tune the mechanical properties of a limb to the specific requirements of a task. For example, many tasks such as tool usage compromise arm stability along specific directions. These tasks only can be completed if the nervous system adapts the mechanical properties of the arm such that the arm, coupled to the tool, remains stable. The purpose of this study was to determine if posture selection is a critical component of endpoint stiffness regulation during unconstrained tasks.Three-dimensional (3D) estimates of endpoint stiffness were used to quantify limb mechanics. Most previous studies examining endpoint stiffness adaptation were completed in 2D using constrained postures to maintain a non-redundant mapping between joint angles and hand location. Our hypothesis was that during unconstrained conditions, subjects would select arm postures that matched endpoint stiffness to the functional requirements of the task. The hypothesis was tested during endpoint tracking tasks in which subjects interacted with unstable haptic environments, simulated using a 3D robotic manipulator. We found that arm posture had a significant effect on endpoint tracking accuracy and that subjects selected postures that improved tracking performance. For environments in which arm posture had a large effect on tracking accuracy, the self-selected postures oriented the direction of maximal endpoint stiffness towards the direction of the unstable haptic environment.These results demonstrate how changes in arm posture can have a dramatic effect on task performance and suggest that postural selection is a fundamental mechanism by which kinematic redundancies can be exploited to regulate arm stiffness in unconstrained tasks.

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.

# Background Clinicians of many specialties within sports medicine care for athletes with shoulder instability, but successful outcomes are inconsistent. Consistency across specialties in the diagnosis of shoulder instability is critical for care of the athlete, yet the extent of divergence in its diagnosis is unknown. # Hypothesis Physicians differ from rehabilitation providers in which findings they deem clinically important to differentiate shoulder instability from impingement, and in how they diagnose athlete scenarios with atraumatic shoulder instability. # Study Design Cross-sectional study. # Methods Physicians (orthopaedic surgeons, primary care sports medicine physicians) and rehabilitation providers (physical therapists, athletic trainers) were asked via an online survey to rate clinical factors used to diagnose shoulder instability. Clinicians were also asked to diagnose two athlete scenarios with concurrent clinical findings of atraumatic shoulder instability and impingement, differentiated by the absence or presence of a positive sulcus sign. # Results Responses were recorded from 888 clinicians. Orthopaedic surgeons (N=170) and primary care sports medicine physicians (N=108) ranked physical examination factors as more important for the diagnosis of shoulder instability than patient history factors, whereas physical therapists (N=379) and athletic trainers (N=231) preferred patient history factors. Orthopaedic surgeons differed from physical therapists and athletic trainers in their clinical diagnoses for both scenarios (*P*≤0.001). # Conclusion A lack of consistency exists among sports medicine clinicians in recognizing which clinical factors are important when used to diagnose shoulder instability and in diagnoses given with concurrent findings of impingement. # Level of Evidence Level 3.

The ability of the classic startle reflex to evoke voluntarily prepared movement involuntarily has captured the attention of neuroscientists for its wide-ranging functional utility and potential uses in patient populations. To date, there is only one documented task resistant to the startReact phenomenon-index finger abduction. Previous reports have suggested the lack of startReact is due to different neural mechanisms driving individuated finger movement and more proximal joint control (e.g. elbow, wrist movement). However, an alternative hypothesis exists. Though not particularly difficult to execute, isolated index finger abduction is rarely performed during activities of daily living and is not a natural correlate to common individuated finger tasks. We propose that startReact can be evoked during individuated finger movements but only during tasks that are highly trained or familiar. The objective of this study was to determine the impact of a 2-week training regimen on the ability to elicit startReact. We found evidence in support of our hypothesis that following training, individuated movements of the hands (specifically index finger abduction) become susceptible to startReact. This is significant not only because it indicates that individuated finger movements are in fact amenable to startReact, but also that startle has differential response characteristics in novel tasks compared to highly trained tasks suggesting that startle is a measurable behavioral indicator of motor learning.

The biceps or the posterior deltoid can be transferred to improve elbow extension function for many individuals with C5 or C6 quadriplegia. Maximum strength after elbow reconstruction is variable; the patient's ability to voluntarily activate the transferred muscle to extend the elbow may contribute to the variability. We compared voluntary activation during maximum isometric elbow extension following biceps transfer (n = 5) and deltoid transfer (n = 6) in three functional postures. Voluntary activation was computed as the elbow extension moment generated during maximum voluntary effort divided by the moment generated with full activation, which was estimated via electrical stimulation. Voluntary activation was on average 96% after biceps transfer and not affected by posture. Individuals with deltoid transfer demonstrated deficits in voluntary activation, which differed by posture (80% in horizontal plane, 69% in overhead reach, and 70% in weight-relief), suggesting inadequate motor re-education after deltoid transfer. Overall, individuals with a biceps transfer better activated their transferred muscle than those with a deltoid transfer. This difference in neural control augmented the greater force-generating capacity of the biceps leading to increased elbow extension strength after biceps transfer (average 9.37 N-m across postures) relative to deltoid transfer (average 2.76 N-m across postures) in our study cohort.

Loss of hand use is considered by many spinal cord injury survivors to be the most devastating consequence of their injury. Functional electrical stimulation (FES) of forearm and hand muscles has been used to provide basic, voluntary hand grasp to hundreds of human patients. Current approaches typically grade pre-programmed patterns of muscle activation using simple control signals, such as those derived from residual movement or muscle activity. However, the use of such fixed stimulation patterns limits hand function to the few tasks programmed into the controller. In contrast, we are developing a system that uses neural signals recorded from a multi-electrode array implanted in the motor cortex; this system has the potential to provide independent control of multiple muscles over a broad range of functional tasks. Two monkeys were able to use this cortically controlled FES system to control the contraction of four forearm muscles despite temporary limb paralysis. The amount of wrist force the monkeys were able to produce in a one-dimensional force tracking task was significantly increased. Furthermore, the monkeys were able to control the magnitude and time course of the force with sufficient accuracy to track visually displayed force targets at speeds reduced by only one-third to one-half of normal. Although these results were achieved by controlling only four muscles, there is no fundamental reason why the same methods could not be scaled up to control a larger number of muscles. We believe these results provide an important proof of concept that brain-controlled FES prostheses could ultimately be of great benefit to paralyzed patients with injuries in the mid-cervical spinal cord.