Regional and bilateral MRI and gene signatures in facioscapulohumeral dystrophy: implications for clinical trial design and mechanisms of disease progression.

Identifying the aberrant expression of DUX4 in skeletal muscle as the cause of facioscapulohumeral dystrophy (FSHD) has led to rational therapeutic development and clinical trials. Several studies support the use of MRI characteristics and the expression of DUX4-regulated genes in muscle biopsies as biomarkers of FSHD disease activity and progression. We performed lower-extremity MRI and muscle biopsies in the mid-portion of the tibialis anterior (TA) muscles bilaterally in FSHD subjects and validated our prior reports of the strong association between MRI characteristics and expression of genes regulated by DUX4 and other gene categories associated with FSHD disease activity. We further show that measurements of normalized fat content in the entire TA muscle strongly predict molecular signatures in the mid-portion of the TA, indicating that regional biopsies can accurately measure progression in the whole muscle and providing a strong basis for inclusion of MRI and molecular biomarkers in clinical trial design. An unanticipated finding was the strong correlations of molecular signatures in the bilateral comparisons, including markers of B-cells and other immune cell populations, suggesting that a systemic immune cell infiltration of skeletal muscle might have a role in disease progression.

Novel 3D MRI-Based Volumetric Assessment of Rotator Cuff Musculature Demonstrates Stronger Correlation with Preoperative Functional Status When Compared to the Goutallier Grading Scheme.

BACKGROUND: The Goutallier classification (GC) is used to assess fatty atrophy in rotator cuff (RC) tears, yet limitations exist. A battery of 3D-magnetic resonance imaging (MRI) volumetric scores (VS) was developed to provide comprehensive characterization of RC pathology. The purposes of this study were to: (1) Describe the correlation between GC and VS for supraspinatus changes in RC tears, (2) Characterize the chronicity of RC tears using the battery of 12 VS measurements, and (3) Compare GC and VS to determine which method most closely corresponds with preoperative patient reported outcome measures (PROMs). METHODS: Preoperative shoulder MRIs were reviewed after arthroscopic RC repair. Preoperative GC stage and Patient-Reported Outcomes Measurement Information System (PROMIS) physical function (PF) and pain interference (PI) scores were collected. The battery of VS included fat infiltration (FIS), muscle size (MSS) and relative volume contribution (RCS) for each RC muscle. Backwards linear regression was performed to compare GC stage with preoperative PROMIS PF/PI to determine which VS measurement most closely correlated with preoperative PROMs. RESULTS: Eighty-two patients underwent RC repair (mean age 55±8.2 years, 63% male, 68% GC stage ≤1). In evaluation of the supraspinatus, there was a moderate positive correlation between GC and FIS (r = 0.459, p < 0.001); strong negative correlations were observed between MSS (r = -0.800, p < 0.001) and RCS (r = -0.745, p < 0.001) when compared to GC. A negligible linear correlation was observed between GC and preoperative PROMIS PF (r = -0.106, p = 0.343) and PI (r = -0.071, p = 0.528). On multivariate analysis, subscapularis MSS (beta > 0, p = 0.064) was a positive predictor, and subscapularis FIS (beta < 0, p = 0.137), teres minor MSS (beta < 0, p = 0.141) and FIS (beta < 0, p = 0.070) were negative predictors of preoperative PF (r = 0.343, p = 0.044); while supraspinatus MSS (beta > 0, p = 0.009) and FIS (beta > 0, p = 0.073), teres minor FIS (beta > 0, p = 0.072) and subscapularis FIS (beta > 0, p = 0.065) were positive predictors of preoperative PI (r = 0.410, p = 0.006). CONCLUSION: Although gold standard in evaluation of RC pathology, GC demonstrated negligible correlation with preoperative functional disability. Alternatively, a battery of 3D VS showed strong correlation with GC through a quantitative, comprehensive evaluation of the RC unit including several moderate predictors of preoperative functional disability.

Validity of Inertial Measurement Units to Measure Lower-Limb Kinematics and Pelvic Orientation at Submaximal and Maximal Effort Running Speeds.

Inertial measurement units (IMUs) have been validated for measuring sagittal plane lower-limb kinematics during moderate-speed running, but their accuracy at maximal speeds remains less understood. This study aimed to assess IMU measurement accuracy during high-speed running and maximal effort sprinting on a curved non-motorized treadmill using discrete (Bland-Altman analysis) and continuous (root mean square error [RMSE], normalised RMSE, Pearson correlation, and statistical parametric mapping analysis [SPM]) metrics. The hip, knee, and ankle flexions and the pelvic orientation (tilt, obliquity, and rotation) were captured concurrently from both IMU and optical motion capture systems, as 20 participants ran steadily at 70%, 80%, 90%, and 100% of their maximal effort sprinting speed (5.36 ± 0.55, 6.02 ± 0.60, 6.66 ± 0.71, and 7.09 ± 0.73 m/s, respectively). Bland-Altman analysis indicated a systematic bias within ±1° for the peak pelvic tilt, rotation, and lower-limb kinematics and -3.3° to -4.1° for the pelvic obliquity. The SPM analysis demonstrated a good agreement in the hip and knee flexion angles for most phases of the stride cycle, albeit with significant differences noted around the ipsilateral toe-off. The RMSE ranged from 4.3° (pelvic obliquity at 70% speed) to 7.8° (hip flexion at 100% speed). Correlation coefficients ranged from 0.44 (pelvic tilt at 90%) to 0.99 (hip and knee flexions at all speeds). Running speed minimally but significantly affected the RMSE for the hip and ankle flexions. The present IMU system is effective for measuring lower-limb kinematics during sprinting, but the pelvic orientation estimation was less accurate.

Agent-based model provides insight into the mechanisms behind failed regeneration following volumetric muscle loss injury.

Skeletal muscle possesses a remarkable capacity for repair and regeneration following a variety of injuries. When successful, this highly orchestrated regenerative process requires the contribution of several muscle resident cell populations including satellite stem cells (SSCs), fibroblasts, macrophages and vascular cells. However, volumetric muscle loss injuries (VML) involve simultaneous destruction of multiple tissue components (e.g., as a result of battlefield injuries or vehicular accidents) and are so extensive that they exceed the intrinsic capability for scarless wound healing and result in permanent cosmetic and functional deficits. In this scenario, the regenerative process fails and is dominated by an unproductive inflammatory response and accompanying fibrosis. The failure of current regenerative therapeutics to completely restore functional muscle tissue is not surprising considering the incomplete understanding of the cellular mechanisms that drive the regeneration response in the setting of VML injury. To begin to address this profound knowledge gap, we developed an agent-based model to predict the tissue remodeling response following surgical creation of a VML injury. Once the model was able to recapitulate key aspects of the tissue remodeling response in the absence of repair, we validated the model by simulating the tissue remodeling response to VML injury following implantation of either a decellularized extracellular matrix scaffold or a minced muscle graft. The model suggested that the SSC microenvironment and absence of pro-differentiation SSC signals were the most important aspects of failed muscle regeneration in VML injuries. The major implication of this work is that agent-based models may provide a much-needed predictive tool to optimize the design of new therapies, and thereby, accelerate the clinical translation of regenerative therapeutics for VML injuries.

A Preliminary Study of Anatomical Changes Following the Use of a Pedicled Buccal Fat Pad Flap During Primary Palatoplasty.

OBJECTIVE: The purpose of this study was to examine the surgical impact of the pedicled buccal fat pad (BFP) flap on the levator veli palatini (LVP) muscle and surrounding velopharyngeal (VP) anatomy following primary palatoplasty using magnetic resonance imaging (MRI). DESIGN: Observational, prospective. SETTING: MRI studies were completed at 3 different facilities. All participants with BFP flap were operated on by the same surgeon. PARTICIPANTS: Five pediatric participants with cleft palate with or without cleft lip (CP±L) who underwent primary palatoplasty with BFP flap placement. Comparison groups consisted of 10 participants: 5 with CP±L who did not receive the BFP flap and 5 healthy controls. INTERVENTIONS: All participants underwent nonsedated MRI 2 to 5 years postoperatively. MAIN OUTCOMES AND MEASURES: Anatomical measures of the velopharynx and LVP among the 3 participant groups. RESULTS: Median values were significantly different among groups for velar length (P = .042), effective velar length (P = .048), effective VP ratio (P = .046), LVP length (P = .021), extravelar LVP length (P = .009), and LVP origin-origin distance (P = .030). Post hoc analysis revealed a statistically significant difference between the BFP and traditional repair groups for effective VP ratio (P = .040), extravelar LVP length (P = .033), and LVP length (P = .022). CONCLUSIONS: This study provides preliminary support that the BFP flap creates a longer velum, with increased distance between the posterior hard palate and the LVP, and a larger effective VP ratio compared to traditional surgical techniques. Future research is needed to determine whether this procedure provides a more favorable mechanism for VP closure.

Quantitative Relationships Between Individual Lower-Limb Muscle Volumes and Jump and Sprint Performances of Basketball Players.

Xie, T, Crump, KB, Ni, R, Meyer, CH, Hart, JM, Blemker, SS, and Feng, X. Quantitative relationships between individual lower-limb muscle volumes and jump and sprint performances of basketball players. J Strength Cond Res 34(3): 623-631, 2020-Lower body skeletal muscles play an essential role in athletic performance; however, because of the difficulty in obtaining detailed information of each individual muscle, the quantitative relationships between individual muscle volumes and performance are not well studied. The aim of this study was to accurately measure individual muscle volumes and identify the muscles with strong correlations with jump and sprint performance metrics for basketball players. Ten male varsity basketball players and 8 club players were scanned using magnetic resonance imaging (MRI) and instructed to perform various jump and sprint tests. The volumes of all lower-limb muscles were calculated from MRI and normalized by body surface area to reduce the effect of the body size differences. In analysis, feature selection was first used to identify the most relevant muscles, followed by correlation analysis to quantify the relationships between the selected muscles and each performance metric. Vastus medialis and semimembranosus were found to be the most relevant muscles for jump while adductor longus and vastus medialis were selected for sprint. Strong correlations (r = 0.664-0.909) between the selected muscles and associated performance tests were found for varsity players, and moderate correlations (r = -0.203 to 0.635) were found for club players. One possible application is that for well-trained varsity players, a targeted training scheme focusing on the selected muscles may be an effective method to further improve jump and sprint performances.

Multiscale computational model of Achilles tendon wound healing: Untangling the effects of repair and loading.

Mechanical stimulation of the healing tendon is thought to regulate scar anisotropy and strength and is relatively easy to modulate through physical therapy. However, in vivo studies of various loading protocols in animal models have produced mixed results. To integrate and better understand the available data, we developed a multiscale model of rat Achilles tendon healing that incorporates the effect of changes in the mechanical environment on fibroblast behavior, collagen deposition, and scar formation. We modified an OpenSim model of the rat right hindlimb to estimate physiologic strains in the lateral/medial gastrocnemius and soleus musculo-tendon units during loading and unloading conditions. We used the tendon strains as inputs to a thermodynamic model of stress fiber dynamics that predicts fibroblast alignment, and to determine local collagen synthesis rates according to a response curve derived from in vitro studies. We then used an agent-based model (ABM) of scar formation to integrate these cell-level responses and predict tissue-level collagen alignment and content. We compared our model predictions to experimental data from ten different studies. We found that a single set of cellular response curves can explain features of observed tendon healing across a wide array of reported experiments in rats-including the paradoxical finding that repairing transected tendon reverses the effect of loading on alignment-without fitting model parameters to any data from those experiments. The key to these successful predictions was simulating the specific loading and surgical protocols to predict tissue-level strains, which then guided cellular behaviors according to response curves based on in vitro experiments. Our model results provide a potential explanation for the highly variable responses to mechanical loading reported in the tendon healing literature and may be useful in guiding the design of future experiments and interventions.

Effect of Impairment-Based Rehabilitation on Lower Leg Muscle Volumes and Strength in Patients With Chronic Ankle Instability: A Preliminary Study.

Context: Patients with chronic ankle instability (CAI) have demonstrated atrophy of foot and ankle musculature and deficits in ankle strength. The effect of rehabilitation on muscle morphology and ankle strength has not previously been investigated in patients with CAI. Objective: Our objective was to analyze the effect of impairment-based rehabilitation on intrinsic and extrinsic foot and ankle muscle volumes and strength in patients with CAI. Design: Controlled laboratory study. Setting: Laboratory. Patients: Five young adults with CAI. Intervention: Twelve sessions of supervised impairment-based rehabilitation that included range of motion, strength, balance, and functional exercises. Main Outcome Measures: Measures of extrinsic and intrinsic foot muscle volume and ankle strength measured before and after 4 weeks of supervised rehabilitation. Novel fast-acquisition magnetic resonance imaging was used to scan from above the femoral condyles through the entire foot. The perimeter of each muscle was outlined on each axial slice and then the 2-dimensional area was multiplied by the slice thickness (5 mm) to calculate muscle volume. Plantar flexion, dorsiflexion, inversion, and eversion isometric strength were measured using a hand-held dynamometer. Results: Rehabilitation resulted in hypertrophy of all extrinsic foot muscles except for the flexor hallucis longus and peroneals. Large improvements were seen in inversion, eversion, and plantar flexion strength following rehabilitation. Effect sizes for significant differences following rehabilitation were all large and ranged from 1.54 to 3.35. No significant differences were identified for intrinsic foot muscle volumes. Conclusion: Preliminary results suggest that impairment-based rehabilitation for CAI can induce hypertrophy of extrinsic foot and ankle musculature with corresponding increases in ankle strength.

Assessment of velopharyngeal function with dual-planar high-resolution real-time spiral dynamic MRI.

PURPOSE: To develop a real-time dynamic MRI method for comprehensive evaluation of velum movement during speech. METHODS: Dynamic MRI has been used to study velopharyngeal insufficiency (VPI) by imaging the movement of the velum during speech, because it can provide good anatomic details with no exposed radiation. To be able to comprehensively evaluate dynamic velum movement, a real-time spiral non-balanced SSFP sequence was developed with simultaneous dual-planar coverage and improved spatial and temporal resolution using a combination of parallel imaging and spatial and temporal compressed sensing to achieve 6 × acceleration. New off-resonance correction and post-processing methods were also developed to reduce blurring and slice crosstalk. RESULTS: The method demonstrated good image quality for visualizing dynamic velum movement with reduced blurring and improved image homogeneity. Spatial resolution of 1.2*1.2 mm2 with 150 mm FOV and temporal resolution of 20 frames-per-second with simultaneous dual-planar coverage was achieved. CONCLUSIONS: This work describes a new technique for studying speech disorders using dual-planar accelerated spiral dynamic MRI.

Computer Simulation and Optimization of Cranial Vault Distraction.

OBJECTIVE: The objective of this study was to validate the proof of concept of a computer-simulated cranial distraction, demonstrating accurate shape and end volume. DESIGN: Detailed modeling was performed on pre- and postoperative computed tomographic (CT) scans to generate accurate measurements of intracranial volume. Additionally, digital distraction simulations were performed on the preoperative scan and the resultant intracranial volume and shape were evaluated. SETTING: Tertiary Children's Hospital. PATIENTS, PARTICIPANTS: Preoperative and postoperative CT images were used from 10 patients having undergone cranial distraction for cephalocranial disproportion. INTERVENTIONS: None; computer simulation. MAIN OUTCOME MEASURE: Computer simulation feasibility of cranial vault distraction was demonstrated through creation of digital osteotomies, simulating distraction through translating skull segments, followed by simulated consolidation. Accuracy of the model was evaluated through comparing the intracranial volumes of actual and simulated distracted skulls. RESULTS: The developed digital distraction simulation was performed on the CT images of 10 patients. Plotting the relationship between the actual and simulated postdistraction volumes for the 10 patients yielded a slope of 1.0 and a correlation coefficient of 0.99. The average actual resultant volume change from distraction was 77.0 mL, compared to a simulated volume change of 76.9 mL. CONCLUSIONS: Digital simulation of cranial distraction was demonstrated through manipulation of the CT images and confirmed by comparing the actual to simulated volume change. This process may provide objective data in designing an individual distraction plan to optimize volume expansion and resultant cranial shape as well as patient education.

MRI-Based Assessment of Lower-Extremity Muscle Volumes in Patients Before and After ACL Reconstruction.

CONTEXT: Study of muscle volumes in patients after anterior cruciate ligament (ACL) injury and reconstruction (ACL-R) is largely limited to cross-sectional assessment of the thigh musculature, which may inadequately describe posttraumatic and postsurgical muscle function. No studies have prospectively examined the influence of ACL injury and reconstruction on lower-extremity muscle volumes. OBJECTIVE: Assess magnetic resonance imaging-derived lower-extremity muscle volumes, and quantify quadriceps strength and activation in patients following ACL injury and reconstruction. DESIGN: Prospective case series. SETTING: Research laboratory and magnetic resonance imaging facility. Patients (or Other Participants): Four patients (2 men and 2 women; age = 27.4 (7.4) y, height = 169.2 (8.1) cm, and mass = 74.3 (18.5) kg) scheduled for ACL-R. INTERVENTION(S): Thirty-five muscle volumes were obtained from a bilateral lower-extremity magnetic resonance imaging before and after ACL-R. MAIN OUTCOME MEASURES: Muscle volumes expressed relative to (1) a normative database presurgery and postsurgery, (2) limb symmetry presurgery and postsurgery, and (3) percentage change presurgery to postsurgery. Quadriceps function was quantified by normalized knee extension maximal voluntary isometric contraction torque and central activation ratio. RESULTS: Involved vastus lateralis and tibialis anterior were consistently smaller than healthy individuals (z < -1 SD) presurgery and postsurgery in all patients. Involved rectus femoris and vastus lateralis were more than 15% smaller than the contralateral limb presurgery, whereas the involved rectus femoris, gracilis, vastus medialis, vastus intermedius, and vastus lateralis muscle volumes exceeded 20% asymmetry postoperatively. Involved gracilis and semitendinosus atrophied more than 30% from presurgery to postsurgery. Involved maximal voluntary isometric contraction torque and central activation ratio increased by 12.7% and 12.5%, respectively, yet strength remained 33.2% asymmetric postsurgery. CONCLUSIONS: Adaptations in lower-extremity muscle volumes are present following ACL injury and reconstruction. Anterior thigh and shank muscles were smaller than healthy individuals, and large asymmetries in quadriceps volumes were observed presurgery and postsurgery. Selective atrophy of the semitendinosus and gracilis occurred following surgery. Volumetric deficits of the quadriceps musculature may exist despite improvements in muscle strength and activation.

Skeletal muscle mechanics, energetics and plasticity.

The following papers by Richard Lieber (Skeletal Muscle as an Actuator), Thomas Roberts (Elastic Mechanisms and Muscle Function), Silvia Blemker (Skeletal Muscle has a Mind of its Own: a Computational Framework to Model the Complex Process of Muscle Adaptation) and Sabrina Lee (Muscle Properties of Spastic Muscle (Stroke and CP) are summaries of their representative contributions for the session on skeletal muscle mechanics, energetics and plasticity at the 2016 Biomechanics and Neural Control of Movement Conference (BANCOM 2016). Dr. Lieber revisits the topic of sarcomere length as a fundamental property of skeletal muscle contraction. Specifically, problems associated with sarcomere length non-uniformity and the role of sarcomerogenesis in diseases such as cerebral palsy are critically discussed. Dr. Roberts then makes us aware of the (often neglected) role of the passive tissues in muscles and discusses the properties of parallel elasticity and series elasticity, and their role in muscle function. Specifically, he identifies the merits of analyzing muscle deformations in three dimensions (rather than just two), because of the potential decoupling of the parallel elastic element length from the contractile element length, and reviews the associated implications for the architectural gear ratio of skeletal muscle contraction. Dr. Blemker then tackles muscle adaptation using a novel way of looking at adaptive processes and what might drive adaptation. She argues that cells do not have pre-programmed behaviors that are controlled by the nervous system. Rather, the adaptive responses of muscle fibers are determined by sub-cellular signaling pathways that are affected by mechanical and biochemical stimuli; an exciting framework with lots of potential. Finally, Dr. Lee takes on the challenging task of determining human muscle properties in vivo. She identifies the dilemma of how we can demonstrate the effectiveness of a treatment, specifically in cases of muscle spasticity following stroke or in children with cerebral palsy. She then discusses the merits of ultrasound based elastography, and the clinical possibilities this technique might hold. Overall, we are treated to a vast array of basic and clinical problems in skeletal muscle mechanics and physiology, with some solutions, and many suggestions for future research.

Computational Modeling of Muscle Regeneration and Adaptation to Advance Muscle Tissue Regeneration Strategies.

Skeletal muscle has an exceptional ability to regenerate and adapt following injury. Tissue engineering approaches (e.g. cell therapy, scaffolds, and pharmaceutics) aimed at enhancing or promoting muscle regeneration from severe injuries are a promising and active field of research. Computational models are beginning to advance the field by providing insight into regeneration mechanisms and therapies. In this paper, we summarize the contributions computational models have made to understanding muscle remodeling and the functional implications thereof. Next, we describe a new agent-based computational model of skeletal muscle inflammation and regeneration following acute muscle injury. Our computational model simulates the recruitment and cellular behaviors of key inflammatory cells (e.g. neutrophils and M1 and M2 macrophages) and their interactions with native muscle cells (muscle fibers, satellite stem cells, and fibroblasts) that result in the clearance of necrotic tissue and muscle fiber regeneration. We demonstrate the ability of the model to track key regeneration metrics during both unencumbered regeneration and in the case of impaired macrophage function. We also use the model to simulate regeneration enhancement when muscle is primed with inflammatory cells prior to injury, which is a putative therapeutic intervention that has not yet been investigated experimentally. Computational modeling of muscle regeneration, pursued in combination with experimental analyses, provides a quantitative framework for evaluating and predicting muscle regeneration and enables the rational design of therapeutic strategies for muscle recovery.

Heterogeneity of muscle sizes in the lower limbs of children with cerebral palsy.

INTRODUCTION: Cerebral palsy (CP) is associated with reduced muscle volumes, but previous studies have reported deficits in only a small number of muscles. The extent of volume deficits across lower limb muscles is not known. This study presents an imaging-based assessment of muscle volume and length deficits in 35 lower limb muscles. METHODS: We imaged and segmented 35 muscles in 10 subjects with CP and 8 typically developing (TD) controls using MRI. Muscle volumes were normalized, and Z-scores were computed using TD data. Volume Z-scores and percent deficits in volume, length, and cross-sectional area are reported. RESULTS: Muscle volumes are 20% lower, on average, for subjects with CP. Volume deficits differ significantly between muscles (12%-43%) and display significant heterogeneity across subjects. Distal muscles, especially the soleus, are commonly and severely small. CONCLUSIONS: Heterogeneity across muscles and across subjects reinforces the subject specificity of CP and the need for individualized treatment planning. Muscle Nerve 53: 933-945, 2016.

Contributions of the Musculus Uvulae to Velopharyngeal Closure Quantified With a 3-Dimensional Multimuscle Computational Model.

The convexity of the dorsal surface of the velum is critical for normal velopharyngeal (VP) function and is largely attributed to the levator veli palatini (LVP) and musculus uvulae (MU). Studies have correlated a concave or flat nasal velar surface to symptoms of VP dysfunction including hypernasality and nasal air emission. In the context of surgical repair of cleft palates, the MU has been given relatively little attention in the literature compared with the larger LVP. A greater understanding of the mechanics of the MU will provide insight into understanding the influence of a dysmorphic MU, as seen in cleft palate, as it relates to VP function. The purpose of this study was to quantify the contributions of the MU to VP closure in a computational model. We created a novel 3-dimensional (3D) finite element model of the VP mechanism from magnetic resonance imaging data collected from an individual with healthy noncleft VP anatomy. The model components included the velum, posterior pharyngeal wall (PPW), LVP, and MU. Simulations were based on the muscle and soft tissue mechanical properties from the literature. We found that, similar to previous hypotheses, the MU acts as (i) a space-occupying structure and (ii) a velar extensor. As a space-occupying structure, the MU helps to nearly triple the midline VP contact length. As a velar extensor, the MU acting alone without the LVP decreases the VP distance 62%. Furthermore, activation of the MU decreases the LVP activation required for closure almost 3-fold, from 20% (without MU) to 8% (with MU). Our study suggests that any possible salvaging and anatomical reconstruction of viable MU tissue in a cleft patient may improve VP closure due to its mechanical function. In the absence or dysfunction of MU tissue, implantation of autologous or engineered tissues at the velar midline, as a possible substitute for the MU, may produce a geometric convexity more favorable to VP closure. In the future, more complex models will provide further insight into optimal surgical reconstruction of the VP musculature in normal and cleft palate populations.

Musculoskeletal simulation can help explain selective muscle degeneration in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a genetic disease that occurs due to the deficiency of the dystrophin protein. Although dystrophin is deficient in all muscles, it is unclear why degeneration progresses differently across muscles in DMD. We hypothesized that each muscle undergoes a different degree of eccentric contraction during gait, which could contribute to the selective degeneration in lower limb muscle, as indicated by various amounts of fatty infiltration. By comparing eccentric contractions quantified from a previous multibody dynamic musculoskeletal gait simulation and fat fractions quantified in a recent imaging study, our preliminary analyses show a strong correlation between eccentric contractions during gait and lower limb muscle fat fractions, supporting our hypothesis. This knowledge is critical for developing safe exercise regimens for the DMD population. This study also provides supportive evidence for using multiscale modeling and simulation of the musculoskeletal system in future DMD research.

A computational model of velopharyngeal closure for simulating cleft palate repair.

The levator veli palatini (LVP) muscle has long been recognized as the muscle that contributes most to velopharyngeal (VP) closure and is therefore of principal importance for restoring normal speech in patients with a cleft palate. Different surgical reconstructive procedures can utilize varying degrees of LVP overlap, and this study developed a new finite-element model of VP closure designed to understand the biomechanical effects of LVP overlap. A three-dimensional finite-element model was created from adult anatomical dimensions and parameters taken from the literature. Velopharyngeal function was simulated and compared with experimental measurements of VP closure force from a previous study. Varying degrees of overlap and separation of the LVP were simulated, and the corresponding closure force was calculated. The computational model compares favorably with the experimental measurements of closure force from the literature. Furthermore, the model predicts that there is an optimal level of overlap that maximizes the potential for the LVP to generate closure force. The model predicts that achieving optimal overlap can increase closure force up to roughly 100% when compared with too little or too much overlap. The results of using this new model of VP closure suggest that optimizing LVP overlap may produce improved surgical outcomes due to the intrinsic properties of muscle. Future work will compare these model predictions with clinical observations and provide further insights into optimal cleft palate repair and other craniofacial surgeries.

Towards undistorted and noise-free speech in an MRI scanner: correlation subtraction followed by spectral noise gating.

Noise cancellation in an MRI environment is difficult due to the high noise levels that are in the spectral range of human speech. This paper describes a two-step method to cancel MRI noise that combines operations in both the time domain (correlation subtraction) and the frequency domain (spectral noise gating). The resulting filtered recording has a noise power suppression of over 100 dB, a significant improvement over previously described techniques on MRI noise cancellation. The distortion is lower and the noise suppression higher than using spectral noise gating in isolation. Implementation of this method will aid in detailed studies of speech in relation to vocal tract and velopharyngeal function.

The need for speed - Does the force-velocity property significantly alter strain distributions within skeletal muscle?

Skeletal muscles are complex structures with nonlinear constitutive properties. This complexity often requires finite element (FE) modeling to better understand muscle behavior and response to activation, especially the fiber strain distributions that can be difficult to measure in vivo. However, many FE muscle models designed to study fiber strain do not include force-velocity behavior. To investigate force-velocity property impact on strain distributions within skeletal muscle, we modified a muscle constitutive model with active and passive force-length properties to include force-velocity properties. We implemented the new constitutive model as a plugin for the FE software FEBio and applied it to four geometries: 1) a single element, 2) a multiple-element model representing a single fiber, 3) a model of tapering fibers, and 4) a model representing the bicep femoris long head (BFLH) morphology. Maximum fiber velocity and boundary conditions of the finite element models were varied to test their influence on fiber strain distribution. We found that force-velocity properties in the constitutive model behaved as expected for the single element and multi-element conditions. In the tapered fiber models, fiber strain distributions were impacted by changes in maximum fiber velocity; the range of strains increased with maximum fiber velocity, which was most noted in isometric contraction simulations. In the BFLH model, maximum fiber velocity had minimal impact on strain distributions, even in the context of sprinting. Taken together, the combination of muscle model geometry, activation, and displacement parameters play a critical part in determining the magnitude of impact of force-velocity on strain distribution.

A new look at an old problem: 3D modeling of accommodation reveals how age-related biomechanical changes contribute to dysfunction in presbyopia.

Presbyopia is an age-related ocular disorder where accommodative ability declines so that an individual's focusing range is insufficient to provide visual clarity for near and distance vision tasks without corrective measures. With age, the eye exhibits changes in biomechanical properties of many components involved in accommodation, including the lens, sclera, and ciliary muscle. Changes occur at different rates, affecting accommodative biomechanics differently, but individual contributions to presbyopia are unknown. We used a finite element model (FEM) of the accommodative mechanism to simulate age-related changes in lens stiffness, scleral stiffness, and ciliary contraction to predict differences in accommodative function. The FEM predicts how ciliary muscle action leads to lens displacement by initializing a tensioned unaccommodated lens (Phase 0) then simulating ciliary muscle contraction in accommodation (Phase 1). Model inputs were calibrated to replicate experimentally measured lens and ciliary muscle in 30-year-old eyes. Predictions of accommodative lens deformation were verified with additional imaging studies. Model variations were created with altered lens component stiffnesses, scleral stiffness, or ciliary muscle section activations, representing fifteen-year incremental age-related changes. Model variations predict significant changes in accommodative function with age-related biomechanical property changes. Lens changes only significantly altered lens thickening with advanced age (46% decrease at 75 years old) while sclera changes produced progressive dysfunction with increasing age (23%, 36%, 49% decrease at 45, 60, and 75 years old). Ciliary muscle changes effected lens position modulation. Model predictions identified potential mechanisms of presbyopia that likely work in combination to reduce accommodative function and could indicate effectiveness of treatment strategies and their dependency on patient age or relative ocular mechanical properties.