Subject-specific musculoskeletal modeling can be applied to study musculoskeletal disorders, allowing inclusion of personalized anatomy and properties. Independent of the tools used for model creation, there are unavoidable uncertainties associated with parameter identification, whose effect on model predictions is still not fully understood. The aim of the present study was to analyze the sensitivity of subject-specific model predictions (i.e., joint angles, joint moments, muscle and joint contact forces) during walking to the uncertainties in the identification of body landmark positions, maximum muscle tension and musculotendon geometry. To this aim, we created an MRI-based musculoskeletal model of the lower limbs, defined as a 7-segment, 10-degree-of-freedom articulated linkage, actuated by 84 musculotendon units. We then performed a Monte-Carlo probabilistic analysis perturbing model parameters according to their uncertainty, and solving a typical inverse dynamics and static optimization problem using 500 models that included the different sets of perturbed variable values. Model creation and gait simulations were performed by using freely available software that we developed to standardize the process of model creation, integrate with OpenSim and create probabilistic simulations of movement. The uncertainties in input variables had a moderate effect on model predictions, as muscle and joint contact forces showed maximum standard deviation of 0.3 times body-weight and maximum range of 2.1 times body-weight. In addition, the output variables significantly correlated with few input variables (up to 7 out of 312) across the gait cycle, including the geometry definition of larger muscles and the maximum muscle tension in limited gait portions. Although we found subject-specific models not markedly sensitive to parameter identification, researchers should be aware of the model precision in relation to the intended application. In fact, force predictions could be affected by an uncertainty in the same order of magnitude of its value, although this condition has low probability to occur.

Multi-scale simulations, combining muscle and joint contact force (JCF) from musculoskeletal simulations with adaptive mechanobiological finite element analysis, allow to estimate musculoskeletal loading and predict femoral growth in children. Generic linearly scaled musculoskeletal models are commonly used. This approach, however, neglects subject-and age-specific musculoskeletal geometry, e.g. femoral neck-shaft angle (NSA) and anteversion angle (AVA). This study aimed to evaluate the impact of proximal femoral geometry, i.e. altered NSA and AVA, on hip JCF and femoral growth simulations. Musculoskeletal models with NSA ranging from 120˚to 150˚and AVA ranging from 20˚to 50˚were created and used to calculate muscle and hip JCF based on the gait analysis data of a typically developing child. A finite element model of a paediatric femur was created from magnetic resonance images. The finite element model was morphed to the geometries of the different musculoskeletal models and used for mechanobiological finite element analysis to predict femoral growth trends. Our findings showed that hip JCF increase with increasing NSA and AVA. Furthermore, the orientation of the hip JCF followed the orientation of the femoral neck axis. Consequently, the osteogenic index, which is a function of cartilage stresses and defines the growth rate, barely changed with altered NSA and AVA. Nevertheless, growth predictions were sensitive to the femoral geometry due to changes in the predicted growth directions. Altered NSA had a bigger impact on the growth results than altered AVA. Growth simulations based on mechanobiological principles were in agreement with reported changes in paediatric populations.

Physics-based simulations of walking have the theoretical potential to support clinical decision-making by predicting the functional outcome of treatments in terms of walking performance. Yet before using such simulations in clinical practice, their ability to identify the main treatment targets in specific patients needs to be demonstrated. In this study, we generated predictive simulations of walking with a medical imaging based neuro-musculoskeletal model of a child with cerebral palsy presenting crouch gait. We explored the influence of altered muscle-tendon properties, reduced neuromuscular control complexity, and spasticity on gait dysfunction in terms of joint kinematics, kinetics, muscle activity, and metabolic cost of transport. We modeled altered muscle-tendon properties by personalizing Hill-type muscle-tendon parameters based on data collected during functional movements, simpler neuromuscular control by reducing the number of independent muscle synergies, and spasticity through delayed muscle activity feedback from muscle force and force rate. Our simulations revealed that, in the presence of aberrant musculoskeletal geometries, altered muscle-tendon properties rather than reduced neuromuscular control complexity and spasticity were the primary cause of the crouch gait pattern observed for this child, which is in agreement with the clinical examination. These results suggest that muscle-tendon properties should be the primary target of interventions aiming to restore an upright gait pattern for this child. This suggestion is in line with the gait analysis following muscle-tendon property and bone deformity corrections. Future work should extend this single case analysis to more patients in order to validate the ability of our physics-based simulations to capture the gait patterns of individual patients pre-and post-treatment. Such validation would open the door for identifying targeted treatment strategies with the aim of designing optimized interventions for neuro-musculoskeletal disorders.

Mediolateral stability during walking can be controlled by adjustment of foot placement. Reactive activity of gluteus medius (GM) is modulated during the gait cycle. However, the mechanisms behind the modulation are yet unclear. We measured reactive GM activity and kinematics in response to a mediolateral platform translation during different phases of the gait cycle. Forward simulations of perturbed walking were used to evaluate the isolated effect of the perturbation and the GM response on gait stability. We showed that the potential of GM to adjust lateral foot placement and prevent collisions during swing varies during the gait cycle and explains the observed modulation. The observed increase in stance, swing or combined GM activity causes an outward foot placement and therefore compensates for the loss of stability caused by a perturbation early in the gait cycle. GM activity of the swing leg in response to a platform translation late in the gait cycle counteracts foot placement, but prevents collision of the swing foot with the stance leg. This study provides insights in the neuromechanics of reactive control of gait stability and proposes a novel method to distinguish between the effect of perturbation force and reactive muscle activity on gait stability.

Gait deficits in cerebral palsy (CP) are often treated with a single-event multi-level surgery (SEMLS). Selecting the treatment options (combination of bony and soft tissue corrections) for a specific patient is a complex endeavor and very often treatment outcome is not satisfying. A deterioration in 22.8% of the parameters describing gait performance has been reported and there is need for additional surgery in 11% of the patients. Computational simulations based on musculoskeletal models that allow clinicians to test the effects of different treatment options before surgery have the potential to drastically improve treatment outcome. However, to date, no such simulation and modeling method is available. Two important challenges are the development of methods to include patient-specific neuromechanical impairments into the models and to simulate the effect of different surgical procedures on post-operative gait performance. Therefore, we developed the SimCP framework that allows the evaluation of the effect of different simulated surgeries on gait performance of a specific patient and includes a graphical user interface (GUI) that enables performing virtual surgery on the models. We demonstrated the potential of our framework for two case studies. Models reflecting the patient-specific musculoskeletal geometry and muscle properties are generated based solely on data collected before the treatment. The patient's motor control is described based on muscle synergies derived from pre-operative EMG. The GUI is then used to modify the musculoskeletal properties according to the surgical plan. Since SEMLS does not affect motor control, the same motor control model is used to define gait performance pre- and post-operative. We use the capability gap (CG), i.e., the difference between the joint moments needed to perform healthy walking and the joint moments the personalized model can generate, to quantify gait performance. In both cases, the CG was smaller post- then pre-operative and this was in accordance with the measured change in gait kinematics after treatment.