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This eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contact

Science: general issues --- Neurosciences --- Gait --- Cerebral Palsy --- pediatric neurology --- MRI --- Upper limb --- Ataxia --- tDCS --- Duchenne muscular dystrophy

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This eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contact

Science: general issues --- Neurosciences --- Gait --- Cerebral Palsy --- pediatric neurology --- MRI --- Upper limb --- Ataxia --- tDCS --- Duchenne muscular dystrophy --- Gait --- Cerebral Palsy --- pediatric neurology --- MRI --- Upper limb --- Ataxia --- tDCS --- Duchenne muscular dystrophy

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Cerebral palsy (CP) is the most common cause of physical disability in children. It is defined as a disorder of the development of movement and posture that is attributed to a non-progressive disturbance of the developing brain. In many CP patients this brain lesion causes spasticity and the elicited increased tone leads to contractures and bony malformations. An optimal use of spasticity reduction with Botulinum toxin type A (BTX) injections, started at a young age, can prevent these complications to some extent. While many clinical studies reported overall good results of this treatment, they also demonstrated considerable variation in outcome. This is partly due to injection variables. BTX blocks neurotransmission by inhibiting the release of Acetylcholine at the motor end plate (MEP). Animal studies already have shown that injecting the toxin near the MEP zone increases its paralytic effect. This was, so far, only confirmed in one human study on the biceps brachii muscle of adults with spastic hemiplegia after acquired brain lesion (Gracies et al, 2009). Besides the lack of strong clinical evidence of the importance of MEP targeted injections in children with CP, the clinician was confronted with the very limited information on the localization of the MEP-zones in the lower limb muscles.The overall goal of this thesis was to improve the effectiveness of lower limb treatment with intramuscular BTX injections in children with CP, by optimizing the injection location.A thorough literature search -collecting all relevant histological and anatomical studies- provided information on the exact localization of the MEP zone or the terminal nerve ramifications of most of the frequently injected lower limb muscles. After comparing these with clinical practice, it became clear that for many muscles its location was somewhat different than the currently injected areas. In the review article, optimal injection sites in relation to external anatomical landmarks were presented. As no information was found on the innervation of the psoas muscle, a cadaver dissection study was performed on 24 adult psoas muscles. With stereoscopic microscopic dissection as far as the terminal nerve ramifications, the region of intramuscular nerve endings, corresponding with the MEP zone, was identified. For both the medial hamstrings (semitendinosus, semimembranosus and gracilis muscle) as well as the psoas muscle, there was enough evidence to conclude that current popular injection techniques were not injecting the toxin at a site close to the MEP zone. To explore the clinical importance of injecting these MEP zones in children with CP, both injection techniques (‘current’ versus MEP targeted) were compared for both muscle groups through the application of innovative assessments.An instrumented spasticity assessment was used to evaluate the effect of BTX in the medial hamstrings. Biomechanical (position and torque) and electrophysiological signals were measured when applying passive stretches to the medial hamstrings at different velocities. First, the sensitivity of this assessment was studied on nineteen children before and after BTX injections. The biomechanical and electrophysiological parameters proved to be adequately sensitive to assess the response to treatment with BTX with an average of 53% reduction in velocity-dependent root mean square electromyography (RMS-EMG) and a 47% reduction in torque. A second methodological study was set up to assess whether parameters obtained from the instrumented spasticity assessment were more sensitive than clinical scales in detecting treatment response and whether they could help explain response variability. Thirty-one children with CP (40 medial hamstring muscle groups) had a clinical and instrumented spasticity assessments of the medial hamstrings before and after BTX injection. It was concluded that the instrumented spasticity assessment showed higher responsiveness than the clinical scales. The amount of RMS-EMG was considered a promising parameter to predict treatment response. Following these methodological studies, a prospective randomized trial was set up, including 34 gracilis muscles which were injected with BTX in 27 children with CP (8.5±2.5y). Seventeen muscles were treated by proximal injections (at 25% of the length of the upper leg) and 17 muscles by MEP targeted injections (half the dosage at 30% and half at 60% of the upper leg). Clinical and instrumented spasticity assessments were performed before and after the injections. The MEP targeted injections showed a significantly better decline in pathological EMG signal compared to the conventional proximal injections, demonstrated by a higher reduction of the normalized RMS-EMG parameter. This difference could not be demonstrated using the clinical scale. It was concluded that BTX injection in the gracilis muscle at the sites with a high concentration of MEPs resulted in improved spasticity reduction in children with CP. Further, we demonstrated that different injection protocols could be compared sensitively and objectively using the instrumented spasticity assessment that integrates biomechanical and electrophysiological measures.The ultimate goal is to optimize motor function and thus to understand the influence of spasticity and tone reduction treatment on functional activities, such as gait. Therefore, a study was set up to search for functional markers of spasticity of the gastrocnemius and hamstring muscles during gait. Because spasticity is a velocity dependent feature, it has been suggested that signs of spasticity during gait may be highlighted by increasing the walking velocity. Gait parameters (kinematic, kinetic and EMG parameters, muscle length and muscle lengthening velocity MLV) of 17 typical developing (TD) children (10.46±2.36y) and 53 patients diagnosed with spastic CP (9.8±3.0y) were collected during a 3D gait analysis at different walking velocities (normal, fast and as fast as possible without running) and compared at two similar non-dimensional velocities, estimated by a linear regression model. A number of gastrocnemius and hamstrings related parameters could be considered as functional markers for spasticity, due to significantly different ‘difference scores’ (between slow and fast walking velocity) between CP and TD. The spastic gastrocnemius muscle, while walking at high velocity, was characterized by a higher ankle angular velocity, plantar flexion moment and power absorption during loading response. Additionally, this muscle demonstrated an increased EMG signal during stance phase. The increased walking velocity affected the spastic hamstrings at the level of the hip and knee joints at mid-stance by a delayed maximum knee extension moment and by an increased hip extension moment and power generation. The hamstrings also presented with a lower MLV during swing phase.To evaluate both injection techniques for the psoas muscle, a quantitative evaluation using muscle volume assessment by digital magnetic resonance imagination (MRI) segmentation was done. The temporary chemical denervation caused by BTX injections leads to muscle atrophy. MRI sensitively identifies these changes in muscle volume as was confirmed by a good intra-class correlation (0.988) and within-subject coefficient of variation of 3.506% in our study. In seven spastic diplegic children, the MEP targeting versus a widely used more distal injection technique were compared. Five patients received two different injection techniques randomly applied to both psoas muscles and in two patients a bilateral MEP targeting technique was used. MRI images of the psoas were taken before, two months and -in three patients- six months after the injections. The average injection volume two months after the injection (in relation to pre-injection volume) for the nine MEP targeted muscles was 79,5% versus 107.8% for the five distal injected psoas muscles. This difference was statistically significant. In all five asymmetric injected patients, the MEP targeted psoas had an average of 27% (range 9-37%) larger volume reduction than the more distal injected psoas muscle. This atrophy remained even six months after the treatment. We therefore concluded that injections in the MEP zone of the muscle, which is the more proximal part of the psoas muscle, caused muscle atrophy -as a demonstration of the effect of the toxin-, in contrary to more distal injections were this atrophy was not observed. The newly developed assessment tools (the instrumented spasticity assessment and the digital MRI segmentation muscle volume assessment) proved to be reliable and valid to compare different BTX injection protocols. The results from the gracilis and psoas study have shown that BTX injections atthe sites with high MEP concentrations, have an improved efficacy compared to injections more distant from these MEPs. It is therefore reasonable to state that all BTX injections preferably should be given close to the MEP zone(s) of the injected skeletal muscles. The effect on function of the child with CP when using these more efficient MEP targeted BTX injections will be further explored by studying the effect on the functional spasticity markers during gait. Future studies comparing different dosage and dilution protocols injected at these MEP zones, documented by the sensitive instrumented spasticity assessment and muscle volume measurement, can further improve the treatment efficacy. This can eventually lead to the use of lower dosages thus decreasing economic costs and the risk of side effects.

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Osteoarthritis (OA) is one of the most common hip joint diseases and with increasing age and obesity, the prevalence of OA is likely to become even higher. Many patients with end-stage hip OA are treated with total hip arthroplasty (THA). As the number of THA surgeries is increasing, also the number of revision surgeries is growing. To prevent bone-implant interface failure, it is important to detect and monitor patients at risk, in which the loading on the hip joint is very important. Besides that, mechanical factors, e.g. joint loading, are a risk factor for OA. However, most often hip pathology patients are evaluated using clinical measures, like abductor strength and dislocation rate, or in terms of kinematics and joint moments that only represent external loading and do not take into account any internal forces, like muscle forces.Hip contact forces are typically used to quantify internal hip joint loading.^ This measure accounts for the joint loading determined by the external forces, e.g. ground reaction forces, as well as internal forces, e.g. muscle forces. Hip contact forces can be measured using instrumented hip prostheses. A dataset containing measured hip contact forces of different subjects has previously been made publicly available. Although these instrumented hip prostheses provide a direct measure of hip contact forces, these measurements are rare and limited to subjects that received a THA. To be able to determine hip loading non-invasively in other subject groups, musculoskeletal modelling in combination with three dimensional motion analysis data, can be used to calculate hip contact forces in vivo. These model-based contact forces have been validated against measured contact forces from instrumented prostheses. Several studies show an overestimation of calculated hip contact forces compared to measured forces, while others find more comparable results.^ Different modelling choices, like including subject-specific detail and the use of different optimization methods to calculate muscle forces can contribute to the reported overestimation of calculated contact forces compared to measured forces. Also differences in movement kinematics and kinetics, based on which hip contact forces are calculated, will affect contact forces. It is important to consider the contribution of all of these factors when assessing the validity of calculated hip contact forces against a measured dataset.The aim of this PhD aim is twofold. First, the sensitivity of the calculated hip contact forces for specific aspects of the musculoskeletal modelling and dynamic simulation workflow is evaluated. Second, once the factors that influence calculated hip contact forces most are identified, insights are used to investigate hip loading in hip pathology patients.^ This results in the following research topics:Evaluate the effect of including different levels of subject-specific detail in musculoskeletal models on hip joint loading (studies I, II and III).Evaluate the effect of the optimization technique on calculated muscle and contact forces (study IV).Evaluate the effect of different gait patterns on hip joint loading (studies V and VI).Evaluate hip function in OA and THA patients (studies VII and VIII).The first four studies investigate the sensitivity of the calculated hip contact forces for different aspects of the musculoskeletal modelling workflow.In study I, we investigated the relative importance of including subject-specific geometrical detail in the musculoskeletal model versus the effect of an altered cost function definition on hip contact forces for healthy control subjects.^ We used computer tomography (CT) and magnetic resonance imaging (MRI) data to create seven model types that each contained a different level of subject-specific detail and simulated gait. Hip contact forces were calculated on the one hand using the standard simulation workflow and analyses implemented in OpenSim. On the other hand, the effect of including a term minimizing the hip contact forces in the optimization criterion underlying muscle force calculation was investigated. Results showed that inclusion of subject-specific detail had a dominant effect on the calculated hip contact forces, although the effect of the level of subject-specific detail varied. The MRI-based model that included subject-specific muscle paths and wrapping surfaces, to account for the effect of the hip capsule, resulted in contact forces that were most comparable to measured hip contact forces, both in magnitude and orientation.^ To generalize the effect of the subject-specific wrapping surfaces, the generic model was updated to include average MRI-based wrapping surfaces. The use of this model also brought contact forces closer to experimental values, but the effect was less pronounced compared to the MRI-based models. Including minimization of the hip contact forces into the cost function (SOmin) had only a limited effect on the contact forces. Specifically, the largest overestimations were not affected. Nevertheless, for the generic model, contact forces decreased on average more by using SOmin than by including wrapping surfaces, but the largest overestimations of the contact forces were not decreased. Therefore, inclusion of subject-specific geometrical detail in the model had a greater effect than altering the cost function definition.The effect of including subject-specific detail in the musculoskeletal model on hip contact forces was also investigated in hip OA and THA patients in study II.^ Besides that, the effect of subject-specific moment generating capacity of the musculoskeletal model was investigated for healthy control subjects as well as OA and THA patients. For all subjects a generic scaled and MRI model was created as well as the respective models including wrapping surfaces and gait was simulated. Maximal isometric muscle forces in the model were on the one hand statically scaled based on dynamometer measurements. On the other hand, muscle forces were functionally scaled based on the external joint moments required during gait and stair ascent and descent, an approach already successfully adopted for the knee. Static scaling decreased the maximal isometric muscle forces of control, OA and THA subjects and for all model types. As a result, the model lacked the capacity to generate the internal joint moments measured during functional activities, hence further results, i.e. hip contact forces, cannot be reliably calculated.^ Functional scaling decreased muscle forces less or even increased muscle forces compared to the unscaled models. Hip contact forces were comparable to the unscaled models. For THA patients, including MRI-based information decreased hip contact forces, specifically by including wrapping surfaces around the hip joint, as was also reported for control subjects in study I. For OA patients, changes in hip contact forces were less pronounced. The deviations of muscle generated moments from internal joint moments of the MRI-based models were not excessively increased compared to the generic model with unscaled muscle forces.^ This indicates that including MRI-based geometrical detail, without scaling muscle forces, results in a model that is strong enough to perform the measured functional tasks while hip contact forces are more comparable to measured hip contact forces.The importance of estimating body segment parameters (BSP) when calculating joint moments and muscle forces during gait was examined in study III. The segment mass, centre of mass (com) and inertial tensor of the left thigh, shank and foot were adjusted from 60% to 140% of the nominal value in steps of 10% both individually as well as for different combinations of BSP values. We found only a limited effect of BSP perturbation on inverse dynamics. The largest effect was found by perturbing the shank com. Further, the additional influence of a combined perturbation of parameters was only very small.^ On the other hand, muscle forces calculated using computed muscle control (CMC) were largely affected by changes in BSP, which resulted from the underlying forward integration. Indeed, post hoc analyses indicated that when using static optimization, a technique that is not based on forward integration, muscle forces were less affected by perturbations in BSP.In study IV, we investigated the effect of different optimization techniques on calculated muscle forces and the magnitude and orientation of resultant hip contact forces for gait and sit to stand using a scaled generic musculoskeletal model. To calculate muscle forces, four different optimization techniques were used, i.e. two different static optimization techniques (SO1 and SO2), computed muscle control (CMC) and the physiological inverse approach (PIA), after which muscle and hip contact forces were calculated. Both static optimization techniques showed the lowest hip contact forces for both gait and sit to stand.^ The additional constraints to include a physiological increase and decrease of muscle activation in time and the inclusion of passive muscle forces (SO2) did not majorly affect the hip contact forces compared to a standard SO formulation (SO1). In contrast, hip contact forces increased drastically when using CMC. These increased contact forces from CMC were potentially caused by higher muscle forces resulting from co-contraction of agonists and antagonists around the hip or the slightly poorer tracking of the net joint moment by the muscle moments. On the other hand, hip contact forces between the SO techniques and PIA were similar, which showed that the activation and contraction dynamics can be integrated without inducing an excessive overestimation of the hip contact forces as observed by CMC.The first four studies showed that the inclusion of subject-specific geometrical detail in the musculoskeletal model is most important in calculating hip contact forces.^ The muscle optimization technique, including m