Kaat Desloovere’s research while affiliated with University of Kansas and other places

Background Robotic exoskeletons have been developed to assist locomotion and address gait abnormalities in children with cerebral palsy (CP). These wearable assistive devices provide powered assistance to the lower-extremity joints, as well as support and stability. Research Question Does exoskeleton-assisted walking improve gait in children with CP? Methods The PRISMA guidelines were used to conduct this systematic review. Articles were obtained in a search of the following electronic databases: Embase, CINAHL Complete, PubMed, Web of Science and MEDLINE. Studies investigating spatiotemporal, kinematic, kinetic, muscle activity and/or physiological parameters during exoskeleton-assisted walking in children with CP were included. All articles were assessed for methodological quality using an adapted version of the Quality Assessment Tool for Before-After (Pre-Post) Studies with No Control Group, provided by NIH. Results Thirteen studies were included. They involved the use of the following exoskeletons: tethered knee exoskeleton, pediatric knee exoskeleton (P.REX), untethered ankle exoskeleton, WAKE-Up ankle module, WAKE-Up ankle & knee module and unilateral ankle exosuit. Methodological quality varied, with key limitations in sample size and allocated time to adapt to the exoskeleton. There was a consensus that robotic exoskeletons improve gait given careful optimisation of exoskeleton torque and sufficient exoskeleton practice time for each participant. Improvements in gait included reduced metabolic cost of walking, increased walking speed, and increased knee and hip extension during stance. Furthermore, exoskeletons with an actuated ankle module were shown to promote normal ankle rocker function. Significance Robotic exoskeletons have the potential to improve the mobility of CP children and may therefore increase community participation and improve quality of life. Future work should involve larger controlled intervention studies utilising robotic exoskeletons to improve gait in children with CP. These studies should ensure sufficient exoskeleton practice time for each participant.

Duchenne muscular dystrophy (DMD) is an X-linked progressive muscle disorder, caused by mutations in the Dystrophin gene. Cardiomyopathy is one of the major causes of early death. In this study, we used DMD patient-specific induced pluripotent stem cells (iPSCs) to model cardiomyopathic features in DMD and unravel novel pathological mechanistic insights. Cardiomyocytes (CMs) differentiated from DMD iPSCs showed enhanced premature cell death, due to significantly elevated intracellular reactive oxygen species (ROS) concentrations, as a result of depolarized mitochondria and high NADPH oxidase 4 (NOX4) protein levels. Genetic correction of Dystrophin through CRISPR/Cas9 editing restored normal ROS levels. Application of ROS reduction by N-acetyl-L-cysteine (NAC), partial Dystrophin re-expression by ataluren (PTC124) and enhancing mitochondrial electron transport chain function by idebenone improved cell survival of DMD iPSC-CMs. We show applications that could counteract the detrimental oxidative stress environment in DMD iPSC-CMs by stimulating adenosine triphosphate (ATP) production. ATP could bind to the ATP-binding domain in the NOX4 enzyme, and we demonstrate that ATP resulted in partial inhibition of the NADPH-dependent ROS production of NOX4. Considering the complexity and the early cellular stress responses in DMD cardiomyopathy, we propose to target ROS production and prevent the detrimental effects of NOX4 on DMD CMs as a promising therapeutic strategy.

Muscle weakness is a common clinical symptom in children with spastic cerebral palsy (SCP). It is caused by impaired neural ability and altered intrinsic capacity of the muscles. To define the contribution of decreased muscle size to muscle weakness, two cohorts were recruited in this cross-sectional investigation: 53 children with SCP [median age, 8.2 (IQR, 4.1) years, 19/34 uni/bilateral] and 31 children with a typical development (TD) [median age, 9.7 (IQR, 2.9) years]. Muscle volume (MV) and muscle belly length for m. rectus femoris, semitendinosus, gastrocnemius medialis, and tibialis anterior were defined from three-dimensional freehand ultrasound acquisitions. A fixed dynamometer was used to assess maximal voluntary isometric contractions for knee extension, knee flexion, plantar flexion, and dorsiflexion from which maximal joint torque (MJT) was calculated. Selective motor control (SMC) was assessed on a 5-point scale for the children with SCP. First, the anthropometrics, strength, and muscle size parameters were compared between the cohorts. Significant differences for all muscle size and strength parameters were found (p ≤ 0.003), except for joint torque per MV for the plantar flexors. Secondly, the associations of anthropometrics, muscle size, gross motor function classification system (GMFCS) level, and SMC with MJT were investigated using univariate and stepwise multiple linear regressions. The associations of MJT with growth-related parameters like age, weight, and height appeared strongest in the TD cohort, whereas for the SCP cohort, these associations were accompanied by associations with SMC and GMFCS. The stepwise regression models resulted in ranges of explained variance in MJT from 29.3 to 66.3% in the TD cohort and from 16.8 to 60.1% in the SCP cohort. Finally, the MJT deficit observed in the SCP cohort was further investigated using the TD regression equations to estimate norm MJT based on height and potential MJT based on MV. From the total MJT deficit, 22.6–57.3% could be explained by deficits in MV. This investigation confirmed the disproportional decrease in muscle size and muscle strength around the knee and ankle joint in children with SCP, but also highlighted the large variability in the contribution of muscle size to muscle weakness.

Background Many children with cerebral palsy (CP) develop skeletal deformities during childhood. So far, it is unknown why some children with CP develop bony deformities whereas others do not. The aims of this study were to (i) investigate what loading characteristics lead to typical and pathological femoral growth, and (ii) evaluate why some children with CP develop femoral deformities whereas other do not. Methods A multi-scale mechanobiological modelling workflow was used to simulate femoral growth based on three-dimensional motion capture data of six typically developing children and 16 children with CP. Based on the growth results, the participants with CP were divided into two groups: typical growth group and pathological growth group. Gait kinematics and femoral loading were compared between simulations resulting in typical growth and those resulting in pathologic growth. Findings Hip joint contact forces were less posteriorly-oriented in the pathological growth simulations compared to the typical ones. Compared to the typically developing participants, the CP group with pathological femoral growth presented increased knee flexion and no hip extension. The CP group with simulated typical growth presented similar sagittal plane joint kinematics but differed in the frontal plane pelvic and hip movement strategy, which normalized the hip joint contact force and therefore contributed to typical femoral growth trends. Interpretation Our simulation results identified specific gait features, which may contribute to pathological femoral growth. Furthermore, the hip joint contact force orientation in the sagittal plane seems to be the dominant factor for determining femoral growth simulations.

This investigation assessed the processer reliability of estimating muscle volume and echo-intensity of the rectus femoris, tibialis anterior and semitendinosus. The muscles of 10 typically developing children (8.15 [1.40] y) and 15 children with spastic cerebral palsy (7.67 [3.80] y; Gross Motor Function Classification System I = 5, II = 5, III = 5) were scanned with 3-D freehand ultrasonography. For the intra-processer analysis, the intra-class correlations coefficients (ICCs) for muscle volume ranged from 0.943–0.997, with relative standard errors of measurement (SEM%) ranging from 1.24%–8.97%. For the inter-processer analysis, these values were 0.853 to 0.988 and 3.47% to 14.02%, respectively. Echo-intensity had ICCs >0.947 and relative SEMs <4% for both analyses. Muscle volume and echo-intensity can be reliably extracted for the rectus femoris, semitendinosus and tibialis anterior in typically developing children and children with cerebral palsy. The need for a single processer to analyze all data is dependent on the size of the expected changes or differences.

Hereditary spastic paraplegia (HSP) is a neurological, genetic disorder that predominantly presents with lower limb spasticity and muscle weakness. Pediatric pure HSP types with infancy or childhood symptom onset resemble in clinical presentation to children with bilateral spastic cerebral palsy (SCP). Hence, treatment approaches in these patient groups are analogous. Altered muscle characteristics, including reduced medial gastrocnemius (MG) muscle growth and hyperreflexia have been quantified in children with SCP, using 3D-freehand ultrasound (3DfUS) and instrumented assessments of hyperreflexia, respectively. However, these muscle data have not yet been studied in children with HSP. Therefore, we aimed to explore these MG muscle characteristics in HSP and to test the hypothesis that these data differ from those of children with SCP and typically developing (TD) children. A total of 41 children were retrospectively enrolled including (1) nine children with HSP (ages of 9–17 years with gross motor function levels I and II), (2) 17 age-and severity-matched SCP children, and (3) 15 age-matched typically developing children (TD). Clinically, children with HSP showed significantly increased presence and severity of ankle clonus compared with SCP (p = 0.009). Compared with TD, both HSP and SCP had significantly smaller MG muscle volume normalized to body mass (p ≤ 0.001). Hyperreflexia did not significantly differ between the HSP and SCP group. In addition to the observed pathological muscle activity for both the low-velocity and the change in high-velocity and low-velocity stretches in the two groups, children with HSP tended to present higher muscle activity in response to increased stretch velocity compared with those with SCP. This exploratory study is the first to reveal MG muscle volume deficits in children with HSP. Moreover, high-velocity-dependent hyperreflexia and ankle clonus is observed in children with HSP. Instrumented impairment assessments suggested similar altered MG muscle characteristics in pure HSP type with pediatric onset compared to bilateral SCP. This finding needs to be confirmed in larger sample sizes. Hence, the study results might indicate analogous treatment approaches in these two patient groups.

In neurological diseases, muscles often become hyper-resistant to stretch due to hyperreflexia, an exaggerated stretch reflex response that is considered to primarily depend on the muscle's stretch velocity. However, there is still limited understanding of how different biomechanical triggers applied during clinical tests evoke these reflex responses. We examined the effect of imposing a rotation with increasing velocity vs. increasing acceleration on triceps surae muscle repsonse in children with spastic paresis (SP) and compared the responses to those measured in typically developing (TD) children. A motor-operated ankle manipulator was used to apply different bell-shaped movement profiles, with three levels of maximum velocity (70, 110, and 150°/s) and three levels of maximum acceleration (500, 750, and 1,000°/s²). For each profile and both groups, we evaluated the amount of evoked triceps surae muscle activation. In SP, we evaluated two additional characteristics: the intensity of the response (peak EMG burst) and the time from movement initiation to onset of the EMG burst. As expected, the amount of evoked muscle activation was larger in SP compared to TD (all muscles: p < 0.001) and only sensitive to biomechanical triggers in SP. Further investigation of the responses in SP showed that peak EMG bursts increased in profiles with higher peak velocity (lateral gastrocnemius: p = 0.04), which was emphasized by fair correlations with increased velocity at EMG burst onset (all muscles: r > 0.33–0.36, p ≤ 0.008), but showed no significant effect for acceleration. However, the EMG burst was evoked faster with higher peak acceleration (all muscles p < 0.001) whereas it was delayed in profiles with higher peak velocity (medial gastrocnemius and soleus: p < 0.006). We conclude that while exaggerated response intensity (peak EMG burst) seems linked to stretch velocity, higher accelerations seem to evoke faster responses (time to EMG burst onset) in triceps surae muscles in SP. Understanding and controlling for the distinct effects of different biological triggers, including velocity, acceleration but also length and force of the applied movement, will contribute to the development of more precise clinical measurement tools. This is especially important when aiming to understand the role of hyperreflexia during functional movements where the biomechanical inputs are multiple and changing.

Background context Radiographic evaluation in adult spinal deformity (ASD) offers no information on spinopelvic alignment and compensation during dynamic conditions. Motion analysis offers the potential to bridge the gap between static radiographic and dynamic alignment measurement, increasing our understanding on how ASD impacts function. Purpose This study aimed to explore the changes in sagittal alignment and compensation strategies in ASD between upright standing and walking, compared to control subjects and within different sagittal alignment groups. Ten patients were measured pre- and six months post-operatively to explore the impact of surgical alignment correction on gait. Study design Prospective study Sample size Full protocol: 58 ASD and 20 controls; Spinal kinematic analysis: 43 ASD and 18 controls; Post-operative analysis: 10 ASD Outcome measures Standing and walking sagittal spinopelvic (thoracic kyphosis (TK), lumbar lordosis (LL), sagittal vertical axis (SVA), pelvis) and lower limb kinematics, spinopelvic changes between standing and walking (∆ i.e. difference between mean dynamic and static angle), lower limb kinetics, spatiotemporal parameters, balance (BESTest), patient-reported outcome scores (SRS-22r, ODI and FES-I) and radiographic parameters. Methods Motion analysis was used to assess the standing and walking spinopelvic and lower limb kinematics, as well as the lower limb kinetics during walking. All parameters were compared between controls and patients with ASD, divided in three groups based on their sagittal alignment (ASD 1: decompensated sagittal malalignment; ASD 2: compensated sagittal malalignment; ASD 3: scoliosis and normal sagittal alignment). 10 patients were reassessed 6 months after spinal corrective surgery. Continuous kinematic and kinetic data were analyzed through statistical parametric mapping. Results All patient groups walked with increased forward trunk tilt (∆SVA=41.43mm, p<0.001) in combination with anterior pelvic tilt (∆Pelvis=2.58°, p<0.001) compared to standing, as was also observed in controls (∆SVA=37.86mm, p<0.001; ∆Pelvis=1.62°, p=0.012). Patients walked with increased SVA, in combination with decreased LL and alterations in lower limb kinematics during terminal stance and initial swing, as well as altered spatiotemporal parameters. Subgroup analysis could link these alterations in gait to sagittal spinopelvic malalignment (ASD 1 and 2). After surgical correction, lower limb kinematics and spatiotemporal parameters during gait were not significantly improved. Conclusions To compensate for increased trunk tilt and pelvic anteversion during walking, patients with sagittal malalignment show altered lower limb gait patterns, which have previously been associated with increased risk of falling and secondary lower limb pathology. Since surgical correction of the deformity did not lead to gait improvements, further research on the underlying mechanisms is necessary to improve our understanding of how ASD impacts function.