Physiological Response to the 6-Minute Frame Running Test in Children and Adults With Cerebral Palsy.

PURPOSE: To determine the physiological response and association to peak oxygen uptake of the 6-minute Frame Running test (6-MFRT) in persons with cerebral palsy (CP). METHODS: Twenty-four participants with CP, Gross Motor Function Classification System II/III/IV, performed the 6-MFRT. Distance, peak heart rate (HR peak ), peak respiratory exchange ratio (RER peak ), and peak oxygen uptake ( O 2peak ) were measured. RESULTS: HR peak ranged from 146 to 201 beats per minute, RER peak from 0.94 to 1.49, 6-MFRT distance from 179 to 1220 m and O 2peak from 0.62 to 2.18 L/min. HR peak was achieved in 63%, RER peak in 71%. A strong correlation was observed between 6-MFRT and O 2peak . CONCLUSIONS: The 6-MFRT represented a (near) maximum effort for 75% of the participants and the 6-MFRT can be used to estimate oxygen consumption on an individual basis.

Reduced mitochondrial DNA and OXPHOS protein content in skeletal muscle of children with cerebral palsy.

AIM: To provide a detailed gene and protein expression analysis related to mitochondrial biogenesis and assess mitochondrial content in skeletal muscle of children with cerebral palsy (CP). METHOD: Biceps brachii muscle samples were collected from 19 children with CP (mean [SD] age 15y 4mo [2y 6mo], range 9-18y, 16 males, three females) and 10 typically developing comparison children (mean [SD] age 15y [4y], range 7-21y, eight males, two females). Gene expression (quantitative reverse transcription polymerase chain reaction [PCR]), mitochondrial DNA (mtDNA) to genomic DNA ratio (quantitative PCR), and protein abundance (western blotting) were analyzed. Microarray data sets (CP/aging/bed rest) were analyzed with a focused query investigating metabolism- and mitochondria-related gene networks. RESULTS: The mtDNA to genomic DNA ratio was lower in the children with CP compared to the typically developing group (-23%, p=0.002). Out of five investigated complexes in the mitochondrial respiratory chain, we observed lower protein levels of all complexes (I, III, IV, V, -20% to -37%; p<0.05) except complex II. Total peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) messenger RNA (p<0.004), isoforms PGC1α1 (p=0.05), and PGC1α4 (p<0.001) were reduced in CP. Transcriptional similarities were observed between CP, aging, and 90 days' bed rest. INTERPRETATION: Mitochondrial biogenesis, mtDNA, and oxidative phosphorylation protein content are reduced in CP muscle compared with typically developing muscle. Transcriptional pathways shared between aging and long-term unloading suggests metabolic dysregulation in CP, which may guide therapeutic strategies for combatting CP muscle pathology. What this paper adds Cerebral palsy (CP) muscle contains fewer energy-generating organelles than typically developing muscle. Gene expression in CP muscle is similar to aging and long-term bed rest.

RaceRunning training improves stamina and promotes skeletal muscle hypertrophy in young individuals with cerebral palsy.

BACKGROUND: Individuals with cerebral palsy (CP) are less physically active, spend more time sedentary and have lower cardiorespiratory endurance as compared to typically developed individuals. RaceRunning enables high-intensity exercise in individuals with CP with limited or no walking ability, using a three-wheeled running bike with a saddle and a chest plate for support, but no pedals. Training adaptations using this type of exercise are unknown. METHODS: Fifteen adolescents/young adults (mean age 16, range 9-29, 7 females/8 males) with CP completed 12 weeks, two sessions/week, of RaceRunning training. Measurements of cardiorespiratory endurance (6-min RaceRunning test (6-MRT), average and maximum heart rate, rate of perceived exertion using the Borg scale (Borg-RPE)), skeletal muscle thickness (ultrasound) of the thigh (vastus lateralis and intermedius muscles) and lower leg (medial gastrocnemius muscle) and passive range of motion (pROM) of hip, knee and ankle were collected before and after the training period. RESULTS: Cardiorespiratory endurance increased on average 34% (6-MRT distance; pre 576 ± 320 m vs. post 723 ± 368 m, p < 0.001). Average and maximum heart rate and Borg-RPE during the 6-MRT did not differ pre vs. post training. Thickness of the medial gastrocnemius muscle increased 9% in response to training (p < 0.05) on the more-affected side. Passive hip flexion increased (p < 0.05) on the less-affected side and ankle dorsiflexion decreased (p < 0.05) on the more affected side after 12 weeks of RaceRunning training. CONCLUSIONS: These results support the efficacy of RaceRunning as a powerful and effective training modality in individuals with CP, promoting both cardiorespiratory and peripheral adaptations.

International multidisciplinary collaboration toward an annotated definition of arthrogryposis multiplex congenita.

Arthrogryposis multiplex congenita (AMC) has been described and defined in thousands of articles, but the terminology used has been inconsistent in clinical and research communities. A definition of AMC was recently developed using a modified Delphi consensus method involving 25 experts in the field of AMC from 8 countries. Participants included health care professionals, researchers, and individuals with AMC. An annotation of the definition provides more in-depth explanations of the different sentences of the AMC definition and is useful to complement the proposed definition. The aim of this study was to provide an annotation of the proposed consensus-based AMC definition. For the annotation process, 17 experts in AMC representing 10 disciplines across 7 countries participated. A paragraph was developed for each sentence of the definition using an iterative process involving multiple authors with varied and complementary expertise, ensuring all points of view were taken into consideration. The annotated definition provides an overview of the different topics related to AMC and is intended for all stakeholders, including youth and adults with AMC, their families, and clinicians and researchers, with the hopes of unifying the understanding of AMC in the international community.

Muscle contractures in patients with cerebral palsy and acquired brain injury are associated with extracellular matrix expansion, pro-inflammatory gene expression, and reduced rRNA synthesis.

INTRODUCTION: Children with cerebral palsy (CP) and acquired brain injury (ABI) commonly develop muscle contractures with advancing age. An underlying growth defect contributing to skeletal muscle contracture formation in CP/ABI has been suggested. METHODS: The biceps muscles of children and adolescents with CP/ABI (n = 20) and typically developing controls (n = 10) were investigated. We used immunohistochemistry, quantitative real-time polymerase chain reaction, and Western blotting to assess gene expression relevant to growth and size homeostasis. RESULTS: Classical pro-inflammatory cytokines and genes involved in extracellular matrix (ECM) production were elevated in skeletal muscle of children with CP/ABI. Intramuscular collagen content was increased and satellite cell number decreased and this was associated with reduced levels of RNA polymerase I transcription factors, 45s pre-rRNA and 28S rRNA. DISCUSSION: The present study provides novel data suggesting a role for pro-inflammatory cytokines and reduced ribosomal production in the development/maintenance of muscle contractures, possibly underlying stunted growth and perimysial ECM expansion. Muscle Nerve 58: 277-285, 2018.

Background to the 2nd International Symposium on Arthrogryposis.

Arthrogryposis multiplex congenital is a relatively uncommon condition, with little consensus on treatment. In 2007, the 1st International Symposium on Arthrogryposis was held in Birmingham, United Kingdom, to bring together patients, their families, and a multinational group of health care experts in the field of arthrogryposis, to discuss various aspects of the care of patients with arthrogryposis multiplex congenital. From that meeting, there was a coalescence of thought on diagnosis and classification, a sharing of practices on treatments and their outcomes, and an agreement on future directions. At the beginning of the 2nd International Symposium on Arthrogryposis held in Saint Petersburg in September 2014, Russia, these "lessons learnt" were synopsized to set the tone for the new meeting.

Treatment of the Lower Extremity Contracture/Deformities.

Lower extremity deformities of patients with arthrogryposis multiplex congenita present a wide spectrum of severity and deformity combinations. Treatment goals range from merely ensuring comfortable seating and shoe wear, to fully independent and active ambulation, but the overarching intention is to help realize the patient's greatest potential for independence and function. Treatment of hip and knee contractures and dislocations has become more interventional, whereas treatment of foot deformities has paradoxically become much less surgical. This article synopsizes the treatment strategies presented in September 2014 in Saint Petersburg, Russia at the second international symposium on arthrogryposis.

Summary of the 2nd International Symposium on Arthrogryposis, St. Petersburg, Russia, September 17-19, 2014.

Enormous progress has been made in understanding the etiology and therapies for arthrogryposis (multiple congenital contractures). A 2nd International Symposium on Arthrogryposis was sponsored by the Turner Institute in St. Petersburg, Russia. Olga Agranovich, Head of the Arthrogryposis Department of the Turner Institute, organized this special meeting. Care providers from multiple disciplines from all over the world representing 18 nations attended. Participants included: Pediatric orthopedic specialists, rehabilitation physicians, occupational therapists, physical therapists, medical geneticists, neurologists, craniofacial physicians, psychologists, developmental biologists, as well as representatives from parent support groups. The 1st symposium established the need for a collaborative and interdisciplinary approach to the treatment of arthrogryposis, engagement of parent support organizations, and the aim for more research. The Second Symposium highlighted the continuing need for more research on various therapies, identification of different types of arthrogryposis, standardized descriptions of severity, development of new orthotics, improved prenatal diagnosis, and studying adult outcome. Major progress has been made on both upper and lower limb treatments.

Gait dynamics in the wide spectrum of children with arthrogryposis: a descriptive study.

BACKGROUND: Arthrogryposis Multiplex Congenita (AMC) is a heterogeneous condition characterized by multiple joint contractures at birth. Greater movements in the trunk and pelvis during walking have been observed in children with AMC using orthoses compared to those wearing only shoes. This study investigated gait dynamics in children with AMC and identified compensatory mechanisms that accommodate walking. METHODS: Twenty-six children with AMC who walked with orthoses or shoes and a control group consisting of 37 typically-developing children were evaluated in 3D gait analysis. Children with AMC were divided into subgroups based on which joints needed to be stabilized in the sagittal plane; AMC1 used knee-ankle-foot orthoses (KAFOs) with locked knee joints, AMC2 used KAFOs with open knee joints or ankle-foot orthoses, and AMC3 used shoes. RESULTS: The Gait Deviation Index was lower in AMC groups than in the control group, with the lowest in AMC1. Excessive trunk movements in frontal and transverse planes were observed in AMC2 and especially in AMC1. Lower hip flexion moment was found in AMC1, while AMC2 and AMC3 showed similar hip flexion moments as the control group. Knee extension moments were similar between the groups. In the frontal plane there were only small differences between the groups in hip abduction moment. A joint work analysis indicated greater contribution from the hip muscles to overall positive work in AMC groups, particularly in AMC1, than in the control group. CONCLUSION: All AMC groups showed less hip extension than the control group, but hip flexion moment was significantly lower only in AMC1, which can be attributed to their gait strategy with bilateral locked KAFOs. AMC1, who had weak knee extensors, were helped by their locked KAFOs and therefore showed similar knee extension moment as the other groups. This finding, together with their gait patterns, demonstrates the children's high reliance on hip muscles and presumably trunk muscles to provide propulsion. Our study shows that with adequate orthotic support, children with AMC and even with severe weakness and contractures can achieve walking.

Determinants of Frame Running Capacity in Athletes With Cerebral Palsy to Improve Training Routines and Classification Strategies: A Cross-sectional Observational Study.

OBJECTIVES: The aim of the study were to (1) investigate what physical and physiological parameters are most important for Frame Running capacity, a parasport for individuals with ambulatory difficulties, and (2) determine whether Frame Running capacity can be predicted in athletes with cerebral palsy. DESIGN: Athletes with cerebral palsy ( N = 62, Gross Motor Classification System I-V; 2/26/11/21/2) completed a 6-min Frame Running test. Before the 6-min Frame Running test, muscle thickness, passive range of motion (hip, knee, ankle), selective motor control, and spasticity (hip, knee, ankle) were measured in both legs. In total, 54 variables per individual were included. Data were analyzed using correlations, principal component analysis, orthogonal partial least square regression, and variable importance in projection analysis. RESULTS: The mean 6-min Frame Running test distance was 789 ± 335 m and decreased with motor function severity. The orthogonal partial least square analysis revealed a modest degree of covariance in the variables analyzed and that the variance in the 6-min Frame Running test distance could be predicted with 75% accuracy based on all the variables measured. Variable importance in projection analysis indicated hip and knee extensor spasticity (negative effect), and muscle thickness (positive effect) arose as the most important factors contributing to Frame Running capacity. CONCLUSIONS: These results are an important resource to enable optimization of training regimes to improve Frame Running capacity and contribute to evidence-based and fair classification for this parasport.

Time-matched accelerometers on limbs and waist in children with CP give new insights into real-life activities after botulinum toxin treatment: A proof of concept study.

PURPOSE: This study aimed to explore the feasibility of using time-matched uniaxial accelerometers for measuring movement in daily life in children with cerebral palsy (CP) before and after botulinum toxin injections. METHODS: This observational study of clinical care with a pre-post design was set in the home and school environment. Participants included eleven children (4-13 years of age) with CP (GMFCS I-III). The children wore uniaxial accelerometers (ActiGraph, model GT1M) for 4 days on both wrists, the right ankle and around the waist before, 3 weeks and 3 months after BoNT-A injections in the legs. Five children also got BoNT-A in the most affected arm. All injections were given according to clinical indications and routine. The accelerometers were all time-matched to define ambulation, arm swing, voluntary activity of arms, and bimanual activity. The feasibility of wearing accelerometers with this setup was evaluated. A linear mixed model was used for analysis of the percentage time and at which intensity the different activities were performed. The confidence interval demonstrated any difference between the dominant and non-dominant arm. RESULTS: Time-matching of accelerometers placed on both wrists, the waist, and one ankle is a feasible method of registering ambulation, arm swing during gait, and arm movements while not ambulating. Before injections, the children spent 5.6% of their time ambulating. This value declined to 3.9% at 3 months. Contrary to clinical goals, arm movement did not increase after injecting the most affected arm with BoNT-A, however, injections may have decreased mirror movements, which are often bothersome for the child. CONCLUSION: A time-matched 4-accelerometer set-up is feasible in children with cerebral palsy. A future study including time-matched multi-axial accelerometers on all four limbs, could provide important information on the effect of BoNT-A in daily life.

Higher expression of myosin heavy chain IIx in wrist flexors in cerebral palsy.

BACKGROUND: Children with cerebral palsy (CP) use their paretic arm less than normal but have a relative overactivity of wrist flexors, causing an impairing flexed position of the wrist. Voluntary use of a muscle downregulates myosin heavy chain (MyHC) IIx, but it is unclear whether the relative overactivity of wrist flexors and extensors in children with CP affects MyHC expression compared to normal subjects. QUESTIONS/PURPOSES: We therefore asked whether MyHC expression composition differs in wrist flexors compared to extensors in children with CP and in controls and whether it is related to clinical findings. METHODS: We took muscle biopsies from wrist flexors and extensors during hand surgery in children with CP (n = 9) and during open reduction of forearm fractures in control children (n = 5). The expression of the MyHC I, IIa, and IIx isoforms were determined on silver-stained 6% SDS-PAGE. RESULTS: CP flexors showed a higher proportion of MyHC IIx (40%) than control flexors (16%) and CP extensors (20%). MyHC IIa isoform proportion was lower in CP flexors (27%) than in control flexors (46%) and in CP extensors (45%). MyHC I expression was lower in CP (36%) than in controls (46%) for wrist extensors only. CONCLUSIONS: Both the brain injury in CP and the different demands on flexors and extensors affect the expression of MyHCs. The higher amount of MyHC IIx in CP could be caused by a decreased voluntary use of the hemiplegic arm. CLINICAL RELEVANCE: More information on the structural difference between flexors and extensors in normal and spastic muscle could improve the understanding of strain of wrist extensors and possibly the development of flexion contractures in CP.

Extracellular vesicle characteristics and microRNA content in cerebral palsy and typically developed individuals at rest and in response to aerobic exercise.

In this study, the properties of circulating extracellular vesicles (EVs) were examined in cerebral palsy (CP) and typically developed (TD) individuals at rest and after aerobic exercise, focusing on the size, concentration, and microRNA cargo of EVs. Nine adult individuals with CP performed a single exercise bout consisting of 45 min of Frame Running, and TD participants completed either 45 min of cycling (n = 10; TD EX) or were enrolled as controls with no exercise (n = 10; TD CON). Blood was drawn before and 30 min after exercise and analyzed for EV concentration, size, and microRNA content. The size of EVs was similar in CP vs. TD, and exercise had no effect. Individuals with CP had an overall lower concentration (∼25%, p < 0.05) of EVs. At baseline, let-7a, let-7b and let-7e were downregulated in individuals with CP compared to TD (p < 0.05), while miR-100 expression was higher, and miR-877 and miR-4433 lower in CP compared to TD after exercise (p < 0.05). Interestingly, miR-486 was upregulated ∼2-fold in the EVs of CP vs. TD both at baseline and after exercise. We then performed an in silico analysis of miR-486 targets and identified the satellite cell stemness factor Pax7 as a target of miR-486. C2C12 myoblasts were cultured with a miR-486 mimetic and RNA-sequencing was performed. Gene enrichment analysis revealed that several genes involved in sarcomerogenesis and extracellular matrix (ECM) were downregulated. Our data suggest that circulating miR-486 transported by EVs is elevated in individuals with CP and that miR-486 alters the transcriptome of myoblasts affecting both ECM- and sarcomerogenesis-related genes, providing a link to the skeletal muscle alterations observed in individuals with CP.

Current concepts in diagnosis and management of common upper limb nerve injuries in children.

Peripheral nerve injuries (PNI) of the upper limb are a common event in the paediatric population, following both fractures and soft tissues injuries. Open injuries should in theory be easier to identify and the repair of injured structures performed as soon as possible in order to obtain a satisfying outcome. Conversely, due to the reduced compliance of younger children during clinical assessment, the diagnosis of a closed nerve injury may sometimes be delayed. As the compliance of patients is influenced by pain, anxiety and stress, the execution of the clinical manoeuvres intended to identify a loss of motor function or sensibility, can be impaired. Although the majority of PNI are neuroapraxias resulting in spontaneous recovery, there are open questions regarding certain aspects of closed PNI, e.g. when to ask for electrophysiological exams, when and how long to wait for a spontaneous recovery and when a surgical approach becomes mandatory. The aim of the article is therefore to analyse the main aspects of the different closed PNI of the upper limb in order to provide recommendations for timely and correct management, and to determine differences in the PNI treatment between children and adults.

Epigenetic Marks at the Ribosomal DNA Promoter in Skeletal Muscle Are Negatively Associated With Degree of Impairment in Cerebral Palsy.

Introduction: Cerebral palsy (CP) is the most common motor impairment in children. Skeletal muscles in individuals with CP are typically weak, thin, and stiff. Whether epigenetic changes at the ribosomal DNA (rDNA) promoter are involved in this dysregulation remains unknown. Methods: Skeletal muscle samples were collected from 19 children with CP and 10 typically developed (TD) control children. Methylation of the rDNA promoter was analyzed using the Agena Epityper Mass array and gene expression by qRT-PCR. Results: Biceps brachii muscle ribosome biogenesis was suppressed in CP as compared to TD. Average methylation of the rDNA promoter was not different between CP and TD but negatively correlated to elbow flexor contracture in the CP group. Discussions: We observed a negative correlation between rDNA promoter methylation and degree of muscle contracture in the CP group. Children with CP with more severe motor impairment had less methylation of the rDNA promoter compared to less affected children. This finding suggests the importance of neural input and voluntary muscle movements for promoter methylation to occur in the biceps muscle.

Comparative analysis of power, work and muscle activation during weight-stack and iso-inertial flywheel resistance exercise in young adults with cerebral palsy.

INTRODUCTION: The development of efficient resistance exercise protocols to counteract muscle dysfunction in cerebral palsy is warranted. Whether individuals with cerebral palsy are able to perform iso-inertial resistance (flywheel) exercise in a comparable manner to typically developed subjects has never been experimentally tested. DESIGN: A comparative, controlled study. SUBJECTS: Eight young ambulatory adults with cerebral palsy (mean age 19 years; Gross Motor Function Classification System (GMFCS) I-III) and 8 typically developed control subjects (mean age 21 years). METHODS: Subjects performed acute bouts on the weight-stack and flywheel leg-press device, respectively. Range of motion, electromyography, power, work and muscle thickness (ultrasound) data were collected. RESULTS: Subjects with cerebral palsy were able to produce a greater eccentric/concentric peak power ratio on the flywheel (p < 0.05 vs ratio in weight-stack), however absolute values were lower (p < 0.05 vs weight-stack). Typically developed subjects produced more power per mm of thigh muscle than the cerebral palsy group, independent of leg, device and action. DISCUSSION: Subjects with cerebral palsy could not elicit the eccentric overload seen in typically developed subjects. Furthermore, peak power production per mm muscle was markedly reduced in both legs in subjects with cerebral palsy. In conclusion, this comparative study of weight-stack and flywheel exercise does not support the implementation of the current iso-inertial protocol for young adults with cerebral palsy.

Effect of acute transcranial magnetic stimulation on intracellular signalling in human skeletal muscle.

OBJECTIVE: To investigate the potential of an acute bout of transcranial electrical stimulation to induce anabolic signalling. DESIGN: Experimental intervention on healthy subjects. SUBJECTS: Ten healthy subjects, 5 women and 5 men (mean age (standard deviation (SD) 32 years (SD 4)). METHODS: The quadriceps muscle was stimulated at a frequency of 10 Hz for 10 s, followed by 20 s of rest, repeated 40 times over 20 min. Electromyography and force data were collected for all transcranial electrical stimulation sequences. Muscle biopsies were obtained from the vastus lateralis muscle before and 1 and 3 h after stimulation. RESULTS: One bout of transcranial electrical stimulation decreased phosphorylation of AKT at Thr308 (1 h: -29%, 3 h: -38%; p < 0.05) and mTOR phosphorylation at Ser2448 (1 h: -10%; ns, 3 h: -21%; p < 0.05), both in the anabolic pathway. Phosphorylation of AMPK, ACC and ULK1 were not affected. c-MYC gene expression was unchanged following transcranial electrical stimulation, but rDNA transcription decreased (1 h: -28%, 3 h: -19%; p < 0.05). PGC1α-ex1b mRNA increased (1 h: 2.3-fold, 3 h: 2.6-fold; p < 0.05), which also correlated with vastus lateralis electromyography activity, while other PGC-1α variants were unchanged. CONCLUSION: Acute transcranial electrical stimulation of skeletal muscle in weight-bearing healthy individuals did not induce anabolic signalling, and some signs of impaired muscle anabolism were detected, suggesting limited potential in preventing muscle wasting.

Feasibility of a day-camp model of modified constraint-induced movement therapy with and without botulinum toxin A injection for children with hemiplegia.

The objective of the study was to investigate the feasibility of modified constraint-induced (CI) therapy provided in a 2-week day-camp model with and without intramuscular botulinum toxin type A (BoNT-A) injections for children with congenital cerebral palsy. Sixteen children with congenital hemiplegia, Manual Ability Classification System (MACS) level I and II, aged 8-17 years, participated in a CI therapy day camp; of whom five participants (aged 11-16 years) received intramuscular BoNT-A prior to CI therapy. Assessments were conducted 4 months and 2 weeks before (baselines 1 and 2), immediately after, and 6 months after the day camp. For the children who received BoNT-A, no statistical analyses were conducted due to the small size of the sample. In this group, consistent improvement was only found according to the Melbourne Unilateral Limb Assessment. The children who received only the CI therapy demonstrated improvements in the Jebsen-Taylor Hand Function Test (p =. 04) at posttest, but improvements were not sustained at 6-month follow-up. No significant improvement was obtained for the Melbourne Assessment or the Assisting Hand Assessment. Children in both groups improved on specially trained tasks: frisbee golf, stacking blocks, and in-hand manipulation. Feedback from the participants suggests that the day-camp model is a feasible intervention following intramuscular BoNT-A injections. The results suggest that children with congenital hemiplegia with varying severity of impairment in hand function may benefit from CI therapy, but not every child demonstrates improvements in hand function. The characteristics of children who respond the best to CI therapy are not clear.