Histological analysis of the gastrocnemius muscle in preschool and school age children with cerebral palsy compared with age-matched typically developing children.

Inconsistent alterations in skeletal muscle histology have been reported in adolescents with cerebral palsy (CP) and whether alterations are present in young children and differ from older children is not yet known. This study aimed to define histological alterations in the medial gastrocnemius (MG) of ambulant CP (gross-motor classification system, GMFCS I-III) stratified in two age groups (preschool children, PS: 2-5 and school age children, SA: 6-9-yr old) compared with age-matched typically developing (TD) children. We hypothesized that alterations in muscle microscopic properties are already present in PS-CP and are GMFCS level specific. Ultrasound guided percutaneous microbiopsies were collected in 46 CP (24-PS) and 45 TD (13-PS) children. Sections were stained to determine fiber cross-sectional area (fCSA) and proportion, capillary, and satellite cell amount. Average absolute and normalized fCSA were similar in CP and TD, but a greater percentage of smaller fibers was found in CP. Coefficient of variation (CV) was significantly larger in PS-CP-GMFCS I-II and for type I fiber. In SA-CP, all fiber types contributed to the higher CV. Type IIx proportion was higher and type I was lower in PS-CP-GMFCS-III and for all SA-CP. Reduced capillary-to-fiber ratio was present in PS-CP-GMFCS II-III and in all SA-CP. Capillary fiber density was lower in SA-CP. Capillary domain was enhanced in all CP, but capillary spatial distribution was maintained as was satellite cell content. We concluded that MG histological alterations are already present in very young CP but are only partly specific for GMFCS level and age.NEW & NOTEWORTHY Inconsistent histological alterations have been reported in children with cerebral palsy (CP) but whether they are present in very young and ambulant CP children and differ from those reported in old CP children is not known. This study highlighted for the first time that enhanced muscle fiber size variability and loss of capillaries are already present in very young CP children, even in the most ambulant ones, and these alterations seem to extend with age.

Collagen architecture and biomechanics of gracilis and adductor longus muscles from children with cerebral palsy.

Cerebral palsy (CP) describes some upper motoneuron disorders due to non-progressive disturbances occurring in the developing brain that cause progressive changes to muscle. While longer sarcomeres increase muscle stiffness in patients with CP compared to typically developing (TD) patients, changes in extracellular matrix (ECM) architecture can increase stiffness. Our goal was to investigate how changes in muscle and ECM architecture impact muscle stiffness, gait and joint function in CP. Gracilis and adductor longus biopsies were collected from children with CP undergoing tendon lengthening surgery for hamstring and hip adduction contractures, respectively. Gracilis biopsies were collected from TD patients undergoing anterior cruciate ligament reconstruction surgery with hamstring autograft. Muscle mechanical testing, two-photon imaging and hydroxyproline assay were performed on biopsies. Corresponding data were compared to radiographic hip displacement in CP adductors (CPA), gait kinematics in CP hamstrings (CPH), and joint range of motion in CPA and CPH. We found at matched sarcomere lengths muscle stiffness and collagen architecture were similar between TD and CP hamstrings. However, CPH stiffness (R2 = 0.1973), collagen content (R2 = 0.5099) and cross-linking (R2 = 0.3233) were correlated to decreased knee range of motion. Additionally, we observed collagen fibres within the muscle ECM increase alignment during muscular stretching. These data demonstrate that while ECM architecture is similar between TD and CP hamstrings, collagen fibres biomechanics are sensitive to muscle strain and may be altered at longer in vivo sarcomere lengths in CP muscle. Future studies could evaluate the impact of ECM architecture on TD and CP muscle stiffness across in vivo operating ranges. KEY POINTS: At matched sarcomere lengths, gracilis muscle mechanics and collagen architecture are similar in TD patients and patients with CP. In both TD and CP muscles, collagen fibres dynamically increase their alignment during muscle stretching. Aspects of muscle mechanics and collagen architecture are predictive of in vivo knee joint motion and radiographic hip displacement in patients with CP. Longer sarcomere lengths in CP muscle in vivo may alter collagen architecture and biomechanics to drive deficits in joint mobility and gait function.

Prefrontal cortex hemodynamic activity during a test of lower extremity functional muscle strength in children with cerebral palsy: A functional near-infrared spectroscopy study.

Children with cerebral palsy (CP) exhibit impaired motor control and significant muscle weakness due to a brain lesion. However, studies that assess the relationship between brain activity and performance on dynamic functional muscle strength assessments in CP are needed. The aim of this study was to determine the effect of a progressive lateral step-up test on prefrontal cortex (PFC) hemodynamic activity in children with CP. Fourteen ambulatory children with spastic CP (Gross Motor Function Classification System level I; 5-11 y) and 14 age- and sex-matched typically developing control children completed a progressive lateral step-up test at incremental step heights (0, 10, 15 and 20 cm) using their non-dominant lower limb. Hemodynamic activity in the PFC was assessed using non-invasive, portable functional neuroimaging (functional near-infrared spectroscopy). Children with CP completed fewer repetitions at each step height and exhibited lower PFC hemodynamic activity across step heights compared to controls. Lower PFC activation in CP was maintained after statistically controlling for the number of repetitions completed at each step height. PFC hemodynamic activity was not associated with LSUT task performance in children with CP, but a positive relationship was observed in controls at the most challenging 20 cm step height. The results suggest there is an altered PFC recruitment pattern in children with CP during a highly dynamic test of functional strength. Further studies are needed to explore the mechanisms underlying the suppressed PFC activation observed in children with CP compared to typically developing children.

Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss.

Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene encoding a protein of unknown function. We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families. In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy. Modeling indicated damaging effect of variants on the protein, largely via destabilizing effects on protein domains. Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals. Immunofluorescent imaging in rat hippocampal neurons revealed localization of Spata5l1 in neuronal and glial cell nuclei and more prominent expression in neurons. In the rodent inner ear, Spata5l1 is expressed in the neurosensory hair cells and inner ear supporting cells. Transcriptomic analysis performed with fibroblasts from affected individuals was able to distinguish affected from controls by principal components. Analysis of differentially expressed genes and networks suggested a role for SPATA5L1 in cell surface adhesion receptor function, intracellular focal adhesions, and DNA replication and mitosis. Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype.

ABHD16A deficiency causes a complicated form of hereditary spastic paraplegia associated with intellectual disability and cerebral anomalies.

ABHD16A (abhydrolase domain-containing protein 16A, phospholipase) encodes the major phosphatidylserine (PS) lipase in the brain. PS lipase synthesizes lysophosphatidylserine, an important signaling lipid that functions in the mammalian central nervous system. ABHD16A has not yet been associated with a human disease. In this report, we present a cohort of 11 affected individuals from six unrelated families with a complicated form of hereditary spastic paraplegia (HSP) who carry bi-allelic deleterious variants in ABHD16A. Affected individuals present with a similar phenotype consisting of global developmental delay/intellectual disability, progressive spasticity affecting the upper and lower limbs, and corpus callosum and white matter anomalies. Immunoblot analysis on extracts from fibroblasts from four affected individuals demonstrated little to no ABHD16A protein levels compared to controls. Our findings add ABHD16A to the growing list of lipid genes in which dysregulation can cause complicated forms of HSP and begin to describe the molecular etiology of this condition.

Muscle morphology and architecture of the medial gastrocnemius between typically developing children with different ancestral background.

Muscle ultrasonography is frequently used to improve the understanding of musculoskeletal impairments in children with spastic cerebral palsy (SCP). So far, most studies on muscle morphology and architecture have included typically developing children and children with SCP with similar ancestry, being mainly Caucasian. Less is known about differences in muscle morphology between children with different ancestral backgrounds. Therefore, the aim of this study was to compare muscle morphology and architecture of the medial gastrocnemius in typically developing children with African, South Asian and Southeast Asian descent from Suriname. This explorative cohort study identified children as Maroon (Ghana, African descent), Hindustani (India, South Asian) or Javanese (Indonesia, Southeast Asian), aged 5-10 years. Using 3D freehand ultrasound with the subject prone, the following medial gastrocnemius parameters were defined: muscle tendon unit (MTU) length, muscle belly length, tendon length, muscle volume, muscle thickness, anatomical cross-sectional area (ACSA), fascicle length, pennation angle, and physiological cross-sectional area (PCSA). In addition, differences between ancestral groups were assessed for the length of the MTU, muscle, tendon and fascicles in two passive stretch conditions corresponding to an externally applied joint torque of 1Nm and 4Nm. One-way ANOVA with post hoc t-tests were used to investigate differences between the ancestral groups. In total, 100 Hindustani (n = 34), Javanese (n = 34) and Maroon (n = 32) children were included. For statistical analyses, we matched the children by age, which resulted in groups of 25 children per ancestral group (n = 75). There were no differences found in MTU length, muscle belly length, ACSA, PCSA and muscle volume. Tendon length, fascicle length and pennation angle were different between ancestral groups. Compared to Javanese children, tendon length was longer (p = 0.001) and pennation angle (p = 0.001) was larger in Maroon children and fascicle length was shorter in both Maroon and Hindustani children (p < 0.001). While there was a difference found in MTU length at different conditions of passive stretch between ancestries, no differences were found in the muscle, tendon and fascicles. This is the first study that investigated macroscopic morphological and architectural parameters for the medial gastrocnemius in one extended cohort of typically developing children, stratified in three ancestral subgroups. The current results imply that ancestry-specific reference data for children are needed, especially for tendon length, fascicle length and pennation angle when investigating altered muscle morphology in neurological or neuromuscular pathologies, such as SCP. Future studies should report the ancestral background when describing muscle morphology and architecture of children and ancestral specifications should be included in normative databases.

Histological chorioamnionitis and pathological stages on very preterm infant outcomes.

AIMS: Histological chorioamnionitis (HCA) is a condition linked to preterm birth and neonatal infection and its relationship with various pathological stages in extremely preterm neonates, and with their associated short- and long-term consequences, remains a subject of research. This study investigated the connection between different pathological stages of HCA and both short-term complications and long-term outcomes in preterm infants born at or before 32 weeks of gestational age. METHODS: Preterm infants born at ≤ 32 weeks of gestation who underwent placental pathology evaluation and were followed-up at 18-24 months of corrected age were included. Neonates were classified based on their exposure to HCA and were further subdivided into different groups according to maternal inflammatory responses (MIR) and fetal inflammatory responses (FIR) stages. We compared short-term complications during their hospital stay between the HCA-exposed and -unexposed groups and examined the influence of HCA stages on long-term outcomes. RESULTS: The HCA group exhibited distinct characteristics such as higher rates of premature rupture of membranes > 18 h, reduced amniotic fluid, early-onset sepsis, bronchopulmonary dysplasia and intraventricular haemorrhage (IVH) grades III-IV (P < 0.05). The moderate-severe HCA group displayed lower gestational age, lower birth weight and higher incidence of IVH (grades III-IV) and preterm sepsis compared with the mild HCA group (P < 0.05). After adjusting for confounders, the MIR stages 2-3 group showed associations with cognitive impairment and cerebral palsy (P < 0.05), and the FIR stages 2-3 group also showed poor long-term outcomes and cognitive impairment (P < 0.05). CONCLUSIONS: Moderate-severe HCA was associated with increased early-onset sepsis, severe IVH and poor long-term outcomes, including cognitive impairment and cerebral palsy. Vigilant prevention strategies are warranted for severe HCA cases in order to mitigate poorer clinical outcomes.

A reliable and cost-effective protocol for creating bilirubin cerebral palsy model in rhesus macaque.

BACKGROUND: Cerebral palsy is a severe motor disability in childhood that poses challenges for children, families, and society. Rhesus macaques are the preferred animals for cerebral palsy model, but surgical excision of motor cortex has low success rate and high cost. In this work, we created cerebral palsy rhesus macaque models by intrathecal injection of bilirubin. METHODS: The puncture point for injection was identified as the intervertebral disc space two, located below the intersection of the iliac crest line and the posterior median line. RESULTS: The models showed abnormal posture and increased muscle tension. Diffuse deposits of bilirubin were found in the basal ganglia from the magnetic resonance imaging. Pathological slides also revealed the presence of brain lesions, such as vacuole formation, contraction of neuronal nuclei, and deep staining of nuclei in the histopathological sections of the hippocampus and basal ganglia. CONCLUSION: The model's symptoms closely resemble those observed in humans with spastic cerebral palsy.

Impaired glymphatic system revealed by DTI-ALPS in cerebral palsy due to periventricular leukomalacia: relation with brain lesion burden and hand dysfunction.

PURPOSE: Preterm children with cerebral palsy (CP) often have varying hand dysfunction, while the specific brain injury with periventricular leukomalacia (PVL) cannot quite explain its mechanism. We aimed to investigate glymphatic activity using diffusion tensor image analysis along the perivascular space (DTI-ALPS) method and evaluate its association with brain lesion burden and hand dysfunction in children with CP secondary to PVL. METHODS: We retrospectively enrolled 18 children with bilateral spastic CP due to PVL and 29 age- and sex-matched typically developing controls. The Manual Ability Classification System (MACS) was used to assess severity of hand dysfunction in CP. A mediation model was performed to explore the relationship among the DTI-ALPS index, brain lesion burden, and the MACS level in children with CP. RESULTS: There were significant differences in the DTI-ALPS index between children with CP and their typically developing peers. The DTI-ALPS index of the children with CP was lower than that of the controls (1.448 vs. 1.625, P = 0.003). The mediation analysis showed that the DTI-ALPS index fully mediated the relationship between brain lesion burden and the MACS level (c' = 0.061, P = 0.665), explaining 80% of the effect. CONCLUSION: This study provides new insights into the neural basis of hand dysfunction in children with CP, demonstrating an important role of glymphatic impairment in such patients. These results suggest that PVL might affect hand function in children with CP by disrupting glymphatic drainage.

Limb-specific thalamocortical tracts are impaired differently in hemiplegic and diplegic subtypes of cerebral palsy.

Thalamocortical pathways are considered crucial in the sensorimotor functioning of children with cerebral palsy (CP). However, previous research has been limited by non-specific tractography seeding and the lack of comparison between different CP subtypes. We compared limb-specific thalamocortical tracts between children with hemiplegic (HP, N = 15) or diplegic (DP, N = 10) CP and typically developed peers (N = 19). The cortical seed-points for the upper and lower extremities were selected (i) manually based on anatomical landmarks or (ii) using functional magnetic resonance imaging (fMRI) activations following proprioceptive-limb stimulation. Correlations were investigated between tract structure (mean diffusivity, MD; fractional anisotropy, FA; apparent fiber density, AFD) and sensorimotor performance (hand skill and postural stability). Compared to controls, our results revealed increased MD in both upper and lower limb thalamocortical tracts in the non-dominant hemisphere in HP and bilaterally in DP subgroup. MD was strongly lateralized in participants with hemiplegia, while AFD seemed lateralized only in controls. fMRI-based tractography results were comparable. The correlation analysis indicated an association between the white matter structure and sensorimotor performance. These findings suggest distinct impairment of functionally relevant thalamocortical pathways in HP and DP subtypes. Thus, the organization of thalamocortical white matter tracts may offer valuable guidance for targeted, life-long rehabilitation in children with CP.

Exploration of the triceps surae muscle in ambulatory children with cerebral palsy using instrumented measurements of stiffness and diffusion tensor magnetic resonance imaging for muscle architecture.

BACKGROUND: Musculoskeletal alterations causing reduced range of motion of the ankle joint are common in children with cerebral palsy (CP). Objective measurements of passive joint resistance and three-dimensional skeletal muscle volume and muscle architecture can lead to a comprehensive understanding of which factors influence joint range of motion. RESEARCH QUESTION: To investigate the relation between the passive dorsiflexion of the ankle joint, biomechanical contributing factors to the passive joint resistance, and muscular architectural properties of the triceps surae muscle in children with CP. METHODS: In this cross-sectional observational study, 14 children with spastic CP (bilateral: 5, unilateral: 9, Gross Motor Function Classification System (GMFCS) level I:11, II:3) naïve to intramuscular tone reducing treatment, and 14 TD children were included. The passive dorsiflexion of the ankle was measured with a goniometer. Passive joint resistance and related parameters were estimated based on a biomechanical model and measurements using a motorized device, the Neuroflexor. Three-dimensional muscle architecture was quantified with diffusion tensor magnetic resonance imaging (DT-MRI). RESULTS: In the CP group, the median [min, max] passive dorsiflexion was decreased in the most affected leg (MAL) compared to the less affected leg (LAL) (2.5° [-25°, 20°] vs. 12.5° [5°, 30°], p = 0.001). The stiffness coefficient (Nm/rad) in the MAL was significantly higher in children with CP compared to TD children (7.10 [3.39, 62.00] vs. 2.82 [1.24, 10.46], p = 0.015). Muscle architecture properties did not differ between CP and TD, except for pennation angle in the medial gastrocnemius (MG) of the MAL (CP 17.64° (2.29) vs. TD 21.46° (3.20), p = 0.017). The stiffness coefficient, in the MAL, correlated negatively to passive dorsiflexion (rs=-0.638) and pennation angle in medial gastrocnemius (rs=-0.964), and the non-linear coefficient (Non-linear 1) correlated negatively to the fascicle length of the medial gastrocnemius (rs=-0.857). CONCLUSION: This study shows that stiffness of the plantarflexors is related to decreased passive dorsiflexion of the ankle and muscle structure of the MG in high-functioning children with spastic CP. Assessments of how dynamic components as well as microscopic muscle alterations contribute to joint stiffness in the plantarflexors in individuals with CP are warranted. TRIAL REGISTRATION: Retrospectively registered in ClinicalTrials.gov, NCT05447299. Observational study. Study start: 2019-01-15, register date: 2022-07-01.

Ex vivo adult stem cell characterization from multiple muscles in ambulatory children with cerebral palsy during early development of contractures.

Cerebral palsy (CP) is one of the most common conditions leading to lifelong childhood physical disability. Literature reported previously altered muscle properties such as lower number of satellite cells (SCs), with altered fusion capacity. However, these observations highly vary among studies, possibly due to heterogeneity in patient population, lack of appropriate control data, methodology and different assessed muscle. In this study we aimed to strengthen previous observations and to understand the heterogeneity of CP muscle pathology. Myogenic differentiation of SCs from the Medial Gastrocnemius (MG) muscle of patients with CP (n = 16, 3-9 years old) showed higher fusion capacity compared to age-matched typically developing children (TD, n = 13). Furthermore, we uniquely assessed cells of two different lower limb muscles and showed a decreased myogenic potency in cells from the Semitendinosus (ST) compared to the MG (TD: n = 3, CP: n = 6). Longitudinal assessments, one year after the first botulinum toxin treatment, showed slightly reduced SC representations and lower fusion capacity (n = 4). Finally, we proved the robustness of our data, by assessing in parallel the myogenic capacity of two samples from the same TD muscle. In conclusion, these data confirmed previous findings of increased SC fusion capacity from MG muscle of young patients with CP compared to age-matched TD. Further elaboration is reported on potential factors contributing to heterogeneity, such as assessed muscle, CP progression and reliability of primary outcome parameters.

Depth-Sensing-Based Algorithm for Chest Morphology Assessment in Children with Cerebral Palsy.

This study introduced a depth-sensing-based approach with robust algorithms for tracking relative morphological changes in the chests of patients undergoing physical therapy. The problem that was addressed was the periodic change in morphological parameters induced by breathing, and since the recording was continuous, the parameters were extracted for the moments of maximum and minimum volumes of the chest (inspiration and expiration moments), and analyzed. The parameters were derived from morphological transverse cross-sections (CSs), which were extracted for the moments of maximal and minimal depth variations, and the reliability of the results was expressed through the coefficient of variation (CV) of the resulting curves. Across all subjects and levels of observed anatomy, the mean CV for CS depth values was smaller than 2%, and the mean CV of the CS area was smaller than 1%. To prove the reproducibility of measurements (extraction of morphological parameters), 10 subjects were recorded in two consecutive sessions with a short interval (2 weeks) where no changes in the monitored parameters were expected and statistical methods show that there was no statistically significant difference between the sessions, which confirms the reproducibility hypothesis. Additionally, based on the representative CSs for inspiration and expirations moments, chest mobility in quiet breathing was examined, and the statistical test showed no difference between the two sessions. The findings justify the proposed algorithm as a valuable tool for evaluating the impact of rehabilitation exercises on chest morphology.

Resident muscle stem cell myogenic characteristics in postnatal muscle growth impairments in children with cerebral palsy.

Children with cerebral palsy (CP), a perinatal brain alteration, have impaired postnatal muscle growth, with some muscles developing contractures. Functionally, children are either able to walk or primarily use wheelchairs. Satellite cells are muscle stem cells (MuSCs) required for postnatal development and source of myonuclei. Only MuSC abundance has been previously reported in contractured muscles, with myogenic characteristics assessed only in vitro. We investigated whether MuSC myogenic, myonuclear, and myofiber characteristics in situ differ between contractured and noncontractured muscles, across functional levels, and compared with typically developing (TD) children with musculoskeletal injury. Open muscle biopsies were obtained from 36 children (30 CP, 6 TD) during surgery; contracture correction for adductors or gastrocnemius, or from vastus lateralis [bony surgery in CP, anterior cruciate ligament (ACL) repair in TD]. Muscle cross sections were immunohistochemically labeled for MuSC abundance, activation, proliferation, nuclei, myofiber borders, type-1 fibers, and collagen content in serial sections. Although MuSC abundance was greater in contractured muscles, primarily in type-1 fibers, their myogenic characteristics (activation, proliferation) were lower compared with noncontractured muscles. Overall, MuSC abundance, activation, and proliferation appear to be associated with collagen content. Myonuclear number was similar between all muscles, but only in contractured muscles were there associations between myonuclear number, MuSC abundance, and fiber cross-sectional area. Puzzlingly, MuSC characteristics were similar between ambulatory and nonambulatory children. Noncontractured muscles in children with CP had a lower MuSC abundance compared with TD-ACL injured children, but similar myogenic characteristics. Contractured muscles may have an intrinsic deficiency in developmental progression for postnatal MuSC pool establishment, needed for lifelong efficient growth and repair.

The role of PQBP1 in neural development and function.

Mutations in the polyglutamine tract-binding protein 1 (PQBP1) gene are associated with Renpenning syndrome, which is characterized by microcephaly, intellectual deficiency, short stature, small testes, and distinct facial dysmorphism. Studies using different models have revealed that PQBP1 plays essential roles in neural development and function. In this mini-review, we summarize recent findings relating to the roles of PQBP1 in these processes, including in the regulation of neural progenitor proliferation, neural projection, synaptic growth, neuronal survival, and cognitive function via mRNA transcription and splicing-dependent or -independent processes. The novel findings provide insights into the mechanisms underlying the pathogenesis of Renpenning syndrome and may advance drug discovery and treatment for this condition.

Altered Somatosensory Cortical Activity Is Associated with Cortical Thickness in Adults with Cerebral Palsy: Multimodal Evidence from MEG/sMRI.

Somatosensory cortical activity is altered in individuals with cerebral palsy (CP). However, previous studies have focused on the lower extremities in children with CP and have given less attention to structural changes that may contribute to these alterations. We used a multimodal neuroimaging approach to investigate the relationship between somatosensory cortical activity and cortical thickness in 17 adults with CP (age = 32.8 ± 9.3 years) and 18 healthy adult controls (age = 30.7 ± 9.8 years). Participants performed a median nerve paired-pulse stimulation paradigm while undergoing magnetoencephalography (MEG) to investigate somatosensory cortical activity and sensory gating. Participants also underwent magnetic resonance imaging to evaluate cortical thickness within the area of the somatosensory cortex that generated the MEG response. We found that the somatosensory responses were attenuated in the adults with CP (P = 0.004). The adults with CP also hypergated the second stimulation (P = 0.030) and had decreased cortical thickness in the somatosensory cortex (P = 0.015). Finally, the strength of the somatosensory response was significantly correlated with the cortical thickness (P = 0.023). These findings demonstrate that the aberrant somatosensory cortical activity in adults with CP extends to the upper extremities and appears to be related to cortical thickness.

Brain volumes and functional outcomes in children without cerebral palsy after therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy.

AIM: To investigate whether brain volumes were reduced in children aged 6 to 8 years without cerebral palsy, who underwent therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy (patients), and matched controls, and to examine the relation between subcortical volumes and functional outcome. METHOD: We measured regional brain volumes in 31 patients and 32 controls (median age 7 years and 7 years 2 months respectively) from T1-weighted magnetic resonance imaging (MRI). We assessed cognition using the Wechsler Intelligence Scales for Children, Fourth Edition and motor ability using the Movement Assessment Battery for Children, Second Edition (MABC-2). RESULTS: Patients had lower volume of whole-brain grey matter, white matter, pallidi, hippocampi, and thalami than controls (false discovery rate-corrected p < 0.05). Differences in subcortical grey-matter volumes were not independent of total brain volume (TBV). In patients, hippocampal and thalamic volumes correlated with full-scale IQ (hippocampi, r = 0.477, p = 0.010; thalami, r = 0.452, p = 0.016) and MABC-2 total score (hippocampi, r = 0.526, p = 0.004; thalami, r = 0.505, p = 0.006) independent of age, sex, and TBV. No significant correlations were found in controls. In patients, cortical injury on neonatal MRI was associated with reduced volumes of hippocampi (p = 0.001), thalami (p = 0.002), grey matter (p = 0.015), and white matter (p = 0.013). INTERPRETATION: Children who underwent therapeutic hypothermia have reduced whole-brain grey and white-matter volumes, with associations between hippocampal and thalamic volumes and functional outcomes.

Brain Outcomes in Runted Piglets: A Translational Model of Fetal Growth Restriction.

Fetal growth restriction (FGR) is associated with long-term neurodevelopmental disabilities including learning and behavioral disorders, autism, and cerebral palsy. Persistent changes in brain structure and function that are associated with developmental disabilities are demonstrated in FGR neonates. However, the mechanisms underlying these changes remain to be determined. There are currently no therapeutic interventions available to protect the FGR newborn brain. With the wide range of long-term neurodevelopmental disorders associated with FGR, the use of an animal model appropriate to investigating mechanisms of injury in the FGR newborn is crucial for the development of effective and targeted therapies for babies. Piglets are ideal animals to explore how perinatal insults affect brain structure and function. FGR occurs spontaneously in the piglet, unlike other animal models that require surgical or chemical intervention, allowing brain outcomes to be studied without the confounding impacts of experimental interventions. The FGR piglet mimics many of the human pathophysiological outcomes associated with FGR including asymmetrical growth restriction with brain sparing. This review will discuss the similarities observed in brain outcomes between the FGR human and FGR piglet from a magnetic resonance imaging in the living and a histological perspective. FGR piglet studies provide the opportunity to determine and track mechanisms of brain injury in a clinically relevant animal model of FGR. Findings from these FGR piglet studies may provide critical information to rapidly translate neuroprotective interventions to clinic to improve outcomes for newborn babies.

Glycine receptor subunit-ß-deficiency in a mouse model of spasticity results in attenuated physical performance, growth, and muscle strength.

Spasticity is the most common neurological disorder associated with increased muscle contraction causing impaired movement and gait. The aim of this study was to characterize the physical performance, skeletal muscle function, and phenotype of mice with a hereditary spastic mutation (B6.Cg-Glrbspa/J). Motor function, gait, and physical activity of juvenile and adult spastic mice and the morphological, histological, and mechanical characteristics of their soleus and gastrocnemius medialis muscles were compared with those of their wild-type (WT) littermates. Spastic mice showed attenuated growth, impaired motor function, and low physical activity. Gait of spastic mice was characterized by a typical hopping pattern. Spastic mice showed lower muscle forces, which were related to the smaller physiological cross-sectional area of spastic muscles. The muscle-tendon complex length-force relationship of adult gastrocnemius medialis was shifted toward shorter lengths, which was explained by attenuated longitudinal tibia growth. Spastic gastrocnemius medialis was more fatigue resistant than WT gastrocnemius medialis. This was largely explained by a higher mitochondrial content in muscle fibers and relatively higher percentage of slow-type muscle fibers. Muscles of juvenile spastic mice showed similar differences compared with WT juvenile mice, but these were less pronounced than between adult mice. This study shows that in spastic mice, disturbed motor function and gait is likely to be the result of hyperactivity of skeletal muscle and impaired skeletal muscle growth, which progress with age.

Pathogenic convergence of CNVs in genes functionally associated to a severe neuromotor developmental delay syndrome.

BACKGROUND: Complex developmental encephalopathy syndromes might be the consequence of unknown genetic alterations that are likely to contribute to the full neurological phenotype as a consequence of pathogenic gene combinations. METHODS: To identify the additional genetic contribution to the neurological phenotype, we studied as a test case a boy, with a KCNQ2 exon-7 partial duplication, by single-nucleotide polymorphism (SNP) microarray to detect copy-number variations (CNVs). RESULTS: The proband presented a cerebral palsy like syndrome with a severe motor and developmental encephalopathy. The SNP array analysis detected in the proband several de novo CNVs, nine partial gene losses (LRRC55, PCDH9, NALCN, RYR3, ELAVL2, CDH13, ATP1A2, SLC17A5, ANO3), and two partial gene duplications (PCDH19, EFNA5). The biological functions of these genes are associated with ion channels such as calcium, chloride, sodium, and potassium with several membrane proteins implicated in neural cell-cell interactions, synaptic transmission, and axon guidance. Pathogenically, these functions can be associated to cerebral palsy, seizures, dystonia, epileptic crisis, and motor neuron dysfunction, all present in the patient. CONCLUSIONS: Severe motor and developmental encephalopathy syndromes of unknown origin can be the result of a phenotypic convergence by combination of several genetic alterations in genes whose physiological function contributes to the neurological pathogenic mechanism.