Very Preterm Early Motor Repertoire and Neurodevelopmental Outcomes at 8 Years

BACKGROUND AND OBJECTIVES: Children born very preterm (<32 weeks' gestation) have more neurodevelopmental problems compared with term-born peers. Aberrant fidgety movements (FMs) are associated with adverse motor outcomes in children born very preterm. However, associations of aberrant FMs combined with additional movements and postures to give a motor optimality score-revised (MOS-R) with school-aged cognitive and motor outcomes are unclear. Our aim with this study was to determine those associations. METHODS: Of 118 infants born <30 weeks' gestation recruited into a randomized controlled trial of early intervention, 97 had a general movements assessment at 3 months' corrected age and were eligible for this study. Early motor repertoire including FMs and MOS-R were scored from videos of infant's spontaneous movement at 3 months' corrected age. At 8 years' corrected age, cognitive and motor performances were evaluated. Associations of early FMs and MOS-R with outcomes at 8 years were determined using linear regression. RESULTS: Seventy-eight (80%) infants with early motor repertoire data had neurodevelopmental assessments at 8 years. A higher MOS-R, and favorable components of the individual subscales of the MOS-R, including the presence of normal FMs, were associated with better performance for general cognition, attention, working memory, executive function and motor function at 8 years; eg, presence of normal FMs was associated with a 21.6 points higher general conceptual ability score (95% confidence interval: 12.8-30.5; P < .001) compared with absent FMs. CONCLUSIONS: Favorable early motor repertoire of infants born <30 weeks is strongly associated with improved cognitive and motor performance at 8 years

Impact of hypercapnia on alveolar Na+-transport : Establishing a system for ENaC-protein detection

Acute respiratory distress syndrome is a life threatening condition triggered by a variety of pulmonary and extrapulmonary causes, that is characterized by pulmonary edema and subsequently impaired gas exchange. Due to lung protective ventilation strategies, its treatment is often associated with systemic accumulation of CO2, a condition termed permissive hypercapnia. Recent studies report a negative effect of CO2 on alveolar fluid clearance, a process mediated by its two key elements the Na+,K+-ATPase and epithelial Na+-channels (ENaCs). A reduced activity of the Na+,K+-ATPase during hypercapnia has already been demonstrated, but regulation of ENaC has never been directly linked to CO2. Many molecular signaling events that are activated during hypercapnia are known to regulate ENaC function, so the present study aimed to generate and subsequently apply techniques to investigate a possible contribution of ENaC to the reduction of alveolar epithelial fluid transport upon hypercapnia. ENaC function was studied in H441 cells by Ussing chamber experiments which revealed no significant regulation during short term hypercapnia, but a clear reduction of ENaC function during sustained hypercapnia. To identify the signaling mechanism on the molecular level, epitope-tagged human ENaC constructs for the &#945;-, &#946;- and &#947;-subunit were cloned and initially expressed in A549 cells. Exposition to hypercapnia up to 4 hours did not significantly reduce cell surface expression of the ENaC-subunits, but after 24 hours, a significant decrease of &#946;-ENaC was observed. Since the molecular sizes of &#945;- and &#947;-ENaC expressed in A549 cells were differing from previously published studies, transfection of ENaC was continued in other cells. H441 cells are commonly used for ENaC studies, so their transfection was established, yielding an efficiency of about 60 %. The molecular sizes of transfected ENaC subunits matched the pattern that was expected, but expression levels were evanescent and too low for further experiments. Since ENaC detection in these two cell lines remained problematic, a novel methodology was applied. Since the primary site of ENaC expression in the lung are epithelial cells, rat primary alveolar epithelial cells type II were used as recipients for ENaC plasmids. Non-viral transfection of ATII cells has been inefficient in the past, but during the present study a protocol was generated to efficiently deliver nucleic acids to exactly this cell type. ENaC expression was largely increased in ATII cells, compared to the cell lines used, indicating that established system might be extremely useful for further studies involving ENaC turnover. Thus, a new and highly relevant, non-viral transfection technique for primary alveolar epithelial type II cells was established, providing ground-breaking opportunities for future pulmonary research.Das Atemnotsyndrom des Erwachsenen ist eine lebensbedrohliche Erkrankung, ausgelöst durch eine Reihe von Faktoren, die direkt oder indirekt auf die Lunge einwirken . Charakteristisch für dieses Syndrom sind pulmonare Ödeme und daraus resultierend ein eingeschränkter Gasaustausch. Die daher benötigte künstliche Beatmung führt im Zuge von protektiven Beatmungsstrategien oft zu einer systemischen Anreicherung von CO2 (Hyperkapnie). Einige Studien zeigen, dass erhöhte CO2-Level den Flüssigkeitstransport der Lunge einschränken. Dieser aktive Prozess wird maßgeblich durch zwei Komponenten, die Na+,K+-ATPase und epitheliale Na+-Kanäle (ENaCs), kontrolliert. Eine Beeinträchtigung der Na+,K+-ATPase durch CO2 gezeigt, für ENaCs ist dies bislang nicht bekannt. Einige bekannte Regulatoren von ENaCs werden jedoch während Hyperkapnie aktiviert. Das Ziel der vorliegenden Arbeit war, Methoden zu etablieren und anzuwenden, die einen möglichen Einfluss von CO2 auf ENaC zeigen. Funktionelle Versuche wurden an H441-Zellen mit Ussing-Kammer-Messungen durchgeführt. Während akuter Hyperkapnie konnte keine signifikante Regulation von ENaC nachgewiesen werden, jedoch war die ENaC-Funktion bei anhaltender Hyperkapnie deutlich verringert. Um die Signalwege auf molekularer Ebene zu untersuchen, wurde die &#945;-, &#946;- und &#947;- Untereinheit des humanen ENaC kloniert, genetisch modifiziert und in A549 Zellen überexprimiert. Nach bis zu vierstündiger Hyperkapnie erfolgte keine Regulation von ENaC, jedoch wurde nach 24 Stunden eine deutlich verminderte Menge &#946;-ENaC in der Zellmembran nachgewiesen. Da die Größen von &#945;- und &#947;-ENaC von den bisher publizierten abwichen, wurden weitere Versuche in H441 Zellen durchgeführt. Die Transfektion dieser Zelllinie wurde etabliert und erreichte eine Effizienz von ungefähr 60 %. Die posttranslationale Regulation der &#945;- und &#947;-Untereinheiten, insbesondere die proteolytische Aktivierung funktionierten wie in der Literatur beschrieben, jedoch waren die Expressionslevel zu gering für weitere Versuche. In der Lunge werden ENaCs überwiegend in epithelialen Zellen exprimiert. Diese Zellen konnten bisher jedoch nicht effizient transfiziert werden, ohne Viren einzusetzen. In der vorliegenden Arbeit wurde jedoch eine effiziente Methode zur Transfektion von primären epithelialen Zellen der Ratte erarbeitet. Die Expression von transfizierten ENaC-Untereinheiten war in diesen Zellen deutlich erhöht, weswegen die Etablierung dieses Systems ausschlaggebend für weitere Versuche ist. Die vorliegende Arbeit beschreibt daher zum ersten Mal die nicht-virale, effiziente Transfektion von primären alveolaren Zellen und liefert damit ein bedeutendes neues Werkzeug für die Lungenforschung

Bike skills training for children with cerebral palsy: protocol for a randomised controlled trial

INTRODUCTION: Two-wheel bike riding can be a goal for children with cerebral palsy (CP) and a means of participating in physical activity. It is possible for some children with CP to ride a two-wheel bike; however, currently far fewer can ride compared with their typically developing peers. Evidence supports training targeted towards goals of the child with CP and their family; yet there is little evidence to guide best-practice bike skills training. Task-specific training may lead to attainment of two-wheel bike-specific goals. This study aims to determine if a novel task-specific approach to training two-wheel bike skills is more effective than a parent-led home programme for attaining individualised two-wheel bike-specific goals in independently ambulant children with CP aged 6-15 years. METHODS AND ANALYSIS: Sixty eligible children with CP (Gross Motor Function Classification System levels I-II) aged 6-15 years with goals relating to riding a two-wheel bike will be randomised to either a novel task-specific centre-based group programme (intervention) or a parent-led home-based programme (comparison), both involving a 1-week intervention period. The primary outcome is goal attainment in the week following the intervention period (T1). Secondary outcomes include: goal attainment and participation in physical activity at 3&thinsp;months postintervention (T2) and bike skills, attendance and involvement in bike riding, self-perception and functional skills at T1 and T2. Economic appraisal will involve cost-effectiveness and cost-utility analyses. Adherence of clinicians and parents to the intervention and comparison protocols will be assessed. Linear and logistic regression will be used to assess the effect of the intervention, adjusted for site as used in the randomisation process. ETHICS AND DISSEMINATION: This study was approved by the Human Research and Ethics Committees at The Royal Children\u27s Hospital (#36209). Results will be disseminated via peer-reviewed publications and conference presentations.<br /

Neurobehaviour between birth and 40 weeks’ gestation in infants born <30 weeks’ gestation and parental psychological wellbeing: predictors of brain development and child outcomes

BACKGROUND: Infants born <30 weeks’ gestation are at increased risk of long term neurodevelopmental problems compared with term born peers. The predictive value of neurobehavioural examinations at term equivalent age in very preterm infants has been reported for subsequent impairment. Yet there is little knowledge surrounding earlier neurobehavioural development in preterm infants prior to term equivalent age, and how it relates to perinatal factors, cerebral structure, and later developmental outcomes. In addition, maternal psychological wellbeing has been associated with child development. Given the high rate of psychological distress reported by parents of preterm children, it is vital we understand maternal and paternal wellbeing in the early weeks and months after preterm birth and how this influences the parent–child relationship and children’s outcomes. Therefore this study aims to examine how 1) early neurobehaviour and 2) parental mental health relate to developmental outcomes for infants born preterm compared with infants born at term. METHODS/DESIGN: This prospective cohort study will describe the neurobehaviour of 150 infants born at <30 weeks’ gestational age from birth to term equivalent age, and explore how early neurobehavioural deficits relate to brain growth or injury determined by magnetic resonance imaging, perinatal factors, parental mental health and later developmental outcomes measured using standardised assessment tools at term, one and two years’ corrected age. A control group of 150 healthy term-born infants will also be recruited for comparison of outcomes. To examine the effects of parental mental health on developmental outcomes, both parents of preterm and term-born infants will complete standardised questionnaires related to symptoms of anxiety, depression and post-traumatic stress at regular intervals from the first week of their child’s birth until their child’s second birthday. The parent–child relationship will be assessed at one and two years’ corrected age. DISCUSSION: Detailing the trajectory of infant neurobehaviour and parental psychological distress following very preterm birth is important not only to identify infants most at risk, further understand the parental experience and highlight potential times for intervention for the infant and/or parent, but also to gain insight into the effect this has on parent–child interaction and child development

Neonatal brain tissue classification with morphological adaptation and unified segmentation

Measuring the distribution of brain tissue types (tissue classification) in neonates is necessary for studying typical and atypical brain development, such as that associated with preterm birth, and may provide biomarkers for neurodevelopmental outcomes. Compared with magnetic resonance images of adults, neonatal images present specific challenges that require the development of specialized, population-specific methods. This paper introduces MANTiS (Morphologically Adaptive Neonatal Tissue Segmentation), which extends the unified segmentation approach to tissue classification implemented in Statistical Parametric Mapping (SPM) software to neonates. MANTiS utilizes a combination of unified segmentation, template adaptation via morphological segmentation tools and topological filtering, to segment the neonatal brain into eight tissue classes: cortical gray matter, white matter, deep nuclear gray matter, cerebellum, brainstem, cerebrospinal fluid (CSF), hippocampus and amygdala. We evaluated the performance of MANTiS using two independent datasets. The first dataset, provided by the NeoBrainS12 challenge, consisted of coronal T2-weighted images of preterm infants (born ≤30 weeks’ gestation) acquired at 30 weeks’ corrected gestational age (n= 5), coronal T2-weighted images of preterm infants acquired at 40 weeks’ corrected gestational age (n= 5) and axial T2-weighted images of preterm infants acquired at 40 weeks’ corrected gestational age (n= 5). The second dataset, provided by the Washington University NeuroDevelopmental Research (WUNDeR) group, consisted of T2-weighted images of preterm infants (born <30 weeks’ gestation) acquired shortly after birth (n= 12), preterm infants acquired at term-equivalent age (n= 12), and healthy term-born infants (born ≥38 weeks’ gestation) acquired within the first nine days of life (n= 12). For the NeoBrainS12 dataset, mean Dice scores comparing MANTiS with manual segmentations were all above 0.7, except for the cortical gray matter for coronal images acquired at 30 weeks. This demonstrates that MANTiS’ performance is competitive with existing techniques. For the WUNDeR dataset, mean Dice scores comparing MANTiS with manually edited segmentations demonstrated good agreement, where all scores were above 0.75, except for the hippocampus and amygdala. The results show that MANTiS is able to segment neonatal brain tissues well, even in images that have brain abnormalities common in preterm infants. MANTiS is available for download as an SPM toolbox from http://developmentalimagingmcri.github.io/mantis

Desikan-Killiany-Tourville Atlas Compatible Version of M-CRIB Neonatal Parcellated Whole Brain Atlas: The M-CRIB 2.0

Our recently published M-CRIB atlas comprises 100 neonatal brain regions including 68 compatible with the widely-used Desikan-Killiany adult cortical atlas. A successor to the Desikan-Killiany atlas is the Desikan-Killiany-Tourville atlas, in which some regions with unclear boundaries were removed, and many existing boundaries were revised to conform to clearer landmarks in sulcal fundi. Our first aim here was to modify cortical M-CRIB regions to comply with the Desikan-Killiany-Tourville protocol, in order to offer: (a) compatibility with this adult cortical atlas, (b) greater labeling accuracy due to clearer landmarks, and (c) optimisation of cortical regions for integration with surface-based infant parcellation pipelines. Secondly, we aimed to update subcortical regions in order to offer greater compatibility with subcortical segmentations produced in FreeSurfer. Data utilized were the T2-weighted MRI scans in our M-CRIB atlas, for 10 healthy neonates (post-menstrual age at MRI 40–43 weeks, four female), and corresponding parcellated images. Edits were performed on the parcellated images in volume space using ITK-SNAP. Cortical updates included deletion of frontal and temporal poles and ‘Banks STS,’ and modification of boundaries of many other regions. Changes to subcortical regions included the addition of ‘ventral diencephalon,’ and deletion of ‘subcortical matter’ labels. A detailed updated parcellation protocol was produced. The resulting whole-brain M-CRIB 2.0 atlas comprises 94 regions altogether. This atlas provides comparability with adult Desikan-Killiany-Tourville-labeled cortical data and FreeSurfer-labeed subcortical data, and is more readily adaptable for incorporation into surface-based neonatal parcellation pipelines. As such, it offers the ability to help facilitate a broad range of investigations into brain structure and function both at the neonatal time point and developmentally across the lifespan

Long term follow up of high risk children: who, why and how?

Background: Most babies are born healthy and grow and develop normally through childhood. There are, however, clearly identifiable high-risk groups of survivors, such as those born preterm or with ill-health, who are destined to have higher than expected rates of health or developmental problems, and for whom more structured and specialised follow-up programs are warranted. Discussion This paper presents the results of a two-day workshop held in Melbourne, Australia, to discuss neonatal populations in need of more structured follow-up and why, in addition to how, such a follow-up programme might be structured. Issues discussed included the ages of follow-up, and the personnel and assessment tools that might be required. Challenges for translating results into both clinical practice and research were identified. Further issues covered included information sharing, best practice for families and research gaps. Summary A substantial minority of high-risk children has long-term medical, developmental and psychological adverse outcomes and will consume extensive health and education services as they grow older. Early intervention to prevent adverse outcomes and the effective integration of services once problems are identified may reduce the prevalence and severity of certain outcomes, and will contribute to an efficient and effective use of health resources. The shared long-term goal for families and professionals is to work toward ensuring that high risk children maximise their potential and become productive and valued members of society. Electronic supplementary material The online version of this article (doi:10.1186/1471-2431-14-279) contains supplementary material, which is available to authorized users

Cerebral Palsy:Early Markers of Clinical Phenotype and Functional Outcome

The Prechtl General Movement Assessment (GMA) has become a cornerstone assessment in early identification of cerebral palsy (CP), particularly during the fidgety movement period at 3-5 months of age. Additionally, assessment of motor repertoire, such as antigravity movements and postural patterns, which form the Motor Optimality Score (MOS), may provide insight into an infant's later motor function. This study aimed to identify early specific markers for ambulation, gross motor function (using the Gross Motor Function Classification System, GMFCS), topography (unilateral, bilateral), and type (spastic, dyskinetic, ataxic, and hypotonic) of CP in a large worldwide cohort of 468 infants. We found that 95% of children with CP did not have fidgety movements, with 100% having non-optimal MOS. GMFCS level was strongly correlated to MOS. An MOS > 14 was most likely associated with GMFCS outcomes I or II, whereas GMFCS outcomes IV or V were hardly ever associated with an MOS > 8. A number of different movement patterns were associated with more severe functional impairment (GMFCS III-V), including atypical arching and persistent cramped-synchronized movements. Asymmetrical segmental movements were strongly associated with unilateral CP. Circular arm movements were associated with dyskinetic CP. This study demonstrated that use of the MOS contributes to understanding later CP prognosis, including early markers for type and severity

Improving the outcome of infants born at <30 weeks' gestation - a randomized controlled trial of preventative care at home

Background: Early developmental interventions to prevent the high rate of neurodevelopmental problems in very preterm children, including cognitive, motor and behavioral impairments, are urgently needed. These interventions should be multi-faceted and include modules for caregivers given their high rates of mental health problems