Altered Cerebellar Biochemical Profiles in Infants Born Prematurely

This study aims to compare the cerebellar biochemical profiles in preterm (PT) infants evaluated at term equivalent age (TEA) and healthy full-term newborns using proton magnetic resonance spectroscopy (1H-MRS). We explore the associations between altered cerebellar metabolite profiles and brain injury topography, severity of injury, and prematurity-related clinical complications. We prospectively collected high quality 1H-MRS in 59 premature infants born ≤32 weeks and 61 healthy full term controls. 1H-MRS data were processed using LCModel software to calculate absolute metabolite concentration for N-acetyl-aspartate (NAA), choline (Cho) and creatine (Cr). PT infants had significantly lower cerebellar NAA (p \u3c 0.025) and higher Cho (p \u3c 0.001) at TEA when compared to healthy controls. Creatine was not different between the two groups. The presence of cerebellar injury was consistently associated with reduced concentrations for NAA, Cho, and Cr. Postnatal infection was negatively associated with NAA and Cr (p \u3c 005), while cerebral cortical brain injury severity was inversely associated with both Cho and Cr (p \u3c 0.01). We report for the first time that premature birth is associated with altered cerebellar metabolite profiles when compared to term born controls. Infection, cerebellar injury and supratentorial injury are important risk factors for impaired preterm cerebellar biochemistry

Regional microstructural organization of the cerebral cortex is affected by preterm birth.

Objectives: To compare regional cerebral cortical microstructural organization between preterm infants at term-equivalent age (TEA) and healthy full-term newborns, and to examine the impact of clinical risk factors on cerebral cortical micro-organization in the preterm cohort. Study design: We prospectively enrolled very preterm infants (gestational age (GA) at birth\u3c32 \u3eweeks; birthweight\u3c1500 \u3eg) and healthy full-term controls. Using non-invasive 3T diffusion tensor imaging (DTI) metrics, we quantified regional micro-organization in ten cerebral cortical areas: medial/dorsolateral prefrontal cortex, anterior/posterior cingulate cortex, insula, posterior parietal cortex, motor/somatosensory/auditory/visual cortex. ANCOVA analyses were performed controlling for sex and postmenstrual age at MRI. Results: We studied 91 preterm infants at TEA and 69 full-term controls. Preterm infants demonstrated significantly higher diffusivity in the prefrontal, parietal, motor, somatosensory, and visual cortices suggesting delayed maturation of these cortical areas. Additionally, postnatal hydrocortisone treatment was related to accelerated microstructural organization in the prefrontal and somatosensory cortices. Conclusions: Preterm birth alters regional microstructural organization of the cerebral cortex in both neurocognitive brain regions and areas with primary sensory/motor functions. We also report for the first time a potential protective effect of postnatal hydrocortisone administration on cerebral cortical development in preterm infants

Determinants of handwriting capacity in children newly diagnosed with attention deficity hyperactivity disorder prior to and following treatment with stimulant medication

Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common disorders of childhood and its consequences extend beyond the child, to include important impacts on the family and community. At present, the primary focus of interventions is on management of symptoms and promoting academic success. There is a common misconception that many of the social, cognitive and motor deficits frequently documented in children with ADHD are attributed to their inattentiveness and other behavioral difficulties. Persisting difficulties in these domains can further challenge the child's developmental trajectory and academic productivity and therefore should be addressed as part of health and educational services. Handwriting is an example of an important life skill that is reportedly impaired in this population, and often requires remediation. Nevertheless, the extent and nature of handwriting difficulties and factors associated with poor legibility are poorly understood in this population. The primary aim of this doctoral thesis was to objectively describe handwriting capacity in medication naïve-children with ADHD, to ascertain relationships between handwriting and motor and attentional abilities and to determine if handwriting improved significantly three months following treatment with stimulant medication. Children in our sample demonstrated wide variability in performance in terms of handwriting speed and legibility. As part of this doctoral project and with the collaboration of expert pediatric occupational therapists, clinical cut-off values that can be used to differentiate between children with and without legibility problems were developed for our outcome measure, the Evaluation Tool of Children's Handwriting. Applying these values, poor letter legibility was noted in 65.3% of the children at baseline (prior to initiation of medication) and persisted in 42.9% of the sample after treatment with stimulant medication. Concomitantly, motor difficulties were also highly prevalent (73.0% at baseline and 55.0% after treatment) with manual dexterity, as measured by the Movement Assessment Battery for Children, the most frequently impaired at both testing periods. Interestingly, handwriting difficulties were not more frequent in children with motor delays. Handwriting legibility was best determined by the visual-motor integration skills, as measured by the Developmental Test of Visual Motor Integration, prior to initiation of medication as well as three months after medication use. Change in legibility and speed of writing was also associated with change in visual-motor integration scores. Preliminary analyses did not consistently highlight particular factors associated with handwriting capacity, when comparing children with and without persisting motor difficulties. However, the severity of behavioral symptoms was significantly associated with components of motor performance. This study confirms that motor skills deficits, poor legibility and slow writing speed are highly prevalent in children with ADHD. The results of this study further suggest that use of stimulant medication to improve behavior in children with ADHD is not sufficient to eliminate these handwriting challenges nor the coexisting motor difficulties. These children would therefore greatly benefit from a routine evaluation by an occupational therapist focusing on motor performance and the child's performance in everyday meaningful activities such as handwriting so that problems may be readily identified and appropriately addressed to optimize the child's functional potential and participation in life roles.Le trouble déficitaire de l'attention avec ou sans hyperactivité (TDA/H) est l'un des diagnostics pédiatriques les plus répandus. Présentement, la gestion des symptômes et la promotion de la réussite académique de l'enfant sont au centre des interventions. La pensée populaire veut que plusieurs des déficits sociaux, cognitifs et moteurs fréquemment observés chez les enfants avec un TDA/H, seraient la conséquence de leurs difficultés d'attention. Lorsque ces déficits persistent, ils peuvent compliquer le développement et la réussite académique de ces enfants. Pour cette raison, ces difficultés doivent être rapidement reconnues et adressées par les ressources du domaine de l'éducation et de la santé. L'écriture manuelle est un exemple d'une habileté importante avec laquelle cette population éprouve souvent des difficultés. Toutefois, la nature et l'étendue des difficultés, ainsi que les facteurs associés avec la performance à l'écriture n'ont encore jamais été étudiés chez cette population. Les aspirations principales de cette thèse de doctorat étaient, dans un premier temps de décrire objectivement la capacité d'écriture manuelle des enfants avec un TDA/H n'ayant encore jamais reçu de médication; d'établir la relation entre leur capacité d'écriture et leurs habiletés motrices et attentionnelles; et finalement de déterminer si leur capacité d'écriture s'améliorera de façon significative après trois mois de traitement avec une médication psychostimulante. Dans le cadre de ce projet de doctorat, et avec la collaboration d'ergothérapeutes experts en pédiatrie, des valeurs limites ont été développées pour notre outil de mesure principal, the Evaluation Tool of Children's Handwriting, afin de différencier les enfants avec des problèmes de lisibilité de ceux qui n'en ont pas. Une pauvre lisibilité des lettres a été notée chez 65.3% des enfants de notre échantillon à l'évaluation initiale (avant le commencement de la médication), et a persisté dans 42.9% des cas lorsque ceux-ci ont été évalués après trois mois de traitement avec une médication psychostimulante. Les difficultés motrices étaient aussi très fréquentes (73.0% à l'évaluation initiale et 55.0% après traitement). La dextérité manuelle, évaluée avec the Movement Assessment Battery for Children, était l'habileté la plus faible et ce, à toutes les périodes d'évaluation. Étonnamment, les difficultés d'écriture n'étaient pas plus présentes chez les enfants avec des difficultés motrices. La lisibilité de l'écriture était fortement déterminée par les habiletés d'intégration visuo-motrice évaluées selon the Developmental Test of Visual Motor Integration, tant avant l'initiation de la médication que trois mois après. Un changement en lisibilité et en vitesse était également associé avec un changement dans les résultats obtenus à l'épreuve d'intégration visuo-motrice. Toutefois, la sévérité des symptômes comportementaux était associée avec certaines composantes motrices. Cette étude confirme que la lisibilité et la vitesse d'écriture sont fréquemment diminuées chez les enfants avec un TDA/H. Les résultats de cette étude suggèrent que l'emploi d'une médication psychostimulante qui améliorent les symptômes comportementaux des enfants avec un TDA/H comme seule intervention n'est pas suffisante pour remédier à leurs problèmes d'écriture ni aux difficultés motrices qui peuvent exister en comorbidité. Ces enfants bénéficieraient grandement d'une évaluation de routine en ergothérapie au moment du diagnostic dans le but d'identifier la présence de déficits moteurs et de déterminer leur performance dans leurs activités significatives de la vie quotidienne, telle que l'écriture. De telles difficultés pourraient alors être rapidement identifiées et adressées de façon appropriée afin d'optimiser le fonctionnement de l'enfant dans ses différents rôles occupationnels

A comparison of altered white matter microstructure in youth born with congenital heart disease or born preterm

IntroductionAlterations to white matter microstructure as detected by diffusion tensor imaging have been documented in both individuals born with congenital heart disease (CHD) and individuals born preterm. However, it remains unclear if these disturbances are the consequence of similar underlying microstructural disruptions. This study used multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) and neurite orientation dispersion and density imaging (NODDI) to characterize and compare alterations to three specific microstructural elements of white matter – myelination, axon density, and axon orientation – in youth born with CHD or born preterm.MethodsParticipants aged 16 to 26 years with operated CHD or born ≤33 weeks gestational age and a group of healthy peers of the same age underwent a brain MRI including mcDESPOT and high angular resolution diffusion imaging acquisitions. Using tractometry, average values of myelin water fraction (MWF), neurite density index (NDI), and orientation dispersion index (ODI) were first calculated and compared between groups for 30 white matter bundles. Afterwards, bundle profiling was performed to further characterize the topology of the detected microstructural alterations.ResultsThe CHD and preterm groups both presented with widespread bundles and bundle segments with lower MWF, accompanied by some occurrences of lower NDI, relative to controls. While there were no differences in ODI between the CHD and control groups, the preterm group presented with both higher and lower ODI compared to the control group and lower ODI compared to the CHD group.DiscussionWhile youth born with CHD or born preterm both presented with apparent deficits in white matter myelination and axon density, youth born preterm presented with a unique profile of altered axonal organization. Future longitudinal studies should aim to better understand the emergence of these common and distinct microstructural alterations, which could orient the development of novel therapeutic approaches

Developmental cerebellar cognitive affective syndrome in ex-preterm survivors following cerebellar injury

Cerebellar injury is increasingly recognized as an important complication of very preterm birth. However, the neurodevelopmental consequences of early life cerebellar injury in prematurely born infants have not been well elucidated. We performed a literature search of studies published between 1997 and 2014 describing neurodevelopmental outcomes of preterm infants following direct cerebellar injury or indirect cerebellar injury/underdevelopment. Available data suggests that both direct and indirect mechanisms of cerebellar injury appear to stunt cerebellar growth and adversely affect neurodevelopment. This review also provides important insights into the highly integrated cerebral-cerebellar structural and functional correlates. Finally, this review highlights that early life impairment of cerebellar growth extends far beyond motor impairments and plays a critical, previously underrecognized role in the long-term cognitive, behavioral, and social deficits associated with brain injury among premature infants. These data point to a developmental form of the cerebellar cognitive affective syndrome previously described in adults. Longitudinal prospective studies using serial advanced magnetic resonance imaging techniques are needed to better delineate the full extent of the role of prematurity-related cerebellar injury and topography in the genesis of cognitive, social-behavioral dysfunction

Early extra-uterine exposure alters regional cerebellar growth in infants born preterm

Objectives: To compare third trimester global and regional cerebellar volumetric growth at two time-points between very preterm (PT) infants and healthy gestational age-matched fetuses in the PT period and at term equivalent age (TEA). Study design: Using a prospective study design, high resolution anatomic magnetic resonance images (MRI) were acquired in PT infants (gestational age at birth < 32 weeks; birthweight < 1500 g) without cerebellar injury and healthy full-term controls. PT infants completed two MRIs, one as soon as medically stable and the other around TEA. Controls also completed two MRIs, one in utero (i.e. fetal MRI) and a postnatal MRI shortly after birth. The cerebellum of each participant was parcellated into 5 regions: left and right hemispheres, the anterior, neo and posterior vermis. Evidence of differences in regional volumes between term and pre-term infants matched for gestational age (GA) at the time of the first MRI were assessed using multiple linear regression. Results: we studied 76 subjects: 38 PT infants were matched to 38 healthy fetuses. At MRI-1, PT infants demonstrated decreased cerebellar hemispheric volumes and increased anterior, neo- and posterior vermian regional volumes when compared to healthy fetuses. At TEA, PT infants demonstrated a persistent increase in anterior, neo- and posterior vermian regional volumes but no longer showed reductions in cerebellar hemispheric volume. Only the neovermis volume demonstrated a significant negative association with birthweight, male gender and supratentorial injury. Conclusions: In the absence of demonstrable cerebellar parenchymal injury evident on conventional MRI, PT birth is associated with cerebellar growth alterations that are regionally- and temporally-specific. Keywords: Prematurity, Fetus, Cerebellum, Volume, Growt

Regional microstructural organization of the cerebral cortex is affected by preterm birth

Objectives: To compare regional cerebral cortical microstructural organization between preterm infants at term-equivalent age (TEA) and healthy full-term newborns, and to examine the impact of clinical risk factors on cerebral cortical micro-organization in the preterm cohort. Study design: We prospectively enrolled very preterm infants (gestational age (GA) at birth<32 weeks; birthweight<1500 g) and healthy full-term controls. Using non-invasive 3T diffusion tensor imaging (DTI) metrics, we quantified regional micro-organization in ten cerebral cortical areas: medial/dorsolateral prefrontal cortex, anterior/posterior cingulate cortex, insula, posterior parietal cortex, motor/somatosensory/auditory/visual cortex. ANCOVA analyses were performed controlling for sex and postmenstrual age at MRI. Results: We studied 91 preterm infants at TEA and 69 full-term controls. Preterm infants demonstrated significantly higher diffusivity in the prefrontal, parietal, motor, somatosensory, and visual cortices suggesting delayed maturation of these cortical areas. Additionally, postnatal hydrocortisone treatment was related to accelerated microstructural organization in the prefrontal and somatosensory cortices. Conclusions: Preterm birth alters regional microstructural organization of the cerebral cortex in both neurocognitive brain regions and areas with primary sensory/motor functions. We also report for the first time a potential protective effect of postnatal hydrocortisone administration on cerebral cortical development in preterm infants. Keywords: Prematurity, Cerebral cortex, Microstructural organization, Diffusion tension imagin