Regional vulnerability of longitudinal cortical association connectivity

Preterm born children with spastic diplegia type of cerebral palsy and white matter injury or periventricular leukomalacia (PVL), are known to have motor, visual and cognitive impairments. Most diffusion tensor imaging (DTI) studies performed in this group have demonstrated widespread abnormalities using averaged deterministic tractography and voxel-based DTI measurements. Little is known about structural network correlates of white matter topography and reorganization in preterm cerebral palsy, despite the availability of new therapies and the need for brain imaging biomarkers. Here, we combined novel post-processing methodology of probabilistic tractography data in this preterm cohort to improve spatial and regional delineation of longitudinal cortical association tract abnormalities using an along-tract approach, and compared these data to structural DTI cortical network topology analysis. DTI images were acquired on 16 preterm children with cerebral palsy (mean age 5.6 ± 4) and 75 healthy controls (mean age 5.7 ± 3.4). Despite mean tract analysis, Tract-Based Spatial Statistics (TBSS) and voxel-based morphometry (VBM) demonstrating diffusely reduced fractional anisotropy (FA) reduction in all white matter tracts, the along-tract analysis improved the detection of regional tract vulnerability. The along-tract map-structural network topology correlates revealed two associations: (1) reduced regional posterior–anterior gradient in FA of the longitudinal visual cortical association tracts (inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, optic radiation, posterior thalamic radiation) correlated with reduced posterior–anterior gradient of intra-regional (nodal efficiency) metrics with relative sparing of frontal and temporal regions; and (2) reduced regional FA within frontal–thalamic–striatal white matter pathways (anterior limb/anterior thalamic radiation, superior longitudinal fasciculus and cortical spinal tract) correlated with alteration in eigenvector centrality, clustering coefficient (inter-regional) and participation co-efficient (inter-modular) alterations of frontal–striatal and fronto-limbic nodes suggesting re-organization of these pathways. Both along tract and structural topology network measurements correlated strongly with motor and visual clinical outcome scores. This study shows the value of combining along-tract analysis and structural network topology in depicting not only selective parietal occipital regional vulnerability but also reorganization of frontal–striatal and frontal–limbic pathways in preterm children with cerebral palsy. These finding also support the concept that widespread, but selective posterior–anterior neural network connectivity alterations in preterm children with cerebral palsy likely contribute to the pathogenesis of neurosensory and cognitive impairment in this group

Parametric Mapping of Oxygen Activity in Human Placenta across Gestation using in utero BOLD imaging

International audienceSynopsis We present here, for the rst time, parametric maps of oxygen activity in normal human placenta using in utero functional MR imaging. Our method highlights anatomical and gestational age dependent patterns in placental activity. These maps can be used to gain insight into normative placental function and identifying insuucient or abnormal placental functioning at various points in gestation. Introduction Our current understanding of placental development and function is based on animal imaging and ex-vivo studies of placenta obtained after delivery or interrupted pregnancies. Previous human imaging studies were restricted to understanding hyperoxygentation or adverse developmental conditions such as fetal growth restriction (FGR), placental previa, placenta accrete, etc.. These studies strongly indicate that improved in-vivo delineation of vasculogenesis and angiogenesis of the placenta has the potential to provide better insight into the pathogenesis of placental dysfunction. By leveraging non-invasive, high-resolution imaging capabilities of in utero fetal MRI, we present a spatiotemporal analysis of normative fetoplacental oxygenation patterns at various time points in gestation. We hypothesize that (a) spatial variance of BOLD placental signal would age-dependent , and (b) that serial parametric maps of BOLD signal would reveal important anatomic insights about the feto-placental and maternal circulation. Methods We conducted a prospective two-site study of placental development in which 20 maternal subjects with normal pregnancies were recruited between 26-37 gestational weeks (GW). Images were acquired using 3T Philips Ingenia or Siemens Skyra machines. Over a 5-10 minute total acquisition time, BOLD images (1.5 mm x 1.5 mm x 4 mm) were acquired using an EPI sequence in blocks of 60 images with TR/TE = 3000/35 ms, ip angle = 90°. In addition, a high resolution T2 weighted images (1 mm x 1 mm x 3 mm) were acquired using a 3D FFE sequence (TR/TE = 3.1/1.6 ms, ip angle = 75°). BOLD images were processed using the "Functional MRI of the Brain" Software Library (FSL). The BOLD signal was motion corrected, co registered to the T2 images and ltered to remove physiological noise such as cardiac, breathing and metabolic uctuations. An F test was used to test the relationship between spatial signal variations and gestational age. To compare oxygenation levels within the placenta, we computed the normalized BOLD values after averaging the amplitude of the BOLD signal over the duration of the study for each time point. Results We found that the spatial variance of the BOLD signal was age dependent (F= 2.25, p<0.001). We then generated parametric maps of oxygen activity in a subset of fetuses at various gestational ages. Figure 1 shows the mean BOLD signal values across the placenta between 26 and 36 GW. The parametric mapping delineates two distinct regions of high oxygenation activity, corresponding to the fetal side (adjacent to the site of umbilical cord attachment) and the maternal side (along the uterine wall). The regions of high activity also occurred in speciic clusters. The size and number if these high-activity regions increased from 26 to 28 GW. We then observed a drop in the number and size of these regions at 29 GW with a further decrease at 36 GW. Discussion Our results clearly indicate that oxygenation is spatially heterogenous across the placenta with oxygen activity concentrated at speciic anatomical locations. The spatial variance in oxygen activity is also age-dependent. The reduction in size and number of high activity clusters at 29 GW and beyond correlates with the involution of the placenta in the third trimester leading to birth. Lower BOLD signal values in the middle of the placenta could correspond to the lack of deoxyhemoglobin as these regions only transport oxygen to the umbilical cord. The oxygenation maps provide a baseline for how oxygen activity occurs and changes over gestation giving us a better understanding of fetoplacental haemodynamics and placental transfer. They may also be used to identify abnormal oxygenation patterns in a placenta thereby acting as a marker for early detection of FGR or insuucient placental function. Conclusion There are age-dependent, spatial variances of BOLD signal in the placenta which may correlate with angiogenesis. Using parametric mapping of placental BOLD signal, we have demonstrated that placental oxygenation activity is concentrated at speciic anatomical locations associated with feto-maternal oxygen exchange. The non-invasive and repeatable methods presented here may facilitate better predictions of placental dysfunction in high-risk pregnancies and inform perinatal care

Organizational topology of brain and its relationship to ADHD in adolescents with d‐transposition of the great arteries

Abstract Objective: Little is currently known about the impact of congenital heart disease (CHD) on the organization of large‐scale brain networks in relation to neurobehavioral outcome. We investigated whether CHD might impact ADHD symptoms via changes in brain structural network topology in a cohort of adolescents with d‐transposition of the great arteries (d‐TGA) repaired with the arterial switch operation in early infancy and referent subjects. We also explored whether these effects might be modified by apolipoprotein E (APOE) genotype, as the APOE ε2 allele has been associated with worse neurodevelopmental outcomes after repair of d‐TGA in infancy. Methods: We applied graph analysis techniques to diffusion tensor imaging (DTI) data obtained from 47 d‐TGA adolescents and 29 healthy referents to construct measures of structural topology at the global and regional levels. We developed statistical mediation models revealing the respective contributions of d‐TGA, APOE genotype, and structural network topology on ADHD outcome as measured by the Connors ADHD/DSM‐IV Scales (CADS). Results: Changes in overall network connectivity, integration, and segregation mediated worse ADHD outcomes in d‐TGA patients compared to healthy referents; these changes were predominantly in the left and right intrahemispheric regional subnetworks. Exploratory analysis revealed that network topology also mediated detrimental effects of the APOE ε4 allele but improved neurobehavioral outcomes for the APOE ε2 allele. Conclusion: Our results suggest that disruption of organization of large‐scale networks may contribute to neurobehavioral dysfunction in adolescents with CHD and that this effect may interact with APOE genotype

Data_Sheet_1_Clinical factors associated with microstructural connectome related brain dysmaturation in term neonates with congenital heart disease.PDF

ObjectiveTerm congenital heart disease (CHD) neonates display abnormalities of brain structure and maturation, which are possibly related to underlying patient factors, abnormal physiology and perioperative insults. Our primary goal was to delineate associations between clinical factors and postnatal brain microstructure in term CHD neonates using diffusion tensor imaging (DTI) magnetic resonance (MR) acquisition combined with complementary data-driven connectome and seed-based tractography quantitative analyses. Our secondary goal was to delineate associations between mild dysplastic structural brain abnormalities and connectome and seed-base tractography quantitative analyses. These mild dysplastic structural abnormalities have been derived from prior human infant CHD MR studies and neonatal mouse models of CHD that were collectively used to calculate to calculate a brain dysplasia score (BDS) that included assessment of subcortical structures including the olfactory bulb, the cerebellum and the hippocampus.MethodsNeonates undergoing cardiac surgery for CHD were prospectively recruited from two large centers. Both pre- and postoperative MR brain scans were obtained. DTI in 42 directions was segmented into 90 regions using a neonatal brain template and three weighted methods. Clinical data collection included 18 patient-specific and 9 preoperative variables associated with preoperative scan and 6 intraoperative (e.g., cardiopulmonary bypass and deep hypothermic circulatory arrest times) and 12 postoperative variables associated with postoperative scan. We compared patient specific and preoperative clinical factors to network topology and tractography alterations on a preoperative neonatal brain MRI, and intra and postoperative clinical factors to network topology alterations on postoperative neonatal brain MRI. A composite BDS was created to score abnormal findings involving the cerebellar hemispheres and vermis, supratentorial extra-axial fluid, olfactory bulbs and sulci, hippocampus, choroid plexus, corpus callosum, and brainstem. The neuroimaging outcomes of this study included (1) connectome metrics: cost (number of connections) and global/nodal efficiency (network integration); (2) seed based tractography methods of fractional anisotropy (FA), radial diffusivity, and axial diffusivity. Statistics consisted of multiple regression with false discovery rate correction (FDR) comparing the clinical risk factors and BDS (including subcortical components) as predictors/exposures and the global connectome metrics, nodal efficiency, and seed based- tractography (FA, radial diffusivity, and axial diffusivity) as neuroimaging outcome measures.ResultsA total of 133 term neonates with complex CHD were prospectively enrolled and 110 had analyzable DTI. Multiple patient-specific factors including d-transposition of the great arteries (d-TGA) physiology and severity of impairment of fetal cerebral substrate delivery (i.e., how much the CHD lesion alters typical fetal circulation such that the highest oxygen and nutrient rich blood from the placenta are not directed toward the fetal brain) were predictive of preoperative reduced cost (p ConclusionPatient-specific (d-TGA anatomy, preoperative impairment of fetal cerebral substrate delivery) and postoperative (e.g., seizures, need for ECMO, or CPR) clinical factors were most predictive of diffuse postnatal microstructural dysmaturation in term CHD neonates. Anthropometric measurements (weight, length, and head size) predicted tractography outcomes. In contrast, subcortical components (cerebellum, hippocampus, olfactory) of a structurally based BDS (derived from CHD mouse mutants), predicted more localized and regional postnatal microstructural differences. Collectively, these findings suggest that brain DTI connectome and seed-based tractography are complementary techniques which may facilitate deciphering the mechanistic relative contribution of clinical and genetic risk factors related to poor neurodevelopmental outcomes in CHD.</p