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Network based statistics reveals trophic and neuroprotective effect of early high dose erythropoetin on brain connectivity in very preterm infants.

ABSTRACT: Periventricular white matter injury is common in very preterm infants and it is associated with long term neurodevelopmental impairments. While evidence supports the protective effects of erythropoetin (EPO) in preventing injury, we currently lack the complete understanding of how EPO affects the emergence and maturation of anatomical brain connectivity and function. In this case-control study, connectomic analysis based on diffusion MRI tractography was applied to evaluate the effect of early high-dose EPO in preterm infants. A whole brain, network-level analysis revealed a sub-network of anatomical brain connections in which connectivity strengths were significantly stronger in the EPO group. This distributed network comprised connections predominantly in the frontal and temporal lobe bilaterally, and the effect of EPO was focused on peripheral and feeder connections of the core structural connectivity network. EPO resulted in a globally increased clustering coefficient, higher global and average local efficiency, while higher strength and increased clustering was found for regions in the frontal lobe and cingulate gyrus. The connectivity network most affected by the EPO treatment showed a steeper increase graph theoretical measures with age compared to the placebo group. Our results demonstrate a weak but widespread effect of EPO on the structural connectivity network and a possible trophic effect of EPO reflected by increasing network segregation, predominantly in local connections.

SUBMITTER: Jakab A

PROVIDER: S-EPMC6451173 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Network based statistics reveals trophic and neuroprotective effect of early high dose erythropoetin on brain connectivity in very preterm infants.

Jakab A A Ruegger C C Bucher H U HU Makki Malek M Huppi P S PS Tuura R R Hagmann C C

NeuroImage. Clinical 20190401

Periventricular white matter injury is common in very preterm infants and it is associated with long term neurodevelopmental impairments. While evidence supports the protective effects of erythropoetin (EPO) in preventing injury, we currently lack the complete understanding of how EPO affects the emergence and maturation of anatomical brain connectivity and function. In this case-control study, connectomic analysis based on diffusion MRI tractography was applied to evaluate the effect of early h ...[more]

PMID: 30991614

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Project description:BackgroundCurrent evidence shows that systemic dexamethasone administration starting after the first week of age reduces bronchopulmonary dysplasia for very preterm (VPT) infants, but its neurological effects remain obscure. Using resting-state functional magnetic resonance imaging (rs-fMRI), we assessed the changes in functional network connectivity (FNC) in very preterm infants treated with late systemic dexamethasone (≥7 days of age).MethodsVPT infants (GA ≤ 32 weeks) who needed to rely on mechanical ventilation for more than 7 days but fewer than 14 days to maintain vital signs were included in the study. The cohort was divided into two groups according to whether they were given systemic dexamethasone. In addition, 26 healthy term infants were recruited as controls. At term-equivalent age (TEA), rs-fMRI and 3D-T1 data from eligible infants were acquired with a 3.0-T MRI scanner. After the MRI data were preprocessed, group-level independent component analysis (ICA), a technique used for blind source separation, was used to identify the components of resting-state networks (RSNs). Then, the functional connectivity between components and RSNs was compared among different groups. Upon follow-up at 3 months of corrected age, the neurodevelopmental outcomes of enrolled infants were assessed with the Bayley Scales of Infant Development-Chinese Revision (BSID-CR), and the Motor Development Index (MDI) and Psychomotor Development Index (PDI) were measured. Finally, the correlations between resting-state FNC and BSID scores were analysed.ResultsUltimately, 59 infants were included in the final analysis, including 19 preterm infants who received dexamethasone, 20 who did not, and 20 healthy term infants as controls. Based on their data, 11 components were identified, belonging to 5 RSNs: the visual network (VN), the dorsal attention network (DAN), the auditory network (AN), the primary sensorimotor network (SMN), and the default-mode network (DMN). Compared with the term infants, the preterm infants showed significantly weakened functional connectivity between the DAN and VN, as well as the VN and AN (P < 0.05). Among preterm infants, those who were given dexamethasone showed significantly stronger functional connectivity between the DAN and VN, as well as the DMN and AN (P < 0.05), than those who were not. The correlation analysis demonstrated that the connectivity values between the DAN and VN and between the VN and AN were positively correlated with the MDI (r = 0.432, P＜0.001, and r = 0.479, P＜0.001, respectively) and the PDI (r = 0.436, P＜0.001 and r = 0.516, P＜0.001, respectively).ConclusionsOur investigation uncovers a noteworthy link between the administration of late systemic dexamethasone (≥7 days of age) in VPT infants and distinct improvements in FNC. Furthermore, the observed positive correlation between inter-network connectivity and scores on the BSID-CR implies a plausible neuroprotective aspect of this therapeutic approach in this specific group of children.

Project description:BACKGROUND:The use of functional connectivity magnetic resonance imaging (fcMRI) in research involving preterm infants is relatively new, and its feasibility in this population is not fully established. However, fcMRI images reveal functional neural connections that may be useful in establishing the mechanisms of neuroprotective interventions in preterm infants. OBJECTIVE:The aim of this study was to determine the feasibility of using fcMRI to measure differences in functional neural connections in nursing intervention studies. METHODS:A pilot study was conducted as part of a longitudinal, randomized controlled trial (RCT) testing the effect of a feeding intervention on neurodevelopmental and clinical outcomes of preterm infants randomly assigned to one of two groups: a patterned feeding experience (PFE) group and a usual feeding care (UFC) group. The fcMRIs were done at term-equivalent age. Visual, motor, and default mode networks were analyzed. RESULTS:Seven infants were studied (four were in the PFE group, and three were in the UFC group). Participants were selected sequentially from the parent RCT. Clear images were obtained from all participants. Differences were noted among PFE and UFC infants: Infants receiving PFE were hyperconnective in the default mode (caudate, anterior cingulate cortex, and precuneus) and motor networks (middle temporal and middle occipital areas) and hypoconnective in others areas of the default mode (hippocampal and lingual regions) and motor networks (precentral and superior frontal cortices) relative to UFC infants. No differences were noted in visual networks. DISCUSSION:The feasibility of using fcMRI at term-equivalent age in preterm infants who participated in an RCT on the effect of a nursing intervention was shown. Differences in connectivity among infants by group were detected. Further research is needed to show the benefit of fcMRI in studies of preterm infants given the costs of the procedure as well as the uncertain relationship of this early outcome measure to long-term neurodevelopment.

Project description:Preterm infants are at high risk for brain injury during the perinatal period. Intraventricular hemorrhage and periventricular leukomalacia, the two most common patterns of brain injury in prematurely-born children, are associated with poor neurodevelopmental outcomes. The hippocampus is known to be critical for learning and memory; however, it remains unknown how these forms of brain injury affect hippocampal growth and how the resulting alterations in hippocampal development relate to childhood outcomes. To investigate these relationships, hippocampal segmentations were performed on term equivalent MRI scans from 55 full-term infants, 85 very preterm infants (born ≤32 weeks gestation) with no to mild brain injury and 73 very preterm infants with brain injury (e.g., grade III/IV intraventricular hemorrhage, post-hemorrhagic hydrocephalus, cystic periventricular leukomalacia). Infants then underwent standardized neurodevelopmental testing using the Bayley Scales of Infant and Toddler Development, 3rd edition at age 2 years, corrected for prematurity. To delineate the effects of brain injury on early hippocampal development, hippocampal volumes were compared across groups and associations between neonatal volumes and neurodevelopmental outcomes at age 2 years were explored. Very preterm infants with brain injury had smaller hippocampal volumes at term equivalent age compared to term and very preterm infants with no to mild injury, with the smallest hippocampi among those with grade III/IV intraventricular hemorrhage and post-hemorrhagic hydrocephalus. Further, larger ventricle size was associated with smaller hippocampal size. Smaller hippocampal volumes were related to worse motor performance at age 2 years across all groups. In addition, smaller hippocampal volumes in infants with brain injury were correlated with impaired cognitive scores at age 2 years, a relationship specific to this group. Consistent with our preclinical findings, these findings demonstrate that perinatal brain injury is associated with hippocampal size in preterm infants, with smaller volumes related to domain-specific neurodevelopmental impairments in this high-risk clinical population.

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Network based statistics reveals trophic and neuroprotective effect of early high dose erythropoetin on brain connectivity in very preterm infants.

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Network based statistics reveals trophic and neuroprotective effect of early high dose erythropoetin on brain connectivity in very preterm infants.

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