Elda Fischi-Gomez1,2, Lana Vasung1, Sebastien Urben3,4, Cristina Borradori-Tolsa1, François Lazeyras5, Jean-Philippe Thiran2,6, and Petra Susan Hüppi1
1Division of Development and Growth. Department of Pediatrics, University Hospital of Geneva, Geneva, Switzerland, 2Signal Processing Laboratory 5, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland, 3Child Clinical Neuropsychology Unit, Department of Psychology, University of Geneva, Geneva, Switzerland, 4Research Unit, University Service of Child and Adolescent Psychiatry, Department of Psychiatry, University Hospital of Lausanne (CHUV), Lausanne, Switzerland, 5Department of Radiology and Medical Informatics, Faculty of Medicine, University of Geneva, Geneva, Switzerland, 6Department of Radiology, University Hospital Center (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
Synopsis
Within preterm-born children, being born male and at a lower gestational
age have both been associated with a heightened risk for developmental
difficulties. However, in this population little is known about the combined
effect and the influence of these risk factors on the structural networks subserving attention and executive. Using a diffusion-based brain
connectome approach, in this work we analyze the effect of these two factors in
the brain networks of school-age preterm born children and provide evidence of
a gender-specific vulnerability in the executive attentional subnetwork.Introduction
Children born prematurely are at high risk for
long-term abnormal development, including deficits in attentional abilities
that persist throughout adolescence [1]. The severity of these
cognitive difficulties varies significantly among preterm-born children, with
the level of prematurity and sex being the most relevant factors for the
determination of their neurodevelopmental outcomes [2,3]. In order to understand
the neurostructural correlate of these disabilities, we used a brain connectome
approach to analyze the effects of gender and degree of prematurity on the
attentional system network related to executive control in school age preterm children.
Our results suggest that extreme prematurity, toghether with being born
male, differentially affects brain connectivity and development.
Purpose
To study the structural network subserving attention
and executive control in prematurely born children at school age.
Methods
We recruited 44 premature born children aged six years old, from the
Child Developmental Unit at the University Hospitals of Geneva and Lausanne.
All subjects were free from premature-associated brain lesions at term equivalent age. The 6 years-old scans were read as
normal by neuroradiologists. Our scanning protocol included: T1-weighted MPRAGE
(TR/TE=2500/2.91, TI=1100, res.=1x1x1mm, 256x154) and diffusion-sensitized EPI
sequence (30 directions, max bvalue=1000 s/mm2, TR/TE=10200/107,
res=1.8x1.8x2 mm) on a Siemens 3T Tim Trio. Children were divided in 4
groups based on GA (extremely preterm (EP) vs very preterm (VPT), < 28 vs ≤
28 <34.3 weeks GA resp.) and gender (boys vs girls). For
each subject we compute the connectivity matrix using the Connectome Mapper
Toolkit [4]. We model the structural brain networks as undirected weigthed
networks with the nodes being the centroid of each cortical (and subcortical)
region of interest (ROI) and the edges the average
connection density of all subjects weighted by the individual connection
efficacy (mean FA along the bundle connecting the two ROIs). The executive attention
subtnetwork (eATN) was defined by selecting the nodes as described by Posner
and Petersen [5,6], including the frontoparietal control system and the
cingulo-opercular system, bilaterally. As an initial examination of
connectivity in the preterm infants brain, we compared the global efficiency of
their whole brain networks among groups, as well as the global efficiency of
the right and left eATN. The eATN connectivity and its behavior with respect to
the overall brain wetwork was examined by disinguishing different types of
connections: local connections between peripheral nodes (peripheral), feeder
connections between peripheral nodes and the core nodes, i.e. nodes belonging
to the eATN (feeders), core
connections between nodes belonging to the eATN only (core) and feeder and core
connections (core+feeders) (Fig. 1). The strenght of these connections was
compared among groups using a ranksum test and correted for multiple
comparisons using FDR.
Results
The overall global efficiency showed no significant
difference among groups. On the contrary, the global efficiency of the eATN of
the right hemisphere was significantly lower when comparing EP boys and girls
with VPT boys and girls. Interestingly, VPT boys showed a reduced efficiency on
the eATN when compared to VPT girls. For the left eATN, EP boys and girls also
showed reduces efficiency when compared to the VPT. EP boys also had smaller
efficiency when compared to VPT girls, and most importantly, the subnetwork
efficiency was reduced in VPT boys when compared to EP girls. The strength the eATN core, feeders and feeders+core connections was
significantly lower in EP boys when compared with girls, independently from
their GA. Moreover, EP boys peripherial connections showed also reduced
connectivity strength when compared to EP girls.
Discussion
Petersen and Posner [6] described the frontoparietal
control system as a part of the executive attention network. This system
enables a moment-to-moment control, responsible for resolving conflicts. Lesions
of this system in adulthood (especially of the dorsolateral prefrontal cortex,
DLPFC) result in executive control deficits, decision-making, and judgment
impairments [7]. Similarly, the impaired executive control abilities in
extremely preterm boys have been related to lower cortical densities in the
DLPFC [1]. Our analysis corroborates these results and provides evidence of
alteration in intrinsic eATN network architecture (core connections) but also
of alteration in hemispheric integration of eATN network (connections between
eATN and feeders), which are related to extreme prematurity and sex. In
addition, having in mind that extreme prematurity has been linked with altered
fronto-striatal and frontoparietal connectivity [8], our results further
suggest that networks related to executive control are differently affected by
the sex and the level of prematurity. In other words, boys and girls are
neurologically differentially impacted by these two factors.
Conclusion
The current findings do shed light on a
gender-specific vulnerability in the executive attentional subnetwork.
Acknowledgements
This work was supported by the Center for
Biomedical Imaging (CIBM) of the Geneva and Lausanne Universities, the Ecole
Polytechnique Fédérale de Lausanne (EPFL) in Switzerland, and the foundations
Leenards and Louis-Jeantet, as well as by the Swiss National Science Foundation
(33CM30_140334 and 32473B_135817) and Leenards Foundation Grant N° 2667 to
P.S.H.
We are grateful to the families that took part
in the study and the medical staff who participated in the study. We thank Dr.Alessanda Griffa for insightful comments.References
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