Long-term reorganization of structural brain networks in a rabbit model of intrauterine growth restriction

Abstract

Characterization of brain changes produced by intrauterine growth restriction (IUGR) is among the main challenges of modern fetal medicine and pediatrics. This condition affects 5-10% of all pregnancies and is associated with a wide range of neurodevelopmental disorders. Better understanding of the brain reorganization produced by IUGR opens a window of opportunity to find potential imaging biomarkers in order to identify the infants with a high risk of having neurodevelopmental problems and apply therapies to improve their outcomes. Structural brain networks obtained from diffusion magnetic resonance imaging (MRI) is a promising tool to study brain reorganization and to be used as a biomarker of neurodevelopmental alterations. In the present study this technique is applied to a rabbit animal model of IUGR, which presents some advantages including a controlled environment and the possibility to obtain high quality MRI with long acquisition times. Using a Q-Ball diffusion model, and a previously published rabbit brain MRI atlas, structural brain networks of 15 IUGR and 14 control rabbits at 70 days of age (equivalent to pre-adolescence human age) were obtained. The analysis of graph theory features showed a decreased network infrastructure (degree and binary global efficiency) associated with IUGR condition and a set of generalized fractional anisotropy (GFA) weighted measures associated with abnormal neurobehavior. Interestingly, when assessing the brain network organization independently of network infrastructure by means of normalized networks, IUGR showed increased global and local efficiencies. We hypothesize that this effect could reflect a compensatory response to reduced infrastructure in IUGR. These results present new evidence on the long-term persistence of the brain reorganization produced by IUGR that could underlie behavioral and developmental alterations previously described. The described changes in network organization have the potential to be used as biomarkers to monitor brain changes produced by experimental therapies in IUGR animal model.

Neurodevelopmental Effects of Undernutrition and Placental Underperfusion in Fetal Growth Restriction Rabbit Models

“…In both models, diffusionweighted images were acquired using a diffusion sequence covering 30 gradient directions with a b value of 3,000 s/mm 2 together with a baseline (b = 0 s/mm 2 ) image. Preprocessing, tractography, brain parcellation, and brain network extraction were performed following the methodology previously described [17] , obtaining a fractional anisotropy (FA)-weighted network for each subject. The Brain Connectivity Toolbox was used to characterize global functioning of each network by means of graph theory network features [18] .…”

Programming the brain: Common outcomes and gaps in knowledge from animal studies of IUGR

“…↓ [93] ↓ [162] = [163] Cerebrum = [79,85] ↓ [93] Midbrain ↓ [93] Hippocampus = [85,93] Cerebellum = [79,85] ↓ [93] …”

“…Axonal density ↓ left hemispheric anxiety and memory pathways [117] Axonal degeneration + cingulate and somatosensory cortices, internal capsule, pontocerebellar tract [115] Microstructural reorganisation + [163] MYELINATION Cerebrum = [162] ↓ [117] Corpus callosum = [222] ↓ d60 [40] Cingulum ↓ d60 [112] Internal and external capsule = d60 [112] Astrogliosis Hippocampus ↑CA1 [113,115] Dentate gyrus ↑ [113,115] Entorhinal cortex ↑ [113,115] Cingulum ↑ [113,115] = [94] Fornix ↑ [113] Motor cortex = [115] Somatosensory cortex ↑ [115] Neonatal neurobehaviour = reflexes [79] ↓ righting reflex, d3-4 males, d3 females [87] ↓cliff avoidance, d7 females, d8, both sexes [87] ↓negative geotaxis, d7-8 males [87] = reflexes d10-21 [165] ↓surface righting, d2-9 ↓ negative geotaxis d 4-15 [129] ↓righting reflexes, locomotion, head turning and smell test scores as d1 neonates [116] Neuromotor ↓ grip strength adult males [165] ↓ motor learning, males [129] ↓motor learning, adults [222] Spatial learning = adult males [95] = adults [97,165] = adult males [167] ↓initial simple maze tests (lambs) [122] = extended simple maze testing, obstacle course tasks, tmaze tasks (lambs) [122] ↓initial simple maze tests (male lambs and young adults) [150] Revers...…”

“…Behavioural anxiety = male pups [79] =/↑ adult males [93,94] ↓ adults [98,216] ↑ reactivity to physical restraint and surprise, adults [84] ↑ adolescent females = adolescent males [131] ↑ adults [117] ↑ low birth weight female lambs [150] Spontaneous ambulation = adult males [94,95] ↑ females [165] ↑ in isolation tasks, adults [84] ↑ adults [113][114][115] ↓ adult males [160] ↓ Hyperactivity ↑ adult females [165] ↑adults [113][114][115] Exploratory behaviour ↑adult females [216] ↑adults [113][114][115] ↓ adults [117,163] Response to novelty ↓novelty seeking, adults [84] = adults [113] …”

“…These range 159 from 4 to 34% in progeny of globally nutrient-restricted rats [79,87,88,[93][94][95][96], whilst more severe 160 restriction is seen in models of maternal protein restriction, with 7 to 52% reduction in birth weight 161 in progeny [91,92,[97][98][99][100][101]. The reported decrease in birth weight following the levels of maternal 162 nutrient restriction used in neurodevelopmental studies in sheep and rabbits is milder ranging from 163 9.5% to 17.5% [83,89,102,103]. Effects on fetal nutrient supply and metabolism also differ 164 between the various models of IUGR (Table 1).…”