Motor and cortico-striatal-thalamic connectivity alterations in intrauterine growth restriction

BACKGROUND: Intrauterine growth restriction is associated with short-and long-term neurodevelopmental problems. Structural brain changes underlying these alterations have been described with the use of different magnetic resonance-based methods that include changes in whole structural brain networks. However, evaluation of specific brain circuits and its correlation with related functions has not been investigated in intrauterine growth restriction.OBJECTIVES: In this study, we aimed to investigate differences in tractography-related metrics in cortico-striatal-thalamic and motor networks in intrauterine growth restricted children and whether these parameters were related with their specific function in order to explore its potential use as an imaging biomarker of altered neurodevelopment.METHODS: We included a group of 24 intrauterine growth restriction subjects and 27 control subjects that were scanned at 1 year old; we acquired T1-weighted and 30 directions diffusion magnetic resonance images. Each subject brain was segmented in 93 regions with the use of anatomical automatic labeling atlas, and deterministic tractography was performed. Brain regions included in motor and cortico-striatal-thalamic networks were defined based in functional and anatomic criteria. Within the streamlines that resulted from the whole brain tractography, those belonging to each specific circuit were selected and tractography-related metrics that included number of streamlines, fractional anisotropy, and integrity were calculated for each network. We evaluated differences between both groups and further explored the correlation of these parameters with the results of socioemotional, cognitive, and motor scales from Bayley Scale at 2 years of age.RESULTS: Reduced fractional anisotropy (cortico-striatal-thalamic, 0.319 +/- 0.018 vs 0.315 +/- 0.015; P =.010; motor, 0.322 +/- 0.019 vs 0.319 +/- 0.020; P =.019) and integrity cortico-striatal-thalamic (0.407 +/- 0.040 vs 0.399 +/- 0.034; P =.018; motor, 0.417 +/- 0.044 vs 0.409 +/- 0.046; P =.016) in both networks were observed in the intrauterine growth restriction group, with no differences in number of streamlines. More importantly, strong specific correlation was found between tractography-related metrics and its relative function in both networks in intrauterine growth restricted children. Motor network metrics were correlated specifically with motor scale results (fractional anisotropy: rho = 0.857; integrity: rho = 0.740); cortico-striatal-thalamic network metrics were correlated with cognitive (fractional anisotropy: rho = 0.793; integrity, rho = 0.762) and socioemotional scale (fractional anisotropy: rho = 0.850; integrity: rho = 0.877).CONCLUSIONS: These results support the existence of altered brain connectivity in intrauterine growth restriction demonstrated by altered connectivity in motor and cortico-striatal-thalamic networks, with reduced fractional anisotropy and integrity. The specific correlation between tractography-related metrics and neurodevelopmental outcomes in intrauterine growth restriction shows the potential to use this approach to develop imaging biomarkers to predict specific neurodevelopmental outcome in infants who are at risk because of intrauterine growth restriction and other prenatal diseases

Long-term functional outcomes and correlation with regional brain connectivity by MRI diffusion tractography metrics in a near-term rabbit model of intrauterine growth restriction

Background: Intrauterine growth restriction (IUGR) affects 5-10% of all newborns and is associated with increased risk of memory, attention and anxiety problems in late childhood and adolescence. The neurostructural correlates of long-term abnormal neurodevelopment associated with IUGR are unknown. Thus, the aim of this study was to provide a comprehensive description of the long-term functional and neurostructural correlates of abnormal neurodevelopment associated with IUGR in a near-term rabbit model (delivered at 30 days of gestation) and evaluate the development of quantitative imaging biomarkers of abnormal neurodevelopment based on diffusion magnetic resonance imaging (MRI) parameters and connectivity. Methodology: At +70 postnatal days, 10 cases and 11 controls were functionally evaluated with the Open Field Behavioral Test which evaluates anxiety and attention and the Object Recognition Task that evaluates short-term memory and attention. Subsequently, brains were collected, fixed and a high resolution MRI was performed. Differences in diffusion parameters were analyzed by means of voxel-based and connectivity analysis measuring the number of fibers reconstructed within anxiety, attention and short-term memory networks over the total fibers. Principal Findings: The results of the neurobehavioral and cognitive assessment showed a significant higher degree of anxiety, attention and memory problems in cases compared to controls in most of the variables explored. Voxel-based analysis (VBA) revealed significant differences between groups in multiple brain regions mainly in grey matter structures, whereas connectivity analysis demonstrated lower ratios of fibers within the networks in cases, reaching the statistical significance only in the left hemisphere for both networks. Finally, VBA and connectivity results were also correlated with functional outcome. Conclusions: The rabbit model used reproduced long-term functional impairments and their neurostructural correlates of abnormal neurodevelopment associated with IUGR. The description of the pattern of microstructural changes underlying functional defects may help to develop biomarkers based in diffusion MRI and connectivity analysis

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

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

A magnetic resonance image based atlas of the rabbit brain for automatic parcellation.

Rabbit brain has been used in several works for the analysis of neurodevelopment. However, there are not specific digital rabbit brain atlases that allow an automatic identification of brain regions, which is a crucial step for various neuroimage analyses, and, instead, manual delineation of areas of interest must be performed in order to evaluate a specific structure. For this reason, we propose an atlas of the rabbit brain based on magnetic resonance imaging, including both structural and diffusion weighted, that can be used for the automatic parcellation of the rabbit brain. Ten individual atlases, as well as an average template and probabilistic maps of the anatomical regions were built. In addition, an example of automatic segmentation based on this atlas is described

Corrigendum: Structural Brain Network Reorganization and Social Cognition Related to Adverse Perinatal Condition from Infancy to Early Adolescence

In the original article, we omitted a reference to Réveillon et al. (2016) regarding the description of the neuropsychological tests performed by the children and the association between IUGR and hyperactivity/inattention symptoms. This reference is cited in the description of the third cohort (Section Materials and Methods. Subjects) and in the Correlation between Network Metrics and Neuropsychological Score section, as appeared below. We also had neglected to thank the invaluable contribution of the team involved in recruitment, imaging acquisition, and neuropsychological testing. The revised version of the acknowledgments is provided below. The authors apologize for the oversight. These errors do not change the scientific conclusions of the article in any way

Neurodevelopmental effects of undernutrition and placental underperfusion in fetal growth restriction rabbit models

Introduction: Chronic reduction of oxygen and nutrient delivery to the fetus has been related to neurodevelopmental problems. Placental underperfusion induces a significant reduction in oxygen and nutrient delivery, whereas maternal undernutrition causes mainly nutrient deficiency. A comparison of the neurodevelopmental effects of both situations in pregnant rabbits was performed. Materials and Methods: The placental underperfusion model was induced after uteroplacental vessel ligation at 25 days of pregnancy. The undernutrition model was induced after a reduction of 70% of the basal maternal intake at 22 days of pregnancy. Neurobehavioral tests were applied in the derived offspring at the neonatal period and over the long term. Structural brain differences were evaluated by brain networks obtained from diffusion magnetic resonance imaging. Results: Birth weight was significantly lower in both cases. However, stillbirth was only increased in the placental underperfusion model. Cases from both models presented poorer neurobehavioral performance and network infrastructure, being more pro-nounced in the placental underperfusion model. Discussion: Prenatal insults during the last third of gestation resulted in functional and structural disturbances. The degree of neurodevelopmental impairment and its association with structural brain reorganization seemed to be related to the type of the prenatal insult, showing stronger effects in the placental underperfusion model. (C) 2017 S. Karger AG, Base

Structural brain network reorganization and social cognition related to adverse perinatal condition from infancy to early adolescence

Adverse conditions during fetal life have been associated to both structural and functional changes in neurodevelopment from the neonatal period to adolescence. In this study, connectomics was used to assess the evolution of brain networks from infancy to early adolescence. Brain network reorganization over time in subjects who had suffered adverse perinatal conditions is characterized and related to neurodevelopment and cognition. Three cohorts of prematurely born infants and children (between 28 and 35 weeks of gestational age), including individuals with a birth weight appropriated for gestational age and with intrauterine growth restriction (IUGR), were evaluated at 1, 6, and 10 years of age, respectively. A common developmental trajectory of brain networks was identified in both control and IUGR groups: network efficiencies of the fractional anisotropy (FA)-weighted and normalized connectomes increase with age, which can be related to maturation and myelination of fiber connections while the number of connections decreases, which can be associated to an axonal pruning process and reorganization. Comparing subjects with or without IUGR, a similar pattern of network differences between groups was observed in the three developmental stages, mainly characterized by IUGR group having reduced brain network efficiencies in binary and FA-weighted connectomes and increased efficiencies in the connectome normalized by its total connection strength (FA). Associations between brain networks and neurobehavioral impairments were also evaluated showing a relationship between different network metrics and specific social cognition-related scores, as well as a higher risk of inattention/hyperactivity and/or executive functional disorders in IUGR children

The ins and outs of the BCCAo model for chronic hypoperfusion: a multimodal and longitudinal MRI approach

Cerebral hypoperfusion induced by bilateral common carotid artery occlusion (BCCAo) in rodents has been proposed as an experimental model of white matter damage and vascular dementia. However, the histopathological and behavioral alterations reported in this model are variable and a full characterization of the dynamic alterations is not available. Here we implemented a longitudinal multimodal magnetic resonance imaging (MRI) design, including time- of-flight angiography, high resolution T1-weighted images, T2 relaxometry mapping, diffusion tensor imaging, and cerebral blood flow measurements up to 12 weeks after BCCAo or sham-operation in Wistar rats. Changes in MRI were related to behavioral performance in executive function tasks and histopathological alterations in the same animals. MRI frequently (70%) showed various degrees of acute ischemic lesions, ranging from very small to large subcortical infarctions. Independently, delayed MRI changes were also apparent. The patterns of MRI alterations were related to either ischemic necrosis or gliosis. Progressive microstructural changes revealed by diffusion tensor imaging in white matter were confirmed by observation of myelinated fiber degeneration, including severe optic tract degeneration. The latter interfered with the visually cued learning paradigms used to test executive functions. Independently of brain damage, BCCAo induced progressive arteriogenesis in the vertebrobasilar tree, a process that was associated with blood flow recovery after 12 weeks. The structural alterations found in the basilar artery were compatible with compensatory adaptive changes driven by shear stress. In summary, BCCAo in rats induces specific signatures in multimodal MRI that are compatible with various types of histological lesion and with marked adaptive arteriogenesis

Brain connectivity network models based on multi-modal MRI to study brain reorganization of prenatal origin using intrauterine growth restriction as a model

[cat] Aquesta tesis doctoral està centrada en l'aplicació de models de xarxa del cervell obtinguts a partir de diferents modalitats de ressonància magnètica (RM) per caracteritzar anomalies en el desenvolupament d'origen prenatal utilitzant la restricció de creixement intrauterí (RCIU) com a model clínic. La tesi està presentada com a compendi de quatre estudis publicats en revistes internacionals de primer quartil. Cada un dels estudis està centrat en la caracterització de la RCIU mitjançant xarxes cerebrals obtingudes a partir d'una modalitat de RM determinada en una etapa pediàtrica diferent, en la vida de subjectes amb RCIU. Així doncs, el primer estudi es centra en la caracterització de la reorganització cerebral produïda per RCIU a l'any de vida mitjançant xarxes cerebrals estructurals basades en RM per difusió. En aquest estudi es demostra que les característiques de xarxa en els subjectes amb RCIU presenten una sèrie d'alteracions relacionades amb un neuro-desenvolupament futur anormal. El segon projecte analitza la utilització de xarxes estructurals cerebrals basades en RM anatòmica convencional per caracteritzar alteracions en nens d'un any amb RCIU. Es demostra que efectivament amb aquesta tècnica també es troben alteracions en els infants amb IUGR, i que aquestes alteracions estan també relacionades amb problemes en el neuro-desenvolupament posterior. En el tercer projecte s'utilitza un model animal de conill amb RCIU per explorar les alteracions en la xarxa cerebral estructural que persisteix a llarg termini. Es demostra que efectivament existeixen alteracions en la organització estructural del cervell persistents a llarg termini i s'observa un efecte compensatori en els subjectes amb RCIU. En el quart projecte s'analitzen les xarxes cerebrals funcional en neonats amb RCIU, demostrant que aquesta condició prenatal genera una reorganització en la connectivitat cerebral que té un substrat funcional, que es pot observar des d'etapes molt precoces de la vida i que està relacionada amb resultats de neuro-comportament.[eng] This PhD thesis is focused in the application of brain network models obtained from different modalities of magnetic resonance imaging (MRI) to characterize anomalies in neurodevelopment of a prenatal origin, using intrauterine growth restriction (IUGR) as a clinical model. Importantly, IUGR due to placental insufficiency affects 5-10% of all pregnancies and is a leading cause of fetal morbidity and mortality. The thesis is presented as a compendium of four studies published in international journals. Each of the studies is focused in the characterization of IUGR using brain networks obtained from a specific MRI modality (structural, diffusion and functional MRI) in a specific pediatric stage in the life of subjects with IUGR (neonatal, early infancy and pre-adolescence age). The first study focuses in the characterization of brain reorganization produced by IUGR at one year of age using brain networks based on a tractography obtain from diffusion MRI, using diffusion tensor imaging (DTI) approach. In this study it is demonstrated that brain network features of IUGR infants have alterations associated with an altered neurodevelopment later in life. The second study assess the viability to use a novel methodology to obtain structural brain networks based on simple anatomical MRI based on the similitude of gray matter (GM) patterns among different areas of the brain. We demonstrated alterations in infants with IUGR using this technique, and that the alterations found are also associated with neurodevelopmental problems found later in life. In the third study we used a rabbit model of IUGR to explore if the alterations in the structural brain network persist at long-term, during preadolescence. We demonstrated that indeed, there are alterations in the structural brain network organization that persist at long-term and that this alterations are associated with neurobehavioral outcomes. Finally, using normalization approaches, we observed a peculiar compensatory effect in the subjects with IUGR. In the forth study, we assessed functional brain networks of neonates with IUGR, demonstrating that this condition produces a reorganization of functional brain connectivity since such an early age, characterized by a pattern of increased co-activation and synchronization of brain regions together with a suboptimal organization when assessing normalized networks. In addition, functional brain network features were also associated to neurobehavioral alterations. Overall, our main conclusion is that IUGR condition produces structural and functional brain reorganization since early life that persists postnatally up to pre-adolescence. We hypothesize that the observed functional and structural reorganization could be a potential substrate of high risk of altered neurodevelopment in infants with IUGR, and postulate this condition as a possible brain network disorder. Importantly, the association of network features with neurobehavior and neurodevelopment since an early age opens the opportunity to further develop early image biomarkers of altered neurodevelopment, a clinical chance to improve the management of a condition that affects up to 10% of deliveries

Motor and cortico-striatal-thalamic connectivity alterations in intrauterine growth restriction

BACKGROUND: Intrauterine growth restriction is associated with short-and long-term neurodevelopmental problems. Structural brain changes underlying these alterations have been described with the use of different magnetic resonance-based methods that include changes in whole structural brain networks. However, evaluation of specific brain circuits and its correlation with related functions has not been investigated in intrauterine growth restriction.OBJECTIVES: In this study, we aimed to investigate differences in tractography-related metrics in cortico-striatal-thalamic and motor networks in intrauterine growth restricted children and whether these parameters were related with their specific function in order to explore its potential use as an imaging biomarker of altered neurodevelopment.METHODS: We included a group of 24 intrauterine growth restriction subjects and 27 control subjects that were scanned at 1 year old; we acquired T1-weighted and 30 directions diffusion magnetic resonance images. Each subject brain was segmented in 93 regions with the use of anatomical automatic labeling atlas, and deterministic tractography was performed. Brain regions included in motor and cortico-striatal-thalamic networks were defined based in functional and anatomic criteria. Within the streamlines that resulted from the whole brain tractography, those belonging to each specific circuit were selected and tractography-related metrics that included number of streamlines, fractional anisotropy, and integrity were calculated for each network. We evaluated differences between both groups and further explored the correlation of these parameters with the results of socioemotional, cognitive, and motor scales from Bayley Scale at 2 years of age.RESULTS: Reduced fractional anisotropy (cortico-striatal-thalamic, 0.319 +/- 0.018 vs 0.315 +/- 0.015; P =.010; motor, 0.322 +/- 0.019 vs 0.319 +/- 0.020; P =.019) and integrity cortico-striatal-thalamic (0.407 +/- 0.040 vs 0.399 +/- 0.034; P =.018; motor, 0.417 +/- 0.044 vs 0.409 +/- 0.046; P =.016) in both networks were observed in the intrauterine growth restriction group, with no differences in number of streamlines. More importantly, strong specific correlation was found between tractography-related metrics and its relative function in both networks in intrauterine growth restricted children. Motor network metrics were correlated specifically with motor scale results (fractional anisotropy: rho = 0.857; integrity: rho = 0.740); cortico-striatal-thalamic network metrics were correlated with cognitive (fractional anisotropy: rho = 0.793; integrity, rho = 0.762) and socioemotional scale (fractional anisotropy: rho = 0.850; integrity: rho = 0.877).CONCLUSIONS: These results support the existence of altered brain connectivity in intrauterine growth restriction demonstrated by altered connectivity in motor and cortico-striatal-thalamic networks, with reduced fractional anisotropy and integrity. The specific correlation between tractography-related metrics and neurodevelopmental outcomes in intrauterine growth restriction shows the potential to use this approach to develop imaging biomarkers to predict specific neurodevelopmental outcome in infants who are at risk because of intrauterine growth restriction and other prenatal diseases