Univariate and multivariate pattern analysis of preterm subjects: a multimodal neuroimaging study

Background: Widespread lasting functional connectivity (FC) and brain volume changes in cortices and subcortices after premature birth have been researched in recent studies. However, the relationship remains unclear between spontaneously slow blood oxygen dependent level (BOLD) fluctuations and gray matter volume (GMV) changes in specific brain areas, such as temporal insular cortices, and whether classification methods based on MRI could be successfully applied to the identification of preterm individuals. In this thesis I hypothesized that in prematurely born adults 1. Ongoing neural excitability and brain activity, as estimated by regional functional connectivity of resting state functional MRI (rs-fMRI) is accompanied with altered low-frequency fluctuations and neonatal complications; 2. Altered regional functional connectivity is connected with superimposed cerebral structural reductions; and 3. multivariate neuroanatomical and functional brain patterns could be treated as features to identify preterm subjects from term subjects individually. Methods: To investigate these hypotheses, the principal results of structural alterations were measured with voxel-based morphometry (VBM), while rs-fMRI outcomes were estimated with amplitude of low-frequency fluctuations (ALFF) in analysis with ninety-four very preterm/very low birth weight (VP/VLBW) and ninety-two full-term (FT) born young adults. Results: The results of the thesis support the hypotheses by showing that, in univariate results, first in VP/VLBW grownups, ALFF was decreased in the left lateral temporal cortices no matter with global signal regression, and this reduction was closely associated with neonatal complications and cognitive variables. Second overlapped brain regions were found between reduced ALFF and reduced brain volumes in the left temporal cortices, and positively associated with each other, demonstrating a potential relationship between VBM and ALFF in this brain area. In multimodal multivariate pattern recognition analysis (MVPA), the gray matter volume (GMV) classifier displayed a higher accuracy (80.7%) contrast with the ALFF classifier (77.4%). The late fusion of GMV and ALFF did not outperform single GMV modality classification by reaching 80.4% accuracy. Moderator analysis from both rs-fMRI and structural MRI (sMRI) uncovered that the neuro-prematurity performance was predominantly determined by neonatal complications. Conclusions: In conclusion, these outcomes exhibit the long term effects of premature labour on lateral temporal cortices, which changed in both ongoing BOLD fluctuations and decreased cerebral structural volumes. This thesis further provided evidence that multivariate pattern analysis such as support vector machine (SVM) may identify imaging-based biomarkers and reliably detect signatures of preterm birth

Univariate and multivariate pattern analysis of preterm subjects: a multimodal neuroimaging study

Background: Widespread lasting functional connectivity (FC) and brain volume changes in cortices and subcortices after premature birth have been researched in recent studies. However, the relationship remains unclear between spontaneously slow blood oxygen dependent level (BOLD) fluctuations and gray matter volume (GMV) changes in specific brain areas, such as temporal insular cortices, and whether classification methods based on MRI could be successfully applied to the identification of preterm individuals. In this thesis I hypothesized that in prematurely born adults 1. Ongoing neural excitability and brain activity, as estimated by regional functional connectivity of resting state functional MRI (rs-fMRI) is accompanied with altered low-frequency fluctuations and neonatal complications; 2. Altered regional functional connectivity is connected with superimposed cerebral structural reductions; and 3. multivariate neuroanatomical and functional brain patterns could be treated as features to identify preterm subjects from term subjects individually. Methods: To investigate these hypotheses, the principal results of structural alterations were measured with voxel-based morphometry (VBM), while rs-fMRI outcomes were estimated with amplitude of low-frequency fluctuations (ALFF) in analysis with ninety-four very preterm/very low birth weight (VP/VLBW) and ninety-two full-term (FT) born young adults. Results: The results of the thesis support the hypotheses by showing that, in univariate results, first in VP/VLBW grownups, ALFF was decreased in the left lateral temporal cortices no matter with global signal regression, and this reduction was closely associated with neonatal complications and cognitive variables. Second overlapped brain regions were found between reduced ALFF and reduced brain volumes in the left temporal cortices, and positively associated with each other, demonstrating a potential relationship between VBM and ALFF in this brain area. In multimodal multivariate pattern recognition analysis (MVPA), the gray matter volume (GMV) classifier displayed a higher accuracy (80.7%) contrast with the ALFF classifier (77.4%). The late fusion of GMV and ALFF did not outperform single GMV modality classification by reaching 80.4% accuracy. Moderator analysis from both rs-fMRI and structural MRI (sMRI) uncovered that the neuro-prematurity performance was predominantly determined by neonatal complications. Conclusions: In conclusion, these outcomes exhibit the long term effects of premature labour on lateral temporal cortices, which changed in both ongoing BOLD fluctuations and decreased cerebral structural volumes. This thesis further provided evidence that multivariate pattern analysis such as support vector machine (SVM) may identify imaging-based biomarkers and reliably detect signatures of preterm birth

Effects of gestational age at birth on perinatal structural brain development in healthy term-born babies

Infants born in early term (37-38 weeks gestation) experience slower neurodevelopment than those born at full term (40-41 weeks gestation). While this could be due to higher perinatal morbidity, gestational age at birth may also have a direct effect on the brain. Here we characterise brain volume and white matter correlates of gestational age at birth in healthy term-born neonates and their relationship to later neurodevelopmental outcome using T2 and diffusion weighted MRI acquired in the neonatal period from a cohort (n = 454) of healthy babies born at term age (>37 weeks gestation) and scanned between 1 and 41 days after birth. Images were analysed using tensor-based morphometry and tract-based spatial statistics. Neurodevelopment was assessed at age 18 months using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). Infants born earlier had higher relative ventricular volume and lower relative brain volume in the deep grey matter, cerebellum and brainstem. Earlier birth was also associated with lower fractional anisotropy, higher mean, axial, and radial diffusivity in major white matter tracts. Gestational age at birth was positively associated with all Bayley-III subscales at age 18 months. Regression models predicting outcome from gestational age at birth were significantly improved after adding neuroimaging features associated with gestational age at birth. This work adds to the body of evidence of the impact of early term birth and highlights the importance of considering the effect of gestational age at birth in future neuroimaging studies including term-born babies

Neural correlates of prenatal stress in young women.

open5noBACKGROUND: Prenatal stress is hypothesized to have a disruptive impact on neurodevelopmental trajectories, but few human studies have been conducted on the long-term neural correlates of prenatal exposure to stress. The aim of this study was to explore the relationship between prenatal stress exposure and gray-matter volume and resting-state functional connectivity in a sample of 35 healthy women aged 14-40 years. METHOD: Voxel-based morphometry and functional connectivity analyses were performed on the whole brain and in specific regions of interest (hippocampus and amygdala). Data about prenatal/postnatal stress and obstetric complications were obtained by interviewing participants and their mothers, and reviewing obstetric records. RESULTS: Higher prenatal stress was associated with decreased gray-matter volume in the left medial temporal lobe (MTL) and both amygdalae, but not the hippocampus. Variance in gray-matter volume of these brain areas significantly correlated with depressive symptoms, after statistically adjusting for the effects of age, postnatal stress and obstetric complications. Prenatal stress showed a positive linear relationship with functional connectivity between the left MTL and the pregenual cortex. Moreover, connectivity between the left MTL and the left medial-orbitofrontal cortex partially explained variance in the depressive symptoms of offspring. CONCLUSIONS: In young women, exposure to prenatal stress showed a relationship with the morphometry and functional connectivity of brain areas involved in the pathophysiology of depressive disorders. These data provide evidence in favor of the hypothesis that early exposure to stress affects brain development and identified the MTL and amygdalae as possible targets of such exposure.openFavaro, Angela; Tenconi, Elena; Degortes, Daniela; Manara, R; Santonastaso, PaoloFavaro, Angela; Tenconi, Elena; Degortes, Daniela; Manara, R; Santonastaso, Paol

The enduring impact of childhood maltreatment on grey matter development

Childhood maltreatment doubles an individual’s risk of developing a psychiatric disorder, yet the neurobiological nature of the enduring impact of childhood maltreatment remains elusive. This thesis explores the long-term effect of childhood maltreatment on grey matter. The primary aims of this thesis are to discern the spatial extent, temporal profile and physiological breadth of the developmental impact of childhood maltreatment amongst young people with emerging mental disorder. Chapter II comprises of a meta-analysis of thirty-eight published articles and demonstrates that adults with a history of childhood maltreatment most commonly exhibit reduced grey matter in the hippocampus, amygdala and right dorsolateral prefrontal cortex, compared to non-maltreated adults. Chapters III-V contain three original studies, involving a cohort of 123 young people, aged 14-26, with emerging mental illness. Chapter III bridges a gap between cross-sectional child and adult studies by longitudinally mapping the developmental trajectory of the hippocampus and amygdala following childhood maltreatment. This study provided the first direct evidence that childhood maltreatment stunts hippocampal development into young adulthood. Chapter IV assesses the utility of the cumulative stress and mismatch hypotheses in understanding the contribution of childhood abuse and recent stress to the structure and function of the limbic system. Chapter V extends on recent advances in connectome research to examine the effect of childhood maltreatment on structural covariance networks. Investigation of the correspondence of structural covariance with structural connectivity and functional connectivity revealed that reduced grey matter across the network is likely related to deceased functional coactivation following childhood maltreatment. Chapter VI discusses the significance of these studies in understanding how maltreatment shapes brain development and increases the risk of psychiatric illness

White Matter and Cognition in Adults Who Were Born Preterm

BACKGROUND AND PURPOSE: Individuals born very preterm (before 33 weeks of gestation, VPT) are at risk of damage to developing white matter, which may affect later cognition and behaviour. METHODS: We used diffusion tensor MRI (DT-MRI) to assess white matter microstructure (fractional anisotropy; FA) in 80 VPT and 41 term-born individuals (mean age 19.1 years, range 17-22, and 18.5 years, range 17-22 years, respectively). VPT individuals were part of a 1982-1984 birth cohort which had been followed up since birth; term individuals were recruited by local press advertisement. General intellectual function, executive function and memory were assessed. RESULTS: The VPT group had reduced FA in four clusters, and increased FA in four clusters relative to the Term group, involving several association tracts of both hemispheres. Clusters of increased FA were associated with more severe neonatal brain injury in the VPT group. Clusters of reduced FA were associated with lower birth weight and perinatal hypoxia, and with reduced adult cognitive performance in the VPT group only. CONCLUSIONS: Alterations of white matter microstructure persist into adulthood in VPT individuals and are associated with cognitive function

PRETERM BIRTH RESULTS IN ALTERATIONS IN NEURAL CONNECTIVITY AT AGE 16 YEARS

Very low birth weight preterm (PT) children are at high risk for brain injury. This study investigates microstructural differences in the brains of PT adolescents relative to term control subjects using diffusion tensor imaging (DTI), as well as studying their neurodevelopmental outcomes. Forty-four PT subjects (600 - 1250 grams birth weight) without neonatal brain injury and 41 term controls were evaluated at age 16 years with DTI, the Wechsler Intelligence Scale for Children - III (WISC), the Peabody Picture Vocabulary Test - Revised (PPVT), and the Comprehensive Test of Phonological Processing (CTOPP). PT subjects scored lower than term subjects on WISC full scale (p = 0.002), verbal (p = 0.027), and performance IQ tests (p = 0.001), as well as CTOPP phonological awareness (p = 0.005), but scored comparably to term subjects on PPVT and CTOPP Rapid Naming tests. PT subjects had lower fractional anisotropy (FA) values, suggestive of white matter disorganization, in multiple regions including bilateral uncinate fasciculi (left: p = 0.004; right: p = 0.002), bilateral external capsules (left: p \u3c 0.0001; right: p = 0.001), the splenium of the corpus callosum (p = 0.014), and white matter serving the inferior frontal gyrus bilaterally (left: p \u3c 0.0001; right: p = 0.005). FA values in both the left and right uncinate fasciculi correlated with PPVT scores (a semantic language task) in the PT subjects (left: R = 0.314, p = 0.038; right: R = 0.336, p = 0.026). FA values in the left and right arcuate fasciculi correlated with CTOPP Rapid Naming scores (a phonologic task) in the PT subjects (left: R = 0.424, p = 0.004; right: R = 0.301, p = 0.047). These data support for the first time that the recently proposed concept of dual pathways underlying language function are present in PT adolescents. These include a left-sided dorsal pathway associated with phonological and articulatory processing (arcuate fasciculus), and a bilateral ventral pathway for semantic, receptive language processing (uncinate fasciculus). The striking bilateral dorsal correlations for the PT group suggest that prematurely born subjects rely more heavily on the right hemisphere than typically developing adolescents for performance of phonological language tasks. These findings may represent either a delay in maturation or the engagement of alternative neural pathways for language in the developing PT brain

Prenatal maternal health and child brain structure: Implications for non-verbal ability and optimizing subcortical segmentation

Brain development starts in utero, and the fetal brain can already be affected by the environment, including chemical exposures and maternal health characteristics. These factors range from exposures to large quantities of teratogens (such as alcohol) to variations in the behaviors and characteristics of healthy individuals (such as age, diet, and subclinical levels of depressive and anxiety symptoms), which can nonetheless have long-lasting adverse effects. In this thesis, we reviewed the literature on the effects of prenatal exposures on human neurodevelopment, as well as cognitive, behavioral, and health outcomes. In Study I we found that prenatal exposures are often reported poorly in infant neuroimaging studies and gave recommendations for reporting in future studies. In Study II, we examined which early life factors predicted cortical structure in 5-year-olds. The results from Study II were utilized to make an informed decision regarding confounders in future studies in the 5-year-old neuroimaging sample of the FinnBrain Birth Cohort study. In Study III, we explored the cortical structural correlates of non-verbal ability in 5-year-olds. The findings were generally in line with prior results from adult and adolescent studies, with the important addition of a positive association between gray matter volume and surface area in the right medial occipital region and non-verbal ability as well as visual abstract reasoning ability. Finally, in Study IV, we compared the results from two common segmentation tools, FSL-FIRST and FreeSurfer, against manual segmentation in the hippocampus and subcortical structures. Overall, the agreement with manual segmentation was good, although results were suboptimal for the hippocampus, amygdala, and nucleus accumbens, and careful visual quality control is still recommended. This thesis summarized different perinatal factors affecting the developing brain, and ensured the high quality of our neuroimaging data. This foundational work, together with the multidisciplinary, longitudinal data collection in the FinnBrain Birth Cohort study, can be used to discover how environmental factors affect brain development.Äidin raskausajan terveys ja lapsen aivojen rakenne: yhteydet ei-kielellisiin taitoihin ja subkortikaalisen segmentaation optimointi Aivojen kehitys alkaa kohdussa ja jatkuu läpi elämän. Jo sikiöaikana aivot ovat alttiina ympäristön vaikutuksille, ml. kemialliset altisteet sekä äidin terveyteen liittyvät tekijät. Nämä altisteet vaihtelevat suurista annoksista teratogeeneille (esim. alkoholille) eroihin terveiden yksilöiden ominaisuuksissa ja toiminnassa (esim. ikä, ruokavalio sekä vähäiset masennus- ja ahdistusoireet ilman mielenterveyshäiriön diagnoosia), joilla voi kuitenkin olla kauaskantoisia seuraamuksia. Tässä väitöskirjassa teemme katsauksen raskaudenaikaisten altisteiden vaikutuksista yksilön kehitykseen sekä siihen liittyviin muutoksiin aivoissa. Tutkimuksessa I toteamme, että raskaudenaikaiset altisteet kuvataan usein puutteellisesti vauvojen aivokuvantamista koskevissa tutkimuksissa ja annamme suosituksia raportoinnista. Tutkimuksessa II tutkimme varhaisten altisteiden yhteyksiä 5-vuotiaiden aivojen rakenteeseen. Tämän tutkimuksen tulokset ohjasivat kontrolloitavien muuttujien valintaa. Tutkimuksessa III tutkimme aivokuoren rakenteen yhteyksiä ei-kielelliseen kognitiiviseen kyvykkyyteen 5-vuotiailla. Tulokset olivat pitkälti linjassa aiempien, vanhemmilla osallistujilla tehtyjen tutkimusten kanssa. Uutena tuloksena löysimme yhteyden oikean takaraivolohkon mediaalisen osan tilavuuden ja pinta-alan olevan yhteydessä ei-kielelliseen kyvykkyyteen sekä erityisesti näönvaraiseen päättelyyn. Tutkimuksessa IV vertailimme kahta yleistä segmentointityökalua (FreeSurfer ja FSL-FIRST) käsin tehtyyn segmentaatioon hippokampuksessa ja aivokuoren alaisissa tumakkeissa. Tulokset vaihtelivat paljon rakenteesta riippuen. Huolellista laadunvarmistusta aivoalueiden koon määrityksen yhteydessä suositellaan vahvasti. Tämä väitöskirja antaa kokonaisvaltaisen ymmärryksen aivoihin vaikuttavista varhaisen elämän altisteista. Yhdessä korkealaatuisen aivokuvantamisdatamme sekä muun FinnBrain-syntymäkohortissa kerättävän aineiston kanssa tätä tietoa voidaan hyödyntää useissa tulevissa aivojen kehitystä selvittävissä tutkimuksissa

Ventricular shape and relative position abnormalities in preterm neonates

abstract: Recent neuroimaging findings have highlighted the impact of premature birth on subcortical development and morphological changes in the deep grey nuclei and ventricular system. To help characterize subcortical microstructural changes in preterm neonates, we recently implemented a multivariate tensor-based method (mTBM). This method allows to precisely measure local surface deformation of brain structures in infants. Here, we investigated ventricular abnormalities and their spatial relationships with surrounding subcortical structures in preterm neonates. We performed regional group comparisons on the surface morphometry and relative position of the lateral ventricles between 19 full-term and 17 preterm born neonates at term-equivalent age. Furthermore, a relative pose analysis was used to detect individual differences in translation, rotation, and scale of a given brain structure with respect to an average. Our mTBM results revealed broad areas of alterations on the frontal horn and body of the left ventricle, and narrower areas of differences on the temporal horn of the right ventricle. A significant shift in the rotation of the left ventricle was also found in preterm neonates. Furthermore, we located significant correlations between morphology and pose parameters of the lateral ventricles and that of the putamen and thalamus. These results show that regional abnormalities on the surface and pose of the ventricles are also associated with alterations on the putamen and thalamus. The complementarity of the information provided by the surface and pose analysis may help to identify abnormal white and grey matter growth, hinting toward a pattern of neural and cellular dysmaturation.The final version of this article, as published in NeuroImage: Clinical, can be viewed online at: http://www.sciencedirect.com/science/article/pii/S221315821730130