42 research outputs found
Developmental malformation of the corpus callosum: a review of typical callosal development and examples of developmental disorders with callosal involvement
This review provides an overview of the involvement of the corpus callosum (CC) in a variety of developmental disorders that are currently defined exclusively by genetics, developmental insult, and/or behavior. I begin with a general review of CC development, connectivity, and function, followed by discussion of the research methods typically utilized to study the callosum. The bulk of the review concentrates on specific developmental disorders, beginning with agenesis of the corpus callosum (AgCC)âthe only condition diagnosed exclusively by callosal anatomy. This is followed by a review of several genetic disorders that commonly result in social impairments and/or psychopathology similar to AgCC (neurofibromatosis-1, Turner syndrome, 22q11.2 deletion syndrome, Williams yndrome, and fragile X) and two forms of prenatal injury (premature birth, fetal alcohol syndrome) known to impact callosal development. Finally, I examine callosal involvement in several common developmental disorders defined exclusively by behavioral patterns (developmental language delay, dyslexia, attention-deficit hyperactive disorder, autism spectrum disorders, and Tourette syndrome)
Mapping Genetic Influence on Brain Structure
Neuroimaging is playing an increasingly crucial role in delineating pathological conditions that cannot be typically defined by non-specific clinical symptom. The goal of this thesis was to characterize the genetic influence on grey and white matter indices and evaluate their potential as a reliable âstructural MRI signaturesâ. We first assessed the effects of spatial resolution and smoothing on heritability estimation (Chapter 3). We then investigated heritability patterns of MRI measures of grey and white matter (Chapters 4-5). We then performed a cross-sectional evaluation of how heritability changes over the lifespan for both grey and white matter (Chapter 6). Finally, multivariate structural equation modeling was used to investigate the genetic correlation between grey matter structure and white matter connectivity (Chapter 7), in the default mode network (DMN). Our results show that several key brain structures were moderate to highly heritable and that this heritability was both spatially and temporally heterogeneous. At a network level, the DMN was found to have distinct genetic factors that modulated the grey matter regions and white matter tracts separately. We conclude that the spatial and temporal heterogeneity are likely to reflect gene expression patterns that are related to the developmental of specific brain regions and circuits over time
Neuroepigenetics of preterm white matter injury
Introduction: Preterm birth is increasing worldwide and is a major cause of neonatal death.
Survivors are at increased risk of neurodisability, cognitive, social and psychiatric disorders in
later life. Alterations to the white matter can be assessed using diffusion tensor imaging (DTI)
MRI and are associated with poor neurodevelopmental outcome. The pathogenesis of white
matter injury is multifactorial and several clinical risk and resilience factors have been
identified. DNA methylation (DNAm) is an epigenetic process which links stressful early life
experience to later life disease and is associated with normal brain development, neuronal
processes and neurological disease. Several studies have shown DNAm is altered by the
perinatal environment, however its role in preterm white mater injury is yet to be
investigated.
Aims: 1. To examine the relationship between preterm birth and white matter integrity 2. To
investigate the effect of neuroprotective treatments and deleterious clinical states on white
matter integrity in preterm infants 3. To assess the best DTI method of quantifying white
matter integrity in a neonatal population 4. To investigate the effect of preterm birth on DNA
methylation and 5. To determine the clinical and imaging factors that contribute to the
variance in DNA Methylation caused by preterm birth
Methods: DTI data was acquired from preterm infants (< 32 weeksâ gestation or < 1500 grams
at birth) at term equivalent age (TEA) and term controls (> 37 weeksâ gestation at birth).
Region-of-interests (ROI) and tract-averaged methods of DTI analysis were performed to
obtain measurements of fractional anisotropy (FA) and mean diffusivity (MD) in the genu of
corpus callosum, posterior limb of internal capsule and centrum semiovale. Clinical data was
collected for all infants and the effect of prematurity, neuroprotective agents and clinical risk
factors on white matter integrity were analysed. 8 major white matter tracts were segmented
using probabilistic neighbourhood tractography (PNT), a tract-averaged technique which also
allowed the calculation of tract shape. The two DTI techniques were compared to evaluate
agreement between results. DNA was collected from preterm infants and term controls at
TEA, and a genome-wide analysis of DNAm was performed. DTI parameters from probabilistic
neighborhood tractography (PNT) methodology and clinical risk and resilience factors were
used to inform a principal components analysis to investigate the contribution of white
matter integrity and clinical variables to variance in DNAm.
Results: FA and MD were significantly affected by preterm birth on ROI analysis. In addition,
DTI parameters were affected by clinical factors that included antenatal magnesium sulphate,
histological chorioamnionitis and bronchopulmonary dysplasia. Evaluation of DTI
methodology revealed good accuracy in repeated ROI measurements but limited agreement
with tract-averaged values. Differential methylation was found within 25 gene bodies and 58
promoters of protein-coding genes in preterm infants, compared with controls. 10 of these
genes have a documented association with neural function or neurological disease.
Differences detected in the array were validated with pyrosequencing which captured
additional differentially methylated CpGs. Ninety-five percent of the variance in DNAm in
preterm infants was explained by 23 principal components (PC); corticospinal tract shape
associated with 6th PC, and gender and early nutritional exposure associated with the 7th PC.
Conclusions: Preterm birth is associated with alterations in white matter integrity which is
modifiable by clinical risk factors and neuroprotective agents. ROI analysis may not provide
sufficient representation of white matter tracts in their entirety. Prematurity is related to
alterations in the methylome at sites that influence neural development and function.
Differential methylation analysis has identified several promising candidate genes for future
work and contributed to the understanding of the pathogenesis of preterm brain injury
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The role of HG in the analysis of temporal iteration and interaural correlation
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.Ăidin raskausajan terveys ja lapsen aivojen rakenne: yhteydet ei-kielellisiin taitoihin ja subkortikaalisen segmentaation optimointi
Aivojen kehitys alkaa kohdussa ja jatkuu lÀpi elÀmÀn. Jo sikiöaikana aivot ovat alttiina ympÀristön vaikutuksille, ml. kemialliset altisteet sekÀ Àidin terveyteen liittyvÀt tekijÀt. NÀmÀ altisteet vaihtelevat suurista annoksista teratogeeneille (esim. alkoholille) eroihin terveiden yksilöiden ominaisuuksissa ja toiminnassa (esim. ikÀ, ruokavalio sekÀ vÀhÀiset masennus- ja ahdistusoireet ilman mielenterveyshÀiriön diagnoosia), joilla voi kuitenkin olla kauaskantoisia seuraamuksia.
TÀssÀ vÀitöskirjassa teemme katsauksen raskaudenaikaisten altisteiden vaikutuksista yksilön kehitykseen sekÀ siihen liittyviin muutoksiin aivoissa. Tutkimuksessa I toteamme, ettÀ raskaudenaikaiset altisteet kuvataan usein puutteellisesti vauvojen aivokuvantamista koskevissa tutkimuksissa ja annamme suosituksia raportoinnista.
Tutkimuksessa II tutkimme varhaisten altisteiden yhteyksiÀ 5-vuotiaiden aivojen rakenteeseen. TÀmÀn tutkimuksen tulokset ohjasivat kontrolloitavien muuttujien valintaa. Tutkimuksessa III tutkimme aivokuoren rakenteen yhteyksiÀ ei-kielelliseen kognitiiviseen kyvykkyyteen 5-vuotiailla. Tulokset olivat pitkÀlti linjassa aiempien, vanhemmilla osallistujilla tehtyjen tutkimusten kanssa. Uutena tuloksena löysimme yhteyden oikean takaraivolohkon mediaalisen osan tilavuuden ja pinta-alan olevan yhteydessÀ ei-kielelliseen kyvykkyyteen sekÀ erityisesti nÀönvaraiseen pÀÀttelyyn.
Tutkimuksessa IV vertailimme kahta yleistÀ segmentointityökalua (FreeSurfer ja FSL-FIRST) kÀsin tehtyyn segmentaatioon hippokampuksessa ja aivokuoren alaisissa tumakkeissa. Tulokset vaihtelivat paljon rakenteesta riippuen. Huolellista laadunvarmistusta aivoalueiden koon mÀÀrityksen yhteydessÀ suositellaan vahvasti.
TÀmÀ vÀitöskirja antaa kokonaisvaltaisen ymmÀrryksen aivoihin vaikuttavista varhaisen elÀmÀn altisteista. YhdessÀ korkealaatuisen aivokuvantamisdatamme sekÀ muun FinnBrain-syntymÀkohortissa kerÀttÀvÀn aineiston kanssa tÀtÀ tietoa voidaan hyödyntÀÀ useissa tulevissa aivojen kehitystÀ selvittÀvissÀ tutkimuksissa
Effect of preterm birth on white matter tracts and infant cognition
Preterm birth (defined as birth before 37 weeks) is a leading cause of neurocognitive
impairment in childhood, including difficulties in social cognition and executive
function. Microstructural divergence from typical brain development in the preterm
brain can be quantified using diffusion magnetic resonance imaging (dMRI)
tractography during the neonatal period. The relationship between dMRI tractography
metrics and later cognitive difficulties remains inconclusive. A general measure of
white matter microstructure (gWM) offers a neural basis for cognitive processes in
adults, however it remains unclear when gWM is first detectable in the developmental
trajectory. Eye-tracking is a technique which assesses eye-gaze behaviour in response
to visual stimuli, which permits inference about underlying cognitive processes, such
as social cognition and executive function in infancy.
The primary aims of this thesis were to test the hypotheses: dMRI tractography reveals
significant differences in tract-average fractional anisotropy (FA) and mean diffusivity
(MD) between preterm and term infants, and variance in tract-average FA and MD is
shared across major tracts. Secondly, infants born preterm have altered social
cognition and executive function compared to term born peers, assessed by eye-tracking
and finally, neonatal MRI gWM is associated with cognitive function in
infancy.
Preterm (birth weight †1500g) and term infants (born â„ 37 weeksâ post-menstrual age
[PMA]) were recruited and underwent a MRI scan at term equivalent age (between 38
- 42 weeksâ PMA) and an eye-tracking assessment six to nine months later. Preterm
infants were assessed at two years using the Bayley Scales of Infant and Toddler
Development, Third Edition (BSID-III). dMRI tractography metrics were generated
using probabilistic neighbourhood tractography (PNT) in eight pre-defined tracts-of-interest.
Principal component analyses (PCA) were used to determine the correlations
between the eight tracts-of-interest for four tract-averaged water diffusion parameters.
dMRI metrics were compared to the eye-tracking performance and two year outcome
data.
Quantitative microstructural changes were identifiable within the preterm brain when
compared to infants born at term. PCA revealed a single variable that accounts for
nearly 50% of shared variance between tracts-of-interest, and all tracts showed
positive loadings. Eye-tracking revealed group-wise differences in infant social
cognition, attributable to preterm birth, but executive functions inferred from eye-tracking
did not differ between groups. dMRI tractography metrics within the neonatal
period did not relate to later outcome measures.
This thesis shows that variance in dMRI parameters is substantially shared across
white matter tracts of the developing brain and suggests that anatomical foundations
of later intelligence are present by term equivalent age. Social cognition is altered by
preterm birth, however social cognitive ability in infancy is independent of gWM
Hétérogénéité neuropsychologique et corrélats structurels du trouble déficit de l'attention / hyperactivité
Previous models of Attention Deficit / Hyperactivity Disorder (ADHD) such as Barkleyâs or Brownâs conceptualized ADHD as essentially a developmental impairment of executive function. Against this view, it is now recognized that ADHD is a heterogeneous disorder, involving multiple deficits and multiple neuronal pathways. Despite this current theoretical framework, most structural brain imaging studies in ADHD have compared groups of children with ADHD with typically developing children, without trying to identify subgroups within the diagnostic category. This approach has yielded heterogeneous findings, possibly due to inter-studies variations in the type and number of comorbidities, the percentage of medicated participants included, the number of girls included, and/or methodological and statistical differences. Patients participating in these studies were also often exposed to methylphenidate, and potential medication effects on grey matter volumes are still unclear in certain brain regions such as the frontal lobe, despite a therapeutic action involving the preferential activation of catecholamine neurotransmission within the prefrontal cortex. In this thesis, we used voxel-based morphometry to study the influence of two important risk factors for the development of comorbid conditions in ADHD. The first of these two factors was gender, and the second a genetic polymorphism of the Catechol-O-methyltransferase gene known to put children with ADHD at risk for developing a conduct disorder (Val158Met). We also compared grey matter volumes in children with ADHD exposed to methylphenidate, never-medicated children with ADHD and typically developing children. These experimental studies were part of a more general discussion of ADHD neuropsychological and neurobiological heterogeneity. In our study exploring the influence of gender on the structural correlates of ADHD, we report for the first time a gender-by-diagnosis interaction, with grey matter volume differences in boys and girls with ADHD in midline cortical structures, involved in emotional regulation and part of the default mode network. We propose that these differences may contribute to explain why girls with ADHD more often develop inattentive and internalizing symptoms, whereas externalizing symptoms are predominant in boys with ADHD. In our study investigating the effects of Val158Met in ADHD, we report the first evidence of a COMT-related genetic modulation of ADHD-related grey matter volume alterations. Indeed, children with ADHD at higher risk for developing a conduct disorder (children homozygotes for the Val158 allele) presented increased grey matter volumes in the caudate nucleus when compared with typically developing children, whereas children carrying a Met158 allele presented with decreased grey matter volumes in the right inferior frontal cortex, a region known for its key role in attention. Finally, we measured grey matter volumes in medicated children with ADHD, never-medicated children with ADHD and typically developing children using both whole-brain voxel-based morphometry and automated tracing procedures in chosen regions of interest. We document potential methylphenidate-related grey matter volume normalization and deviation in previously unexplored frontal and temporal regions, and report a positive association between treatment history and grey matter volume in the nucleus accumbens, a key region for reward processing. Our first two experimental studies therefore contribute to a better understanding of the influence of important sources of within-category heterogeneity, while the third helps clarifying the potential confounding effect of medication exposure in previous structural brain imaging studies in ADHD.SuccĂ©dant Ă une thĂ©orisation centrĂ©e sur le rĂŽle des dĂ©ficits des fonctions exĂ©cutives, les modĂšles contemporains du trouble dĂ©ficit de l'attention / hyperactivitĂ© (TDAH) mettent en avant lâhĂ©tĂ©rogĂ©nĂ©itĂ© dâune catĂ©gorie diagnostique impliquant des dĂ©ficits neuropsychologiques, voies cĂ©rĂ©brales et mĂ©canismes Ă©tiopathogĂ©niques multiples. En dĂ©pit de cette Ă©volution, la majoritĂ© des Ă©tudes d'imagerie cĂ©rĂ©brale des corrĂ©lats structurels du trouble menĂ©es Ă ce jour ont Ă©tĂ© conduites au niveau de la catĂ©gorie diagnostique, sans spĂ©cification supplĂ©mentaire. Cette approche comparant en moyenne un groupe de patients avec TDAH Ă un groupe de sujets sains a donnĂ© des rĂ©sultats trĂšs variables d'une Ă©tude Ă l'autre, la comparaison inter-Ă©tude Ă©tant toutefois rendue difficile par la prĂ©sence de facteurs confondants, tels que des diffĂ©rences en terme de rĂ©gions dâintĂ©rĂȘt examinĂ©es, de comorbiditĂ©s acceptĂ©es chez les patients, de pourcentages de sujets masculins et fĂ©minins, de fenĂȘtre dâĂąge sĂ©lectionnĂ©e, de mĂ©thodologie d'analyse ou encore de pourcentage de patients traitĂ©s par mĂ©thylphĂ©nidate. Dans ce doctorat, nous nous sommes appuyĂ©s sur la morphomĂ©trie voxel-Ă -voxel pour isoler lâinfluence sur les volumes de matiĂšre grise de deux facteurs dâhĂ©tĂ©rogĂ©nĂ©itĂ© intra-catĂ©gorielle dans le TDAH : le genre dâune part, et un polymorphisme gĂ©nĂ©tique (Val158Met du gĂšne CatĂ©chol-O-mĂ©thyltransferase (COMT)) dâautre part ; ces deux facteurs prĂ©sentant lâintĂ©rĂȘt de moduler le risque associĂ© de dĂ©velopper un trouble de type externalisĂ©. Nous avons Ă©galement comparĂ© les volumes de matiĂšre grise dâenfants avec TDAH ayant reçu un traitement par mĂ©thylphĂ©nidate, de patients n'ayant jamais Ă©tĂ© exposĂ© Ă la mĂ©dication, et de sujet sains. Ces recherches expĂ©rimentales ont Ă©tĂ© inscrites dans une discussion plus gĂ©nĂ©rale de lâhĂ©tĂ©rogĂ©nĂ©itĂ© des rĂ©sultats de la littĂ©rature structurelle consacrĂ©e au TDAH et des sources neuropsychologiques de cette hĂ©tĂ©rogĂ©nĂ©itĂ©. Dans notre Ă©tude des effets du genre sur les volumes de matiĂšre grise dans le TDAH, nous reportons pour la premiĂšre fois une interaction entre genre et diagnostic, avec des corrĂ©lats structurels du trouble diffĂ©rents chez les garçons et les filles avec TDAH dans des rĂ©gions de la ligne mĂ©diane du cerveau, impliquĂ©es Ă la fois dans la rĂ©gulation Ă©motionnelle et dans le fonctionnement du mode de rĂ©seau par dĂ©faut. Nous suggĂ©rons que ces diffĂ©rences structurelles pourraient contribuer aux diffĂ©rences de risque associĂ© pour les troubles internalisĂ©s et externalisĂ©s prĂ©sentĂ©es par les garçons et filles avec TDAH. Dans notre Ă©tude explorant l'influence du polymorphisme Val158Met sur les volumes de matiĂšre grise, nous mettons en Ă©vidence une modulation gĂ©nĂ©tique des corrĂ©lats structurels du trouble : les sujets homozygotes pour l'allĂšle Val158, identifiĂ©s dans la littĂ©rature comme Ă risque pour le dĂ©veloppement d'un trouble des conduites, prĂ©sentent des volumes de matiĂšre grise supĂ©rieurs dans le noyau caudĂ© comparativement aux sujets sains, tandis que les patients avec TDAH porteurs d'un allĂšle Met158 prĂ©sentent des volumes de matiĂšre grise plus faibles dans le cortex prĂ©frontal infĂ©rieur droit, une rĂ©gion cruciale pour les processus de contrĂŽle attentionnel. Enfin, dans notre Ă©tude des corrĂ©lats structurels de l'exposition au mĂ©thylphĂ©nidate, nous reportons un effet potentiellement normalisateur du traitement sur les volumes de matiĂšre grise de l'insula et du pole temporal, des volumes de matiĂšre grise plus faibles chez les patients traitĂ©s comparativement aux sujets sains dans le gyrus frontal moyen et dans le gyrus prĂ©central, et une association entre volume de matiĂšre grise dans le nucleus accumbens gauche et durĂ©e d'exposition au mĂ©thylphĂ©nidate chez les sujets traitĂ©s. (...