Diffusion tensor imaging in frontostriatal tracts is associated with executive functioning in very preterm children at 9 years of age

Background Very preterm birth can disturb brain maturation and subject these high-risk children to neurocognitive difficulties later. Objective The aim of the study was to evaluate the impact of prematurity on microstructure of frontostriatal tracts in children with no severe neurologic impairment, and to study whether the diffusion tensor imaging metrics of frontostriatal tracts correlate to executive functioning. Materials and methods The prospective cohort study comprised 54 very preterm children (mean gestational age 28.8 weeks) and 20 age- and gender-matched term children. None of the children had severe neurologic impairment. The children underwent diffusion tensor imaging and neuropsychological assessments at a mean age of 9 years. We measured quantitative diffusion tensor imaging metrics of frontostriatal tracts using probabilistic tractography. We also administered five subtests from the Developmental Neuropsychological Assessment, Second Edition, to evaluate executive functioning. Results Very preterm children had significantly higher fractional anisotropy and axial diffusivity values (PPeer reviewe

Diffusion tensor imaging in frontostriatal tracts is associated with executive functioning in very preterm children at 9 years of age

Background Very preterm birth can disturb brain maturation and subject these high-risk children to neurocognitive difficulties later. Objective The aim of the study was to evaluate the impact of prematurity on microstructure of frontostriatal tracts in children with no severe neurologic impairment, and to study whether the diffusion tensor imaging metrics of frontostriatal tracts correlate to executive functioning. Materials and methods The prospective cohort study comprised 54 very preterm children (mean gestational age 28.8 weeks) and 20 age- and gender-matched term children. None of the children had severe neurologic impairment. The children underwent diffusion tensor imaging and neuropsychological assessments at a mean age of 9 years. We measured quantitative diffusion tensor imaging metrics of frontostriatal tracts using probabilistic tractography. We also administered five subtests from the Developmental Neuropsychological Assessment, Second Edition, to evaluate executive functioning. Results Very preterm children had significantly higher fractional anisotropy and axial diffusivity values (PConclusion Prematurity has a long-term effect on frontostriatal white matter microstructure that might contribute to difficulties in executive functioning.</div

Born Too Early and Too Small: Higher Order Cognitive Function and Brain at Risk at Ages 8-16

Prematurity presents a risk for higher order cognitive functions. Some of these deficits manifest later in development, when these functions are expected to mature. However, the causes and consequences of prematurity are still unclear. We conducted a longitudinal study to first identify clinical predictors of ultrasound brain abnormalities in 196 children born very preterm (VP; gestational age 32 weeks) and with very low birth weight (VLBW; birth weight 1500 g). At ages 8–16, the subset of VP-VLBW children without neurological findings (124) were invited for a neuropsychological assessment and an MRI scan (41 accepted). Of these, 29 met a rigorous criterion for MRI quality and an age, and gender-matched control group (n = 14) was included in this study. The key findings in the VP-VLBW neonates were: (a) 37% of the VP-VLBW neonates had ultrasound brain abnormalities; (b) gestational age and birth weight collectively with hospital course (i.e., days in hospital, neonatal intensive care, mechanical ventilation and with oxygen therapy, surgeries, and retinopathy of prematurity) predicted ultrasound brain abnormalities. At ages 8–16, VP-VLBW children showed: a) lower intelligent quotient (IQ) and executive function; b) decreased gray and white matter (WM) integrity; (c) IQ correlated negatively with cortical thickness in higher order processing cortical areas. In conclusion, our data indicate that facets of executive function and IQ are the most affected in VP-VLBW children likely due to altered higher order cortical areas and underlying W

Decreased amygdala volume in adults after premature birth

Premature-born infants have impaired amygdala structure, presumably due to increased stress levels of premature birth mediated by the amygdala. However, accounting for lifelong plasticity of amygdala, it is unclear whether such structural changes persist into adulthood. To address this problem, we stated the following questions: first, are whole amygdala volumes reduced in premature-born adults? And second, as adult anxiety traits are often increased after prematurity and linked with amygdala structure, are alterations in amygdala associated with adults’ anxiety traits after premature birth? We addressed these questions by automated amygdala segmentation of MRI volumes in 101 very premature-born adults (< 32 weeks of gestation and/or birth weight below 1500 g) and 108 full-term controls at 26 years of age of a prospectively and longitudinally collected cohort. We found significantly lower whole amygdala volumes in premature-born adults. While premature-born adults had significantly higher T score for avoidant personality reflecting increased social anxiety trait, this trait was not correlated with amygdala volume alterations. Results demonstrate reduced amygdala volumes in premature born adults. Data suggest lasting effects of prematurity on amygdala structure

Investigation into DNAm and brain structural and connectomic covariance: a life course approach

Early life environmental stress, indexed by perinatal factors such as birth weight and gestational age, is associated with differences in brain structure and connectivity in early life, as well as being associated with a range of neurodevelopmental, psychiatric and cognitive outcomes, from childhood and into adulthood. While studies have investigated how these early life factor influence brain structure in early life, few have investigated this in older age. The molecular underpinnings of these relationships are not well understood. DNA methylation is an epigenetic mechanism that regulates gene expression; it is developmentally dynamic and responsive to environmental factors, making it a promising candidate for providing mechanistic insight into how early life stressors exert their effects. The aims of this thesis are as follows: to better characterise the associations between birth weight and brain structure and connectivity in later-life; to evaluate the evidence that DNAm is implicated in brain structure and function; to investigate the impact of gestational age at birth on the neonatal methylome and its association with brain connectivity. In the first study, I investigated the associations between variation in normal birth weight and measures of brain structure and connectivity in participants aged 73 years from the Lothian Birth Cohort 1936. Larger birth weight was associated with larger brain volume, and with regional cortical surface area, but not with white matter microstructure. This relationship between birth weight and brain size did not appear to be related to the degree of atrophy that had taken place. Early life growth is likely to be associated with brain tissue reserve, in evidence in later life. In the second study, I conducted a systematic review to evaluate the evidence linking DNA methylation to brain structure and function across the life-course. Sixty studies, encompassing both health and disease contexts, were identified. Together, these studies indicated that differential DNAm is associated with brain structure and function for 8 categories of disease across the life course, although uncertainties remain. Modest consistency between DNAm and neuroimaging features precluded the possibility of quantitative synthesis. I identified potential sources of bias in existing literature, enabling the development of guidelines that could reduce methodological heterogeneity in imaging-DNAm studies. Finally, I identified a DNAm signature of gestational age in neonatal saliva samples and tested its association with brain white matter microstructure. Participants were neonates, born preterm or term, recruited to the Theirworld Edinburgh Birth Cohort. There was widespread differential methylation associated with gestational age at birth, at term equivalent age. Several genes were identified that have previously been implicated in association with gestational age in cord blood, and with disorders known to contribute to the aetiology of preterm birth, such as pre-eclampsia. An epigenome-wide variable of the DNAm signature was associated with white matter microstructure, suggesting that DNAm contributes to white matter dysconnectivity in the neonatal period. This thesis provides evidence that early life exerts an effect on brain structure into later life, that DNAm and MRI neuroimaging are associated across the life-course and in a range of health and disease contexts, and that DNAm is profoundly altered in association with variation in gestational age and that this may contribute to white matter connectivity in the neonatal period

Within amygdala : basolateral parts are selectively impaired in premature-born adults

While it is known that whole amygdala volume is lastingly reduced after premature birth, it is unknown whether different amygdala nuclei are distinctively affected by prematurity. This question is motivated by two points: First, the observation that developmental trajectories of superficial, centromedial and basolateral amygdala nuclei are different. And second, the expectation that these different developmental pathways are distinctively affected by prematurity. Furthermore, we stated the question whether alterations in amygdala nuclei are associated with increased adults’ anxiety traits after premature birth. We investigated 101 very premature-born adults (<32 weeks of gestation and/or birth weight below 1500 g) and 108 full-term controls of a prospectively and longitudinally collected cohort at 26 years of age using automated amygdala nuclei segmentation based on structural MRI. We found selectively reduced volumes of bilateral accessory basal nuclei (pertaining to the basolateral amygdala of claustral developmental trajectory) adjusted for whole amygdala volume. Volumes of bilateral accessory basal nuclei were positively associated with gestational age and negatively associated with duration of ventilation. Furthermore, structural covariance within the basolateral amygdala was increased in premature-born adults. We did not find an association between reduced volumes of basolateral amygdala and increased social anxiety in the prematurity group. These results demonstrate specifically altered basolateral amygdala structure in premature-born adults. Data suggest that prematurity has distinct effects on amygdala nuclei

An In-Vivo Structural MRI Investigation of Newborn Infants’ Brains: Preterm Infants and Infants born with Intrauterine Growth Restriction

Introduction: It is well documented that preterm infants are less developed than term infants at term age and infants with IUGR are said to be of higher vulnerability. Fractional Anisotropy (FA) and Apparent Diffusion Coefficient (ADC) are sensitive to micro structural abnormalities and increases in anisotropy associated with premyelination are the earliest indications of the beginning processes of myelination. Furthermore reductions in brain volumes have been found in preterm infants compared to controls and IUGR infants. Thyroxine (T4) is necessary for normal growth and development of the central nervous system. Infants born preterm miss out on the maternal transfer of T4 that occurs during the third trimester and are born with an underdeveloped thyroid gland that is not yet producing sufficient amounts of T4. Method: Sixty nine infants (51 preterm, 9 IUGR and 9 controls) were imaged on a 1.5 Telsa MRI Scanner. DTI analysis was performed using medical imaging software (DTIstudio). FA and ADC maps were used to draw regions of interest around the posterior limb of the internal capsule (PLIC), corpus callosum (CC), frontal lobes (FL) and occipital lobes (OL). The software Brain Voyager QX (version 1.9.10) was used for image realignment and demarcation of T2 Weighted images and the images were analysed using medical imaging software for structure- specific brain volume measurements (Easymeasure). Statistical analysis was conducted with repeated measures ANOVA using SPSS version 18. Results: A significant interaction when investigating anterior vs. posterior structures and laterality of structures with treatment in the frontal lobes and posterior limb of the internal capsule was found suggesting a group difference between infants treated with levothyroxine and those receiving placebo. IUGR infants generally had lower FA and ADC than the control group. Generally lower structural volumes were found in the placebo and IUGR group. Conclusion: Administration of levothyroxine affects the structures on different sides of the brain differently and raises structural volumes. Levothyroxine may be of particular benefit to infants with low levels of thyroxine in their blood (hypothyroxinemia) and male preterm infants. Preterm infants born with intrauterine growth restriction are of higher vulnerability than appropriate for gestational age preterm infants with lower FA, higher ADC and lower structural volumes. Further research is required to fully explore asymmetries in the preterm and IUGR brain and should look at administering levothyroxine to infants with low levels of thyroxine in their blood

Newborn brain structural characteristics and their relationships with maternal prenatal distress : Findings from the FinnBrain Birth Cohort MRI Study

Plasticity renders the brain sensitive to its intrauterine environment and susceptible to alterations during early brain development. The amygdala and hippocampus, structures key in socioemotional functions, are susceptible to these alterations. Understanding the normal variation in the newborn brain facilitates the recognition of such aberrant developmental trajectories, which may occur after exposure to maternal prenatal psychological distress (PPD) and result in a predisposition to psychopathology. This study aimed to 1) describe the normal variation of newborn brain volumetric measures in relation to newborn characteristics; 2) assess the prevalence and risk factors of incidental findings in newborn brain magnetic resonance imaging (MRI); 3) investigate how different types and timings of maternal PPD associate with newborn amygdalar and hippocampal volumes, and whether this association is modified by newborn sex. Information on maternal depressive and anxiety symptoms was gathered at gestational weeks (GW) 14, 24 and 34, and pregnancy¬specific anxiety (PSA) symptoms at GW24. Newborns were imaged with MRI at two to five weeks of postnatal age (n=175). The sub studies constituted variant samples sizes from the total population. Newborn brain lobar volumes were similarly asymmetric in both sexes. Modest sex differences were observed in regional brain volumes. Newborn age predicted larger volumes of gray and white matter. The prevalence of incidental findings in brain MRI was 7.4 % and that of hemorrhages 6.9 %. Risk factors for hemorrhages were vaginal and vacuum-assisted deliveries. All the different types of PPD associated with the left newborn amygdalar volume at GW24 in a sex-specific manner. In males, PPD predicted smaller amygdalar volumes, while in females larger amygdalar volumes. Further analyses suggested a negative association between PSA and the right hippocampal volume in females. Newborn sex appears to be a significant factor moderating the relationship between PPD and newborn brain structures, suggesting sex-specific susceptibility to psychopathologies.Vastasyntyneen aivojen rakenteelliset ominaisuudet ja niiden yhteydet äidin raskaudenaikaiseen stressiin – tuloksia FinnBrain syntymäkohortin MRI-tutkimuksesta Aivojen muovautuvuus herkistää aivot kohdunsisäiselle ympäristölle ja lisää alttiutta muutoksille niiden kehityksessä. Muutoksille herkkiä rakenteita ovat mantelitumake ja aivoturso, jotka ovat tärkeitä sosioemotionaalisissa toiminnoissa. Aivorakenteiden normaalivaihtelun ymmärtäminen helpottaa poikkeavien kehityssuuntien havait¬semista, jollaisia voi kehittyä äidin raskaudenaikaiselle psykologiselle stressille (RPS) altistumisen jälkeen ja jotka voivat altistaa psykiatrisille häiriöille. Tutkimuksen tavoitteena oli 1) kuvata vastasyntyneiden aivorakenteiden tilavuuksien normaalivaihtelua suhteessa vastasyntyneen ominaisuuksiin; 2) kartoittaa vastasyntyneiden aivojen magneettikuvantamisen sattumalöydösten esiin¬tyvyys ja riskitekijät; 3) tutkia äidin RPS:n eri tyyppien ja ajoituksen yhteyttä vastasyntyneen mantelitumakkeen ja aivoturson tilavuuksiin, sekä vaikuttaako vastasyntyneen sukupuoli yhteyteen. Raskaana olevien äitien masennus-ja ahdistuneisuusoireita mitattiin raskausviikoilla (RV) 14, 24, 34 ja raskausspesifistä ahdistuneisuutta (RSA) RV:lla 24. Vastasyntyneet (n=175) kuvattiin magneetti¬kameralla kahden-viiden viikon ikäisinä syntymän jälkeen. Osatutkimuksien otoskoot koostuivat vaihtelevista osista koko tutkimuspopulaatiota. Vastasyntyneen aivolohkojen asymmetriassa ei ollut eroa sukupuolten välillä. Maltillisia sukupuolieroja havaittiin aivotilavuuksissa rajatuilla alueilla. Vasta¬syntyneen ikä ennusti suurempia harmaan ja valkean aineen tilavuuksia. Sattuma¬löydösten esiintyvyys aivokuvissa oli 7.4 % ja verenvuotojen 6.9 %. Verenvuotojen riskitekijät olivat alatie-ja imukuppisynnytykset. RPS:n eri tyypit olivat vahvimmin yhteydessä vastasyntyneiden vasemman mantelitumaketilavuuden kanssa RV:lla 24 sukupuoliriippuvaisella tavalla, mikä ilmeni pienempinä tilavuuksina poikavauvoilla ja suurempina tilavuuksina tyttövauvoilla. Lisäanalyysit viittasivat negatiiviseen yhteyteen RPS:n ja tyttöjen oikean aivotursotilavuuden välillä. Sukupuoli vaikuttaisi säätelevän RPS:n vaikutuksia vastasyntyneen aivoihin mahdollisesti lisäten alttiutta tietyllä sukupuolella toista useammin esiintyville psykiatrisille häiriöille.Vastasyntyneen aivojen rakenteelliset ominaisuudet ja niiden yhteydet äidin raskaudenaikaiseen stressiin – tuloksia FinnBrain syntymäkohortin MRI-tutkimuksesta Aivojen muovautuvuus herkistää aivot kohdunsisäiselle ympäristölle ja lisää alttiutta muutoksille niiden kehityksessä. Muutoksille herkkiä rakenteita ovat mantelitumake ja aivoturso, jotka ovat tärkeitä sosioemotionaalisissa toiminnoissa. Aivorakenteiden normaalivaihtelun ymmärtäminen helpottaa poikkeavien kehityssuuntien havait¬semista, jollaisia voi kehittyä äidin raskaudenaikaiselle psykologiselle stressille (RPS) altistumisen jälkeen ja jotka voivat altistaa psykiatrisille häiriöille. Tutkimuksen tavoitteena oli 1) kuvata vastasyntyneiden aivorakenteiden tilavuuksien normaalivaihtelua suhteessa vastasyntyneen ominaisuuksiin; 2) kartoittaa vastasyntyneiden aivojen magneettikuvantamisen sattumalöydösten esiin¬tyvyys ja riskitekijät; 3) tutkia äidin RPS:n eri tyyppien ja ajoituksen yhteyttä vastasyntyneen mantelitumakkeen ja aivoturson tilavuuksiin, sekä vaikuttaako vastasyntyneen sukupuoli yhteyteen. Raskaana olevien äitien masennus-ja ahdistuneisuusoireita mitattiin raskausviikoilla (RV) 14, 24, 34 ja raskausspesifistä ahdistuneisuutta (RSA) RV:lla 24. Vastasyntyneet (n=175) kuvattiin magneetti¬kameralla kahden-viiden viikon ikäisinä syntymän jälkeen. Osatutkimuksien otoskoot koostuivat vaihtelevista osista koko tutkimuspopulaatiota. Vastasyntyneen aivolohkojen asymmetriassa ei ollut eroa sukupuolten välillä. Maltillisia sukupuolieroja havaittiin aivotilavuuksissa rajatuilla alueilla. Vasta¬syntyneen ikä ennusti suurempia harmaan ja valkean aineen tilavuuksia. Sattuma¬löydösten esiintyvyys aivokuvissa oli 7.4 % ja verenvuotojen 6.9 %. Verenvuotojen riskitekijät olivat alatie-ja imukuppisynnytykset. RPS:n eri tyypit olivat vahvimmin yhteydessä vastasyntyneiden vasemman mantelitumaketilavuuden kanssa RV:lla 24 sukupuoliriippuvaisella tavalla, mikä ilmeni pienempinä tilavuuksina poikavauvoilla ja suurempina tilavuuksina tyttövauvoilla. Lisäanalyysit viittasivat negatiiviseen yhteyteen RPS:n ja tyttöjen oikean aivotursotilavuuden välillä. Sukupuoli vaikuttaisi säätelevän RPS:n vaikutuksia vastasyntyneen aivoihin mahdollisesti lisäten alttiutta tietyllä sukupuolella toista useammin esiintyville psykiatrisille häiriöille