Characterisation of Longitudinal Brain Morphology, Neurometabolism and Prenatal to Neonatal Brain Growth in Patients with Congenital Heart Disease

Congenital heart disease (CHD) affect 8 in 1000 newborns (Liu et al. 2019). The consequences of CHD vary greatly, depending on the specific type of CHD. While advancements in surgical techniques and patient care have led to a high survival rate for severe types of CHD, patients are still at risk of impaired neurodevelopment (ND). Early ND impairment can manifest in various domains, including motor, cognitive or language development (Latal 2016). As a result, one area of CHD research is dedicated to studying the brain development of these patients. This thesis focuses on the longitudinal description of brain development during the late fetal and neonatal period. First, we explored whether deformation-based morphometry (DBM) could be a suitable tool to study CHD patients from fetal to neonatal time period by applying this method to a healthy control cohort. Next, we analysed longitudinally collected data from two studies, primarily focusing on quantifying brain development and searching for associations with ND outcomes in CHD patients. In the first study we explored how DBM could be applied to fetal and neonatal MRI data to observe asymmetry changes during this period. By using DBM, we were able to reveal temporal changes of asymmetry patterns. However, the results may greatly depend on the various combinations of analysis tools and their parameters used. In the second study, where we compared brain development in CHD patients to healthy controls, we therefore relied on volume and surface measurements to quantify growth. Here, we could show that the total brain volume growth trajectory for CHD patients was reduced compared to healthy controls. Finally, we investigated neurometabolite ratios in CHD patients and their association to ND outcome. While we found that a specific neurometabolite ratio (NAA/Cho; N-acetylaspartate to choline-containing compounds) was reduced in the CHD cohort compared to healthy controls, we could not find any association with ND outcome measured at one year of age. In conclusion, the work presented in this thesis uses various methods to study brain development in a longitudinal manner. The findings provide further evidence that brain 4 development in CHD patients is altered while its association with ND outcome requires further investigation

Computerized Analysis of Magnetic Resonance Images to Study Cerebral Anatomy in Developing Neonates

The study of cerebral anatomy in developing neonates is of great importance for the understanding of brain development during the early period of life. This dissertation therefore focuses on three challenges in the modelling of cerebral anatomy in neonates during brain development. The methods that have been developed all use Magnetic Resonance Images (MRI) as source data. To facilitate study of vascular development in the neonatal period, a set of image analysis algorithms are developed to automatically extract and model cerebral vessel trees. The whole process consists of cerebral vessel tracking from automatically placed seed points, vessel tree generation, and vasculature registration and matching. These algorithms have been tested on clinical Time-of- Flight (TOF) MR angiographic datasets. To facilitate study of the neonatal cortex a complete cerebral cortex segmentation and reconstruction pipeline has been developed. Segmentation of the neonatal cortex is not effectively done by existing algorithms designed for the adult brain because the contrast between grey and white matter is reversed. This causes pixels containing tissue mixtures to be incorrectly labelled by conventional methods. The neonatal cortical segmentation method that has been developed is based on a novel expectation-maximization (EM) method with explicit correction for mislabelled partial volume voxels. Based on the resulting cortical segmentation, an implicit surface evolution technique is adopted for the reconstruction of the cortex in neonates. The performance of the method is investigated by performing a detailed landmark study. To facilitate study of cortical development, a cortical surface registration algorithm for aligning the cortical surface is developed. The method first inflates extracted cortical surfaces and then performs a non-rigid surface registration using free-form deformations (FFDs) to remove residual alignment. Validation experiments using data labelled by an expert observer demonstrate that the method can capture local changes and follow the growth of specific sulcus

Neonatal brain tissue classification with morphological adaptation and unified segmentation

Measuring the distribution of brain tissue types (tissue classification) in neonates is necessary for studying typical and atypical brain development, such as that associated with preterm birth, and may provide biomarkers for neurodevelopmental outcomes. Compared with magnetic resonance images of adults, neonatal images present specific challenges that require the development of specialized, population-specific methods. This paper introduces MANTiS (Morphologically Adaptive Neonatal Tissue Segmentation), which extends the unified segmentation approach to tissue classification implemented in Statistical Parametric Mapping (SPM) software to neonates. MANTiS utilizes a combination of unified segmentation, template adaptation via morphological segmentation tools and topological filtering, to segment the neonatal brain into eight tissue classes: cortical gray matter, white matter, deep nuclear gray matter, cerebellum, brainstem, cerebrospinal fluid (CSF), hippocampus and amygdala. We evaluated the performance of MANTiS using two independent datasets. The first dataset, provided by the NeoBrainS12 challenge, consisted of coronal T2-weighted images of preterm infants (born ≤30 weeks’ gestation) acquired at 30 weeks’ corrected gestational age (n= 5), coronal T2-weighted images of preterm infants acquired at 40 weeks’ corrected gestational age (n= 5) and axial T2-weighted images of preterm infants acquired at 40 weeks’ corrected gestational age (n= 5). The second dataset, provided by the Washington University NeuroDevelopmental Research (WUNDeR) group, consisted of T2-weighted images of preterm infants (born <30 weeks’ gestation) acquired shortly after birth (n= 12), preterm infants acquired at term-equivalent age (n= 12), and healthy term-born infants (born ≥38 weeks’ gestation) acquired within the first nine days of life (n= 12). For the NeoBrainS12 dataset, mean Dice scores comparing MANTiS with manual segmentations were all above 0.7, except for the cortical gray matter for coronal images acquired at 30 weeks. This demonstrates that MANTiS’ performance is competitive with existing techniques. For the WUNDeR dataset, mean Dice scores comparing MANTiS with manually edited segmentations demonstrated good agreement, where all scores were above 0.75, except for the hippocampus and amygdala. The results show that MANTiS is able to segment neonatal brain tissues well, even in images that have brain abnormalities common in preterm infants. MANTiS is available for download as an SPM toolbox from http://developmentalimagingmcri.github.io/mantis

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

Diffusion tensor imaging and resting state functional connectivity as advanced imaging biomarkers of outcome in infants with hypoxic-ischaemic encephalopathy treated with hypothermia

Therapeutic hypothermia confers significant benefit in term neonates with hypoxic-ischaemic encephalopathy (HIE). However, despite the treatment nearly half of the infants develop an unfavourable outcome. Intensive bench-based and early phase clinical research is focused on identifying treatments that augment hypothermic neuroprotection. Qualified biomarkers are required to test these promising therapies efficiently. This thesis aims to assess advanced magnetic resonance imaging (MRI) techniques, including diffusion tensor imaging (DTI) and resting state functional MRI (fMRI) as imaging biomarkers of outcome in infants with HIE who underwent hypothermic neuroprotection. FA values in the white matter (WM), obtained in the neonatal period and assessed by tract-based spatial statistics (TBSS), correlated with subsequent developmental quotient (DQ). However, TBSS is not suitable to study grey matter (GM), which is the primary site of injury following an acute hypoxic-ischaemic event. Therefore, a neonatal atlas-based automated tissue labelling approach was applied to segment central and cortical grey and whole brain WM. Mean diffusivity (MD) in GM structures, obtained in the neonatal period correlated with subsequent DQ. Although the central GM is the primary site of injury on conventional MRI following HIE; FA within WM tissue labels also correlated to neurodevelopmental performance scores. As DTI does not provide information on functional consequences of brain injury functional sequel of HIE was studied with resting state fMRI. Diminished functional connectivity was demonstrated in infants who suffered HIE, which associated with an unfavourable outcome. The results of this thesis suggest that MD in GM tissue labels and FA either determined within WM tissue labels or analysed with TBSS correlate to subsequent neurodevelopmental performance scores in infants who suffered HIE treated with hypothermia and may be applied as imaging biomarkers of outcome in this population. Although functional connectivity was diminished in infants with HIE, resting state fMRI needs further study to assess its utility as an imaging biomarker following a hypoxic-ischaemic brain injury.Open Acces

Brain volume estimation from post-mortem newborn and fetal MRI

AbstractObjectiveMinimally invasive autopsy using post-mortem magnetic resonance imaging (MRI) is a valid alternative to conventional autopsy in fetuses and infants. Estimation of brain weight is an integral part of autopsy, but manual segmentation of organ volumes on MRI is labor intensive and prone to errors, therefore unsuitable for routine clinical practice. In this paper we aim to show that volumetric measurements of the post-mortem fetal and neonatal brain can be accurately estimated using semi-automatic techniques and a high correlation can be found with the weights measured from conventional autopsy results.MethodsThe brains of 17 newborn subjects, part of Magnetic Resonance Imaging Autopsy Study (MaRIAS), were segmented from post-mortem MR images into cerebrum, cerebellum and brainstem using a publicly available neonate brain atlas and semi-automatic segmentation algorithm. The results of the segmentation were averaged to create a new atlas, which was then used for the automated atlas-based segmentation of 17 MaRIAS fetus subjects. As validation, we manually segmented the MR images from 8 subjects of each cohort and compared them with the automatic ones. The semi-automatic estimation of cerebrum weight was compared with the results of the conventional autopsy.ResultsThe Dice overlaps between the manual and automatic segmentations are 0.991 and 0.992 for cerebrum, 0.873 and 0.888 for cerebellum and 0.819 and 0.815 for brainstem, for newborns and fetuses, respectively. Excellent agreement was obtained between the estimated MR weights and autopsy gold standard ones: mean absolute difference of 5 g and 2% maximum error for the fetus cohort and mean absolute difference of 20 g and 11% maximum error for the newborn one.ConclusionsThe high correlation between the obtained segmentation and autopsy weights strengthens the idea of using post-mortem MRI as an alternative for conventional autopsy of the brain

Mapping White Matter Microstructure in the One Month Human Brain

White matter microstructure, essential for efficient and coordinated transmission of neural communications, undergoes pronounced development during the first years of life, while deviations to this neurodevelopmental trajectory likely result in alterations of brain connectivity relevant to behavior. Hence, systematic evaluation of white matter microstructure in the normative brain is critical for a neuroscientific approach to both typical and atypical early behavioral development. However, few studies have examined the infant brain in detail, particularly in infants under 3 months of age. Here, we utilize quantitative techniques of diffusion tensor imaging and neurite orientation dispersion and density imaging to investigate neonatal white matter microstructure in 104 infants. An optimized multiple b-value diffusion protocol was developed to allow for successful acquisition during non-sedated sleep. Associations between white matter microstructure measures and gestation corrected age, regional asymmetries, infant sex, as well as newborn growth measures were assessed. Results highlight changes of white matter microstructure during the earliest periods of development and demonstrate differential timing of developing regions and regional asymmetries. Our results contribute to a growing body of research investigating the neurobiological changes associated with neurodevelopment and suggest that characteristics of white matter microstructure are already underway in the weeks immediately following birth

Thalamic connectivity topography in newborns with spina bifida: association with neurological functional level but not developmental outcome at 2 years

Spina bifida affects spinal cord and cerebral development, leading to motor and cognitive delay. We investigated whether there are associations between thalamocortical connectivity topography, neurological function, and developmental outcomes in open spina bifida. Diffusion tensor MRI was used to assess thalamocortical connectivity in 44 newborns with open spina bifida who underwent prenatal surgical repair. We quantified the volume of clusters formed based on the strongest probabilistic connectivity to the frontal, parietal, and temporal cortex. Developmental outcomes were assessed using the Bayley III Scales, while the functional level of the lesion was assessed by neurological examination at 2 years of age. Higher functional level was associated with smaller thalamo-parietal, while lower functional level was associated with smaller thalamo-temporal connectivity clusters (Bonferroni-corrected P < 0.05). Lower functional levels were associated with weaker thalamic temporal connectivity, particularly in the ventrolateral and ventral anterior nuclei. No associations were found between thalamocortical connectivity and developmental outcomes. Our findings suggest that altered thalamocortical circuitry development in open spina bifida may contribute to impaired lower extremity function, impacting motor function and independent ambulation. We hypothesize that the neurologic function might not merely be caused by the spinal cord lesion, but further impacted by the disruption of cerebral neuronal circuitry

Automatic segmentation of the hippocampus for preterm neonates from early-in-life to term-equivalent age.

INTRODUCTION: The hippocampus, a medial temporal lobe structure central to learning and memory, is particularly vulnerable in preterm-born neonates. To date, segmentation of the hippocampus for preterm-born neonates has not yet been performed early-in-life (shortly after birth when clinically stable). The present study focuses on the development and validation of an automatic segmentation protocol that is based on the MAGeT-Brain (Multiple Automatically Generated Templates) algorithm to delineate the hippocampi of preterm neonates on their brain MRIs acquired at not only term-equivalent age but also early-in-life. METHODS: First, we present a three-step manual segmentation protocol to delineate the hippocampus for preterm neonates and apply this protocol on 22 early-in-life and 22 term images. These manual segmentations are considered the gold standard in assessing the automatic segmentations. MAGeT-Brain, automatic hippocampal segmentation pipeline, requires only a small number of input atlases and reduces the registration and resampling errors by employing an intermediate template library. We assess the segmentation accuracy of MAGeT-Brain in three validation studies, evaluate the hippocampal growth from early-in-life to term-equivalent age, and study the effect of preterm birth on the hippocampal volume. The first experiment thoroughly validates MAGeT-Brain segmentation in three sets of 10-fold Monte Carlo cross-validation (MCCV) analyses with 187 different groups of input atlases and templates. The second experiment segments the neonatal hippocampi on 168 early-in-life and 154 term images and evaluates the hippocampal growth rate of 125 infants from early-in-life to term-equivalent age. The third experiment analyzes the effect of gestational age (GA) at birth on the average hippocampal volume at early-in-life and term-equivalent age using linear regression. RESULTS: The final segmentations demonstrate that MAGeT-Brain consistently provides accurate segmentations in comparison to manually derived gold standards (mean Dice\u27s Kappa \u3e 0.79 and Euclidean distance CONCLUSIONS: MAGeT-Brain is capable of segmenting hippocampi accurately in preterm neonates, even at early-in-life. Hippocampal asymmetry with a larger right side is demonstrated on early-in-life images, suggesting that this phenomenon has its onset in the 3rd trimester of gestation. Hippocampal volume assessed at the time of early-in-life and term-equivalent age is linearly associated with GA at birth, whereby smaller volumes are associated with earlier birth