Changes in white matter microstructure in the developing brain—A longitudinal diffusion tensor imaging study of children from 4 to 11 years of age

The purpose of the present study was to detail the childhood developmental course of different white matter (WM) characteristics. In a longitudinal diffusion tensor imaging (DTI) study of 159 healthy children between 4 and 11 years scanned twice, we used tract-based spatial statistics as well as delineation of 15 major WM tracts to characterize the regional pattern of change in fractional anisotropy (FA), mean (MD), radial (RD) and axial diffusivity (AD). We tested whether there were decelerations of change with increasing age globally and tract-wise, and also illustrated change along medial-to-lateral, posterior-to-anterior and inferior-to-superior gradients. We found a significant linear increase in global FA, and decrease in MD and RD over time. For mean AD, a weak decrease was observed. The developmental changes in specific WM tracts showed regional differences. Eight WM tracts showed non-linear development patterns for one or several DTI metrics, with a deceleration in change with age. Sex did not affect change in any DTI metric. Overall, greater rate of change was found in the left hemisphere. Spatially, there was a posterior-to-anterior gradient of change with greater change in frontal regions for all metrics. The current study provides a comprehensive characterization of the regional patters of change in WM microstructure across pre-adolescence childhood

Diffusion MRI of white matter microstructure development in childhood and adolescence: Methods, challenges and progress

Diffusion magnetic resonance imaging (dMRI) continues to grow in popularity as a useful neuroimaging method to study brain development, and longitudinal studies that track the same individuals over time are emerging. Over the last decade, seminal work using dMRI has provided new insights into the development of brain white matter (WM) microstructure, connections and networks throughout childhood and adolescence. This review provides an introduction to dMRI, both diffusion tensor imaging (DTI) and other dMRI models, as well as common acquisition and analysis approaches. We highlight the difficulties associated with ascribing these imaging measurements and their changes over time to specific underlying cellular and molecular events. We also discuss selected methodological challenges that are of particular relevance for studies of development, including critical choices related to image acquisition, image analysis, quality control assessment, and the within-subject and longitudinal reliability of dMRI measurements. Next, we review the exciting progress in the characterization and understanding of brain development that has resulted from dMRI studies in childhood and adolescence, including brief overviews and discussions of studies focusing on sex and individual differences. Finally, we outline future directions that will be beneficial to the field

Neurological soft signs in adolescents are associated with brain structure and postural control

Neurological soft signs (NSS) are minor deviations from the norm in sensory and motor performance. NSS exist in the general population but are more frequently found in cohorts with neurodevelopmental disorders. NSS are considered a diffuse and unspecific marker of altered neurodevelopment but receive increasing attention since the presence of NSS in children has been found to be predictive of psychiatric disorders in late adolescence. To date, only little is known about potential neurodevelopmental alterations that may underlay the presence of NSS. The prevalence of NSS has been shown to decrease during adolescence as part of continued neural development and brain re-wiring processes. Therefore, adolescence has been proposed as an important phase for the manifestation or outgrowing of NSS. The underlying mechanisms that may underly this process, however, are largely unknown. As NSS are subtle signs and commonly identified by subjective observer-based neurological examinations, quantitative tools may help to objectively investigate functional and structural correlates associated with NSS. For the work included in this dissertation, healthy adolescent athletes from three European countries were investigated. All participants underwent a neurological examination, resulting in a categorization of participants into groups with and without NSS (NSS+/NSS-). A total NSS score was calculated to provide a continuous measure spanning the whole spectrum of NSS. Two quantitative tools were used to investigate functional and structural correlates of NSS in healthy adolescents: Study I) Instrumented force plate measures to investigate postural control (Bonke et al., 2023), and Study II) Structural magnetic resonance imaging to investigate brain morphology and white matter microstructure (Bonke et al., 2022). Study I aimed to investigate the incremental value of instrumented force plate measures in addition to observer-based neurological examinations. Such associations have not been assessed before but are important for capturing subtle alterations in postural control. This will help to acquire a more comprehensive assessment of motor development. We found no statistically significant differences in postural control between NSS+ and NSS- group. However, participants performing non-optimal in the diadochokinesis sub-test measuring pronation/supination of forearms showed significantly reduced postural control in the medial-lateral (ML) direction. Moreover, the total NSS score correlated significantly with postural control performance in the ML direction. Findings from this study reveal that adolescents with NSS, and in particular adolescents that perform non-optimal in pronation/supination movements of the forearms also perform worse in ML postural control assessed by force plate assessments. As pronation/supination movements of forearms and ML postural control continue to mature until adolescence, it can be assumed that these functions are related and may indicate altered motor development. Study II aimed to identify and characterize NSS-related brain structure alterations using structural magnetic resonance imaging. NSS-related brain structure alterations have not yet been investigated in healthy adolescents. However, this investigation is of high relevance to better understand potential alterations in adolescent brain-rewiring processes related to NSS. Using T1-weighted imaging, we found significantly higher gyrification in the left superior frontal and parietal lobe in the group of adolescents with NSS, likely reflecting alterations in synaptic pruning. We did not find differences in cortical volume or thickness. Using diffusion tensor imaging, we found lower tissue fractional anisotropy (FAt) and higher tissue radial diffusivity (RDt) in widespread white matter clusters in the group of adolescents with NSS, likely indicating alterations in myelination. Findings from this study reveal that NSS in healthy adolescents are associated with brain structure alterations that can be objectively quantified using magnetic resonance imaging. As of now, the relevance of NSS-related brain structure alterations in otherwise healthy adolescents is not fully understood. Future studies should assess whether these alterations may explain the described association between NSS and psychiatric disorders. In summary, the work presented in this doctoral dissertation uses two different quantitative measures to objectively investigate functional and structural differences between adolescents with and without NSS. Insights derived from this work show the beneficial use of instrumented tools to complement neurological examinations for a better understanding of functional and structural correlates of NSS. This work will help to generate a more complete picture of NSS-related developmental alterations and potentially related psychiatric vulnerabilities. Future research should make use of larger and more representative datasets to replicate, as well as extend our findings. Specific attention should be drawn on the investigation of factors that contribute to the development of NSS, longitudinal studies that allow to capture NSS-related alterations in developmental trajectories, as well as on investigating the underlying neural mechanisms of NSS

Artificial Intelligence for Detection, Characterization, and Classification of Complex Visual Patterns in Medical Imaging; Applications in Pulmonary and Neuro-imaging

Medical imaging is widely used in current healthcare and research settings for various purposes such as diagnosis, treatment options, patient monitoring, longitudinal studies, etc. The two most commonly used imaging modalities in the United States are Computed Tomography (CT) and Magnetic Resonance Imaging (MRI). Raw images acquired via CT or MRI need to undergo a variety of processing steps prior to being used for the purposes explained above. These processing steps include quality control, noise reduction, anatomical segmentation, tissue classification, etc. However, since medical images often include millions of voxels (smallest 3D units in the image containing information) it is extremely challenging to process them manually by relying on visual inspection and the experience of trained clinicians. In light of this, the field of medical imaging is seeking ways to automate data processing. With the impressive performance of Artificial Intelligence (AI) in the field of Computer Vision, researchers in the medical imaging community have shown increasing interest in utilizing this powerful tool to automate the task of processing medical imaging data. Despite AI’s significant contributions to the medical imaging field, large cohorts of data still remain without optimized and robust AI-based tools to process images efficiently and accurately. This thesis focuses on exploiting large cohorts of CT and MRI data to design AI-based methods for processing medical images using weakly-supervised and supervised learning strategies, as well as mathematical (and/or statistical) modeling and signal processing methods. In particular, we address four image processing problems in this thesis. Namely: 1) We propose a weakly-supervised deep learning method to automate binary quality control of diffusion MRI scans into ‘poor’ and ‘good’ quality classes; 2) We design a weakly-supervised deep learning framework to learn and detect visual patterns related to a set of different artifact categories considered in this work, in order to identify major artifact types present in dMRI volumes; 3) We develop a supervised deep learning method to classify multiple lung texture patterns with association to Emphysema disease on human lung CT scans; 4) We investigate and characterize the properties of two types of negative BOLD response elicited in human brain fMRI scans during visual stimulation using mathematical modeling and signal processing tools. Our results demonstrate that through the use of artificial intelligence and signal processing algorithms: 1) dMRI scans can be automatically categorized into two quality groups (i.e., ‘poor’ vs ‘good’) with a high classification accuracy, enabling rapid sifting of large cohorts of dMRI scans to be utilized in research or clinical settings; 2) Type of the major artifact present in ‘poor’ quality dMRI volumes can be identified robustly and automatically with high precision enabling exclusion/correction of corrupt volumes according to the artifact type contaminating them; 3) Multiple lung texture patterns related to Emphysema disease can be automatically and robustly classified across various large cohorts of CT scans enabling investigation of the disease through longitudinal studies on multiple cohorts; 4) Negative BOLD responses of different categories can be fully characterized on fMRI data collected from visual stimulation of human brain enabling researchers to better understand the human brain functionality through studying cohorts of fMRI scans

The brain structure during language development: neural correlates of sentence comprehension in preschool children

Language skills increase as the brain matures and language specialization is linked to the left hemisphere. Among distinct language domains, sentence comprehension is particularly vital in language acquisition and, by comparison, requires a much longer time-span before full mastery in children. Although accumulating studies have revealed the neural mechanism underlying sentence comprehension acquisition, the development of the brain’s gray matter and its relation to sentence comprehension had not been fully understood. This thesis employs structural magnetic resonance imaging and diffusion-weighted imaging data to investigate the neural correlates of sentence comprehension in preschoolers both cross-sectionally and longitudinally. The first study examines how cortical thick- ness covariance is relevant for syntax in preschoolers and changes across development. Results suggest that the cortical thickness covariance of brain regions relevant for syntax increases from preschoolers to adults, whilst preschoolers with superior language abilities show a more adult-like covariance pattern. Reconstructing the white matter fiber tract connecting the left inferior frontal and superior temporal cortices using diffusion-weighted imaging data, the second study suggests that the reduced cortical thickness covariance in the left frontotemporal regions is likely due to immature white matter connectivity during preschool. The third study then investigated the cortical thickness asymmetry and its relation to sentence comprehension abilities. Results show that longitudinal cortical thick- ness asymmetry in the inferior frontal cortex was associated with improvements in sentence comprehension, further suggesting the crucial role of the inferior frontal cortex for sentence comprehension acquisition. Taken together, evidence from gray and white matter data provides new insights into the neuroscientific model of language acquisition and the emergence of syntactic processing during language development

Brain white matter development, associations to maternal perinatal psychological distress and emotional attention at the age of 5 years

Development of the brain white matter (WM) is highly plastic, and myelination continues from the second trimester into early adulthood which predisposes the brain to effects of both adverse and supporting factors during early life. Maternal perinatal psychological distress is acknowledged as an important contributor to the offspring’s development. Furthermore, sex is known to affect the WM microstructure as well as the emergence of psychopathologies. Understanding the normal variation of microstructure in the developing brain WM is a prerequisite for recognizing alterations inflicted by early adversity that have possible long-term programming effects on behavioral and socio-emotional outcomes. This study aimed to 1) investigate the incidence, risk factors and consequences of incidental findings in brain magnetic resonance imaging of infants; 2) optimize data acquisition parameters and pre-processing pipeline of diffusion tensor imaging (DTI) protocol applied with children; 3) describe the normal microstructural features of WM in infants and 5-year-old children; 4) investigate the associations between WM integrity and exposure to maternal perinatal psychological distress; 5) explore the associations of WM integrity and child’s emotional attention. Vacuum assistance and vaginal birth were observed to increase the risk for subdural hemorrhages (incidence 6.9%) with no effects on early neurological development. In 5-year-olds, higher WM integrity in widespread regions was observed in girls, and we found marked asymmetry in the WM, resembling patterns previously shown in adults. Maternal perinatal psychological distress showed sexand timing-specific associations with WM integrity: prenatal symptoms predicting higher integrity in boys and postnatal symptoms lower integrity in girls. Maternal postpartum anxiety increased girls’ vigilance toward fearful faces, which was also associated with reduced WM integrity. The results imply that maternal psychological distress affects WM development with effects especially on girls. Collectively, these studies provide fundamental insight for future studies addressing the mediating mechanisms and longer-term effects between the observed associations.Aivojen valkean aineen kehitys, äidin raskauden ympärillä esiintyvän psykologisen stressin vaikutus ja tunneperäinen huomion kohdentaminen 5-vuotiailla Aivojen valkean aineen kehitys jatkuu toiselta raskauskolmannekselta varhaiseen aikuisuuteen, mikä altistaa sen muovautuvuutensa vuoksi sekä epäsuotuisten että tukevien tekijöiden vaikutukselle varhaisen elämän aikana. Äidin raskauden ympärillä esiintyvä psykologinen stressi on tunnettu jälkeläisten kehitykseen vaikuttava tekijä. Lisäksi sukupuoli vaikuttaa valkean aineen rakenteeseen ja psykiatristen häiriöiden ilmaantuvuuteen. Kehittyvien aivojen rakenteen normaalivaihtelun ymmärtäminen on oleellista, jotta voidaan tunnistaa aikaisten vastoinkäymisten aiheuttamia muutoksia sekä niiden mahdollisia pitkäaikaisia ohjelmoivia vaikutuksia käytökseen ja tunnepohjaisiin toimintoihin. Tämän väitöskirjan tavoitteena oli 1) raportoida vastasyntyneiden aivojen magneettikuvien sattumalöydösten esiintyvyyttä, riskitekijöitä ja neurologisia seurauksia; 2) optimoida lasten diffuusiotensorikuvantamisaineiston keräämistä ja esikäsittelyä; 3) tarkastella 5-vuotiaiden valkean aineen normaalipiirteitä; 4) tutkia äidin raskauden ympärillä esiintyvän psykologisen stressin vaikutusta jälkeläisten valkean aineen rakenteeseen; ja 5) selvittää valkean aineen yhteyksiä lapsen tunnepohjaiseen huomion kohdentamiseen silmänliikemittausten avulla. Imukuppiavustus ja alatiesynnytys lisäsivät sattumalöydöksinä havaittujen kovakalvonalaisten vuotojen (6.9 %) riskiä, mutta eivät vaikuttaneet varhaiseen neurologiseen kehitykseen. 5-vuotiaiden tyttöjen valkean aineen integriteetti oli laajaalaisesti korkeampi poikiin verrattuna, ja epäsymmetrisyys vastasi aiemmin aikuisilla havaittua rakennetta. Äidin psykologinen stressi liittyi jälkeläisten valkean aineen integriteettiin sukupuoli- ja ajankohtariippuvaisesti: pojilla raskaudenaikainen altistus lisäsi valkean aineen integriteettiä, kun taas tytöillä raskaudenjälkeinen altistus vähensi sitä. Äidin raskauden jälkeinen ahdistus lisäsi tyttöjen tarkkaavaisuutta pelokkaisiin ilmeisiin, joka liittyi myös alentuneeseen valkean aineen integriteettiin. Aiempia tutkimustuloksia tukien äidin psykologisen stressin havaittiin muovaavan valkean aineen kehitystä etenkin tytöillä, ja tämä luo pohjaa mekanismien ja kausaliteetin tarkastelulle myös tulevissa tutkimuksissa

Sex Differences in White Matter Hyperintensities in the Ageing Brain

Cerebral white matter hyperintensities (WMH) appear in the brain magnetic resonance imaging scan at early age and become more prevalent at older age. Despite that old age is known as the main risk factor for WMH accumulation, the literature has shown that many vascular risk factors contribute significantly to the existence and progression of WMH. Women were shown to have higher WMH volume compared to men in the literature. However, the existing literature lacks comprehensive evidence to address why such pattern is noted. Therefore, this thesis aims to examine sex differences in WMH. Specifically, three studies were conducted: (1) investigating sex differences in the associations between vascular risk factors and WMH, (2) examining the contribution of the hormonal risk factors to WMH and their moderation effects on the associations between vascular risk factors and WMH, and (3) examining sex differences in longitudinal associations between vascular risk factors and WMH, and the effects of WMH progression on cognitive decline. Results showed that the pattern of higher WMH in women compared to men was identified across the studies, however, men had stronger contributions of vascular risk factors, especially obesity measures, to WMH. The second study showed that hypertensive postmenopausal women benefited significantly from using hormone replacement therapy, especially when taken early and for longer duration. Diabetic women and women with increased pulse wave velocity had increased deep WMH when post-menopausal duration was one standard deviation below the mean. In men, smokers with higher testosterone levels had significant increase in WMH. In the third study, significant sex differences were found in the association between WMH progression and cognition. Specifically, increases in periventricular WMH volume over time was associated with greater decline in visuospatial abilities in men, but not in women. In women, but not in men, higher average periventricular WMH volumes across time-points was associated with poorer executive function. The thesis comprehensively examined sex differences in vascular and hormonal risk factors associated with WMH, as well as in cognitive consequences of the progression of WMH. The findings highlight the importance of taking sex differences into consideration clinically and for future clinical research of WMH

Understanding the Association of Breastfeeding and Food Insecurity on Brain Function in Early Childhood

Introduction: The present study aims to understand how the absence of food security and breastfeeding in children at one year of age, which can be considered as adverse childhood experiences, may be associated with brain function as measured by the relative and absolute power spectral density of four frequency bands of brain waves (theta, alpha, beta, and gamma) among a sample of infants from low-socioeconomic (SES) backgrounds at age 12 months old. Methods: A cross-sectional survey was used by the parent study, Baby’s First Years (BFY), to collect quantitative data to understand the associations between breastfeeding, food insecurity, and brain function in a sample of 243 low-SES mothers and their infants at age 12 months old. Breastfeeding was measured as ever breastfed, to understand if a mother had ever initiated breastfeeding of their infant, and breastfeeding duration, measured in months. Household food insecurity (HFI) was measured using the U.S. Household Food Security Survey Module Short Form devised by the USDA. Electroencephalography (EEG) data was collected to assess brain function. Data Analysis: Data was analyzed to determine associations between being ever breastfed, breastfeeding duration, and the presence of HFI and EEG measured relative and absolute theta, alpha, beta, and gamma power in infants at 12 months of age using multiple linear regression (MLR) models based on ordinary least squares (OLS). Results: 77% (n=187) of mothers reported breastfeeding their child at least one time. The mean breastfeeding duration (including the mothers that never breastfed) was 3.6 months (SD=4.12). 27.6% (n=67) of mothers were found to be food insecure. Ever breastfeeding an infant during the first year of life was found to be associated with higher absolute theta power (p<0.05), and higher relative and absolute alpha power (p<0.01). Breastfeeding duration was not found to be associated with relative and absolute theta, alpha, beta or gamma power. Finally, the presence of food insecurity was not found to be associated with relative and absolute theta, alpha, beta or gamma power. Discussion: Differences in brain function may be adaptive for children experiencing adversity because of their lower SES, amongst other factors (Ellis et al., 2020). Ever breastfeeding an infant was associated with higher absolute theta power, which was an unexpected finding. However, relative theta power was not associated with ever breastfeeding, and therefore this finding must cautiously be interpreted. Ever breastfeeding an infant was associated with higher relative and absolute alpha power. It is possible that the increases in relative and absolute alpha power within the sample of infants who were ever breastfed are in part due to the emotional connection that breastfeeding elicits and the characteristics of mothers that decide to initiate breastfeeding as compared to those that do not initiate breastfeeding. This research demonstrates significant associations between ever breastfeeding an infant with brain function in a population of infants from diverse, low SES backgrounds. In contextualizing these changes in brain function as plausible adaptations that infants are developing due to their experiences, an opportunity exists to further explore these associations with brain function to understand the skills that low SES infants are developing during the first year of life

Handbook of Positive Psychology, Religion, and Spirituality

This handbook aims to bridge the gap between the fields of positive psychology and the psychology of religion and spirituality. It is the authoritative guide to the intersections among religion, spirituality, and positive psychology and includes the following sections: (1) historical and theoretical considerations, (2) methodological considerations, (3) cultural considerations, (4) developmental considerations, (5) empirical research on happiness and well-being in relation to religion and spirituality, (6) empirical research on character strengths and virtues in relation to religion and spirituality, (7) clinical and applied considerations, and (8) field unification and advancement. Leading positive psychologists and psychologists of religion/spirituality have coauthored the chapters, drawing on expertise from their respective fields. The handbook is useful for social and clinical scientists, practitioners in helping professions, practitioners in religious and spiritual fields, and students of psychology and religion/spirituality. This is an open access book