Diffusion kurtosis imaging with tract-based spatial statistics reveals white matter alterations in preschool children

Diffusion kurtosis imaging (DKI), an extension of diffusion tensor imaging (DTI), provides a practical method to describe non-Gaussian water diffusion in neural tissues. The sensitivity of DKI to detect the subtle changes in several chosen brain structures has been studied. However, intuitive and holistic methods to validate the merits of DKI remain to be explored. In this paper, tract-based spatial statistics (TBSS) was used to demonstrate white matter alterations in both DKI and DTI parameters in preschool children (1-6 years; n=10). Correlation analysis was also performed in multiple regions of interest (ROIs). Fractional anisotropy, mean kurtosis, axial kurtosis and radial kurtosis increased with age, while mean diffusivity and radial diffusivity decreased significantly with age. Fractional anisotropy of kurtosis and axial diffusivity were found to be less sensitive to the changes with age. These preliminary findings indicated that TBSS could be used to detect subtle changes of DKI parameters on the white matter tract. Kurtosis parameters, except fractional anisotropy of kurtosis, demonstrated higher sensitivity than DTI parameters. TBSS may be a convenient method to yield higher sensitivity of DKI.published_or_final_versio

Altered neural connectivity in females, but not males with autism: preliminary evidence for the female protective effect from a quality-controlled diffusion tensor imaging study

Previous studies using diffusion tensor imaging (DTI) to investigate white matter (WM) structural connectivity have suggested widespread, although inconsistent WM alterations in autism spectrum disorder (ASD), such as greater reductions in fractional anisotropy (FA). However, findings may lack generalizability because: (a) most have focused solely on the ASD male brain phenotype, and not sex-differences in WM integrity; (b) many lack stringent and transparent data quality control such as controlling for head motion in analysis. This study addressed both issues by using Tract-Based Spatial Statistics (TBSS) to separately compare WM differences in 81 ASD (56 male, 25 female; 4–21 years old) and 39 typically developing (TD; 23 males, 16 females; 5–18 years old) children and young people, carefully group-matched on sex, age, cognitive abilities, and head motion. ASD males and females were also matched on autism symptom severity. Two independent-raters completed a multistep scan quality assurance to remove images that were significantly distorted by motion artifacts before analysis. ASD females exhibited significant widespread reductions in FA compared to TD females, suggesting altered WM integrity. In contrast, no significant localized or widespread WM differences were found between ASD and TD males. This study highlights the importance of data quality control in DTI, and outlines important sex-differences in WM alterations in ASD females. Future studies can explore the extent to which neural structural differences might underlie sex-differences in ASD behavioral phenotype, and guide clinical interventions to be tailored toward the unique needs of ASD females and males

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

Development and Maturation of the Brain Following Pediatric mTBI

Pediatric mild traumatic brain injury (mTBI) is a major public health concern with the potential to produce long-lasting cognitive, adaptive, and socio-behavioral outcomes. However, our understanding of how TBI pathophysiology evolves in the developing brain is lacking. Our central hypothesis was that pediatric mTBI results in evolving microstructural dysregulation that leads to functional and structural deficits late in life. To test this hypothesis, we first sought to assess the influence of pediatric mTBI on white matter (WM) dysregulation in early adulthood. To accomplish this, we investigated the effects of single and repeated pediatric mTBI on white matter, focusing on the anterior commissure (AC), a white matter structure distant from the injury site. We demonstrated that mTBI leads to myelin-related diffusion changes in white matter and abnormal oligodendrocyte (OL) development in the AC which are accompanied by behavioral deficits two months after the initial injury. Second, we sought to examine the lifespan evolution of pediatric mTBI. To accomplish this, we investigated the long-term effects of pediatric mTBI at postnatal day 17 and mapped the temporal evolution of the long-term behavioral and associated structural deficits up to late adulthood (18 m) using clinically relevant in-vivo diffusion tensor imaging (DTI) in mice. We demonstrated that a single exposure to a pediatric mTBI in childhood can result in early temporally evolving structural deficits detectable through early diffusion neuroimaging and are correlated to spatial learning and memory impairments late in life. Our results suggest that early in life mTBIs elicit long-term behavioral alterations and OL-associated white matter dysregulation in the developing brain and that such early injuries have the potential to elicit temporally-evolving behavioral and structural deficits late in life. This dissertation provides new insights into how post-pediatric mTBI deficits are manifested both in early adulthood and later in life and describe how such injury evolves over a lifespan resulting in modified tissue characteristics and behavioral profile following pediatric mTBI. Such information will not only provide a deeper understanding of the complex pediatric mTBI pathophysiological development but can serve as the basis for long-term outcome prediction in pediatric mTBI

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

Development of white matter microstructure and executive functions during childhood and adolescence: a review of diffusion MRI studies

Diffusion magnetic resonance imaging (dMRI) provides indirect measures of white matter microstructure that can be used to make inferences about structural connectivity within the brain. Over the last decade, a growing literature of cross-sectional and longitudinal studies have documented relationships between dMRI indices and cognitive development. In this review, we provide a brief overview of dMRI methods and how they can be used to study white matter and connectivity and review the extant literature examining the links between dMRI indices and executive functions during development. We explore the links between white matter microstructure and specific executive functions: inhibition, working memory and cognitive shifting, as well as performance on complex executive function tasks. Concordance in findings across studies are highlighted, and potential explanations for discrepancies between results, together with challenges with using dMRI in child and adolescent populations, are discussed. Finally, we explore future directions that are necessary to better understand the links between child and adolescent development of structural connectivity of the brain and executive functions

SOCIOECONOMIC AND NEUROANATOMIC CONTRIBUTIONS TO LANGUAGE PERFORMANCE IN CHILDREN BORN VERY PRETERM AT PRESCHOOL AND SCHOOL AGE

Background: Children born very preterm are more likely to have difficulties with language acquisition and use that persist throughout childhood. Preterm birth occurs at a critical time in brain development and interrupts neurodevelopment, which has downstream implications for altered neural structure and function. Prematurity and socioeconomic status greatly impact language performance in children, but the neural substrates are poorly understood. Here the neural constituents of language performance are examined in select cortical and subcortical regions. Methods: Fifty-one children born preterm (24-31 weeks) and 20 born full-term were seen at preschool (mean age = 47 months) and school age (mean age = 74 months). Diverse aspects of language performance were evaluated at preschool and school age and were also aggregated into a single score using principle components analysis. At preschool age, measures of cortical thickness, surface area, subcortical volumes, and fractional anisotropy of white matter tracts were calculated for select frontotemporal regions implicated in language. Caregivers reported on many sociodemographic variables which were reduced using principle components analysis. Repeated measures general linear models were used to examine group differences in language performance and to determine the contributions of group, socioeconomic status, and neuroanatomical substrates to language performance. Results: Children born very preterm performed more poorly than children born full-term on tests of receptive language, verbal fluency and verbal working memory at preschool and school age. Five measures of language performance were reduced to one principle component at both preschool and school age. Socioeconomic status significantly accounted for language performance across groups and time points. Initial neuroanatomical analyses found that subcortical volumes significantly accounted for language performance. Analyses of language performance including neuroanatomy and socioeconomic status revealed that socioeconomic status had a significant main effect, as did some specific measures of cortical thickness, subcortical volumes and white matter tracts. Conclusions: Our findings provide support for poorer language performance in children born very preterm at preschool and school age. The relationship between structural neuroanatomic variations associated with preterm birth and language deficits is supported by our findings that language performance was significantly associated with subcortical volumes. This result highlights the possible importance of corticostriatal learning circuits in poorer language performance in children born very preterm. Importantly, our findings that socioeconomic status substantially accounted for language performance also emphasizes the multifactorial determinants of language problems in preterm birth, which is still poorly understood despite decades of research. Finally, these results have important implications for early intervention on an individual level, as well as policy reform to improve the broader social conditions and medical resources needed by so many Americans

What do ADHD neuroimaging studies reveal for teachers, teacher educators and inclusive education?

Background: Ongoing debate about Attention Deficit Hyperactivity Disorder (ADHD) has not resolved ambivalent teacher beliefs about ADHD. This is an important matter since teachers’ beliefs influence their pedagogy, classroom management, and their referral procedures for formal diagnoses of ADHD. They therefore must be provided with up-to-date professional learning about ADHD. Objective: To synthesise neuroimaging studies, which examined differences in brain organisation and function in those with ADHD compared to matched unaffected controls. The overarching goal was to enhance teachers’ understanding of ADHD by providing synthesised research findings around the neurological basis of ADHD. Method: The PRISMA method was used to search the Medline, PsycINFO, Web of Science and Scopus databases to complete a systematic review of peer-reviewed research that compared individuals with ADHD with matched controls published between 2010 and December 2015. Results: The identification and analyses of 174 MRI and fMRI relevant studies across a sample of over 24,000 showed that there are significant differences in neural anatomy and processing in ADHD compared to unaffected matched controls. Conclusions: Compelling evidence shows ADHD is a neurodevelopmental disability, not a socially determined set of behaviours. Results point to an urgent need for teacher professional learning and systematic up-to-date preservice teacher education along with inclusive education policy reform

Brain Imaging Correlates of Developmental Coordination Disorder and Associated Impairments

Developmental Coordination Disorder (DCD) is a common developmental disorder characterised by an inability to learn age appropriate complex motor skills. The first aim of this thesis was to characterise additional cognitive impairments and their relationship with motor difficulties in school aged children with DCD. The second aim was to investigate grey and white matter neuroimaging correlates of motor and cognitive deficits identified. Thirty six children aged 8-10 years who met DSM-5 criteria for DCD and an age-matched typically developing group (N=17) underwent standardised assessments of motor, intellectual, attention, speech and language skills as well as structural and diffusion-weighted MRI scans. Grey matter correlates of impairments were identified using subcortical volumetrics and surface-based analyses of cortical morphology. White matter correlates were examined using tractography and fixel-based fibre morphology of the pyramidal tracts, corpus callosum and cerebellar peduncles. Alongside impaired motor skills, children with DCD performed poorer than controls on several domains of executive function (attention and processing speed) and speech motor control. Motor skills did not correlate with impairments in other domains. Cortical thickness was significantly reduced in the left central sulcus in children with DCD compared to controls. Poor motor skills correlated with measures in left sensorimotor circuitry, posterior cingulate cortex and anterior insula. Poor speech motor control was associated with measures in the thalamus and corticobulbar tract. Poor sustained attention was linked to measures in the right superior cerebellar peduncle. Lower processing speed was associated with reduced mean cortical surface area. Children with DCD show co-occurring impairments in attention and speech motor control. DCD is associated with sensorimotor circuits as well as regions that form part of the default mode and salience networks. Disruption of subcortical circuits may underlie additional impairments. This study provides novel evidence of the neural correlates of DCD