The effects of prenatal bisphenol A exposure on brain volume of children and young mice.

Bisphenol A (BPA) is a synthetic chemical used for the manufacturing of plastics, epoxy resin, and many personal care products. This ubiquitous endocrine disruptor is detectable in the urine of over 80% of North Americans. Although adverse neurodevelopmental outcomes have been observed in children with high gestational exposure to BPA, the effects of prenatal BPA on brain structure remain unclear. Here, using magnetic resonance imaging (MRI), we studied the associations of maternal BPA exposure with children's brain structure, as well as the impact of comparable BPA levels in a mouse model. Our human data showed that most maternal BPA exposure effects on brain volumes were small, with the largest effects observed in the opercular region of the inferior frontal gyrus (ρ = -0.2754), superior occipital gyrus (ρ = -0.2556), and postcentral gyrus (ρ = 0.2384). In mice, gestational exposure to an equivalent level of BPA (2.25 µg BPA/kg bw/day) induced structural alterations in brain regions including the superior olivary complex (SOC) and bed nucleus of stria terminalis (BNST) with larger effect sizes (1.07≤ Cohens d ≤ 1.53). Human (n = 87) and rodent (n = 8 each group) sample sizes, while small, are considered adequate to perform the primary endpoint analysis. Combined, these human and mouse data suggest that gestational exposure to low levels of BPA may have some impacts on the developing brain at the resolution of MRI.

Amygdala-Prefrontal Structural Connectivity Mediates the Relationship between Prenatal Depression and Behavior in Preschool Boys.

Prenatal depression is common, underrecognized, and undertreated. It has negative consequences on child behavior and brain development, yet the relationships among prenatal depression, child behavior, and children's brain structure remain unclear. The aim of this study was to determine whether altered brain connectivity mediates relationships between prenatal maternal depressive symptoms and child behavior. This study included 54 human mother-child pairs. Mothers completed the Edinburgh Postnatal Depression Scale during the second and third trimesters of pregnancy and 3 months postpartum. Their children had diffusion MRI at age 4.1 ± 0.8 years, and children's behavior was assessed using the Child Behavior Checklist within 6 months of their MRI scan. Structural brain connectivity of the amygdala, fornix, uncinate fasciculus, and cingulum was assessed using fractional anisotropy and mean diffusivity and analyzed with maternal prenatal depressive symptoms as well as child behavior. Third trimester maternal Edinburgh Postnatal Depression Scale scores were positively associated with mean diffusivity in the amygdala-frontal tract and the cingulum, controlling for postpartum depression. Externalizing behavior had a sex interaction in the amygdala-frontal pathway; weaker connectivity (lower fractional anisotropy, higher mean diffusivity) was associated with worse behavior in boys. Amygdala-frontal connectivity mediated the relationship between third trimester depressive symptoms and child externalizing behavior in males. These findings suggest that altered brain structure is a mechanism via which prenatal depressive symptoms can impact child behavior, highlighting the importance of both recognition and intervention in prenatal depression.SIGNIFICANCE STATEMENT Understanding how prenatal maternal depression impacts child behavior is critical for appropriately treating prenatal maternal mental health problems and improving child outcomes. Here, we show white matter changes in young children exposed to maternal prenatal depressive symptoms. Children of mothers with worse depressive symptoms had weaker white matter connectivity between areas related to emotional processing. Furthermore, connectivity between the amygdala and prefrontal cortex mediated the relationship between maternal depressive symptoms and externalizing behavior in boys, showing that altered brain structure is a possible mechanism via which maternal prenatal depression impacts children's behavior. This provides important information for understanding why children of depressed mothers may be more vulnerable to depression themselves and may help shape future guidelines on maternal prenatal care.

Association between breastfeeding during infancy and white matter microstructure in early childhood.

INTRODUCTION: Associations between breastfeeding and brain development, in the context of child, perinatal, and sociodemographic variables, remain unclear. This study investigated whether exclusive breastfeeding for the first 6 months and total duration of breastfeeding were associated with brain white matter microstructure in young children. METHODS: This study included 85 typically developing children (42 males) born to 83 mothers that were predominantly white, highly educated, and in high income households. Children underwent their first diffusion tensor imaging scan between ages 2.34 and 6.97 years; some children returned multiple times, providing a total of 331 datasets. Feeding information was collected from mothers at 3, 6, and 12 months postpartum and at their child's scan to calculate breastfeeding status at 6 months (exclusive or not) as well as total duration of any breastfeeding. Linear regression was used to investigate associations between breastfeeding exclusivity/duration and fractional anisotropy (FA) for the whole brain and 10 individual white matter tracts. RESULTS: Breastfeeding exclusivity and duration were associated with global and regional white matter microstructure, even after controlling for perinatal and sociodemographic factors. Greater exclusivity was associated with higher FA in females and lower FA in males. CONCLUSIONS: These findings suggest white matter differences associated with breastfeeding that differ by sex. These may stem from different trajectories in white matter development between males and females in early childhood and suggest possible long-term white matter differences associated with breastfeeding.

White matter microstructure mediates the association between prenatal exposure to phthalates and behavior problems in preschool children.

BACKGROUND: Previous research reports associations between prenatal exposure to phthalates and childhood behavior problems; however, the neural mechanisms that may underlie these associations are relatively unexplored. OBJECTIVE: This study examined microstructural white matter as a possible mediator of the associations between prenatal phthalate exposure and behavior problems in preschool-aged children. METHODS: Data are from a subsample of a prospective pregnancy cohort, the Alberta Pregnancy Outcomes and Nutrition (APrON) study (n = 76). Mother-child pairs were included if mothers provided a second trimester urine sample, if the child completed a successful magnetic resonance imaging (MRI) scan at age 3-5 years, and if the Child Behavior Checklist was completed within 6 months of the MRI scan. Molar sums of high (HMWP) and low molecular weight phthalates (LMWP) were calculated from levels in urine samples. Associations between prenatal phthalate concentrations, fractional anisotropy (FA) and mean diffusivity (MD) in 10 major white matter tracts, and preschool behavior problems were investigated. RESULTS: Maternal prenatal phthalate concentrations were associated with MD of the right inferior fronto-occipital fasciculus (IFO), right pyramidal fibers, left and right uncinate fasciculus (UF), and FA of the left inferior longitudinal fasciculus (ILF). Mediation analyses showed that prenatal exposure to HMWP was indirectly associated with Internalizing (path ab = 0.09, CI.95 = 0.02, 0.20) and Externalizing Problems (path ab = 0.09, CI.95 = 0.01, 0.19) through MD of the right IFO, and to Internalizing Problems (path ab = 0.11, CI.95 = 0.01, 0.23) through MD of the right pyramidal fibers. DISCUSSION: This study provides the first evidence of childhood neural correlates of prenatal phthalate exposure. Results suggest that prenatal phthalate exposure may be related to microstructural white matter in the IFO, pyramidal fibers, UF, and ILF. Further, MD of the right IFO and pyramidal fibers may transmit childhood risk for behavioral problems.

Global and regional white matter development in early childhood.

White matter development continues throughout childhood and into early adulthood, but few studies have examined early childhood, and the specific trajectories and regional variation in this age range remain unclear. The aim of this study was to characterize developmental trajectories and sex differences of white matter in typically developing young children. Three hundred and ninety-six diffusion tensor imaging datasets from 120 children (57 male) aged 2-8 years were analyzed using tractography. Fractional anisotropy (FA) increased and mean diffusivity (MD) decreased in all white matter tracts by 5-15% over the 6-year period, likely reflecting increases in myelination and axonal packing. Males showed steeper slopes in a number of brain areas. Overall, early childhood is associated with substantial development of all white matter and appears to be an important period for the development of occipital and limbic connections, which showed the largest changes. This study provides a detailed characterization of age-related white matter changes in early childhood, offering baseline data that can be used to understand cognitive and behavioural development, as well as to identify deviations from normal development in children with various diseases, disorders, or brain injuries.

Prenatal maternal and childhood bisphenol a exposure and brain structure and behavior of young children.

BACKGROUND: Bisphenol A (BPA) is commonly used in the manufacture of plastics and epoxy resins. In North America, over 90% of the population has detectable levels of urinary BPA. Human epidemiological studies have reported adverse behavioral outcomes with BPA exposure in children, however, corresponding effects on children's brain structure have not yet been investigated. The current study examined the association between prenatal maternal and childhood BPA exposure and white matter microstructure in children aged 2 to 5 years, and investigated whether brain structure mediated the association between BPA exposure and child behavior. METHODS: Participants were 98 mother-child pairs who were recruited between January 2009 and December 2012. Total BPA concentrations in spot urine samples obtained from mothers in the second trimester of pregnancy and from children at 3-4 years of age were analyzed. Children participated in a diffusion magnetic resonance imaging (MRI) scan at age 2-5 years (3.7 ± 0.8 years). Associations between prenatal maternal and childhood BPA and children's fractional anisotropy and mean diffusivity of 10 isolated white matter tracts were investigated, controlling for urinary creatinine, child sex, and age at the time of MRI. Post-hoc analyses examined if alterations in white matter mediated the relationship of BPA and children's scores on the Child Behavior Checklist (CBCL). RESULTS: Prenatal maternal urinary BPA was significantly associated with child mean diffusivity in the splenium and right inferior longitudinal fasciculus. Splenium diffusivity mediated the relationship between maternal prenatal BPA levels and children's internalizing behavior (indirect effect: ß = 0.213, CI [0.0167, 0.564]). No significant associations were found between childhood BPA and white matter microstructure. CONCLUSIONS: This study provides preliminary evidence for the neural correlates of BPA exposure in humans. Our findings suggest that prenatal maternal exposure to BPA may lead to alterations in white matter microstructure in preschool aged children, and that such alterations mediate the relationship between early life exposure to BPA and internalizing problems.

Corpus callosum microstructure is associated with motor function in preschool children.

The preschool period is a time of significant physical and behavioral growth, including the improvement of gross and fine motor skills. Although motor development has been comprehensively mapped from infancy to adulthood, the neural correlates associated with motor advancements during early childhood remain unclear. The current study used diffusion tensor imaging (DTI) to delineate key motor pathways and characterize their relationships with motor performance in 80 typically developing preschool children, aged 3-6 years. The Movement Assessment Battery for Children-2nd edition (MABC-II) was used to assess motor functioning. Partial correlations between DTI parameters and motor performance, controlling for sex and age, revealed a positive correlation between motor performance and fractional anisotropy of corpus callosum motor fibers, as well as negative correlations of motor performance with mean and radial diffusivity. These results appear to be driven by females, as correlations were significant in girls but not boys when analyzed separately. Mean corticospinal tract (CST) diffusion parameters were not significantly related to motor performance, but relationships were observed at regionally specific locations along the bilateral CST. These findings suggest preschool-aged children with better motor performance show more mature white matter patterns within motor pathways, and that the structural variation in these pathways may partially account for the natural variability in motor performance.

Unimanual and bimanual motor performance in children with developmental coordination disorder (DCD) provide evidence for underlying motor control deficits.

Much of our understanding of motor control deficits in children with developmental coordination disorder (DCD) comes from upper limb assessments focusing on the dominant limb. Here, using two robotic behavioural tasks, we investigated motor control in both the dominant and non-dominant limbs of children with DCD. Twenty-six children with diagnosed DCD (20 males; mean age 10.6 years ± 1.3 years) and 155 controls were included in this cross-sectional study. Participants completed a visually guided reaching task with their dominant and non-dominant limbs and a bimanual object hitting task. Motor performance was quantified across nine parameters. We determined the number of children with DCD who fell outside of the typical performance range of the controls on these parameters and compared the DCD and control groups using ANCOVAs, accounting for age. Children with DCD demonstrated impairments in six out of nine parameters; deficits were more commonly noted in the non-dominant limb. Interestingly, when looking at individual performance, several children with DCD performed in the range of controls. These findings indicate that children with DCD display deficits in motor control in both the dominant and non-dominant limb and highlight the importance of including detailed assessments of both limbs when investigating children with DCD. They also demonstrate the variability in motor control performance evidenced by children with DCD.

Subcortical brain structure in children with developmental coordination disorder: A T1-weighted volumetric study.

Developmental coordination disorder (DCD) is a neurodevelopmental disorder occurring in 5-6% of school-aged children. Converging evidence suggests that dysfunction within cortico-striatal and cortico-cerebellar networks may contribute to motor deficits in DCD, yet limited research has examined the brain morphology of these regions. Using T1-weighted magnetic resonance imaging the current study investigated cortical and subcortical volumes in 37 children with DCD, aged 8 to 12 years, and 48 controls of a similar age. Regional brain volumes of the thalamus, basal ganglia, cerebellum and primary motor and sensory cortices were extracted using the FreeSurfer recon-all pipeline and compared between groups. Reduced volumes within both the left and right pallidum (Left: F = 4.43, p = 0.039; Right: F = 5.24, p = 0.025) were observed in children with DCD; however, these results did not withstand correction for multiple comparisons. These findings provide preliminary evidence of altered subcortical brain structure in DCD. Future studies that examine the morphology of these subcortical regions are highly encouraged in order replicate these findings.

White matter alterations in young children with prenatal alcohol exposure.

Prenatal alcohol exposure (PAE) can lead to cognitive, behavioural, and social-emotional challenges. Previous neuroimaging research has identified structural brain alterations in newborns, older children, adolescents, and adults with PAE; however, little is known about brain structure in young children. Extensive brain development occurs during early childhood; therefore, understanding the neurological profiles of young children with PAE is critical for early identification and effective intervention. We studied 54 children (5.21 ± 1.11 years; 27 males) with confirmed PAE (94% also had other prenatal exposures, 74% had adverse postnatal experiences) compared with 54 age- and sex-matched children without PAE. Children underwent diffusion tensor imaging between 2 and 7 years of age. Mean fractional anisotropy (FA) and mean diffusivity (MD) were obtained for 10 major white matter tracts. Univariate analyses of covariance were used to test group differences (PAE vs. control) controlling for age and sex. The PAE group had higher FA in the genu of the corpus callosum and lower MD in the bilateral uncinate fasciculus. The PAE group also had lower tract volume in the corpus callosum, the bilateral inferior fronto-occipital fasciculi, and the right superior longitudinal fasciculus. Our findings align with studies of newborns with PAE reporting lower diffusivity, but contrast those in older populations with PAE, which consistently report lower FA and higher MD. Further research is needed to understand trajectories of white matter development and how our results of higher FA/lower MD in young children connect with lower FA/higher MD observed at older ages.

Effects of Transcranial Direct Current Stimulation on Motor Function in Children 8-12 Years With Developmental Coordination Disorder: A Randomized Controlled Trial.

Background and objectives: Developmental coordination disorder (DCD) is a neurodevelopmental motor disorder occurring in 5-6% of school-aged children. It is suggested that children with DCD show deficits in motor learning. Transcranial direct current stimulation (tDCS) enhances motor learning in adults and children but is unstudied in DCD. We aimed to investigate if tDCS, paired with motor skill training, facilitates motor learning in a pediatric sample with DCD. Methods: Twenty-eight children with diagnosed DCD (22 males, mean age: 10.62 ± 1.44 years) were randomized and placed into a treatment or sham group. Anodal tDCS was applied (1 mA, 20 min) in conjunction with fine manual training over 5 consecutive days. Children's motor functioning was assessed with the Purdue Pegboard Test and Jebsen-Taylor Hand Function Test at baseline, post-intervention and 6 weeks following intervention. Group differences in rates of motor learning and skill transfer/retention were examined using linear mixed modeling and repeated measures ANOVAs, respectively. Results: There were no serious adverse events or drop-outs and procedures were well-tolerated. Independent of group, all participants demonstrated improved motor scores over the 5 training days [F (69.280), p < 0.001, 95% CI (0.152, 0.376)], with no skill decay observed at retention. There was no interaction between intervention group and day [F (2.998), p = 0.086, 95% CI (-0.020, 0.297)]. Conclusion: Children with DCD demonstrate motor learning with long-term retention of acquired skill. Motor cortex tDCS did not enhance motor learning as seen in other populations. Before conclusions of tDCS efficacy can be drawn, additional carefully designed trials with reproducible results are required. Clinical Trial Registration: ClinicalTrials.gov: NCT03453983.

Two types of memory-based (pantomime) reaches distinguished by gaze anchoring in reach-to-grasp tasks.

Comparisons of target-based reaching vs memory-based (pantomime) reaching have been used to obtain insight into the visuomotor control of reaching. The present study examined the contribution of gaze anchoring, reaching to a target that is under continuous gaze, to both target-based and memory-based reaching. Participants made target-based reaches for discs located on a table or food items located on a pedestal or they replaced the objects. They then made memory-based reaches in which they pantomimed their target-based reaches. Participants were fitted with hand sensors for kinematic tracking and an eye tracker to monitor gaze. When making target-based reaches, participants directed gaze to the target location from reach onset to offset without interrupting saccades. Similar gaze anchoring was present for memory-based reaches when the surface upon which the target had been placed remained. When the target and its surface were both removed there was no systematic relationship between gaze and the reach. Gaze anchoring was also present when participants replaced a target on a surface, a movement featuring a reach but little grasp. That memory-based reaches can be either gaze anchor-associated or gaze anchor-independent is discussed in relation to contemporary views of the neural control of reaching.

Structural and functional asymmetry of the language network emerge in early childhood.

Structural and functional neuroimaging studies show language and reading processes are left-lateralized, and associated with a dispersed group of left brain regions. However, it is unclear when and how asymmetry of these regions emerges. We characterized the development of structural and functional asymmetry of the language network in 386 datasets from 117 healthy children (58 male) across early childhood (2-7.5 years). Structural asymmetry was investigated using diffusion tensor imaging (DTI) and manual delineation of the arcuate fasciculus. Functional connectivity asymmetry was calculated from seed regions in the inferior frontal gyrus (IFG) and middle temporal gyrus (MTG). We show that macrostructural asymmetry of the arcuate fasciculus is present by age 2 years, while leftward asymmetry of microstructure and functional connectivity with the IFG increases across the age range. This emerging microstructural and functional asymmetry likely underlie the development of language and reading skills during this time.

Microstructural neuroimaging of white matter tracts in persistent post-concussion syndrome: A prospective controlled cohort study.

INTRODUCTION: Children with mild traumatic brain injury (mTBI) typically recover quickly, however approximately 15% experience persistent post-concussive symptoms (PPCS) past 3 months. The microstructural pathology associated with underlying persistent symptoms is poorly understood but is suggested to involve axonal injury to white matter tracts. Diffusion tensor imaging (DTI) can be used to visualize and characterize damage to white matter microstructure of the brain. OBJECTIVE: We aimed to investigate white matter microstructure in children with persistent concussive symptoms as compared to typically developing controls, alongside evaluating differences in white matter changes over time and how this relates to symptom recovery. METHODS: The current study is a prospective, longitudinal, controlled cohort study of children with mTBI. 104 children aged 8 to 18 years with a mTBI (72 symptomatic; 32 asymptomatic) were recruited from the Alberta Children's Hospital and compared to 20 healthy controls. Microstructural evidence of white matter injury was evaluated using DTI one month post injury and repeated 4 to 6 weeks later. Primary outcomes included fractional anisotropy and mean diffusivity of the corticospinal tracts, uncinate fasciculi, and motor fibers of the corpus callosum. Post-concussive symptoms were also measured using the Post-Concussion Symptom Inventory (PCSI) taken at both time points. RESULTS: Fractional anisotropy of the left uncinate fasciculi was lower in symptomatic children compared to controls (F(2,119) = 3.582, p = 0.031). No other significant differences were observed. CONCLUSIONS: Our findings provide evidence of microstructural injury following mTBI in children with ongoing post-concussive symptoms one month post injury. The changes were persistent 4-6 weeks later. Further longitudinal studies of white matter microstructure in PPCS will be helpful to clarify whether these white matter alterations resolve over time.