Associations of Behavioral Problems and White Matter Properties of the Cerebellar Peduncles in Boys and Girls Born Full Term and Preterm.

Accumulating evidence suggests that the role of cerebellum includes regulation of behaviors; cerebellar impairment may lead to behavioral problems. Behavioral problems differ by sex: internalizing problems are more common in girls, externalizing problems in boys. Behavioral problems are also elevated in children born preterm (PT) compared to children born full term (FT). The current study examined internalizing and externalizing problems in 8-year-old children in relation to sex, birth-group, fractional anisotropy (FA) of the three cerebellar peduncles (superior, middle, and inferior), and interactions among these predictor variables. Participants (N = 78) were 44 boys (28 PT) and 34 girls (15 PT). We assessed behavioral problems via standardized parent reports and FA of the cerebellar peduncles using deterministic tractography. Internalizing problems were higher in children born PT compared to children born FT (p = .032); the interaction of sex and birth-group was significant (p = .044). When considering the contribution of the mean-tract FA of cerebellar peduncles to behavioral problems, there was a significant interaction of sex and mean-tract FA of the inferior cerebellar peduncle (ICP) with internalizing problems; the slope was negative in girls (p = .020) but not in boys. In boys, internalizing problems were only associated with mean-tract FA ICP in those born preterm (p = .010). We found no other significant associations contributing to internalizing or externalizing problems. Thus, we found sexual dimorphism and birth-group differences in the association of white matter metrics of the ICP and internalizing problems in school-aged children. The findings inform theories of the origins of internalizing behavioral problems in middle childhood and may suggest approaches to treatment at school age.

White Matter Microstructural Properties of the Cerebellar Peduncles Predict Change in Symptoms of Psychopathology in Adolescent Girls.

Internalizing symptoms typically emerge in adolescence and are more prevalent in females than in males; in contrast, externalizing symptoms typically emerge in childhood and are more commonly observed in males. Previous research has implicated aspects of white matter organization, including fractional anisotropy (FA), of cerebral tracts in both internalizing and externalizing symptoms. Although the cerebellum has been posited to integrate limbic and cortical regions, its role in psychopathology is not well understood. In this longitudinal study, we investigated whether FA of the superior (SCP), middle (MCP), and inferior cerebellar peduncles (ICP) predict change in symptoms and whether sex moderates this association. One hundred eleven adolescents completed the Youth Self-Report, assessing symptoms at baseline (ages 9-13 years) and again 2 years later. Participants also underwent diffusion-weighted imaging at baseline. We used deterministic tractography to segment and compute mean FA of the cerebellar peduncles. Lower FA of the right SCP at baseline predicted increases in internalizing symptoms in females only. Lower FA in the right SCP and ICP also predicted increases in externalizing symptoms in females, but these associations did not survive multiple comparison correction. There was no association between FA of the cerebellar peduncles and change in symptoms in males or between MCP FA and symptom changes in males or females. Organizational properties of the SCP may be a sex-specific marker of internalizing symptom changes in adolescence. The cerebellar peduncles should be explored further in future studies to elucidate sex differences in symptoms.

Sex differences in pubertal associations with fronto-accumbal white matter morphometry: Implications for understanding sensitivity to reward and punishment.

Researchers have reported sex-differentiated maturation of white matter (WM) during puberty. It is not clear, however, whether such distinctions contribute to documented sex differences in sensitivity to reward and punishment during adolescence. Given the role of the orbitofrontal cortex (OFC) and nucleus accumbens (NAcc) in reward and punishment-related behaviors, we tested in a cross-sectional study whether males and females (N = 156, 89 females; ages 9-14 years) differ in the association between pubertal stage and fixel-based morphometry of WM fibers connecting the OFC and NAcc (i.e., the fronto-accumbal tract). Further, we examined whether males and females differ in associations between fronto-accumbal WM measures and self-reported sensitivity to reward and punishment. Pubertal stage was positively associated with fronto-accumbal fiber density and cross-section (FDC) in males, but not in females. Consistent with previous reports, males reported higher reward sensitivity than did females, although fronto-accumbal combined FDC was not related to reward sensitivity in either sex. Meanwhile, only males showed a negative association between fronto-accumbal tract FDC and sensitivity to punishment. Follow-up analyses revealed that fiber cross-section, but not density, was related to pubertal stage and punishment sensitivity in males, as well as to reward sensitivity in all participants. Our findings suggest there are sex differences in puberty-related maturation of the fronto-accumbal tract, and this tract is related to lower punishment sensitivity in adolescent males compared to females.

Age-Dependent White Matter Characteristics of the Cerebellar Peduncles from Infancy Through Adolescence.

Cerebellum-cerebrum connections are essential for many motor and cognitive functions and cerebellar disorders are prevalent in childhood. The middle (MCP), inferior (ICP), and superior cerebellar peduncles (SCP) are the major white matter pathways that permit communication between the cerebellum and the cerebrum. Knowledge about the microstructural properties of these cerebellar peduncles across childhood is limited. Here, we report on a diffusion magnetic resonance imaging tractography study to describe age-dependent characteristics of the cerebellar peduncles in a cross-sectional sample of infants, children, and adolescents from newborn to 17 years of age (N = 113). Scans were collected as part of clinical care; participants were restricted to those whose scans showed no abnormal findings and whose history and exam had no risk factors for cerebellar abnormalities. A novel automated tractography protocol was applied. Results showed that mean tract-FA increased, while mean tract-MD decreased from infancy to adolescence in all peduncles. Rapid changes were observed in both diffusion measures in the first 24 months of life, followed by gradual change at older ages. The shape of the tract profiles was similar across ages for all peduncles. These data are the first to characterize the variability of diffusion properties both across and within cerebellar white matter pathways that occur from birth through later adolescence. The data represent a rich normative data set against which white matter alterations seen in children with posterior fossa conditions can be compared. Ultimately, the data will facilitate the identification of sensitive biomarkers of cerebellar abnormalities.

White matter properties associated with pre-reading skills in 6-year-old children born preterm and at term.

AIM: To assess associations between white matter properties and pre-reading skills (phonological awareness and receptive and expressive language) in children born preterm and at term at the onset of reading acquisition. METHOD: Six-year-old children born preterm (n=36; gestational age 22-32wks) and at term (n=43) underwent diffusion magnetic resonance imaging and behavioural assessments. Tracts were selected a priori based on findings from a study of 6-year-old children born at term: the left-hemisphere arcuate fasciculus and superior longitudinal fasciculus, and right-hemisphere uncinate fasciculus. Using linear regression, we assessed associations between fractional anisotropy of tracts and phonological awareness and receptive and expressive language scores. We investigated whether associations were moderated by prematurity. RESULTS: Fractional anisotropy of the left-hemisphere arcuate fasciculus contributed unique variance to phonological awareness across birth groups. The association between fractional anisotropy of the right-hemisphere uncinate fasciculus and receptive and expressive language was significantly moderated by prematurity. INTERPRETATION: A left-hemisphere tract was associated with phonological awareness in both birth groups. A right-hemisphere tract was associated with language only in the term group, suggesting that expressive and receptive language is mediated by different white matter pathways in 6-year-old children born preterm. These findings provide novel insights into similarities and differences of the neurobiology of pre-reading skills between children born preterm and at term at reading onset. WHAT THIS PAPER ADDS: White matter properties and pre-reading abilities were associated in children born preterm at the onset of reading. The neurobiology of phonological awareness was similar in children born preterm versus children born at term at 6 years. The neurobiology of language was different in children born preterm versus children born at term at 6 years.

Threat- and reward-related brain circuitry, perceived stress, and anxiety in adolescents during the COVID-19 pandemic: a longitudinal investigation.

The Coronavirus disease (COVID-19) pandemic led to heightened anxiety in adolescents. The basolateral amygdala (BLA) and the nucleus accumbens (NAcc) are implicated in response to stress and may contribute to anxiety. The role of threat- and reward-related circuitry in adolescent anxiety during the COVID-19 pandemic, however, is not clear. Ninety-nine adolescents underwent resting-state fMRI ∼1 year before the pandemic. Following shelter-in-place orders, adolescents reported their perceived stress and, 1 month later, their anxiety. Generalized multivariate analyses identified BLA and NAcc seed-based whole-brain functional connectivity maps with perceived stress. In the resulting significant clusters, we examined the association between seed-based connectivityand subsequent anxiety. Perceived stress was associated with bilateral BLA and NAcc connectivity across distributed clusters that included prefrontal, limbic, temporal, and cerebellar regions. Several NAcc connectivity clusters located in ventromedial prefrontal, parahippocampal, and temporal cortices were positively associated with anxiety; NAcc connectivity with the inferior frontal gyrus was negatively associated. BLA connectivity was not associated with anxiety. These results underscore the integrative role of the NAcc in responding to acute stressors and its relation to anxiety in adolescents. Elucidating the involvement of subcortical-cortical circuitry in adolescents' capacity to respond adaptively to environmental challenges can inform treatment for anxiety-related disorders.

Sex-Specific Vulnerability to Externalizing Problems: Sensitivity to Early Stress and Nucleus Accumbens Activation Over Adolescence.

BACKGROUND: Exposure and sensitivity to early-life stress (ELS) are related to increased risk for psychopathology in adolescence. While cross-sectional studies have reported blunted nucleus accumbens (NAcc) activation in the context of these associations, researchers have not yet assessed the effects of ELS on developmental trajectories of activation. We examined whether trajectories are affected by stress and the moderating role of biological sex in predicting vulnerability to symptoms of psychopathology. METHODS: Adolescents (n = 173) completed 3 assessments at 2-year intervals across puberty (ages 9-18 years). At baseline, we assessed objective ELS and stress sensitivity using the Traumatic Events Screening Inventory for Children. At all time points, we assessed NAcc activation using the Monetary Incentive Delay task and externalizing, internalizing, and total problems using the Youth Self-Report. We examined correlations between NAcc trajectories (extracted using linear mixed-effects models) with ELS and stress sensitivity and conducted multivariate regression analysis to examine the interaction of NAcc trajectories and biological sex in predicting symptoms of psychopathology. RESULTS: Symptoms increased over adolescence. Stress sensitivity, but not objective ELS, was associated with decreasing trajectories of NAcc activation. Biological sex interacted with NAcc trajectories to predict psychopathology; boys, but not girls, with decreasing NAcc activation had more severe externalizing problems in adolescence. These findings were replicated in the putamen and caudate but not in the medial prefrontal cortex or control brain regions. CONCLUSIONS: NAcc activation may be a sex-specific marker of externalizing problems in adolescence. Efforts to reduce stress sensitivity may help to decrease symptoms of psychopathology in adolescent boys.

Sex-specific vulnerability to depressive symptoms across adolescence and during the COVID-19 pandemic: The role of the cingulum bundle.

Background: Females are at higher risk for developing depression during adolescence than are males, particularly during exposure to stressors like the COVID-19 pandemic. Examining structural connections between brain regions involved in executive functioning may advance our understanding of sex biases in stress and depression. Here, we examined the role of the cingulum bundle in differentiating trajectories of depressive symptoms in males and females across adolescence and during the pandemic. Methods: In a longitudinal study of 214 youth (121 females; ages 9-13 years at baseline), we examined whether fixel-based properties of the cingulum bundle at baseline predict changes in females' and males' severity of depressive symptoms across four timepoints (4-7 years) in adolescence, including during the COVID-19 pandemic. We also tested whether cingulum properties predict self-reported resilience and stress during the pandemic. Results: Females had lower fiber density and cross-section (FDC) of the cingulum than did males, a neural pattern that predicted greater increases in depressive symptoms, lower resilience, and higher stress during the COVID-19 pandemic. Cingulum morphometry predicted changes in depressive trajectories in females, but not in males; specifically, females with lower FDC had significant increases in symptoms throughout adolescence, whereas females with higher cingulum FDC did not. Conversely, males had low, stable depressive symptoms throughout adolescence and higher resilience and lower stress during the pandemic compared to females. Higher cingulum FDC predicted higher resilience and lower stress in both sexes. Conclusions: In adults, the cingulum has been implicated in sex differences in stress reactivity. We show that in adolescents, the cingulum reflects sex differences in reports of stress and resilience that might contribute to the increased risk of stress-related mood disorders in females. Adolescent females might benefit from cognitive interventions that strengthen the structural properties of the cingulum and increase their perceived resilience during periods of adversity and disruption.

Effects of the COVID-19 Pandemic on Mental Health and Brain Maturation in Adolescents: Implications for Analyzing Longitudinal Data.

Background: The COVID-19 pandemic has caused significant stress and disruption for young people, likely leading to alterations in their mental health and neurodevelopment. In this context, it is not clear whether youth who lived through the pandemic and its shutdowns are comparable psychobiologically to their age- and sex-matched peers assessed before the pandemic. This question is particularly important for researchers who are analyzing longitudinal data that span the pandemic. Methods: In this study we compared carefully matched youth assessed before the pandemic (n=81) and after the pandemic-related shutdowns ended (n=82). Results: We found that youth assessed after the pandemic shutdowns had more severe internalizing mental health problems, reduced cortical thickness, larger hippocampal and amygdala volume, and more advanced brain age. Conclusions: Thus, not only does the COVID-19 pandemic appear to have led to poorer mental health and accelerated brain aging in adolescents, but it also poses significant challenges to researchers analyzing data from longitudinal studies of normative development that were interrupted by the pandemic.

Prenatal and postnatal depressive symptoms, infant white matter, and toddler behavioral problems.

BACKGROUND: Maternal depression is prevalent during and following pregnancy and is related to adverse outcomes in offspring. Perinatal depression is associated with risk for difficulties in offspring; however, the mechanisms underlying this association are not clear. We examined whether maternal prenatal and postnatal depressive symptoms were associated with infant white matter organization and with behavioral problems in toddlerhood. METHODS: 37 mother-infant dyads (20 male; ages 5.95-7.66 months) participated in this study. We conducted diffusion MRI with infants during natural sleep. Mothers reported on their prenatal and postnatal depressive symptoms at six months postpartum. We calculated fractional anisotropy (FA), radial, axial, and mean diffusivity, and assessed offspring behavioral problems at age 18 months. RESULTS: Prenatal depressive symptoms were associated with FA of the corpus callosum; postnatal depressive symptoms were not associated with FA of limbic tracts or corpus callosum segmentations. Higher levels of prenatal depressive symptoms were associated with higher FA and lower radial diffusivity of the corpus callosum genu; FA of this region was positively associated with behavioral problems at age 18 months. LIMITATIONS: This study had a small sample size; therefore, findings should be replicated. Further, we used retrospective reports of maternal prenatal depression, but validated them in this study. CONCLUSIONS: Depressive symptoms during pregnancy may affect infant corpus callosum development and, in turn, offspring behaviors. These findings suggest that early maternal stress accelerates infant neurodevelopment in a manner that may increase risk for behavioral problems. Thus, efforts to reduce maternal prenatal depression should be a public health priority.

Early Life Stress Predicts Depressive Symptoms in Adolescents During the COVID-19 Pandemic: The Mediating Role of Perceived Stress.

BACKGROUND: Exposure to early life stress (ELS) is alarmingly prevalent and has been linked to the high rates of depression documented in adolescence. Researchers have theorized that ELS may increase adolescents' vulnerability or reactivity to the effects of subsequent stressors, placing them at higher risk for developing symptoms of depression. METHODS: We tested this formulation in a longitudinal study by assessing levels of stress and depression during the COVID-19 pandemic in a sample of adolescents from the San Francisco Bay Area (N = 109; 43 male; ages 13-20 years) who had been characterized 3-7 years earlier (M = 5.06, SD = 0.86 years) with respect to exposure to ELS and symptoms of depression. RESULTS: As expected, severity of ELS predicted levels of depressive symptoms during the pandemic [r(107) = 0.26, p = 0.006], which were higher in females than in males [t(107) = -3.56, p < 0.001]. Importantly, the association between ELS and depression was mediated by adolescents' reported levels of stress, even after controlling for demographic variables. CONCLUSIONS: These findings underscore the importance of monitoring the mental health of vulnerable children and adolescents during this pandemic and targeting perceived stress in high-risk youth.

Predicting text reading skills at age 8 years in children born preterm and at term.

BACKGROUND: Children born preterm are at risk for developing reading difficulties and for decrements in other cognitive skills compared to children born at term. AIMS: To assess how domains of function, often negatively impacted by preterm birth, predict reading development in children born preterm and at term. STUDY DESIGN: Longitudinal descriptive cohort study. SUBJECTS: Preterm (n = 48; gestational age 22-32 weeks, 30 males) and term (n = 41, 18 males) participants were assessed at age 6 years on a battery of verbal and non-verbal cognitive skills and reassessed at age 8 using the Gray Oral Reading Tests-5. Linear regressions assessed the contributions of phonological awareness, language, executive function, and non-verbal IQ at age 6 to reading outcome at age 8. RESULTS: Children born preterm had lower scores than children born at term on all measures (Cohen's d from 0.46 to 1.08, all p < .05). Phonological awareness and language abilities predicted reading in both groups (accounting for 19.9% and 25.0% of variance, respectively, p < .001). Birth group did not moderate the association. By contrast, the association between executive function and non-verbal intelligence and reading outcome was moderated by birth group (interaction accounted for 3.9-6.7% of variance, respectively, p < .05). Positive predictions to reading from executive function and non-verbal IQ were found only in children born preterm. CONCLUSIONS: Non-verbal cognitive skills improved the prediction of reading outcome only in the preterm group, suggesting that reading decrements represent a component of global deficits. These findings have implications for evaluation of children born preterm at school entry and treatment of reading difficulties.

Microstructural properties of white matter pathways in relation to subsequent reading abilities in children: a longitudinal analysis.

Microstructural properties of white matter pathways are associated with concurrent reading abilities in children. In this longitudinal study, we asked whether properties of white matter pathways at the onset of learning to read would be associated with reading abilities at older ages. Children (N = 37) with a wide range of reading abilities completed standardized measures of language and phonological awareness and diffusion MRI at age 6 years. Mean tract-fractional anisotropy (FA) was extracted from reading-related pathways. At age 8, the same children were re-assessed using a standardized reading measure. Using linear regressions, we examined the contribution of tract-FA at age 6 to reading outcome at age 8, beyond known demographic and pre-literacy predictors of reading. Tract-FA of the left arcuate, left and right superior longitudinal fasciculus (SLF), and left inferior cerebellar peduncle (ICP) made unique contributions to reading outcome after consideration of sex and family history of reading delays. Tract-FA of the left and right SLF and left ICP made unique contributions to reading outcome after the addition of pre-literacy skills. Thus, cerebellar and bilateral cortical pathways represented a network associated with subsequent reading abilities. Early white matter properties may be associated with other neuropsychological functions that predict reading or may influence reading development, independent of reading-related abilities. Tract FA at early stages of learning to read may serve as a biomarker of later reading abilities.

White Matter Plasticity in Reading-Related Pathways Differs in Children Born Preterm and at Term: A Longitudinal Analysis.

Children born preterm (PT) are at risk for white matter injuries based on complications of prematurity. They learn to read but on average perform below peers born full term (FT). Studies have yet to establish whether properties of white matter pathways at the onset of learning to read are associated with individual variation later in reading development in PT children. Here, we asked whether fractional anisotropy (FA) at age 6 years is associated with reading outcome at age 8 years in PT children in the same pathways as previously demonstrated in a sample of FT children. PT (n = 34, mean gestational age = 29.5 weeks) and FT children (n = 37) completed diffusion MRI and standardized measures of non-verbal IQ, language, and phonological awareness at age 6 years. Reading skills were assessed at age 8 years. Mean tract-FA was extracted from pathways that predicted reading outcome in children born FT: left arcuate fasciculus (Arc), bilateral superior longitudinal fasciculus (SLF), and left inferior cerebellar peduncle (ICP). We explored associations in additional pathways in the PT children: bilateral inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, and uncinate fasciculus. Linear regression models examined whether the prediction of reading outcome at age 8 years based on mean tract-FA at age 6 years was moderated by birth group. Children born PT and FT did not differ significantly in tract-FA at age 6 years or in reading at age 8 years. Sex, socioeconomic status, and non-verbal IQ at age 6 years were associated with reading outcome and were included as covariates in all models. Birth group status significantly moderated associations between reading outcome and mean tract-FA only in the left Arc, right SLF, and left ICP, before and after consideration of pre-literacy skills. Microstructural properties of these cerebral and cerebellar pathways predicted later reading outcome in FT but not in PT children. Children born PT may rely on alternative pathways to achieve fluent reading. These findings have implications for plasticity of neural organization after early white matter injury.