Examining the relationship between psychosocial adversity and inhibitory control: A functional magnetic resonance imaging study of children growing up in extreme poverty.

Exposure to psychosocial adversity (PA) is associated with poor behavioral, physical, and mental health outcomes in adulthood. As these outcomes are related to alterations in developmental processes, growing evidence suggests that deficits in executive functions-inhibitory control in particular-may in part explain this relationship. However, literature examining the development of inhibitory control has been based on children in higher-resource environments, and little is known how low-resource settings might exacerbate the link between inhibitory control and health outcomes. In this context, we collected functional magnetic resonance imaging data during a Go/No-Go inhibitory control task and PA variables for 68 children aged 5 to 7 years living in Dhaka, Bangladesh, an area with a high prevalence of PA. The children's mothers completed behavioral questionnaires to assess the children's PA and their own PA. Whole-brain activation underlying inhibitory control was examined using the No-Go versus Go contrast, and associations with PA variables were assessed using whole-brain regressions. Childhood neglect was associated with weaker activation in the right posterior cingulate, whereas greater family conflict, economic stress, and maternal PA factors were associated with greater activation in the left medial frontal gyrus, right superior and middle frontal gyri, and left cingulate gyrus. These data suggest that neural networks supporting inhibitory control processes may vary as a function of exposure to different types of PA, particularly between those related to threat and deprivation. Furthermore, increased activation in children with greater PA may serve as a compensatory mechanism, allowing them to maintain similar behavioral task performance.

Longitudinal trajectories of brain development from infancy to school age and their relationship to literacy development.

Reading is one of the most complex skills that we utilize daily, and it involves the early development and interaction of various lower-level subskills, including phonological processing and oral language. These subskills recruit brain structures, which begin to develop long before the skill manifests and exhibit rapid development during infancy. However, how longitudinal trajectories of early brain development in these structures supports long-term acquisition of literacy subskills and subsequent reading is unclear. Children underwent structural and diffusion MRI scanning at multiple timepoints between infancy and second grade and were tested for literacy subskills in preschool and decoding and word reading in early elementary school. We developed and implemented a reproducible pipeline to generate longitudinal trajectories of early brain development to examine associations between these trajectories and literacy (sub)skills. Furthermore, we examined whether familial risk of reading difficulty and a child's home literacy environment, two common literacy-related covariates, influenced those trajectories. Results showed that individual differences in curve features (e.g., intercepts and slopes) for longitudinal trajectories of volumetric, surface-based, and white matter organization measures in left-hemispheric reading-related regions and tracts were linked directly to phonological processing and indirectly to second-grade decoding and word reading skills via phonological processing. Altogether, these findings suggest that the brain bases of phonological processing, previously identified as the strongest behavioral predictor of reading and decoding skills, may already begin to develop early in infancy but undergo further refinement between birth and preschool. The present study underscores the importance of considering academic skill acquisition from the very beginning of life.

Longitudinal associations between language network characteristics in the infant brain and school-age reading abilities are mediated by early-developing phonological skills.

Reading acquisition is a prolonged learning process relying on language development starting in utero. Behavioral longitudinal studies reveal prospective associations between infant language abilities and preschool/kindergarten phonological development that relates to subsequent reading performance. While recent pediatric neuroimaging work has begun to characterize the neural network underlying language development in infants, how this neural network scaffolds long-term language and reading acquisition remains unknown. We addressed this question in a 7-year longitudinal study from infancy to school-age. Seventy-six infants completed resting-state fMRI scanning, and underwent standardized language assessments in kindergarten. Of this larger cohort, forty-one were further assessed on their emergent word reading abilities after receiving formal reading instructions. Hierarchical clustering analyses identified a modular infant language network in which functional connectivity (FC) of the inferior frontal module prospectively correlated with kindergarten-age phonological skills and emergent word reading abilities. These correlations were obtained when controlling for infant age at scan, nonverbal IQ and parental education. Furthermore, kindergarten-age phonological skills mediated the relationship between infant FC and school-age reading abilities, implying a critical mid-way milestone for long-term reading development from infancy. Overall, our findings illuminate the neurobiological mechanisms by which infant language capacities could scaffold long-term reading acquisition.

Longitudinal associations between language network characteristics in the infant brain and school-age reading abilities are mediated by early-developing phonological skills.

Reading acquisition is a prolonged learning process relying on language development starting in utero. Behavioral longitudinal studies reveal prospective associations between infant language abilities and preschool/kindergarten phonological development that relates to subsequent reading performance. While recent pediatric neuroimaging work has begun to characterize the neural network underlying language development in infants, how this neural network scaffolds long-term language and reading acquisition remains unknown. We addressed this question in a 7-year longitudinal study from infancy to school-age. Seventy-six infants completed resting-state fMRI scanning, and underwent standardized language assessments in kindergarten. Of this larger cohort, forty-one were further assessed on their emergent word reading abilities after receiving formal reading instructions. Hierarchical clustering analyses identified a modular infant language network in which functional connectivity (FC) of the inferior frontal module prospectively correlated with kindergarten-age phonological skills and emergent word reading abilities. These correlations were obtained when controlling for infant age at scan, nonverbal IQ and parental education. Furthermore, kindergarten-age phonological skills mediated the relationship between infant FC and school-age reading abilities, implying a critical mid-way milestone for long-term reading development from infancy. Overall, our findings illuminate the neurobiological mechanisms by which infant language capacities could scaffold long-term reading acquisition.

Examining the relationship between psychosocial adversity and inhibitory control: an fMRI study of children growing up in extreme poverty.

Exposure to psychosocial adversity (PA) is associated with poor behavioral, physical, and mental health outcomes in adulthood. As these outcomes are related to alterations in developmental processes, growing evidence suggests that deficits in executive functions-inhibitory control in particular-may, in part, explain this relationship. However, literature examining the development of inhibitory control has been based on children in higher resource environments, and little is known how low resource settings might exacerbate the link between inhibitory control and health outcomes. In this context, we collected fMRI data during a Go/No-Go inhibitory control task and PA variables for 68 children 5 to 7 years of age living in Dhaka, Bangladesh, an area with a high prevalence of PA. The children's mothers completed behavioral questionnaires to assess the child's PA and their own PA. Whole-brain activation underlying inhibitory control was examined using the No-Go versus Go contrast, and associations with PA variables were assessed using whole-brain regressions. Childhood neglect was associated with weaker activation in the right posterior cingulate, whereas greater family conflict, economic stress, and maternal PA factors were associated with greater activation in the left medial frontal gyrus, right superior and middle frontal gyri, and left cingulate gyrus. These data suggest that neural networks supporting inhibitory control processes may vary as a function of exposure to different types of PA, particularly between those related to threat and deprivation. Furthermore, increased activation in children with greater PA may serve as a compensatory mechanism, allowing them to maintain similar behavioral task performance.

A global multicohort study to map subcortical brain development and cognition in infancy and early childhood.

The human brain grows quickly during infancy and early childhood, but factors influencing brain maturation in this period remain poorly understood. To address this gap, we harmonized data from eight diverse cohorts, creating one of the largest pediatric neuroimaging datasets to date focused on birth to 6 years of age. We mapped the developmental trajectory of intracranial and subcortical volumes in ∼2,000 children and studied how sociodemographic factors and adverse birth outcomes influence brain structure and cognition. The amygdala was the first subcortical volume to mature, whereas the thalamus exhibited protracted development. Males had larger brain volumes than females, and children born preterm or with low birthweight showed catch-up growth with age. Socioeconomic factors exerted region- and time-specific effects. Regarding cognition, males scored lower than females; preterm birth affected all developmental areas tested, and socioeconomic factors affected visual reception and receptive language. Brain-cognition correlations revealed region-specific associations.

An fMRI study of finger movements in children with and without dyslexia.

Introduction: Developmental dyslexia is a language-based reading disability, yet some have reported motor impairments, usually attributed to cerebellar dysfunction. Methods: Using fMRI, we compared children with and without dyslexia during irregularly paced, left or right-hand finger tapping. Next, we examined seed-to-voxel intrinsic functional connectivity (iFC) using six seed regions of the motor system (left and right anterior lobe of the cerebellum, SM1 and SMA). Results: A whole-brain task-evoked analysis revealed relatively less activation in the group with dyslexia in right anterior cerebellum during right hand tapping. For iFC, we found the group with dyslexia to have greater iFC between the right SM1 seed and a medial aspect of right postcentral gyrus for left hand tapping; and greater iFC between the left SM1 seed and left thalamus, as well as weaker local iFC around the left SM1 seed region for right hand tapping. Lastly, extracted activity and connectivity values that had been identified in these between-group comparisons were not correlated with measures of reading. Discussion: We conclude that there are some aberrations in motor system function in children with dyslexia, but these are not tied to reading ability.

Longitudinal changes in brain activation underlying reading fluency.

Reading fluency-the speed and accuracy of reading connected text-is foundational to educational success. The current longitudinal study investigates the neural correlates of fluency development using a connected-text paradigm with an individualized presentation rate. Twenty-six children completed a functional MRI task in 1st/2nd grade (time 1) and again 1-2 years later (time 2). There was a longitudinal increase in activation in the ventral occipito-temporal (vOT) cortex from time 1 to time 2. This increase was also associated with improvements in reading fluency skills and modulated by individual speed demands. These findings highlight the reciprocal relationship of the vOT region with reading proficiency and its importance for supporting the developmental transition to fluent reading. These results have implications for developing effective interventions to target increased automaticity in reading.

Home language and literacy environment and its relationship to socioeconomic status and white matter structure in infancy.

The home language and literacy environment (HLLE) in infancy has been associated with subsequent pre-literacy skill development and HLLE at preschool-age has been shown to correlate with white matter organization in tracts that subserve pre-reading and reading skills. Furthermore, childhood socioeconomic status (SES) has been linked with both HLLE and white matter organization. It is important to understand whether the relationships between environmental factors such as HLLE and SES and white matter organization can be detected as early as infancy, as this period is characterized by rapid brain development that may make white matter pathways particularly susceptible to these early experiences. Here, we hypothesized that HLLE (1) relates to white matter organization in pre-reading and reading-related tracts in infants, and (2) mediates a link between SES and white matter organization. To test these hypotheses, infants (mean age: 8.6 ± 2.3 months, N = 38) underwent diffusion-weighted imaging MRI during natural sleep. Image processing was performed with an infant-specific pipeline and fractional anisotropy (FA) was estimated from the arcuate fasciculus (AF) and superior longitudinal fasciculus (SLF) bilaterally using the baby automated fiber quantification method. HLLE was measured with the Reading subscale of the StimQ (StimQ-Reading) and SES was measured with years of maternal education. Self-reported maternal reading ability was also quantified and applied to our statistical models as a proxy for confounding genetic effects. StimQ-Reading positively correlated with FA in left AF and to maternal education, but did not mediate the relationship between them. Taken together, these findings underscore the importance of considering HLLE from the start of life and may inform novel prevention and intervention strategies to support developing infants during a period of heightened brain plasticity.

Distinctive neural correlates of phonological and reading impairment in fetal alcohol-exposed adolescents with and without facial dysmorphology.

Prenatal alcohol exposure (PAE) has been linked to atypical brain and cognitive development, including poor academic performance in reading. This study utilized functional magnetic resonance imaging and diffusion tensor imaging to characterize functional and structural mechanisms mediating reading deficits in 26 adolescents with PAE-related facial dysmorphology (fetal alcohol syndrome (FAS)/partial FAS (PFAS)), 29 heavily-exposed (HE) non-syndromal adolescents, in comparison with 19 typically developing controls. The FAS/PFAS and HE groups were balanced in terms of levels of PAE and reading (dis)ability. While neural alterations in the posterior association cortices were evident in both PAE groups, distinctive neural correlates of reading (dis)abilities were observed between adolescents with and without facial dysmorphology. Specifically, compared to the HE and control groups, the syndromal adolescents showed greater activation in the right precentral gyrus during phonological processing and rightward lateralization in an important reading-related tract (inferior longitudinal fasciculus, ILF), suggesting an atypical reliance on the right hemisphere. By contrast, in the HE, better reading skills were positively correlated with neural activation in the left angular gyrus and white matter organization of the left ILF, although the brain function-behavior relation was weaker than among the controls, suggesting less efficient function of the typical reading network. Our findings provide converging evidence at both the neural functional and structural levels for distinctive brain mechanisms underlying atypical reading and phonological processing in PAE adolescents with and without facial dysmorphology.

Brain morphometry and diminished physical growth in Bangladeshi children growing up in extreme poverty: A longitudinal study.

Diminished physical growth is a common marker of malnutrition and it affects approximately 200 million children worldwide. Despite its importance and prevalence, it is not clear whether diminished growth relates to brain development and general cognitive ability. Further, diminished growth is more common in areas of extreme poverty, raising the possibility that it may mediate previously shown links between socioeconomic status (SES) and brain structure. To address these gaps, 79 children growing up in an extremely poor, urban area of Bangladesh underwent MRI at age six years. Structural brain images were submitted to Mindboggle software, a Docker-compliant and high-reproducibility tool for tissue segmentation and regional estimations of volume, surface area, cortical thickness, sulcal depth, and mean curvature. Diminished growth predicted brain morphometry and mediated the link between SES and brain morphometry most consistently for subcortical and white matter subcortical volumes. Meanwhile, brain volume in left pallidum and right ventral diencephalon mediated the relationship between diminished growth and full-scale IQ. These findings offer malnutrition as one possible pathway through which SES affects brain development and general cognitive ability in areas of extreme poverty.

White matter in infancy is prospectively associated with language outcomes in kindergarten.

Language acquisition is of central importance to child development. Although this developmental trajectory is shaped by experience postnatally, the neural basis for language emerges prenatally. Thus, a fundamental question remains: do structural foundations for language in infancy predict long-term language abilities? Longitudinal investigation of 40 children from infancy to kindergarten reveals that white matter in infancy is prospectively associated with subsequent language abilities, specifically between: (i) left arcuate fasciculus and phonological awareness and vocabulary knowledge, (ii) left corticospinal tract and phonological awareness, and bilateral corticospinal tract with phonological memory; controlling for age, cognitive, and environmental factors. Findings link white matter in infancy with school-age language abilities, suggesting that white matter organization in infancy sets a foundation for long-term language development.

Intergenerational Transmission of Cortical Sulcal Patterns from Mothers to their Children.

Intergenerational effects are described as the genetic, epigenetic, as well as pre- and postnatal environmental influence parents have on their offspring's behavior, cognition, and brain. During fetal brain development, the primary cortical sulci emerge with a distinctive folding pattern that are under strong genetic influence and show little change of this pattern throughout postnatal brain development. We examined intergenerational transmission of cortical sulcal patterns by comparing primary sulcal patterns between children (N = 16, age 5.5 ± 0.81 years, 8 males) and their biological mothers (N = 15, age 39.72 ± 4.68 years) as well as between children and unrelated adult females. Our graph-based sulcal pattern comparison method detected stronger sulcal pattern similarity for child-mother pairs than child-unrelated pairs, where higher similarity between child-mother pairs was observed mostly for the right lobar regions. Our results also show that child-mother versus child-unrelated pairs differ for daughters and sons with a trend toward significance, particularly for the left hemisphere lobar regions. This is the first study to reveal significant intergenerational transmission of cortical sulcal patterns, and our results have important implications for the study of the heritability of complex behaviors, brain-based disorders, the identification of biomarkers, and targets for interventions.

Imaging the rapidly developing brain: Current challenges for MRI studies in the first five years of life.

Rapid and widespread changes in brain anatomy and physiology in the first five years of life present substantial challenges for developmental structural, functional, and diffusion MRI studies. One persistent challenge is that methods best suited to earlier developmental stages are suboptimal for later stages, which engenders a trade-off between using different, but age-appropriate, methods for different developmental stages or identical methods across stages. Both options have potential benefits, but also biases, as pipelines for each developmental stage can be matched on methods or the age-appropriateness of methods, but not both. This review describes the data acquisition, processing, and analysis challenges that introduce these potential biases and attempts to elucidate decisions and make recommendations that would optimize developmental comparisons.

The relationship between biological and psychosocial risk factors and resting-state functional connectivity in 2-month-old Bangladeshi infants: A feasibility and pilot study.

Childhood poverty has been associated with structural and functional alterations in the developing brain. However, poverty does not alter brain development directly, but acts through associated biological or psychosocial risk factors (e.g. malnutrition, family conflict). Yet few studies have investigated risk factors in the context of infant neurodevelopment, and none have done so in low-resource settings such as Bangladesh, where children are exposed to multiple, severe biological and psychosocial hazards. In this feasibility and pilot study, usable resting-state fMRI data were acquired in infants from extremely poor (n = 16) and (relatively) more affluent (n = 16) families in Dhaka, Bangladesh. Whole-brain intrinsic functional connectivity (iFC) was estimated using bilateral seeds in the amygdala, where iFC has shown susceptibility to early life stress, and in sensory areas, which have exhibited less susceptibility to early life hazards. Biological and psychosocial risk factors were examined for associations with iFC. Three resting-state networks were identified in within-group brain maps: medial temporal/striatal, visual, and auditory networks. Infants from extremely poor families compared with those from more affluent families exhibited greater (i.e. less negative) iFC in precuneus for amygdala seeds; however, no group differences in iFC were observed for sensory area seeds. Height-for-age, a proxy for malnutrition/infection, was not associated with amygdala/precuneus iFC, whereas prenatal family conflict was positively correlated. Findings suggest that it is feasible to conduct infant fMRI studies in low-resource settings. Challenges and practical steps for successful implementations are discussed.

An fMRI study of finger tapping in children and adults.

Functional brain imaging studies have characterized the neural bases of voluntary movement for finger tapping in adults, but equivalent information for children is lacking. When contrasted to adults, one would expect children to have relatively greater activation, reflecting compensation for an underdeveloped motor system combined with less experience in the execution of voluntary movement. To test this hypothesis, we acquired functional magnetic resonance imaging (fMRI) data on 17 healthy right-handed children (7.48 ± 0.66 years) and 15 adults (24.9 ± 2.9 years) while they performed an irregularly paced finger-tapping task in response to a visual cue (left- and right-hand examined separately). Whole-brain within-group analyses revealed that finger tapping in either age group and for either hand activated contralateral SM1, SMA, ipsilateral anterior cerebellum, and occipital cortices. We used an ANOVA factorial design to test for main effects of Age Group (children vs adults), Hand (left vs. right), and their interactions. For main effects of Age Group, children showed relatively greater activity in left SM1 (extending into bilateral SMA), and, surprisingly, adults exhibited relatively greater activity in right pre-SMA/SMA (extending into left pre-SMA/SMA), right lateral globus pallidus, left putamen, and right anterior cerebellum. The interaction of Age Group × Hand revealed that while both groups activated right SM1 during left finger tapping and exhibited signal decreases (i.e., below fixation baseline) during right finger tapping, both these responses were attenuated in children relative to adults. These data provide an important foundation by which to study children with motor disorders.

An Activation Likelihood Estimation Meta-Analysis Study of Simple Motor Movements in Older and Young Adults.

The functional neuroanatomy of finger movements has been characterized with neuroimaging in young adults. However, less is known about the aging motor system. Several studies have contrasted movement-related activity in older versus young adults, but there is inconsistency among their findings. To address this, we conducted an activation likelihood estimation (ALE) meta-analysis on within-group data from older adults and young adults performing regularly paced right-hand finger movement tasks in response to external stimuli. We hypothesized that older adults would show a greater likelihood of activation in right cortical motor areas (i.e., ipsilateral to the side of movement) compared to young adults. ALE maps were examined for conjunction and between-group differences. Older adults showed overlapping likelihoods of activation with young adults in left primary sensorimotor cortex (SM1), bilateral supplementary motor area, bilateral insula, left thalamus, and right anterior cerebellum. Their ALE map differed from that of the young adults in right SM1 (extending into dorsal premotor cortex), right supramarginal gyrus, medial premotor cortex, and right posterior cerebellum. The finding that older adults uniquely use ipsilateral regions for right-hand finger movements and show age-dependent modulations in regions recruited by both age groups provides a foundation by which to understand age-related motor decline and motor disorders.

Intrinsic network activity in tinnitus investigated using functional MRI.

Tinnitus is an increasingly common disorder in which patients experience phantom auditory sensations, usually ringing or buzzing in the ear. Tinnitus pathophysiology has been repeatedly shown to involve both auditory and non-auditory brain structures, making network-level studies of tinnitus critical. In this magnetic resonance imaging (MRI) study, two resting-state functional connectivity (RSFC) approaches were used to better understand functional network disturbances in tinnitus. First, we demonstrated tinnitus-related reductions in RSFC between specific brain regions and resting-state networks (RSNs), defined by independent components analysis (ICA) and chosen for their overlap with structures known to be affected in tinnitus. Then, we restricted ICA to data from tinnitus patients, and identified one RSN not apparent in control data. This tinnitus RSN included auditory-sensory regions like inferior colliculus and medial Heschl's gyrus, as well as classically non-auditory regions like the mediodorsal nucleus of the thalamus, striatum, lateral prefrontal, and orbitofrontal cortex. Notably, patients' reported tinnitus loudness was positively correlated with RSFC between the mediodorsal nucleus and the tinnitus RSN, indicating that this network may underlie the auditory-sensory experience of tinnitus. These data support the idea that tinnitus involves network dysfunction, and further stress the importance of communication between auditory-sensory and fronto-striatal circuits in tinnitus pathophysiology. Hum Brain Mapp 37:2717-2735, 2016. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Diffusion imaging of auditory and auditory-limbic connectivity in tinnitus: preliminary evidence and methodological challenges.

Subjective tinnitus, or "ringing in the ears," is perceived by 10 to 15 percent of the adult population and causes significant suffering in a subset of patients. While it was originally thought of as a purely auditory phenomenon, there is increasing evidence that the limbic system influences whether and how tinnitus is perceived, far beyond merely determining the patient's emotional reaction to the phantom sound. Based on functional imaging and electrophysiological data, recent articles frame tinnitus as a "network problem" arising from abnormalities in auditory-limbic interactions. Diffusion-weighted magnetic resonance imaging is a noninvasive method for investigating anatomical connections in vivo. It thus has the potential to provide anatomical evidence for the proposed changes in auditory-limbic connectivity. However, the few diffusion imaging studies of tinnitus performed to date have inconsistent results. In the present paper, we briefly summarize the results of previous studies, aiming to reconcile their results. After detailing analysis methods, we then report findings from a new dataset. We conclude that while there is some evidence for tinnitus-related increases in auditory and auditory-limbic connectivity that counteract hearing-loss related decreases in auditory connectivity, these results should be considered preliminary until several technical challenges have been overcome.

Functional MRI evidence for a role of ventral prefrontal cortex in tinnitus.

It has long been known that subjective tinnitus, a constant or intermittent phantom sound perceived by 10 to 15% of the adult population, is not a purely auditory phenomenon but is also tied to limbic-related brain regions. Supporting evidence comes from data indicating that stress and emotion can modulate tinnitus, and from brain imaging studies showing functional and anatomical differences in limbic-related brain regions of tinnitus patients and controls. Recent studies from our lab revealed altered blood oxygen level-dependent (BOLD) responses to stimulation at the tinnitus frequency in the ventral striatum (specifically, the nucleus accumbens) and gray-matter reductions (i.e., anatomical changes) in ventromedial prefrontal cortex (vmPFC), of tinnitus patients compared to controls. The present study extended these findings by demonstrating functional differences in vmPFC between 20 tinnitus patients and 20 age-matched controls. Importantly, the observed BOLD response in vmPFC was positively correlated with tinnitus characteristics such as subjective loudness and the percent of time during which the tinnitus was perceived, whereas correlations with tinnitus handicap inventory scores and other variables known to be affected in tinnitus (e.g., depression, anxiety, noise sensitivity, hearing loss) were weaker or absent. This suggests that the observed group differences are indeed related to the strength of the tinnitus percept and not to an affective reaction to tinnitus. The results further corroborate vmPFC as a region of high interest for tinnitus research.This article is part of a Special Issue entitled: Tinnitus Neuroscience.