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In adults, the neural substrate associated with encoding memories connected to a specific time and place include the prefrontal cortex and medial temporal lobe (MTL). Using functional magnetic resonance imaging, this research studied the developmental trajectory of this frontal-MTL system by comparing 7- and 8-year-old children to those who were 10 or older in conditions that promoted episodic encoding. In 1 condition, participants generated verbs from nouns heard; in another, they listened to short stories for comprehension. Regions in which brain activation predicted subsequent recognition memory performance were identified. These included the left prefrontal cortex, but not MTL, in the verb generation condition for both age groups. In the story comprehension condition, activation in left posterior MTL predicted subsequent memory performance in both age groups, and activation in left anterior MTL (including the hippocampus proper) and left prefrontal cortex predicted subsequent memory only for the older children. These results illustrate both similarities and differences in how brain systems interact in development to mediate the formation of episodic memories. [ABSTRACT FROM AUTHOR]

Objective: Functional MRI was used to determine differences in patterns of cortical activation between children who suffered perinatal left middle cerebral artery (MCA) stroke and healthy children performing a silent verb generation task.Methods: Ten children with prior perinatal left MCA stroke (age 6-16 years) and ten healthy age matched controls completed an executive language activation task. fMRI scans were acquired on a 3T scanner using T2* weighted gradient echo, echo-planar imaging (EPI) sequence. Random effects analysis and independent component analysis (ICA) were used to compute activation maps.Results: Both analysis methods demonstrated alternative activation of cortical areas in children with perinatal stroke. Following perinatal stroke, typical left dominant productive language areas in the inferior frontal gyrus were displaced to anatomical identical areas in the right hemisphere (p=.001). In addition, stroke patients showed more bilateral activation in superior temporal and anterior cingulate gyri and increased activation in primary visual cortex when compared to healthy controls. There was no relation between lesion size and the degree of right hemisphere activation. ICA showed that the healthy controls had a negative correlation with the time course in the right inferior frontal gyrus in the same region that was activated in stroke subjects.Interpretation: This functional MRI study in children revealed novel patterns of cortical language reorganization following perinatal stroke. The addition of ICA is complementary to Random Effects Analysis, allowing for the exploration of potential subtle differences in pathways in functional MRI data obtained from both healthy and pathological groups. [ABSTRACT FROM AUTHOR]

Background: High levels of infant negative emotionality (NE) and low positive emotionality (PE) predict future emotional and behavioral problems. The prefrontal cortex (PFC) supports emotional regulation, with each PFC subregion specializing in specific emotional processes. Neurite orientation dispersion and density imaging estimates microstructural integrity and myelination via the neurite density index (NDI) and dispersion via the orientation dispersion index (ODI), with potential to more accurately evaluate microstructural alterations in the developing brain. Yet, no study has used these indices to examine associations between PFC microstructure and concurrent or developing infant emotionality., Methods: We modeled PFC subregional NDI and ODI at 3 months with caregiver-reported infant NE and PE at 3 months (n = 61) and at 9 months (n = 50), using multivariable and subsequent bivariate regression models., Results: The most robust statistically significant findings were positive associations among 3-month rostral anterior cingulate cortex (ACC) ODI and caudal ACC NDI and concurrent NE, a positive association between 3-month lateral orbitofrontal cortex ODI and prospective NE, and a negative association between 3-month dorsolateral PFC ODI and concurrent PE. Multivariate models also revealed that other PFC subregional microstructure measures, as well as infant and caregiver sociodemographic and clinical factors, predicted infant 3- and 9-month NE and PE., Conclusions: Greater NDI and ODI, reflecting greater microstructural complexity, in PFC regions supporting salience perception (rostral ACC), decision making (lateral orbitofrontal cortex), action selection (caudal ACC), and attentional processes (dorsolateral PFC) might result in greater integration of these subregions with other neural networks and greater attention to salient negative external cues, thus higher NE and/or lower PE. These findings provide potential infant cortical markers of future psychopathology risk., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Elucidating the neural basis of infant positive emotionality and negative emotionality can identify biomarkers of pathophysiological risk. Our goal was to determine how functional interactions among large-scale networks supporting emotional regulation influence white matter (WM) microstructural-emotional behavior relationships in 3-month-old infants. We hypothesized that microstructural-emotional behavior relationships would be differentially mediated or suppressed by underlying resting-state functional connectivity (rsFC), particularly between default mode network and central executive network structures., Methods: The analytic sample comprised primary caregiver-infant dyads (52 infants [42% female, mean age at scan = 15.10 weeks]), with infant neuroimaging and emotional behavior assessments conducted at 3 months. Infant WM and rsFC were assessed by diffusion-weighted imaging/tractography and resting-state magnetic resonance imaging during natural, nonsedated sleep. The Infant Behavior Questionnaire-Revised provided measures of infant positive emotionality and negative emotionality., Results: After significant WM-emotional behavior relationships were observed, multimodal analyses were performed using whole-brain voxelwise mediation. Results revealed that greater cingulum bundle volume was significantly associated with lower infant positive emotionality (β = -0.263, p = .031); however, a pattern of lower rsFC between central executive network and default mode network structures suppressed this otherwise negative relationship. Greater uncinate fasciculus volume was significantly associated with lower infant negative emotionality (β = -0.296, p = .022); however, lower orbitofrontal cortex-amygdala rsFC suppressed this otherwise negative relationship, while greater orbitofrontal cortex-central executive network rsFC mediated this relationship., Conclusions: Functional interactions among neural networks have an important influence on WM microstructural-emotional behavior relationships in infancy. These relationships can elucidate neural mechanisms that contribute to future behavioral and emotional problems in childhood., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

High levels of infant negative emotionality (NE) are associated with emotional and behavioral problems later in childhood. Identifying neural markers of high NE as well as low positive emotionality (PE) in infancy can provide neural markers to aid early identification of vulnerability, and inform interventions to help delay or even prevent psychiatric disorders before the manifestation of symptoms. Prefrontal cortical (PFC) subregions support the regulation of NE and PE, with each PFC subregion differentially specializing in distinct emotional regulation processes. Gray matter (GM) volume measures show good test-retest reliability, and thus have potential use as neural markers of NE and PE. Yet, while studies showed PFC GM structural abnormalities in adolescents and young adults with affective disorders, few studies examined how PFC subregional GM measures are associated with NE and PE in infancy. We aimed to identify relationships among GM in prefrontal cortical subregions at 3 months and caregiver report of infant NE and PE, covarying for infant age and gender and caregiver sociodemographic and clinical variables, in two independent samples at 3 months (Primary: n = 75; Replication sample: n = 40) and at 9 months (Primary: n = 44; Replication sample: n = 40). In the primary sample, greater 3-month medial superior frontal cortical volume was associated with higher infant 3-month NE (p < 0.05); greater 3-month ventrolateral prefrontal cortical volume predicted lower infant 9-month PE (p < 0.05), even after controlling for 3-month NE and PE. GM volume in other PFC subregions also predicted infant 3- and 9-month NE and PE, together with infant demographic factors, caregiver age, and/or caregiver affective instability and anxiety. These findings were replicated in the independent sample. To our knowledge, this is the first study to determine in primary and replication samples associations among infant PFC GM volumes and concurrent and prospective NE and PE, and identify promising, early markers of future psychopathology risk., (© 2023. The Author(s).)

To identify regional cerebral blood flow (rCBF) alterations in children and adolescents with congenital heart disease (CHD) in relation to neurocognitive outcomes using a nonbiased data-driven approach. This is a prospective, observational study of children and adolescents with CHD without brain injury and healthy controls using pseudo-continuous arterial spin labeling (pCASL) MRI. Quantitative rCBF was compared between participants with CHD and healthy controls using a voxelwise data-driven method. Mediation analysis was then performed on a voxelwise basis, with the grouping variable as the independent variable, neurocognitive outcomes (from the NIH Toolbox Cognitive Battery) as the dependent variables, and rCBF as the mediator. After motion correction, a total of 80 studies were analyzable (27 for patients with CHD, 53 for controls). We found steeper age-related decline in rCBF among those with CHD compared to normal controls in the insula/ventromedial prefrontal regions (salience network) and the dorsal anterior cingulate and precuneus/posterior cingulate (default mode network), and posterior parietal/dorsolateral prefrontal (central executive network) (FWE-corrected P< 0.05). The reduced rCBF in the default mode/salience network was found to mediate poorer performance on an index of crystallized cognition from the NIH Toolbox Cognitive Battery in those with CHD compared to controls. In contrast, reduced rCBF in the central executive network/salience network mediated reduced deficits in fluid cognition among patients with CHD compared to controls. Regional cerebral blood flow alterations mediate domain-specific differences in cognitive performance in children and adolescents with CHD compared to healthy controls, independent of injury, and are likely related to brain and cognitive reserve mechanisms. Further research is needed to evaluate the potential of interventions in CHD targeting regional cerebral blood flow across lifespan., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Term congenital heart disease (CHD) neonates display abnormalities of brain structure and maturation, which are possibly related to underlying patient factors, abnormal physiology and perioperative insults. Our primary goal was to delineate associations between clinical factors and postnatal brain microstructure in term CHD neonates using diffusion tensor imaging (DTI) magnetic resonance (MR) acquisition combined with complementary data-driven connectome and seed-based tractography quantitative analyses. Our secondary goal was to delineate associations between mild dysplastic structural brain abnormalities and connectome and seed-base tractography quantitative analyses. These mild dysplastic structural abnormalities have been derived from prior human infant CHD MR studies and neonatal mouse models of CHD that were collectively used to calculate to calculate a brain dysplasia score (BDS) that included assessment of subcortical structures including the olfactory bulb, the cerebellum and the hippocampus., Methods: Neonates undergoing cardiac surgery for CHD were prospectively recruited from two large centers. Both pre- and postoperative MR brain scans were obtained. DTI in 42 directions was segmented into 90 regions using a neonatal brain template and three weighted methods. Clinical data collection included 18 patient-specific and 9 preoperative variables associated with preoperative scan and 6 intraoperative (e.g., cardiopulmonary bypass and deep hypothermic circulatory arrest times) and 12 postoperative variables associated with postoperative scan. We compared patient specific and preoperative clinical factors to network topology and tractography alterations on a preoperative neonatal brain MRI, and intra and postoperative clinical factors to network topology alterations on postoperative neonatal brain MRI. A composite BDS was created to score abnormal findings involving the cerebellar hemispheres and vermis, supratentorial extra-axial fluid, olfactory bulbs and sulci, hippocampus, choroid plexus, corpus callosum, and brainstem. The neuroimaging outcomes of this study included (1) connectome metrics: cost (number of connections) and global/nodal efficiency (network integration); (2) seed based tractography methods of fractional anisotropy (FA), radial diffusivity, and axial diffusivity. Statistics consisted of multiple regression with false discovery rate correction (FDR) comparing the clinical risk factors and BDS (including subcortical components) as predictors/exposures and the global connectome metrics, nodal efficiency, and seed based- tractography (FA, radial diffusivity, and axial diffusivity) as neuroimaging outcome measures., Results: A total of 133 term neonates with complex CHD were prospectively enrolled and 110 had analyzable DTI. Multiple patient-specific factors including d-transposition of the great arteries (d-TGA) physiology and severity of impairment of fetal cerebral substrate delivery (i.e., how much the CHD lesion alters typical fetal circulation such that the highest oxygen and nutrient rich blood from the placenta are not directed toward the fetal brain) were predictive of preoperative reduced cost ( p < 0.0073) and reduced global/nodal efficiency ( p < 0.03). Cardiopulmonary bypass time predicted postoperative reduced cost ( p < 0.04) and multiple postoperative factors [extracorporeal membrane oxygenation (ECMO), seizures and cardiopulmonary resuscitation (CPR)] were predictive of postoperative reduced cost and reduced global/nodal efficiency ( p < 0.05). Anthropometric measurements (weight, length, and head size) predicted tractography outcomes. Total BDS was not predictive of brain network topology. However, key subcortical components of the BDS score did predict key global and nodal network topology: abnormalities of the cerebellum predicted reduced cost ( p < 0.0417) and of the hippocampus predicted reduced global efficiency ( p < 0.0126). All three subcortical structures predicted unique alterations of nodal efficiency ( p < 0.05), including hippocampal abnormalities predicting widespread reduced nodal efficiency in all lobes of the brain, cerebellar abnormalities predicting increased prefrontal nodal efficiency, and olfactory bulb abnormalities predicting posterior parietal-occipital nodal efficiency., Conclusion: Patient-specific (d-TGA anatomy, preoperative impairment of fetal cerebral substrate delivery) and postoperative (e.g., seizures, need for ECMO, or CPR) clinical factors were most predictive of diffuse postnatal microstructural dysmaturation in term CHD neonates. Anthropometric measurements (weight, length, and head size) predicted tractography outcomes. In contrast, subcortical components (cerebellum, hippocampus, olfactory) of a structurally based BDS (derived from CHD mouse mutants), predicted more localized and regional postnatal microstructural differences. Collectively, these findings suggest that brain DTI connectome and seed-based tractography are complementary techniques which may facilitate deciphering the mechanistic relative contribution of clinical and genetic risk factors related to poor neurodevelopmental outcomes in CHD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Votava-Smith, Gaesser, Harbison, Lee, Tran, Rajagopalan, del Castillo, Kumar, Herrup, Baust, Johnson, Gabriel, Reynolds, Wallace, Meyers, Ceschin, Lo, Schmithorst and Panigrahy.)

We use a non-invasive MRI proxy of neurovascular function (pnvf) to assess the ability of the vasculature to supply baseline metabolic demand, to compare pediatric and young adult congenital heart disease (CHD) patients to normal referents and relate the proxy to neurocognitive outcomes and nitric oxide bioavailability. In a prospective single-center study, resting-state blood-oxygen-level-dependent (BOLD) and arterial spin labeling (ASL) MRI scans were successfully obtained from 24 CHD patients (age = 15.4 ± 4.06 years) and 63 normal referents (age = 14.1 ± 3.49) years. Pnvf was computed on a voxelwise basis as the negative of the ratio of functional connectivity strength (FCS) estimated from the resting-state BOLD acquisition to regional cerebral blood flow (rCBF) as estimated from the ASL acquisition. Pnvf was used to predict end-tidal CO2 (P ET CO2) levels and compared to those estimated from the BOLD data. Nitric oxide availability was obtained via nasal measurements (nNO). Pnvf was compared on a voxelwise basis between CHD patients and normal referents and correlated with nitric oxide availability and neurocognitive outcomes as assessed via the NIH Toolbox. Pnvf was shown as highly predictive of P ET CO2 using theoretical modeling. Pnvf was found to be significantly reduced in CHD patients in default mode network (DMN, comprising the ventromedial prefrontal cortex and posterior cingulate/precuneus), salience network (SN, comprising the insula and dorsal anterior cingulate), and central executive network (CEN, comprising posterior parietal and dorsolateral prefrontal cortex) regions with similar findings noted in single cardiac ventricle patients. Positive correlations of Pnvf in these brain regions, as well as the hippocampus, were found with neurocognitive outcomes. Similarly, positive correlations between Pnvf and nitric oxide availability were found in frontal DMN and CEN regions, with particularly strong correlations in subcortical regions (putamen). Reduced Pnvf in CHD patients was found to be mediated by nNO. Mediation analyses further supported that reduced Pnvf in these regions underlies worse neurocognitive outcome in CHD patients and is associated with nitric oxide bioavailability. Impaired neuro-vascular function, which may be non-invasively estimated via combined arterial-spin label and BOLD MR imaging, is a nitric oxide bioavailability dependent factor implicated in adverse neurocognitive outcomes in pediatric and young adult CHD., Competing Interests: The authors declare no conflicts of interest.

Background: Behavioral research indicates that caregiver mood disorders and emotional instability in the early months following childbirth are associated with lower positive emotionality and higher negative emotionality in infants, but the neural mechanisms remain understudied., Methods: Using resting-state functional connectivity as a measure of the functional architecture of the early infant brain, we aimed to determine the extent to which connectivity between the amygdala, a key region supporting emotional learning and perception, and large-scale neural networks mediated the association between caregiver affect and anxiety and early infant negative emotionality and positive emotionality. Two samples of infants (first sample: n = 58; second sample: n = 31) 3 months of age underwent magnetic resonance imaging during natural sleep., Results: During infancy, greater resting-state functional connectivity between the amygdala and the salience network and, to a lesser extent, lower amygdala and executive control network resting-state functional connectivity mediated the effect of greater caregiver postpartum depression and trait anxiety on reducing infant smiling (familywise error-corrected p < .05). Furthermore, results from the first sample were replicated in the second, independent sample, to a greater extent for caregiver depression than for caregiver anxiety., Conclusions: We provide evidence of early objective neural markers that can help identify infants who are more likely to be at risk from, versus those who might be protected against, the deleterious effects of caregiver depression and anxiety and reduced positive emotionality., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Little is known about how early alterations in white matter relate to clinically relevant behaviors such as emotional dysregulation. Thus, our goal was to examine how the white matter structural integrity of key limbic (i.e., uncinate fasciculus and cingulum) and commissural (i.e., forceps minor) bundles in 3-month-old infants prospectively predicts emotional regulation behaviors at 9 months., Methods: Three-month-old infants underwent multishell diffusion-weighted imaging. Following image processing, tractography was performed for each tract within each infant's native space (n=20). Measures of white matter integrity, including microstructure and morphology, were extracted from each tract. At 9 months, negative emotionality (NE) and positive emotionality (PE) were elicited using Laboratory Assessment of Temperament tasks. Elastic net regressions were performed for variable selection, which included white matter integrity variables from each of the 3 tracts, along with several covariates, including age, sex, use of public assistance, and the mother's depressive symptoms. Outcome variables were NE and PE composite scores evaluated in two separate models., Results: Notably, following hierarchical regression using elastic net-selected variables, uncinate structural integrity was the most robust predictor of NE (ß=-0.631, p=0.005)., Limitations: The sample size of our study is a limitation, however, as a preliminary study, our goal was to describe our findings to inform future, larger studies., Conclusions: Greater uncinate structural integrity predicted lower NE, suggesting that greater uncinate structural integrity at 3 months allows greater emotional regulation capacity at 9 months. To our knowledge, this is the first study to demonstrate prospective brain-to-emotional behavior relationships in infants., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Although self-report pain ratings are the gold standard in clinical pain assessment, they are inherently subjective in nature and significantly influenced by multidimensional contextual variables. Although objective biomarkers for pain could substantially aid pain diagnosis and development of novel therapies, reliable markers for clinical pain have been elusive. In this study, individualized physical maneuvers were used to exacerbate clinical pain in patients with chronic low back pain (N = 53), thereby experimentally producing lower and higher pain states. Multivariate machine-learning models were then built from brain imaging (resting-state blood-oxygenation-level-dependent and arterial spin labeling functional imaging) and autonomic activity (heart rate variability) features to predict within-patient clinical pain intensity states (ie, lower vs higher pain) and were then applied to predict between-patient clinical pain ratings with independent training and testing data sets. Within-patient classification between lower and higher clinical pain intensity states showed best performance (accuracy = 92.45%, area under the curve = 0.97) when all 3 multimodal parameters were combined. Between-patient prediction of clinical pain intensity using independent training and testing data sets also demonstrated significant prediction across pain ratings using the combined model (Pearson's r = 0.63). Classification of increased pain was weighted by elevated cerebral blood flow in the thalamus, and prefrontal and posterior cingulate cortices, and increased primary somatosensory connectivity to frontoinsular cortex. Our machine-learning approach introduces a model with putative biomarkers for clinical pain and multiple clinical applications alongside self-report, from pain assessment in noncommunicative patients to identification of objective pain endophenotypes that can be used in future longitudinal research aimed at discovery of new approaches to combat chronic pain.

The extent to which neural networks underlying emotional behavior in infancy serve as precursors of later behavioral and emotional problems is unclear. Even less is known about caregiving influences on these early brain-behavior relationships. To study brain-emotional behavior relationships in infants, we examined resting-state functional network metrics and infant emotional behavior in the context of early maternal caregiving. We assessed 46 3-month-old infants and their mothers from a community sample. Infants underwent functional MRI during sleep. Resting-state data were processed using graph theory techniques to examine specific nodal metrics as indicators of network functionality. Infant positive and negative emotional behaviors, and positive, negative and mental-state talk (MST) indices of maternal caregiving were coded independently from filmed interactions. Regression analyses tested associations among nodal metrics and infant emotionality, and the moderating effects of maternal behavior on these relationships. All results were FDR corrected at alpha = 0.05. While relationships between infant emotional behavior or maternal caregiving, and nodal metrics were weak, higher levels of maternal MST strengthened associations between infant positive emotionality and nodal metrics within prefrontal ( p < 0.0001), and occipital ( p < 0.0001) cortices more generally. Positive and negative aspects of maternal caregiving had little effect. Our findings suggest that maternal MST may play an important role in strengthening links between emotion regulation neural circuitry and early infant positive behavior. They also provide objective neural markers that could inform and monitor caregiving-based interventions designed to improve the health and well-being of vulnerable infants at-risk for behavioral and emotional problems.

Objectives: Although the Default Mode Network (DMN) has been examined extensively in adults, developmental characteristics of this network during childhood are not fully understood., Methods: In this longitudinal study, we characterized the developmental changes in the DMN in fifteen children who were each scanned three times during a narrative comprehension task using magnetic resonance imaging., Results: Despite similar brain-activation patterns along developmental ages 5 to 18 years when listening to stories, increased, widely distributed deactivation of the DMN was observed in children between the ages of 11 and 18 years. Our findings suggest that changes occurring with increased age, primarily brain maturation and cognitive development drive deactivation of the DMN, which in turn might facilitate attendance to the task., Conclusions: The interpretation of our results is as a possible reference for the typical course of deactivation of the DMN and to explain the impaired patterns in this neural network associated with different language-related pathologies.

Objective: Little is currently known about the impact of congenital heart disease (CHD) on the organization of large-scale brain networks in relation to neurobehavioral outcome. We investigated whether CHD might impact ADHD symptoms via changes in brain structural network topology in a cohort of adolescents with d-transposition of the great arteries (d-TGA) repaired with the arterial switch operation in early infancy and referent subjects. We also explored whether these effects might be modified by apolipoprotein E (APOE) genotype, as the APOE ε2 allele has been associated with worse neurodevelopmental outcomes after repair of d-TGA in infancy., Methods: We applied graph analysis techniques to diffusion tensor imaging (DTI) data obtained from 47 d-TGA adolescents and 29 healthy referents to construct measures of structural topology at the global and regional levels. We developed statistical mediation models revealing the respective contributions of d-TGA, APOE genotype, and structural network topology on ADHD outcome as measured by the Connors ADHD/DSM-IV Scales (CADS)., Results: Changes in overall network connectivity, integration, and segregation mediated worse ADHD outcomes in d-TGA patients compared to healthy referents; these changes were predominantly in the left and right intrahemispheric regional subnetworks. Exploratory analysis revealed that network topology also mediated detrimental effects of the APOE ε4 allele but improved neurobehavioral outcomes for the APOE ε2 allele., Conclusion: Our results suggest that disruption of organization of large-scale networks may contribute to neurobehavioral dysfunction in adolescents with CHD and that this effect may interact with APOE genotype.

Objective: Late preterm birth confers increased risk of developmental delay, academic difficulties and social deficits. The late third trimester may represent a critical period of development of neural networks including the default mode network (DMN), which is essential to normal cognition. Our objective is to identify functional and structural connectivity differences in the posteromedial cortex related to late preterm birth., Methods: Thirty-eight preadolescents (ages 9-13; 19 born in the late preterm period (≥32 weeks gestational age) and 19 at term) without access to advanced neonatal care were recruited from a low socioeconomic status community in Brazil. Participants underwent neurocognitive testing, 3-dimensional T1-weighted imaging, diffusion-weighted imaging and resting state functional MRI (RS-fMRI). Seed-based probabilistic diffusion tractography and RS-fMRI analyses were performed using unilateral seeds within the posterior DMN (posterior cingulate cortex, precuneus) and lateral parietal DMN (superior marginal and angular gyri)., Results: Late preterm children demonstrated increased functional connectivity within the posterior default mode networks and increased anti-correlation with the central-executive network when seeded from the posteromedial cortex (PMC). Key differences were demonstrated between PMC components with increased anti-correlation with the salience network seen only with posterior cingulate cortex seeding but not with precuneus seeding. Probabilistic tractography showed increased streamlines within the right inferior longitudinal fasciculus and inferior fronto-occipital fasciculus within late preterm children while decreased intrahemispheric streamlines were also observed. No significant differences in neurocognitive testing were demonstrated between groups., Conclusion: Late preterm preadolescence is associated with altered functional connectivity from the PMC and lateral parietal cortex to known distributed functional cortical networks despite no significant executive neurocognitive differences. Selective increased structural connectivity was observed in the setting of decreased posterior interhemispheric connections. Future work is needed to determine if these findings represent a compensatory adaptation employing alternate neural circuitry or could reflect subtle pathology resulting in emotional processing deficits not seen with neurocognitive testing.

Introduction: Altered thalamocortical development is hypothesized to be a key substrate underlying neurodevelopmental disabilities in preterm infants. However, the pathogenesis of this abnormality is not well-understood. We combined magnetic resonance spectroscopy of the parietal white matter and morphometric analyses of the thalamus to investigate the association between white matter metabolism and thalamic volume and tested the hypothesis that thalamic volume would be associated with diminished N-acetyl-aspartate (NAA), a measure of neuronal/axonal maturation, independent of white matter injury., Methods: Data from 106 preterm infants (mean gestational age at birth: 31.0 weeks ± 4.3; range 23-36 weeks) who underwent MR examinations under clinical indications were included in this study., Results: Linear regression analyses demonstrated a significant association between parietal white matter NAA concentration and thalamic volume. This effect was above and beyond the effect of white matter injury and age at MRI and remained significant even when preterm infants with punctate white matter lesions (pWMLs) were excluded from the analysis. Furthermore, choline, and among the preterm infants without pWMLs, lactate concentrations were also associated with thalamic volume. Of note, the associations between NAA and choline concentration and thalamic volume remained significant even when the sample was restricted to neonates who were term-equivalent age or older., Conclusion: These observations provide convergent evidence of a neuroimaging phenotype characterized by widespread abnormal thalamocortical development and suggest that the pathogenesis may involve impaired axonal maturation.

Magnetic resonance imaging (MRI) evaluation of the developing brain has dramatically increased over the last decade. Faster acquisitions and the development of advanced MRI sequences, such as magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI), perfusion imaging, functional MR imaging (fMRI), and susceptibility-weighted imaging (SWI), as well as the use of higher magnetic field strengths has made MRI an invaluable tool for detailed evaluation of the developing brain. This article will provide an overview of the use and challenges associated with 1.5-T and 3-T static magnetic fields for evaluation of the developing brain. This review will also summarize the advantages, clinical challenges, and safety concerns specifically related to MRI in the fetus and newborn, including the implications of increased magnetic field strength, logistics related to transporting and monitoring of neonates during scanning, and sedation considerations, and a discussion of current technologies such as MRI conditional neonatal incubators and dedicated small-foot print neonatal intensive care unit (NICU) scanners., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Patients with congenital heart disease (CHD) are at risk for neurocognitive impairments. Little is known about the impact of CHD on the organization of large-scale brain networks. We applied graph analysis techniques to diffusion tensor imaging (DTI) data obtained from 49 adolescents with dextro-transposition of the great arteries (d-TGA) repaired with the arterial switch operation in early infancy and 29 healthy referent adolescents. We examined whether differences in neurocognitive functioning were related to white matter network topology. We developed mediation models revealing the respective contributions of peri-operative variables and network topology on cognitive outcome. Adolescents with d-TGA had reduced global efficiency at a trend level (p = 0.061), increased modularity (p = 0.012), and increased small-worldness (p = 0.026) as compared to controls. Moreover, these network properties mediated neurocognitive differences between the d-TGA and referent adolescents across every domain assessed. Finally, structural network topology mediated the neuroprotective effect of longer duration of core cooling during reparative neonatal cardiac surgery, as well as the detrimental effects of prolonged hospitalization. Taken together, worse neurocognitive function in adolescents with d-TGA is mediated by global differences in white matter network topology, suggesting that disruption of this configuration of large-scale networks drives neurocognitive dysfunction. These data provide new insights into the interplay between perioperative factors, brain organization, and cognition in patients with complex CHD.

Late preterm birth is increasingly recognized as a risk factor for cognitive and social deficits. The prefrontal cortex is particularly vulnerable to injury in late prematurity because of its protracted development and extensive cortical connections. Our study examined children born late preterm without access to advanced postnatal care to assess structural and functional connectivity related to the prefrontal cortex. Thirty-eight preadolescents [19 born late preterm (34-36 /7 weeks gestational age) and 19 at term] were recruited from a developing community in Brazil. Participants underwent neuropsychological testing. Individuals underwent three-dimensional T1-weighted, diffusion-weighted, and resting state functional MRI. Probabilistic tractography and functional connectivity analyses were carried out using unilateral seeds combining the medial prefrontal cortex and the anterior cingulate cortex. Late preterm children showed increased functional connectivity within regions of the default mode, salience, and central-executive networks from both right and left frontal cortex seeds. Decreased functional connectivity was observed within the right parahippocampal region from left frontal seeding. Probabilistic tractography showed a pattern of decreased streamlines in frontal white matter pathways and the corpus callosum, but also increased streamlines in the left orbitofrontal white matter and the right frontal white matter when seeded from the right. Late preterm children and term control children scored similarly on neuropsychological testing. Prefrontal cortical connectivity is altered in late prematurity, with hyperconnectivity observed in key resting state networks in the absence of neuropsychological deficits. Abnormal structural connectivity indicated by probabilistic tractography suggests subtle changes in white matter development, implying disruption of normal maturation during the late gestational period.

Functional MRI using blood-oxygen-level-dependent (BOLD) imaging has provided unprecedented insights into the maturation of the human brain. Task-based fMRI studies have shown BOLD signal increases with age during development (ages 5-18) for many cognitive domains such as language and executive function, while functional connectivity (resting-state) fMRI studies investigating regionally synchronous BOLD fluctuations have revealed a developing functional organization of the brain from a local into a more distributed architecture. However, interpretation of these results is confounded by the fact that the BOLD signal is directly related to blood oxygenation driven by changes in blood flow and only indirectly related to neuronal activity, and may thus be affected by changing neuronal-vascular coupling. BOLD signal and cerebral blood flow (CBF) were measured simultaneously in a cohort of 113 typically developing awake participants ages 3-18 performing a narrative comprehension task. Using a novel voxelwise wild bootstrap analysis technique, an increased ratio of BOLD signal to relative CBF signal change with age (indicative of increased neuronal-vascular coupling) was seen in the middle temporal gyri and the left inferior frontal gyrus. Additionally, evidence of decreased relative oxygen metabolism (indicative of decreased neuronal activity) with age was found in the same regions. These findings raise concern that results of developmental BOLD studies cannot be unambiguously attributed to neuronal activity. Astrocytes and astrocytic processes may significantly affect the maturing functional architecture of the brain, consistent with recent research demonstrating a key role for astrocytes in mediating increased CBF following neuronal activity and for astrocyte processes in modulating synaptic connectivity., (© 2014 Wiley Periodicals, Inc.)

The posteromedial cortex (PMC) including the posterior cingulate, retrosplenial cortex, and medial parietal cortex/precuneus is an epicenter of cortical interactions in a wide spectrum of neural activity. Anatomic connections between PMC and thalamic components have been established in animal studies, but similar studies do not exist for the fetal and neonatal period. Magnetic resonance spectroscopy (MRS) allows for noninvasive measurement of metabolites in early development. Using single-voxel 3-T MRS, healthy term neonates (n = 31, mean postconception age 41.5 weeks ± 3.8 weeks) were compared with control children (n = 23, mean age 9.4 years ± 5.1 years) and young adults (n = 10, mean age 24.1 years ± 2.6 years). LCModel-based calculations compared metabolites within medial parietal gray matter (colocalizing to the PMC), posterior thalamus, and parietal white matter voxels. Common metabolic changes existed for neuronal-axonal maturation and structural markers in the PMC, thalamus, and parietal white matter with increasing NAA and glutamate and decreasing myoinositol and choline with age. Key differences in creatine and glucose metabolism were noted in the PMC, in contrast to the thalamic and parietal white matter locations, suggesting a unique role of energy metabolism. Significant parallel metabolite developmental changes of multiple other metabolites including aspartate, glutamine, and glutathione with age were present between PMC and parietal white matter but not between PMC and thalamus. These findings offer insight into the metabolic architecture of the interface between structural and functional topology of brain networks. Further investigation unifying metabolic changes with functional and anatomic pathways may further enhance the understanding of the PMC in posterior default mode network development., (© 2014 Wiley Periodicals, Inc.)

Introduction: Punctate white matter lesions (pWMLs) and diffuse excessive high signal intensity (DEHSI) are commonly observed signal abnormalities on MRI scans of high-risk preterm infants near term-equivalent age. To establish whether these features are indicative abnormalities in axonal development or astroglia, we compared pWMLs and DEHSI to markers of axons and astrogliosis, derived from magnetic resonance spectroscopy (MRS)., Methods: Data from 108 preterm infants (gestational age at birth 31.0 weeks ± 4.3; age at scan 41.2 weeks ± 6.0) who underwent MR examinations under clinical indications were included in this study. Linear regression analyses were used to test the effects of pWMLs and DEHSI on N-acetyl-aspartate (NAA) and myoinositol concentrations, respectively., Results: Across the full sample, pWMLs were associated with a reduction in NAA whereas moderate to severe DEHSI altered the normal age-dependent changes in myoinositol such that myoinositol levels were lower at younger ages with no change during the perinatal period. Subgroup analyses indicated that the above associations were driven by the subgroup of neonates with both pWMLs and moderate to severe DEHSI., Conclusion: Overall, these findings suggest that pWMLs in conjunction with moderate/severe DEHSI may signify a population of infants at risk for long-term adverse neurodevelopmental outcome due to white matter injury and associated axonopathy. The loss of normal age-associated changes in myoinositol further suggests disrupted astroglial function and/or osmotic dysregulation.

Introduction: The purpose of the present study was to identify biomarkers of listening difficulties by investigating white matter microstructure in children suspected of auditory processing disorder (APD) using diffusion tensor imaging (DTI). Behavioral studies have suggested that impaired cognitive and/or attention abilities rather than a pure sensory processing deficit underlie listening difficulties and auditory processing disorder (APD) in children. However, the neural signature of listening difficulties has not been investigated., Methods: Twelve children with listening difficulties and atypical left ear advantage (LEA) in dichotic listening and twelve age- and gender-matched typically developing children with typical right ear advantage (REA) were tested. Using voxel-based analysis, fractional anisotropy (FA), and mean, axial and radial diffusivity (MD, AD, RD) maps were computed and contrasted between the groups., Results: Listening difficulties were associated with altered white matter microstructure, reflected by decreased FA in frontal multifocal white matter regions centered in prefrontal cortex bilaterally and left anterior cingulate. Increased RD and decreased AD accounted for the decreased FA, suggesting delayed myelination in frontal white matter tracts and disrupted fiber organization in the LEA group. Furthermore, listening difficulties were associated with increased MD (with increase in both RD and AD) in the posterior limb of the internal capsule (sublenticular part) at the auditory radiations where auditory input is transmitted between the thalamus and the auditory cortex., Conclusions: Our results provide direct evidence that listening difficulties in children are associated with altered white matter microstructure and that both sensory and supramodal deficits underlie the differences between the groups.

Purpose: To compare a double-excitation combined arterial-spin labeling/blood-oxygenation level dependent (ASL/BOLD) functional imaging method to a double-echo method. ASL provides a useful complement to standard BOLD functional imaging, to map effects of cerebral hemodynamics. Whole-brain imaging is necessary to properly characterize large functional networks. A challenge of whole-brain ASL/BOLD is that images for ASL functional contrast must be acquired before significant longitudinal relaxation of the inverted spins occurs; however, a longer echo time (TE) is required for optimal BOLD functional contrast, lengthening the acquisition time. Thus, existing combined ASL/BOLD studies have only partial-brain coverage., Materials and Methods: The proposed method allows acquisition of images for ASL contrast within a short period after the ASL labeling pulse and postinversion delay, then subsequent acquisition of images with longer TE for BOLD contrast. The technique is demonstrated using a narrative comprehension task in 35 normal children, and the double-excitation method is empirically compared with the double-echo method in 7 normal adults., Results: Compared with a double-echo sequence, simulations show the double-excitation method improves ASL contrast-to-noise ratio (CNR) (∼50%) in later-acquired slices with minimal (<1%) reduction in BOLD CNR in earlier-acquired slices if reduced excitation flip angles for the ASL acquisitions are used. Empirical results from adult data are in agreement with the simulations. Group analyses from the narrative comprehension task also show greater intersubject sensitivity in BOLD versus ASL., Conclusion: Our method simultaneously optimizes ASL and BOLD acquisitions for CNR while economizing acquisition time., (Copyright © 2013 Wiley Periodicals, Inc.)

Monaural auditory input due to congenital or acquired unilateral hearing loss (UHL) may have neurobiological effects on the developing brain. Using functional magnetic resonance imaging (fMRI), we investigated the effect of UHL on the development of functional brain networks used for cross-modal processing. Children ages 7-12 with moderate or greater unilateral hearing loss of sensorineural origin (UHL-SN; N = 21) and normal-hearing controls (N = 23) performed an fMRI-compatible adaptation of the Token Test involving listening to a sentence such as "touched the small green circle and the large blue square" and simultaneously viewing an arrow touching colored shapes on a video. Children with right or severe-to-profound UHL-SN displayed smaller activation in a region encompassing the right inferior temporal, middle temporal, and middle occipital gyrus (BA 19/37/39), evidencing differences due to monaural hearing in cross-modal modulation of the visual processing pathway. Children with UHL-SN displayed increased activation in the left posterior superior temporal gyrus, likely the result either of more effortful low-level processing of auditory stimuli or differences in cross-modal modulation of the auditory processing pathway. Additionally, children with UHL-SN displayed reduced deactivation of anterior and posterior regions of the default mode network. Results suggest that monaural hearing affects the development of brain networks related to cross-modal sensory processing and the regulation of the default network during processing of spoken language.

Dichotic listening (DL) tests are among the most frequently included in batteries for the diagnosis of auditory processing disorders (APD) in children. A finding of atypical left ear advantage (LEA) for speech-related stimuli is often taken by clinical audiologists as an indicator for APD. However, the precise etiology of ear advantage in DL tests has been a source of debate for decades. It is uncertain whether a finding of LEA is truly indicative of a sensory processing deficit such as APD, or whether attentional or other supramodal factors may also influence ear advantage. Multivariate machine learning was used on diffusion tensor imaging (DTI) and functional MRI (fMRI) data from a cohort of children ages 7-14 referred for APD testing with LEA, and typical controls with right-ear advantage (REA). LEA was predicted by: increased axial diffusivity in the left internal capsule (sublenticular region), and decreased functional activation in the left frontal eye fields (BA 8) during words presented diotically as compared to words presented dichotically, compared to children with right-ear advantage (REA). These results indicate that both sensory and attentional deficits may be predictive of LEA, and thus a finding of LEA, while possibly due to sensory factors, is not a specific indicator of APD as it may stem from a supramodal etiology.

This fMRI study investigated the development of language lateralization in left- and righthanded children between 5 and 18 years of age. Twenty-seven left-handed children (17 boys, 10 girls) and 54 age- and gender-matched right-handed children were included. We used functional MRI at 3T and a verb generation task to measure hemispheric language dominance based on either frontal or temporo-parietal regions of interest (ROIs) defined for the entire group and applied on an individual basis. Based on the frontal ROI, in the left-handed group, 23 participants (85%) demonstrated left-hemispheric language lateralization, 3 (11%) demonstrated symmetric activation, and 1 (4%) demonstrated right-hemispheric lateralization. In contrast, 50 (93%) of the right-handed children showed left-hemispheric lateralization and 3 (6%) demonstrated a symmetric activation pattern, while one (2%) demonstrated a right-hemispheric lateralization. The corresponding values for the temporo-parietal ROI for the left-handed children were 18 (67%) left-dominant, 6 (22%) symmetric, 3 (11%) right-dominant and for the right-handed children 49 (91%), 4 (7%), 1 (2%), respectively. Left-hemispheric language lateralization increased with age in both groups but somewhat different lateralization trajectories were observed in girls when compared to boys. The incidence of atypical language lateralization in left-handed children in this study was similar to that reported in adults. We also found similar rates of increase in left-hemispheric language lateralization with age between groups (i.e., independent of handedness) indicating the presence of similar mechanisms for language lateralization in left- and right-handed children., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Speech sound disorders (SSD) are the largest group of communication disorders observed in children. One explanation for these disorders is that children with SSD fail to form stable phonological representations when acquiring the speech sound system of their language due to poor phonological memory (PM). The goal of this study was to examine PM in individuals with histories of SSD employing functional MR imaging (fMRI). Participants were six right-handed adolescents with a history of early childhood SSD and seven right-handed matched controls with no history of speech and language disorders. We performed an fMRI study using an overt non-word repetition (NWR). Right lateralized hypoactivation in the inferior frontal gyrus and middle temporal gyrus was observed. The former suggests a deficit in the phonological processing loop supporting PM, while the later may indicate a deficit in speech perception. Both are cognitive processes involved in speech production. Bilateral hyperactivation observed in the pre and supplementary motor cortex, inferior parietal, supramarginal gyrus and cerebellum raised the possibility of compensatory increases in cognitive effort or reliance on the other components of the articulatory rehearsal network and phonologic store. These findings may be interpreted to support the hypothesis that individuals with SSD may have a deficit in PM and to suggest the involvement of compensatory mechanisms to counteract dysfunction of the normal network., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The authors used functional magnetic resonance imaging (fMRI) to investigate neural activation during a semantic-classification/object-recognition task in 13 persons with Down syndrome and 12 typically developing control participants (age range  =  12-26 years). A comparison between groups suggested atypical patterns of brain activation for the individuals with Down syndrome. Correlation analyses between an index of visual spatial ability and brain activation depicted a positive relationship between (a) this index and brain activation in regions of the occipital and parietal lobes for the typically developing individuals and (b) the middle and dorsal frontal gyri in the individuals with Down syndrome. These findings supported the authors' hypothesis that persons with Down syndrome demonstrate atypical neural activation compared with typically developing individuals matched for chronological age.

Human language is a complex and protean cognitive ability. Young children, following well defined developmental patterns learn language rapidly and effortlessly producing full sentences by the age of 3 years. However, the language circuitry continues to undergo significant neuroplastic changes extending well into teenage years. Evidence suggests that the developing brain adheres to two rudimentary principles of functional organization: functional integration and functional specialization. At a neurobiological level, this distinction can be identified with progressive specialization or focalization reflecting consolidation and synaptic reinforcement of a network (Lenneberg, 1967; Muller et al., 1998; Berl et al., 2006). In this paper, we used group independent component analysis and linear structural equation modeling (McIntosh and Gonzalez-Lima, 1994; Karunanayaka et al., 2007) to tease out the developmental trajectories of the language circuitry based on fMRI data from 336 children ages 5-18 years performing a blocked, covert verb generation task. The results are analyzed and presented in the framework of theoretical models for neurocognitive brain development. This study highlights the advantages of combining both modular and connectionist approaches to cognitive functions; from a methodological perspective, it demonstrates the feasibility of combining data-driven and hypothesis driven techniques to investigate the developmental shifts in the semantic network.

Objective: Correlation of white matter microstructure with various cognitive processing tasks and with overall intelligence has been previously demonstrated. We investigate the correlation of white matter microstructure with various higher-order auditory processing tasks, including interpretation of speech-in-noise, recognition of low-pass frequency filtered words, and interpretation of time-compressed sentences at two different values of compression. These tests are typically used to diagnose auditory processing disorder (APD) in children. Our hypothesis is that correlations between white matter microstructure in tracts connecting the temporal, frontal, and parietal lobes, as well as callosal pathways, will be seen. Previous functional imaging studies have shown correlations between activation in temporal, frontal, and parietal regions from higher-order auditory processing tasks. In addition, we hypothesize that the regions displaying correlations will vary according to the task because each task uses a different set of skills., Design: Diffusion tensor imaging (DTI) data were acquired from a cohort of 17 normal-hearing children aged 9 to 11 yrs. Fractional anisotropy (FA), a measure of white matter fiber tract integrity and organization, was computed and correlated on a voxelwise basis with performance on the auditory processing tasks, controlling for age, sex, and full-scale IQ., Results: Divergent correlations of white matter FA depending on the particular auditory processing task were found. Positive correlations were found between FA and speech-in-noise in white matter adjoining prefrontal areas and between FA and filtered words in the corpus callosum. Regions exhibiting correlations with time-compressed sentences varied depending on the degree of compression: the greater degree of compression (with the greatest difficulty) resulted in correlations in white matter adjoining prefrontal (dorsal and ventral), whereas the smaller degree of compression (with less difficulty) resulted in correlations in white matter adjoining audiovisual association areas and the posterior cingulate. Only the time-compressed sentences with the lowest degree of compression resulted in positive correlations in the centrum semiovale; all the other tasks resulted in negative correlations., Conclusions: The dependence of performance on higher-order auditory processing tasks on brain anatomical connectivity was seen in normal-hearing children aged 9 to 11 yrs. Results support a previously hypothesized dual-stream (dorsal and ventral) model of auditory processing, and that higher-order processing tasks rely less on the dorsal stream related to articulatory networks and more on the ventral stream related to semantic comprehension. Results also show that the regions correlating with auditory processing vary according to the specific task, indicating that the neurological bases for the various tests used to diagnose APD in children may be partially independent.

Semantic language skills are an integral part of early childhood language development. The semantic association between verbs and nouns constitutes an important building block for the construction of sentences. In this large-scale functional magnetic resonance imaging (fMRI) study, involving 336 subjects between the ages of 5 and 18 years, we investigated the neural correlates of covert verb generation in children. Using group independent component analysis (ICA), seven task-related components were identified including the mid-superior temporal gyrus, the most posterior aspect of the superior temporal gyrus, the parahippocampal gyrus, the inferior frontal gyrus, the angular gyrus, and medial aspect of the parietal lobule (precuneus/posterior cingulate). A highly left-lateralized component was found including the medial temporal gyrus, the frontal gyrus, the inferior frontal gyrus, and the angular gyrus. The associated independent component (IC) time courses were analyzed to investigate developmental changes in the neural elements supporting covert verb generation. Observed age effects may either reflect specific local neuroplastic changes in the neural substrates supporting language or a more global transformation of neuroplasticity in the developing brain. The results are analyzed and presented in the framework of two theoretical models for neurocognitive brain development. In this context, group ICA of fMRI data from our large sample of children aged 5-18 years provides strong evidence in support of the regionally weighted model for cognitive neurodevelopment of language networks., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Previous volumetric developmental MRI studies of the brain have shown white matter development continuing through adolescence and into adulthood. This review presents current findings regarding white matter development and organization from diffusion MRI studies. The general trend during adolescence (age 12-18 years) is towards increasing fractional anisotropy (FA) with age and decreasing mean diffusivity (MD) with age, findings primarily due to decreasing radial diffusivity with age. However, results of studies vary as to the regional specificity of such age-related changes, likely due in part to methodological issues. Another general trend is for FA to positively correlate and MD to negatively correlate with cognitive function. This trend is however region-specific, task-specific, and population-specific; some studies have in fact found negative correlations of FA and positive correlations of MD in specific regions with specific measures of cognitive performance. There are also published reports of sexual dimorphism in white matter development, indicating differing developmental trajectories between males and females as well as differing relationships developmentally between white matter architecture and cognitive function. There is a need for more research to further elucidate the development of white matter and its relation to cognitive function during this critical developmental period., (2009 Elsevier Inc. All rights reserved.)

Childhood lead exposure is associated with adverse cognitive, neurobehavioral and motor outcomes, suggesting altered brain structure and function. The purpose of this work was to assess the long-term impact of childhood lead exposure on white matter integrity in young adults. We hypothesized that childhood lead exposure would alter adult white matter architecture via deficits in axonal integrity and myelin organization. Adults (22.9+/-1.5 years, range 20.0-26.1 years) from the Cincinnati Lead Study were recruited to undergo a study employing diffusion tensor imaging (DTI). The anatomic regions of association between water diffusion characteristics in white matter and mean childhood blood lead level were determined for 91 participants (52 female). Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were measured on an exploratory voxel-wise basis. In adjusted analyses, mean childhood blood lead levels were associated with decreased FA throughout white matter. Regions of the corona radiata demonstrated highly significant lead-associated decreases in FA and AD and increases in MD and RD. The genu, body, and splenium of the corpus callosum demonstrated highly significant lead-associated decreases in RD, smaller and less significant decreases in MD, and small areas with increases in AD. The results of this analysis suggest multiple insults appear as distinct patterns of white matter diffusion abnormalities in the adult brain. Neurotoxic insults from the significant lead burden the participants experienced throughout childhood affect neural elements differently and may be related to the developmental stage of myelination at periods of exposure. This study indicates that childhood lead exposure is associated with a significant and persistent impact on white matter microstructure as quantified with diffusivity changes suggestive of altered myelination and axonal integrity.

Objective: The purpose of our study was to review functional MRI and other neuroimaging studies of language skills in children from infancy to adulthood., Conclusion: Functional MRI (fMRI) and other neuroimaging studies show developmental changes in the networks of brain regions supporting language, which can be affected by brain injuries or neurologic disorders. Particular aspects of language rely on networks that lateralize to the dominant hemisphere; others rely on bilateral or nondominant mechanisms. Multiple fMRI tasks for pediatric patients characterize functional brain reorganization that may accompany language deficits.

Purpose: To use functional MRI (fMRI) methods to visualize a network of auditory and language-processing brain regions associated with processing an aurally-presented story. We compare a passive listening (PL) story paradigm to an active-response (AR) version including online performance monitoring and a sparse acquisition technique., Materials and Methods: Twenty children (ages 11-13 years) completed PL and AR story processing tasks. The PL version presented alternating 30-second blocks of stories and tones; the AR version presented story segments, comprehension questions, and 5-second tone sequences, with fMRI acquisitions between stimuli. fMRI data was analyzed using a general linear model approach and paired t-test identifying significant group activation., Results: Both tasks showed activation in the primary auditory cortex, superior temporal gyrus bilaterally, and left inferior frontal gyrus (IFG). The AR task demonstrated more extensive activation, including the dorsolateral prefrontal cortex and anterior/posterior cingulate cortex. Comparison of effect size in each paradigm showed a larger effect for the AR paradigm in a left inferior frontal region-of-interest (ROI)., Conclusion: Activation patterns for story processing in children are similar in PL and AR tasks. Increases in extent and magnitude of activation in the AR task are likely associated with memory and attention resources engaged across acquisition intervals.

Objective: The purpose of our study was to develop a new method for quantifying the severity of cystic lung disease using chest CT and to evaluate this method in patients with lymphangioleiomyomatosis (LAM)., Subjects and Methods: Eighteen patients with LAM (all women; mean age, 43.6 years) underwent chest CT and pulmonary function testing including diffusing capacity for carbon monoxide (DLCO). All patients were at their clinical baseline on the day of imaging. Standard quantitative CT metrics including the percentage of the lung volume < -910 HU and the 15th percentile of Hounsfield units were computed from the histogram of lung voxels. A new histogram analysis method was developed to compute the cyst volume and the volume of the remaining lung by segmenting the entire lung attenuation histogram into two underlying distributions, one from the cysts and the other from the remaining lung tissue., Results: The mean +/- SD for quantitative lung metrics was 21% +/- 16% for percentage < -910 HU, -915 +/- 47 HU for 15th percentile of Hounsfield units, and 19% +/- 13% for cyst volume. The correlation between pulmonary function tests and CT metrics was strongest for the percentage of cyst volume for all pulmonary function testing indexes, with correlations between forced expiratory volume in 1 second (FEV(1)) percentage predicted and the CT metrics of r = -0.52, r = 0.50, and r = -0.86 for the percentage of lung < -910 HU, the 15th percentile of Hounsfield units, and the percentage of cyst volume, respectively., Conclusion: A new method for quantifying cyst volume as a percentage of total lung volume using chest CT correlates with pulmonary function parameters in patients with LAM and may have utility in the assessment of disease severity and progression of cystic lung diseases.

Recent neuroimaging research has shown sex-related differences in the relationship between brain structure and cognitive function. Anatomical studies have shown a greater reliance for cognitive function on white matter structure in adult females, and a greater reliance on gray matter structure in adult males. Functional neuroimaging studies have also shown a greater correlation between brain connectivity and cognitive function in females. However, this relationship is not present in young childhood (5 years old) but appears during the developmental period. Here sex differences in structure-function relationships and their developmental trajectory are investigated using diffusion tensor imaging (DTI) on a large cohort of over 100 normal children ages 5-18. Significant sex-X-IQ interactions on fractional anisotropy (FA), a marker for white matter organization, were seen in the left frontal lobe, in fronto-parietal areas bilaterally, and in the arcuate fasciculus bilaterally, with girls showing positive correlations of FA with IQ, and boys showing a negative correlation. Significant sex-X-IQ-X-age interactions on FA were also seen in the left frontal lobe and in fronto-parietal areas bilaterally, showing a developmental effect. These results strongly corroborate previous findings regarding sex differences in structure-function relationships regarding intelligence. Results also indicate that a naïve interpretation of "more is better" with respect to FA may not be accurate, especially in adult males.

Purpose: To evaluate the performance of different contrast functions used in Independent Component Analysis (ICA) of functional magnetic resonance imaging (fMRI) data at low signal-to-noise ratio (SNR), present in fMRI paradigms such as resting-state acquisitions., Materials and Methods: Metrics were defined to estimate both the accuracy and robustness of contrast functions under varying source distributions. Simulations were performed to compare the performance of lower-order (such as ln cosh) to higher-order (such as kurtosis) contrast functions using Laplacian source distributions corrupted with Gaussian noise. The ln cosh and kurtosis contrast functions were also compared using resting-state fMRI data from 10 normal adult volunteers., Results: Higher-order contrast functions provided superior performance compared to lower-order contrast functions in the evaluation of metrics and via the simulations in the presence of a significant amount of noise. The performance of kurtosis was not statistically significantly different from that of a theoretically optimized contrast function. The choice of contrast function was found to result in substantial (R < 0.9) differences in 40% of the components found from the resting-state fMRI data., Conclusion: The use of higher-order contrast functions, such as kurtosis, may provide superior performance in ICA analysis of fMRI data with low SNR.

Previous studies have found developmental differences between males and females in brain structure. During childhood and adolescence, relative white matter volume increases faster in boys than in girls. Sex differences in the development of white matter microstructure were investigated in a cohort of normal children ages 5-18 in a cross-sectional diffusion tensor imaging (DTI) study. Greater fractional anisotropy (FA) in boys was shown in associative white matter regions (including the frontal lobes), while greater FA in girls was shown in the splenium of the corpus callosum. Greater mean diffusivity (MD) in boys was shown in the corticospinal tract and in frontal white matter in the right hemisphere; greater MD in girls was shown in occipito-parietal regions and the most superior aspect of the corticospinal tract in the right hemisphere. Significant sex-age interactions on FA and MD were also shown. Girls displayed a greater rate of fiber density increase with age when compared with boys in associative regions (reflected in MD values). However, girls displayed a trend toward increased organization with age (reflected in FA values) only in the right hemisphere, while boys displayed this trend only in the left hemisphere. These results indicate differing developmental trajectories in white matter for boys and girls and the importance of taking sex into account in developmental DTI studies. The results also may have implications for the study of the relationship of brain architecture with intelligence., (Copyright 2007 Wiley-Liss, Inc.)

Objective: Functional MRI was used to determine differences in patterns of cortical activation between children who suffered perinatal left middle cerebral artery (MCA) stroke and healthy children performing a silent verb generation task., Methods: Ten children with prior perinatal left MCA stroke (age 6-16 years) and ten healthy age matched controls completed an executive language activation task. fMRI scans were acquired on a 3T scanner using T2* weighted gradient echo, echo-planar imaging (EPI) sequence. Random effects analysis and independent component analysis (ICA) were used to compute activation maps., Results: Both analysis methods demonstrated alternative activation of cortical areas in children with perinatal stroke. Following perinatal stroke, typical left dominant productive language areas in the inferior frontal gyrus were displaced to anatomical identical areas in the right hemisphere (p=.001). In addition, stroke patients showed more bilateral activation in superior temporal and anterior cingulate gyri and increased activation in primary visual cortex when compared to healthy controls. There was no relation between lesion size and the degree of right hemisphere activation. ICA showed that the healthy controls had a negative correlation with the time course in the right inferior frontal gyrus in the same region that was activated in stroke subjects., Interpretation: This functional MRI study in children revealed novel patterns of cortical language reorganization following perinatal stroke. The addition of ICA is complementary to Random Effects Analysis, allowing for the exploration of potential subtle differences in pathways in functional MRI data obtained from both healthy and pathological groups.

The objective of this case study was to describe the clinical and electroencephalography (EEG)/functional magnetic resonance imaging (fMRI) data of a case of isolated hemifacial spasm due to epilepsia partialis continua in a 59-year-old man with abnormal hemifacial movements that disappeared during voluntary tasks, were absent during sleep, and responded to carbamazepine. His neurological examination was normal; EEG revealed right inferior frontal epileptiform discharges. EEG/fMRI demonstrated increased blood oxygenation level-dependent contrast in the right inferior and middle frontal gyri corresponding to the contralateral motor and premotor cortex responsible for facial movements (BA 44, 45, 45, 9), with widespread BOLD signal deactivations suggestive of epileptic network involvement despite a very focal epileptogenic process. We hypothesize that the response of some cases of hemifacial spasm to carbamazepine, a first-line treatment in the pre-botulinum toxin era, may have been due to its antiepileptic effects, rather than to modulation of facial nerve hyperexcitability.

Background: Angiomyolipomas in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis are associated with mutations in tuberous sclerosis genes resulting in constitutive activation of the mammalian target of rapamycin (mTOR). The drug sirolimus suppresses mTOR signaling., Methods: We conducted a 24-month, nonrandomized, open-label trial to determine whether sirolimus reduces the angiomyolipoma volume in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. Sirolimus was administered for the first 12 months only. Serial magnetic resonance imaging of angiomyolipomas and brain lesions, computed tomography of lung cysts, and pulmonary-function tests were performed., Results: Of the 25 patients enrolled, 20 completed the 12-month evaluation, and 18 completed the 24-month evaluation. The mean (+/-SD) angiomyolipoma volume at 12 months was 53.2+/-26.6% of the baseline value (P<0.001) and at 24 months was 85.9+/-28.5% of the baseline value (P=0.005). At 24 months, five patients had a persistent reduction in the angiomyolipoma volume of 30% or more. During the period of sirolimus therapy, among patients with lymphangioleiomyomatosis, the mean forced expiratory volume in 1 second (FEV1) increased by 118+/-330 ml (P=0.06), the forced vital capacity (FVC) increased by 390+/-570 ml (P<0.001), and the residual volume decreased by 439+/-493 ml (P=0.02), as compared with baseline values. One year after sirolimus was discontinued, the FEV1 was 62+/-411 ml above the baseline value, the FVC was 346+/-712 ml above the baseline value, and the residual volume was 333+/-570 ml below the baseline value; cerebral lesions were unchanged. Five patients had six serious adverse events while receiving sirolimus, including diarrhea, pyelonephritis, stomatitis, and respiratory infections., Conclusions: Angiomyolipomas regressed somewhat during sirolimus therapy but tended to increase in volume after the therapy was stopped. Some patients with lymphangioleiomyomatosis had improvement in spirometric measurements and gas trapping that persisted after treatment. Suppression of mTOR signaling might constitute an ameliorative treatment in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. (ClinicalTrials.gov number, NCT00457808.), (2008 Massachusetts Medical Society)

Background and Purpose: Diffusion tensor imaging (DTI) can noninvasively quantify white matter (WM) integrity. Although its application in adult traumatic brain injury (TBI) is common, few studies in children have been reported. The purposes of this study were to examine the alteration of fractional anisotropy (FA) in children with TBI experienced during early childhood and to quantify the association between FA and injury severity., Materials and Methods: FA was assessed in 9 children with TBI (age = 7.89 +/- 1.00 years; Glasgow Coma Scale [GCS] = 10.11 +/- 4.68) and a control group of 12 children with orthopedic injuries without central nervous system involvement (age = 7.51 +/- 0.95 years). All of the subjects were at minimum 12 months after injury. We examined group differences in a series of predetermined WM regions of interest with t test analysis. We subsequently conducted a voxel-wise comparison with Spearman partial correlation analysis. Correlations between FA and injury severity were also calculated on a voxel-wise basis., Results: FA values were significantly reduced in the TBI group in genu of corpus callosum (CC), posterior limb of internal capsule (PLIC), superior longitudinal fasciculus (SLF), superior fronto-occipital fasciculus (SFO), and centrum semiovale (CS). GCS scores were positively correlated with FA in several WM areas including CC, PLIC, SLF, CS, SFO, and inferior fronto-occipital fasciculus (IFO)., Conclusion: This DTI study provides evidence that WM integrity remains abnormal in children with moderate-to-severe TBI experienced during early childhood and that injury severity correlated strongly with FA.