Structural network topology correlates of microstructural brain dysmaturation in term infants with congenital heart disease.

Neonates with complex congenital heart disease (CHD) demonstrate microstructural brain dysmaturation, but the relationship with structural network topology is unknown. We performed diffusion tensor imaging (DTI) in term neonates with CHD preoperatively (N = 61) and postoperatively (N = 50) compared with healthy term controls (N = 91). We used network topology (graph) analyses incorporating different weighted and unweighted approaches and subject-specific white matter segmentation to investigate structural topology differences, as well as a voxel-based analysis (VBA) to confirm the presence of microstructural dysmaturation. We demonstrate cost-dependent network inefficiencies in neonatal CHD in the pre- and postoperative period compared with controls, related to microstructural differences. Controlling for cost, we show the presence of increased small-worldness (hierarchical fiber organization) in CHD infants preoperatively, that persists in the postoperative period compared with controls, suggesting the early presence of brain reorganization. Taken together, topological microstructural dysmaturation in CHD infants is accompanied by hierarchical fiber organization during a protracted critical period of early brain development. Our methodology also provides a pipeline for quantitation of network topology changes in neonates and infants with microstructural brain dysmaturation at risk for perinatal brain injury.

Evidence that neurovascular coupling underlying the BOLD effect increases with age during childhood.

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.

Reduced thalamic volume in preterm infants is associated with abnormal white matter metabolism independent of injury.

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.

Optimized simultaneous ASL and BOLD functional imaging of the whole brain.

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.

Magnetic resonance spectroscopy markers of axons and astrogliosis in relation to specific features of white matter injury in preterm infants.

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.

Relationships Between Regional Cerebral Blood Flow and Neurocognitive Outcomes in Children and Adolescents With Congenital Heart Disease.

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.

Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis.

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.)

Diffusion tensor imaging reveals white matter microstructure correlations with auditory processing ability.

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.

Patterns of Infant Amygdala Connectivity Mediate the Impact of High Caregiver Affect on Reducing Infant Smiling: Discovery and Replication.

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.

A group independent component analysis of covert verb generation in children: a functional magnetic resonance imaging study.

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.

White matter development during adolescence as shown by diffusion MRI.

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.

Limbic white matter structural integrity at 3 months prospectively predicts negative emotionality in 9-month-old infants: a preliminary study.

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.

Language networks in children: evidence from functional MRI studies.

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.

Automated algorithm for quantifying the extent of cystic change on volumetric chest CT: initial results in Lymphangioleiomyomatosis.

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.

DEVELOPMENTAL SEX DIFFERENCES IN THE RELATION OF NEUROANATOMICAL CONNECTIVITY TO INTELLIGENCE.

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.

Machine learning-based prediction of clinical pain using multimodal neuroimaging and autonomic metrics.

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.

Developmental differences in white matter architecture between boys and girls.

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.

The Impact of Caregiving on the Association Between Infant Emotional Behavior and Resting State Neural Network Functional Topology.

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.

Development of effective connectivity for narrative comprehension in children.

A large-scale study of narrative comprehension using functional MRI was performed involving children of ages 5-18 years old using a recently published method, multivariate autoregressive modeling, modified for multi subject analyses to investigate effective connectivity and its development with age. Feedback networks were found during a narrative processing task and involved effective connectivity from Broca's area and the medial aspect of the superior frontal gyrus to the posterior aspects of the superior temporal gyrus bilaterally. The effective connectivity from Broca's area to the superior temporal gyrus in the left hemisphere was shown to increase with age. The results demonstrate the feasibility of performing multi subject multivariate autoregressive modeling analyses to investigate effective connectivity in the absence of an a priori model.

Maturation of Brain Regions Related to the Default Mode Network during Adolescence Facilitates Narrative Comprehension.

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.