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.

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.

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.

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.

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.

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.

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.

Organizational topology of brain and its relationship to ADHD in adolescents with d-transposition of the great arteries.

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.

Altered Structural and Functional Connectivity in Late Preterm Preadolescence: An Anatomic Seed-Based Study of Resting State Networks Related to the Posteromedial and Lateral Parietal Cortex.

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.

MRI evaluation and safety in the developing brain.

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.

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.

Relationship of white matter network topology and cognitive outcome in adolescents with d-transposition of the great arteries.

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.

Alterations of resting state networks and structural connectivity in relation to the prefrontal and anterior cingulate cortices in late prematurity.

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.

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.

Altered white matter microstructure underlies listening difficulties in children suspected of auditory processing disorders: a DTI study.

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.

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.

Early metabolic development of posteromedial cortex and thalamus in humans analyzed via in vivo quantitative magnetic resonance spectroscopy.

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.

Unilateral deafness in children affects development of multi-modal modulation and default mode networks.

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.

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.

Left ear advantage in speech-related dichotic listening is not specific to auditory processing disorder in children: A machine-learning fMRI and DTI study.

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.