A Mega-analytic Study of White Matter Microstructural Differences Across 5 Cohorts of Youths With Attention-Deficit/Hyperactivity Disorder.

BACKGROUND: While attention-deficit/hyperactivity disorder (ADHD) has been associated with differences in the structural connections formed by the brain's white matter tracts, studies of such differences have yielded inconsistent findings, likely reflecting small sample sizes. Thus, we conducted a mega-analysis on in vivo measures of white matter microstructure obtained through diffusion tensor imaging of more than 6000 participants from 5 cohorts. METHODS: In a mega-analysis, linear mixed models were used to test for associations between the fractional anisotropy of 42 white matter tracts and ADHD traits and diagnosis. Contrasts were made against measures of mood, anxiety, and other externalizing problems. RESULTS: Overall, 6993 participants (ages 6-18 years, mean age 10.62 years [SD 1.99]; 3368 girls, 3625 boys; 764 African American, 4146 non-Hispanic White, and 2083 other race/ethnicities) had measures of ADHD and other emotional/behavioral symptoms (N = 6933) and/or enough clinical data to allow a diagnosis of ADHD (n = 951) or its absence (n = 4884). Both the diagnosis and symptoms of ADHD were associated with lower fractional anisotropy of the inferior longitudinal and left uncinate fasciculi (at a false discovery rate-adjusted p < .05). Associated effect sizes were small (the strongest association with ADHD traits had an effect size of partial r = -0.14, while the largest case-control difference was associated with an effect size of d = -0.3). Similar microstructural anomalies were not present for anxiety, mood, or externalizing problems. Findings held when ADHD cases and control subjects were matched on in-scanner motion. CONCLUSIONS: While present across cohorts, ADHD-associated microstructural differences had small effects, underscoring the limited clinical utility of this imaging modality used in isolation.

An examination of the relationships between attention/deficit hyperactivity disorder symptoms and functional connectivity over time.

Previous cross-sectional work has demonstrated resting-state connectivity abnormalities in children and adolescents with attention/deficit hyperactivity disorder (ADHD) relative to typically developing controls. However, it is unclear to what extent these neural abnormalities confer risk for later symptoms of the disorder, or represent the downstream effects of symptoms on functional connectivity. Here, we studied 167 children and adolescents (mean age at baseline = 10.74 years (SD = 2.54); mean age at follow-up = 13.3 years (SD = 2.48); 56 females) with varying levels of ADHD symptoms, all of whom underwent resting-state functional magnetic resonance imaging and ADHD symptom assessments on two occasions during development. Resting-state functional connectivity was quantified using eigenvector centrality mapping. Using voxelwise cross-lag modeling, we found that less connectivity at baseline within right inferior frontal gyrus was associated with more follow-up symptoms of inattention (significant at an uncorrected cluster-forming threshold of p ≤ 0.001 and a cluster-level familywise error corrected threshold of p < 0.05). Findings suggest that previously reported cross-sectional abnormalities in functional connectivity within inferior frontal gyrus in patients with ADHD may represent a longitudinal risk factor for the disorder, in line with efforts to target this region with novel therapeutic methods.

A Longitudinal Study of Resting-State Connectivity and Response to Psychostimulant Treatment in ADHD.

OBJECTIVE: Psychostimulants are first-line pharmacological treatments for attention deficit hyperactivity disorder (ADHD), although symptom reduction varies widely between patients and these individual differences in treatment response are poorly understood. The authors sought to examine whether the resting-state functional connectivity within and between cingulo-opercular, striato-thalamic, and default mode networks was associated with treatment response to psychostimulant medication, and whether this relationship changed with development. METHODS: Patients with ADHD (N=110; 196 observations; mean age at first observation, 10.83 years, SD=2.2) and typically developing control subjects (N=142; 330 observations; mean age at first observation, 10.49 years, SD=2.81) underwent functional neuroimaging on up to five occasions during development (age range, 6-17 years). For patients, symptoms were assessed on and off psychostimulant medication (methylphenidate-based treatments: N=132 observations, 67%; amphetamine-based treatments: N=64 observations, 33%) using the Diagnostic Interview for Children and Adolescents for parents. Linear mixed-effects models examined whether resting-state connectivity was associated with treatment response and its interaction with age. Comparisons with typically developing control subjects were performed to contextualize any significant associations. RESULTS: Resting-state connectivity within the cingulo-opercular network was associated with a significant interaction between treatment response and age. Specifically, worse responses to treatment compared with better responses to treatment among patients and compared with typically developing control subjects were associated with an atypical increase in cingulo-opercular connectivity with increasing age from childhood to adolescence. CONCLUSIONS: This work delineates how resting-state connectivity may be associated over development with response to psychostimulants in ADHD. Functioning and development within the cingulo-opercular network may warrant further investigation as a contributor to differential response to psychostimulants.

Estimating the Heritability of Developmental Change in Neural Connectivity, and Its Association With Changing Symptoms of Attention-Deficit/Hyperactivity Disorder.

BACKGROUND: Twin studies show that age-related change in symptoms of attention-deficit/hyperactivity disorder (ADHD) is heritable. However, we do not know the heritability of the development of the neural substrates underlying the disorder. Here, we estimated the heritability of developmental change in white matter tracts and the brain's intrinsic functional connectivity using longitudinal data. We further determined associations with change in ADHD symptoms. METHODS: The study reports on 288 children, which included 127 siblings, 19 cousins, and 142 singletons; 150 (52%) had a diagnosis of ADHD (determined by clinician interview with parent); 188 were male. All had two clinical assessments (overall baseline mean age: 9.4 ± 2.4 years; follow-up: 12.5 ± 2.6 years). Diffusion tensor imaging estimated microstructural properties of white matter tracts on 252 participants. Resting-state functional magnetic resonance imaging estimated intrinsic connectivity within and between major brain networks on 226 participants. Total additive genetic heritability (h2) of the annual rate of change in these neural phenotypes was calculated using SOLAR (Sequential Oligogenic Linkage Analysis Routines). RESULTS: Significant heritability was found for the rates of change of 6 white matter tract microstructural properties and for change in the connectivity between the ventral attention network and both the cognitive control and dorsal attention networks. Change in hyperactivity-impulsivity was associated with heritable change in white matter tracts metrics and change in the connectivity between the ventral attention and cognitive networks. CONCLUSIONS: The relatively small number of heritable, ADHD-associated developmental neural phenotypes can serve as phenotypes for future gene discovery and understanding.

Predicting the course of ADHD symptoms through the integration of childhood genomic, neural, and cognitive features.

Childhood attention deficit hyperactivity disorder (ADHD) shows a highly variable course with age: some individuals show improving, others stable or worsening symptoms. The ability to predict symptom course could help individualize treatment and guide interventions. By studying a cohort of 362 youth, we ask if polygenic risk for ADHD, combined with baseline neural and cognitive features could aid in the prediction of the course of symptoms over an average period of 4.8 years. Compared to a never-affected comparison group, we find that participants with worsening symptoms carried the highest polygenic risk for ADHD, followed by those with stable symptoms, then those whose symptoms improved. Participants with worsening symptoms also showed atypical baseline cognition. Atypical microstructure of the cingulum bundle and anterior thalamic radiation was associated with improving symptoms while reduction of thalamic volume was found in those with stable symptoms. Machine-learning algorithms, trained and tested on independent groups, performed well in classifying those never affected against groups with worsening, stable, and improving symptoms (area under the curve >0.79). We conclude that some measures of polygenic risk, cognition, and neuroimaging show significant associations with the future course of ADHD symptoms and may have modest predictive power. These features warrant further exploration as prognostic tools.

Altered Functional Brain Network Integration, Segregation, and Modularity in Infants Born Very Preterm at Term-Equivalent Age.

OBJECTIVES: To determine the functional network organization of the brain in infants born very preterm at term-equivalent age and to relate network alterations to known clinical risk factors for poor neurologic outcomes in prematurity. STUDY DESIGN: Resting-state functional magnetic resonance imaging data from 66 infants born very preterm (gestational age <32 weeks and birth weight <1500 g) and 66 healthy neonates born at full term, acquired as part of a prospective, cross-sectional study, were compared at term age using graph theory. Features of resting-state networks, including integration, segregation, and modularity, were derived from correlated hemodynamic activity arising from 93 cortical and subcortical regions of interest and compared between groups. RESULTS: Despite preserved small-world topology and modular organization, resting-state networks of infants born very preterm at term-equivalent age were less segregated and less integrated than those of infants born full term. Chronic respiratory illness (ie, bronchopulmonary dysplasia and the length of oxygen support) was associated with decreased global efficiency and increased path lengths (P < .05). In both cohorts, 4 functional modules with similar composition were observed (parietal/temporal, frontal, subcortical/limbic, and occipital). The density of connections in 3 of the 4 modules was decreased in the very preterm network (P < .01); however, in the occipital/visual cortex module, connectivity was increased in infants born very preterm relative to control infants (P < .0001). CONCLUSIONS: Early exposure to the ex utero environment is associated with altered resting-state network functional organization in infants born very preterm at term-equivalent age, likely reflecting disrupted brain maturational processes.

Regional microstructural organization of the cerebral cortex is affected by preterm birth.

Objectives: To compare regional cerebral cortical microstructural organization between preterm infants at term-equivalent age (TEA) and healthy full-term newborns, and to examine the impact of clinical risk factors on cerebral cortical micro-organization in the preterm cohort. Study design: We prospectively enrolled very preterm infants (gestational age (GA) at birth<32 weeks; birthweight<1500 g) and healthy full-term controls. Using non-invasive 3T diffusion tensor imaging (DTI) metrics, we quantified regional micro-organization in ten cerebral cortical areas: medial/dorsolateral prefrontal cortex, anterior/posterior cingulate cortex, insula, posterior parietal cortex, motor/somatosensory/auditory/visual cortex. ANCOVA analyses were performed controlling for sex and postmenstrual age at MRI. Results: We studied 91 preterm infants at TEA and 69 full-term controls. Preterm infants demonstrated significantly higher diffusivity in the prefrontal, parietal, motor, somatosensory, and visual cortices suggesting delayed maturation of these cortical areas. Additionally, postnatal hydrocortisone treatment was related to accelerated microstructural organization in the prefrontal and somatosensory cortices. Conclusions: Preterm birth alters regional microstructural organization of the cerebral cortex in both neurocognitive brain regions and areas with primary sensory/motor functions. We also report for the first time a potential protective effect of postnatal hydrocortisone administration on cerebral cortical development in preterm infants.

Author Correction: Altered Cerebellar Biochemical Profiles in Infants Born Prematurely.

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Altered Cerebral Perfusion in Infants Born Preterm Compared with Infants Born Full Term.

OBJECTIVES: To compare regional cerebral cortical blood flow (CBF) in infants born very preterm at term-equivalent age (TEA) and healthy newborns born full term and to examine the impact of clinical risk factors on CBF in the cohort born preterm. STUDY DESIGN: This prospective, cross-sectional study included infants born very preterm (gestational age at birth <32 weeks; birth weight <1500 g) and healthy infants born full term. Using noninvasive 3T arterial spin labeling magnetic resonance imaging, we quantified regional CBF in the cerebral cortex: sensorimotor/auditory/visual cortex, superior medial/dorsolateral prefrontal cortex, anterior cingulate cortex (ACC)/posterior cingulate cortex, insula, and lateral posterior parietal cortex, as well as in the brainstem, and deep gray matter. Analyses were performed controlling for sex, gestational age, and age at magnetic resonance imaging. RESULTS: We studied 202 infants: 98 born preterm and 104 born full term at TEA. Infants born preterm demonstrated greater global CBF (ß = 9.03; P < .0001) and greater absolute regional CBF in all brain regions except the insula. Relative CBF in the insula, ACC and auditory cortex were decreased significantly in infants born preterm compared with their peers born at full term (P < .0001; P = .026; P = .036, respectively). In addition, the presence of parenchymal brain injury correlated with lower global and regional CBF (insula, ACC, sensorimotor, auditory, and visual cortices) whereas the need for cardiac vasopressor support correlated with lower regional CBF in the insula and visual cortex. CONCLUSIONS: Altered regional cortical CBF in infants born very preterm at TEA may reflect early brain dysmaturation despite the absence of cerebral cortical injury. Furthermore, specific cerebral cortical areas may be vulnerable to early hemodynamic instability and parenchymal brain injury.

Altered Cerebellar Biochemical Profiles in Infants Born Prematurely.

This study aims to compare the cerebellar biochemical profiles in preterm (PT) infants evaluated at term equivalent age (TEA) and healthy full-term newborns using proton magnetic resonance spectroscopy (1H-MRS). We explore the associations between altered cerebellar metabolite profiles and brain injury topography, severity of injury, and prematurity-related clinical complications. We prospectively collected high quality 1H-MRS in 59 premature infants born ≤32 weeks and 61 healthy full term controls. 1H-MRS data were processed using LCModel software to calculate absolute metabolite concentration for N-acetyl-aspartate (NAA), choline (Cho) and creatine (Cr). PT infants had significantly lower cerebellar NAA (p < 0.025) and higher Cho (p < 0.001) at TEA when compared to healthy controls. Creatine was not different between the two groups. The presence of cerebellar injury was consistently associated with reduced concentrations for NAA, Cho, and Cr. Postnatal infection was negatively associated with NAA and Cr (p < 005), while cerebral cortical brain injury severity was inversely associated with both Cho and Cr (p < 0.01). We report for the first time that premature birth is associated with altered cerebellar metabolite profiles when compared to term born controls. Infection, cerebellar injury and supratentorial injury are important risk factors for impaired preterm cerebellar biochemistry.

Cerebellar Microstructural Organization is Altered by Complications of Premature Birth: A Case-Control Study.

OBJECTIVES: To compare regional cerebellar microstructure, as measured by diffusion tensor imaging (DTI), between preterm infants at term-equivalent age and healthy term-born control neonates, and to explore associations between DTI findings and clinical risk factors. STUDY DESIGN: In this case-control study, DTI studies were performed in 73 premature infants born ≤32 weeks and ≤1500 g birth weight and 73 full-term-born controls from healthy pregnancies. Using a region of interest approach, fractional anisotropy (FA) and mean diffusivity (MD) were extracted in 7 cerebellar regions including the anterior vermis, the right/left superior cerebellar peduncles, the middle cerebellar peduncle, and the dentate nuclei. To validate further our DTI measurements, we measured FA and MD in the genu of the corpus callosum and splenium. FA and MD were compared between groups using analyses of multiple linear regression models. RESULTS: Preterm infants at term-equivalent age presented with higher FA in the dentate nuclei (<.001) and middle cerebellar peduncle (.028), and lower MD in the vermis (.023) compared with controls. Conversely, preterm infants showed reduced FA and increased MD in both the genu of the corpus callosum and splenium (P < .001). Independent risk factors associated with altered FA and MD in the cerebellum included low Apgar score, supratentorial injury, compromised cardiorespiratory function, and surgery for necrotizing enterocolitis and patent ductus arteriosus. CONCLUSIONS: This DTI study provides evidence that complications of premature birth are associated with altered cerebellar microstructural organization when compared with term-born control infants.

Third Trimester Brain Growth in Preterm Infants Compared With In Utero Healthy Fetuses.

BACKGROUND AND OBJECTIVES: Compared with term infants, preterm infants have impaired brain development at term-equivalent age, even in the absence of structural brain injury. However, details regarding the onset and progression of impaired preterm brain development over the third trimester are unknown. Our primary objective was to compare third-trimester brain volumes and brain growth trajectories in ex utero preterm infants without structural brain injury and in healthy in utero fetuses. As a secondary objective, we examined risk factors associated with brain volumes in preterm infants over the third-trimester postconception. METHODS: Preterm infants born before 32 weeks of gestational age (GA) and weighing <1500 g with no evidence of structural brain injury on conventional MRI and healthy pregnant women were prospectively recruited. Anatomic T2-weighted brain images of preterm infants and healthy fetuses were parcellated into the following regions: cerebrum, cerebellum, brainstem, and intracranial cavity. RESULTS: We studied 205 participants (75 preterm infants and 130 healthy control fetuses) between 27 and 39 weeks' GA. Third-trimester brain volumes were reduced and brain growth trajectories were slower in the ex utero preterm group compared with the in utero healthy fetuses in the cerebrum, cerebellum, brainstem, and intracranial cavity. Clinical risk factors associated with reduced brain volumes included dexamethasone treatment, the presence of extra-axial blood on brain MRI, confirmed sepsis, and duration of oxygen support. CONCLUSIONS: These preterm infants exhibited impaired third-trimester global and regional brain growth in the absence of cerebral/cerebellar parenchymal injury detected by using conventional MRI.

Functional properties of resting state networks in healthy full-term newborns.

Objective, early, and non-invasive assessment of brain function in high-risk newborns is critical to initiate timely interventions and to minimize long-term neurodevelopmental disabilities. A prerequisite to identifying deviations from normal, however, is the availability of baseline measures of brain function derived from healthy, full-term newborns. Recent advances in functional MRI combined with graph theoretic techniques may provide important, currently unavailable, quantitative markers of normal neurodevelopment. In the current study, we describe important properties of resting state networks in 60 healthy, full-term, unsedated newborns. The neonate brain exhibited an efficient and economical small world topology: densely connected nearby regions, sparse, but well integrated, distant connections, a small world index greater than 1, and global/local efficiency greater than network cost. These networks showed a heavy-tailed degree distribution, suggesting the presence of regions that are more richly connected to others ('hubs'). These hubs, identified using degree and betweenness centrality measures, show a more mature hub organization than previously reported. Targeted attacks on hubs show that neonate networks are more resilient than simulated scale-free networks. Networks fragmented faster and global efficiency decreased faster when betweenness, as opposed to degree, hubs were attacked suggesting a more influential role of betweenness hub in the neonate network.

Fetal magnetic resonance imaging: exposure times and functional outcomes at preschool age.

BACKGROUND: Fetal magnetic resonance imaging (MRI) has been routinely used as a noninvasive diagnostic tool for more than a decade; however, there is a paucity of follow-up studies examining the effects of prenatal exposure to 1.5-T MRI on developmental outcome. OBJECTIVE: The objective of this study was to assess the safety of 1.5-T fetal MRI by evaluating functional outcomes of preschool children who were exposed in utero. MATERIALS AND METHODS: In the context of a prospective observational study, healthy pregnant women underwent a 1.5-T MRI study using single-shot fast spin echo (SSFSE) sequences during the second or third trimester of pregnancy. The study was approved by the institutional review board at our institution, and written informed consent was obtained from all study participants. MRI scanning times were recorded, and prenatal/postnatal clinical data were collected prospectively. Functional outcomes were assessed using the Vineland Adaptive Behavior Scale (VABS), a widely used, norm-referenced and psychometrically sound functional assessment. RESULTS: We studied 72 healthy pregnant women, who underwent fetal MRI at a mean gestational age of 30.5 ± 3.1 weeks. The cohort of fetuses was composed of 43% females, and 18 fetuses were scanned during the second trimester. All fetuses were born at term with appropriate birth weights (3.54 ± 0.5 kg) for gestational age. Mean age at follow-up testing was 24.5 ± 6.7 months. All children had age-appropriate scores in the communication, daily living, socialization and motor skills subdomains of the VABS (z-scores, P > 0.05). Furthermore, all children passed their newborn otoacoustic emission test and had normal hearing at preschool age. MRI study duration and exposure time to radio frequency waves and SSFSE sequences were not associated with adverse functional outcomes or hearing impairment. CONCLUSION: Prenatal exposure to 1.5-T MRI during the second or third trimester of pregnancy in a cohort of healthy fetuses is not associated with disturbances in functional outcomes or hearing impairment at preschool age.

Brain volume and neurobehavior in newborns with complex congenital heart defects.

OBJECTIVE: To investigate the relationship between tissue-specific alterations in brain volume and neurobehavioral status in newborns with complex congenital heart defects preoperatively. STUDY DESIGN: Three-dimensional volumetric magnetic resonance imaging was used to calculate tissue-specific brain volumes and a standardized neurobehavioral assessment was performed to assess neurobehavioral status in 35 full-term newborns admitted to the hospital before cardiopulmonary bypass surgery. Multiple linear regression models were performed to evaluate relationships between neurobehavioral status and brain volumes. RESULTS: Reduced subcortical gray matter (SCGM) volume and increased cerebrospinal fluid (CSF) volume were associated with poor behavioral state regulation (SCGM, P = .04; CSF, P = .007) and poor visual orienting (CSF, P = .003). In cyanotic newborns, reduced SCGM was associated with higher overall abnormal scores on the assessment (P = .001) and poor behavioral state regulation (P = .04), and increased CSF volume was associated with poor behavioral state regulation (P = .02), and poor visual orienting (P = .02). Conversely, acyanotic newborns showed associations between reduced cerebellar volume and poor behavioral state regulation (P = .03). CONCLUSION: Abnormal neurobehavior is associated with impaired volumetric brain growth before open heart surgery in infants with complex congenital heart defects. This study highlights a need for routine preoperative screening and early intervention to improve neurodevelopmental outcomes.

Optimized methodology for neonatal diffusion tensor imaging processing and study-specific template construction.

Diffusion tensor imaging (DTI) has been widely used to study cerebral white matter microstructure in vivo. There is a plethora of open source tools available to perform pre-processing, analysis and template or atlas construction, however very few have been optimized for use with neonatal DTI data. Here we present a fully automated modular pipeline optimized for neonatal DTI data and the construction of study-specific tensor templates. We compare our methodology to an existing one. It is anticipated that the construction of population or study-specific templates will facilitate better group comparisons of neonatal populations both in health and disease.

Quantitative in vivo MRI measurement of cortical development in the fetus.

Normal brain development is associated with expansion and folding of the cerebral cortex following a highly orchestrated sequence of gyral-sulcal formation. Although several studies have described the evolution of cerebral cortical development ex vivo or ex utero, to date, very few studies have characterized and quantified the gyrification process for the in vivo fetal brain. Recent advances in fetal magnetic resonance imaging and post-processing computational methods are providing new insights into fetal brain maturation in vivo. In this study, we investigate the in vivo fetal cortical folding pattern in healthy fetuses between 25 and 35 weeks gestational age using 3-D reconstructed fetal cortical surfaces. We describe the in vivo fetal gyrification process using a robust feature extraction algorithm applied directly on the cortical surface, providing an explicit delineation of the sulcal pattern during fetal brain development. We also delineate cortical surface measures, including surface area and gyrification index. Our data support an exuberant third trimester gyrification process and suggest a non-linear evolution of sulcal development. The availability of normative indices of cerebral cortical developing in the living fetus may provide critical insights on the timing and progression of impaired cerebral development in the high-risk fetus.