Complex Regulation of Protocadherin Epigenetics on Aging-Related Brain Health.

Life expectancy continues to increase in the high-income world due to advances in medical care; however, quality of life declines with increasing age due to normal aging processes. Current research suggests that various aspects of aging are genetically modulated and thus may be slowed via genetic modification. Here, we show evidence for epigenetic modulation of the aging process in the brain from over 1800 individuals as part of the Framingham Heart Study. We investigated the methylation of genes in the protocadherin (PCDH) clusters, including the alpha (PCHDA), beta (PCDHB), and gamma (PCDHG) clusters. Reduced PCDHG, elevated PCDHA, and elevated PCDHB methylation levels were associated with substantial reductions in the rate of decline of regional white matter volume as well as certain cognitive skills, independent of overall accelerated or retarded aging as estimated by a DNA clock. These results are likely due to the different effects of the expression of genes in the alpha, beta, and gamma PCHD clusters and suggest that experience-based aging processes related to a decline in regional brain volume and select cognitive skills may be slowed via targeted epigenetic modifications.

Psychometric properties of the NIH Toolbox Cognition and Emotion Batteries among children and adolescents with congenital heart defects.

The NIH Toolbox offers brief, computerized measures of cognitive and psychosocial functioning. However, its psychometric properties were established among typically developing children and adolescents. The current study provides the first comprehensive assessment of its psychometric properties among young patients with congenital heart defects (CHD). We prospectively recruited 58 patients with CHD and 80 healthy controls between the ages of 6 and 17. Participants completed the NIH Toolbox Cognition and Emotion Batteries, a battery of clinician-administered neuropsychological tests, and ratings of their quality of life. Their parents also completed ratings of their functioning. On the Cognition Battery, we found expectable group differences and developmentally expected gains across ages. For the most part, composites and subtests were significantly correlated with neuropsychological measures of similar constructs. Higher scores were generally associated with ratings of better day-to-day functioning among children with CHD. On the Emotion Battery, we found no significant group differences, echoing prior research. For the most part, scales showed acceptable internal consistency among both groups. There was adequate construct coherence for most of questionnaires among healthy control but not participants with CHD. Correlations with a comparison tool were largely within expectable directions. The NIH Toolbox may provide a valid and useful assessment of cognitive functioning among youths with CHD. While it may offer reliable and valid scales of psychosocial functioning, further research is needed to understand the meaningfulness of the scales for participants with CHD.

Cerebral Spinal Fluid Volumetrics and Paralimbic Predictors of Executive Dysfunction in Congenital Heart Disease: A Machine Learning Approach Informing Mechanistic Insights.

The relationship between increased cerebral spinal fluid (CSF) ventricular compartments, structural and microstructural dysmaturation, and executive function in patients with congenital heart disease (CHD) is unknown. Here, we leverage a novel machine-learning data-driven technique to delineate interrelationships between CSF ventricular volume, structural and microstructural alterations, clinical risk factors, and sub-domains of executive dysfunction in adolescent CHD patients. We trained random forest regression models to predict measures of executive function (EF) from the NIH Toolbox, the Delis-Kaplan Executive Function System (D-KEFS), and the Behavior Rating Inventory of Executive Function (BRIEF) and across three subdomains of EF - mental flexibility, working memory, and inhibition. We estimated the best parameters for the random forest algorithm via a randomized grid search of parameters using 10-fold cross-validation on the training set only. The best parameters were then used to fit the model on the full training set and validated on the test set. Algorithm performance was measured using root-mean squared-error (RMSE). As predictors, we included patient clinical variables, perioperative clinical measures, microstructural white matter (diffusion tensor imaging- DTI), and structural volumes (volumetric magnetic resonance imaging- MRI). Structural white matter was measured using along-tract diffusivity measures of 13 inter-hemispheric and cortico-association fibers. Structural volumes were measured using FreeSurfer and manual segmentation of key structures. Variable importance was measured by the average Gini-impurity of each feature across all decision trees in which that feature is present in the model, and functional ontology mapping (FOM) was used to measure the degree of overlap in feature importance for each EF subdomain and across subdomains. We found that CSF structural properties (including increased lateral ventricular volume and reduced choroid plexus volumes) in conjunction with proximate cortical projection and paralimbic-related association white matter tracts that straddle the lateral ventricles and distal paralimbic-related subcortical structures (basal ganglia, hippocampus, cerebellum) are predictive of two-specific subdomains of executive dysfunction in CHD patients: cognitive flexibility and inhibition. These findings in conjunction with combined RF models that incorporated clinical risk factors, highlighted important clinical risk factors, including the presence of microbleeds, altered vessel volume, and delayed PDA closure, suggesting that CSF-interstitial fluid clearance, vascular pulsatility, and glymphatic microfluid dynamics may be pathways that are impaired in CHD, providing mechanistic information about the relationship between CSF and executive dysfunction.

Design and Harmonization Approach for the Multi-Institutional Neurocognitive Discovery Study (MINDS) of Adult Congenital Heart Disease (ACHD) Neuroimaging Ancillary Study: A Technical Note.

Dramatic advances in the management of congenital heart disease (CHD) have improved survival to adulthood from less than 10% in the 1960s to over 90% in the current era, such that adult CHD (ACHD) patients now outnumber their pediatric counterparts. ACHD patients demonstrate domain-specific neurocognitive deficits associated with reduced quality of life that include deficits in educational attainment and social interaction. Our hypothesis is that ACHD patients exhibit vascular brain injury and structural/physiological brain alterations that are predictive of specific neurocognitive deficits modified by behavioral and environmental enrichment proxies of cognitive reserve (e.g., level of education and lifestyle/social habits). This technical note describes an ancillary study to the National Heart, Lung, and Blood Institute (NHLBI)-funded Pediatric Heart Network (PHN) "Multi-Institutional Neurocognitive Discovery Study (MINDS) in Adult Congenital Heart Disease (ACHD)". Leveraging clinical, neuropsychological, and biospecimen data from the parent study, our study will provide structural-physiological correlates of neurocognitive outcomes, representing the first multi-center neuroimaging initiative to be performed in ACHD patients. Limitations of the study include recruitment challenges inherent to an ancillary study, implantable cardiac devices, and harmonization of neuroimaging biomarkers. Results from this research will help shape the care of ACHD patients and further our understanding of the interplay between brain injury and cognitive reserve.

Increased Cerebello-Prefrontal Connectivity Predicts Poor Executive Function in Congenital Heart Disease.

BACKGROUND: Children and adolescents with congenital heart disease (CHD) are at risk for cognitive impairments, such as executive function deficits and motor delays, which can impact their academic and adaptive functioning as well as their quality of life. We investigated whether alterations in connectivity between the prefrontal and cerebellar brain structures exist between CHD and control cohorts and if these alterations could predict cognitive or motor impairment among youths with CHD. METHODS: 53 participants with CHD and 73 healthy control participants completed multi-modal magnetic resonance imaging (MRI) of the brain, including high-resolution diffusion tensor imaging at 3T. We measured connectivity from masked regions of interest in the cerebellum to the frontal cortex using a probabilistic tractography method. Participants also completed neuropsychological tests of cognitive and motor skills using the NIH Toolbox. RESULTS: In the CHD group, fractional anisotropy (FA) was increased in the cognitive loop connectivity pathways, including from the right cerebellum to the left thalamus (p = 0.0002) and from the left thalamus to the left medial frontal gyrus (MFG) (p = 0.0048) compared with the healthy control group. In contrast, there were no differences between CHD and controls in motor loop connectivity pathways. An increase in FA from the right thalamus to the MFG tract in the cognitive loop (posterior subdivision) predicted (p = 0.03) lower scores on the NIHTB tests, including those of executive functioning. A transient increase in connectivity of the cognitive loop in the adolescent group was observed relative to the child and adult groups. CONCLUSIONS: Our results suggest that selective alteration of cerebellum-cerebral connectivity circuitry within the cognitive loops predicts cognitive dysfunction in CHD youth. Our study suggests a critical period of cerebellar circuitry plasticity in the adolescent period in CHD subjects that drives neurocognitive function. Further replication and validation in other pediatric CHD cohorts is warranted for future work.

Assessment of Brain Magnetic Resonance and Spectroscopy Imaging Findings and Outcomes After Pediatric Cardiac Arrest.

Importance: Morbidity and mortality after pediatric cardiac arrest are chiefly due to hypoxic-ischemic brain injury. Brain features seen on magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) after arrest may identify injury and aid in outcome assessments. Objective: To analyze the association of brain lesions seen on T2-weighted MRI and diffusion-weighted imaging and N-acetylaspartate (NAA) and lactate concentrations seen on MRS with 1-year outcomes after pediatric cardiac arrest. Design, Setting, and Participants: This multicenter cohort study took place in pediatric intensive care units at 14 US hospitals between May 16, 2017, and August 19, 2020. Children aged 48 hours to 17 years who were resuscitated from in-hospital or out-of-hospital cardiac arrest and who had a clinical brain MRI or MRS performed within 14 days postarrest were included in the study. Data were analyzed from January 2022 to February 2023. Exposure: Brain MRI or MRS. Main Outcomes and Measures: The primary outcome was an unfavorable outcome (either death or survival with a Vineland Adaptive Behavior Scales, Third Edition, score of <70) at 1 year after cardiac arrest. MRI brain lesions were scored according to region and severity (0 = none, 1 = mild, 2 = moderate, 3 = severe) by 2 blinded pediatric neuroradiologists. MRI Injury Score was a sum of T2-weighted and diffusion-weighted imaging lesions in gray and white matter (maximum score, 34). MRS lactate and NAA concentrations in the basal ganglia, thalamus, and occipital-parietal white and gray matter were quantified. Logistic regression was performed to determine the association of MRI and MRS features with patient outcomes. Results: A total of 98 children, including 66 children who underwent brain MRI (median [IQR] age, 1.0 [0.0-3.0] years; 28 girls [42.4%]; 46 White children [69.7%]) and 32 children who underwent brain MRS (median [IQR] age, 1.0 [0.0-9.5] years; 13 girls [40.6%]; 21 White children [65.6%]) were included in the study. In the MRI group, 23 children (34.8%) had an unfavorable outcome, and in the MRS group, 12 children (37.5%) had an unfavorable outcome. MRI Injury Scores were higher among children with an unfavorable outcome (median [IQR] score, 22 [7-32]) than children with a favorable outcome (median [IQR] score, 1 [0-8]). Increased lactate and decreased NAA in all 4 regions of interest were associated with an unfavorable outcome. In a multivariable logistic regression adjusted for clinical characteristics, increased MRI Injury Score (odds ratio, 1.12; 95% CI, 1.04-1.20) was associated with an unfavorable outcome. Conclusions and Relevance: In this cohort study of children with cardiac arrest, brain features seen on MRI and MRS performed within 2 weeks after arrest were associated with 1-year outcomes, suggesting the utility of these imaging modalities to identify injury and assess outcomes.

Single Ventricle Reconstruction III: Brain Connectome and Neurodevelopmental Outcomes: Design, Recruitment, and Technical Challenges of a Multicenter, Observational Neuroimaging Study.

Patients with hypoplastic left heart syndrome who have been palliated with the Fontan procedure are at risk for adverse neurodevelopmental outcomes, lower quality of life, and reduced employability. We describe the methods (including quality assurance and quality control protocols) and challenges of a multi-center observational ancillary study, SVRIII (Single Ventricle Reconstruction Trial) Brain Connectome. Our original goal was to obtain advanced neuroimaging (Diffusion Tensor Imaging and Resting-BOLD) in 140 SVR III participants and 100 healthy controls for brain connectome analyses. Linear regression and mediation statistical methods will be used to analyze associations of brain connectome measures with neurocognitive measures and clinical risk factors. Initial recruitment challenges occurred related to difficulties with: 1) coordinating brain MRI for participants already undergoing extensive testing in the parent study, and 2) recruiting healthy control subjects. The COVID-19 pandemic negatively affected enrollment late in the study. Enrollment challenges were addressed by 1) adding additional study sites, 2) increasing the frequency of meetings with site coordinators and 3) developing additional healthy control recruitment strategies, including using research registries and advertising the study to community-based groups. Technical challenges that emerged early in the study were related to the acquisition, harmonization, and transfer of neuroimages. These hurdles were successfully overcome with protocol modifications and frequent site visits that involved human and synthetic phantoms. Trial registration number: ClinicalTrials.gov Registration Number: NCT02692443.

Psychometric Properties of the NIH Toolbox Cognition and Emotion Batteries Among Children and Adolescents with Congenital Heart Defects.

Objective: The NIH Toolbox offers brief, computerized measures of cognitive and psychosocial functioning. However, its psychometric properties were established among typically developing children and adolescents. The current study provides the first comprehensive assessment of its psychometric properties among young patients with congenital heart defects (CHD). Study Design: We prospectively recruited 58 patients with CHD and 80 healthy controls between the ages of 6 and 17. Participants completed the NIH Toolbox Cognition and Emotion Batteries, a battery of clinician-administered neuropsychological tests, and ratings of their quality of life. Their parents also completed ratings of their functioning. Results: On the Cognition Battery, we found expectable group differences and developmentally expected gains across ages. For the most part, composites and subtests were significantly correlated with neuropsychological measures of similar constructs. Higher scores were generally associated with ratings of better day-to-day functioning among children with CHD. On the Emotion Battery, we found no significant group differences, echoing prior research. For the most part, scales showed acceptable internal consistency among both groups. There was adequate construct coherence for most of questionnaires among healthy control but not participants with CHD. Correlations with a comparison tool were largely within expectable directions. Conclusion: The NIH Toolbox may provide a valid and useful assessment of cognitive functioning among children and adolescents with CHD. While it may offer reliable and valid scales of psychosocial functioning, further research is needed to understand the meaningfulness of the scales for participants with CHD.

Limbic pathway vulnerability associates with neurologic outcome in children after cardiac arrest.

AIM: To analyze whether brain connectivity sequences including diffusion tensor imaging (DTI) and resting state functional magnetic resonance imaging (rsfMRI) identify vulnerable brain regions and networks associated with neurologic outcome after pediatric cardiac arrest. METHODS: Children aged 2 d-17 y with cardiac arrest were enrolled in one of 2 parent studies at a single center. Clinically indicated brain MRI with DTI and rsfMRI and performed within 2 weeks after arrest were analyzed. Tract-wise fractional anisotropy (FA) and axial, radial, and mean diffusivity assessed DTI, and functional connectivity strength (FCS) assessed rsfMRI between outcome groups. Unfavorable neurologic outcome was defined as Pediatric Cerebral Performance Category score 4-6 or change > 1 between 6 months after arrest vs baseline. RESULTS: Among children with DTI (n = 28), 57% had unfavorable outcome. Mean, radial, axial diffusivity and FA of varying direction of magnitude in the limbic tracts, including the right cingulum parolfactory, left cingulum parahippocampal, corpus callosum forceps major, and corpus callosum forceps minor tracts, were associated with unfavorable neurologic outcome (p < 0.05). Among children with rsfMRI (n = 12), 67% had unfavorable outcome. Decreased FCS in the ventromedial and dorsolateral prefrontal cortex, insula, precentral gyrus, anterior cingulate, and inferior parietal lobule were correlated regionally with unfavorable neurologic outcome (p < 0.05 Family-Wise Error corrected). CONCLUSION: Decreased multimodal connectivity measures of paralimbic tracts were associated with unfavorable neurologic outcome after pediatric cardiac arrest. Longitudinal analysis correlating brain connectivity sequences with long term neuropsychological outcomes to identify the impact of pediatric cardiac arrest in vulnerable brain networks over time appears warranted.

Clinical factors associated with microstructural connectome related brain dysmaturation in term neonates with congenital heart disease.

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

Pharmacodynamic and immunomodulatory effects of polymyxin B in combination with fosfomycin against KPC-2-producing klebsiella pneumoniae

Abstract Determining the role of the immune response in preventing antimicrobial resistance and optimizing antibiotic regimens against carbapenemase-producing Klebsiella pneumoniae (KPC) is a research gap that exists and needs to be further explored. The objective of this study was to determine the pharmacodynamics and immunomodulatory effects of fosfomycin alone and in combination with polymyxin B against KPC-2-producing K. pneumoniae clinical isolates. Six K. pneumoniae isolates were selected (polymyxin B_MIC: 0.5-64 mg/L; Fosfomycin MIC: 16-128 mg/L) to evaluate the pharmacodynamics of mono- and combination therapies in static time-kill studies. A mechanism based model was used to characterize the joint activity of polymyxin B and fosfomycin. A549 human airway epithelial cells were infected with four isolates to evaluate the immunomodulatory effects of treatment. Our mechanism-based model indicated greater bacterial killing efficacy of fosfomycin with polymyxin B compared to monotherapy. In combination, polymyxin B was assumed to exert an outer membrane effect which resulted in an increase in fosfomycin's ability to reach its target site. The mechanism based model described the data well across all six strains with R2 values ranging from 0.705 to 0.935. The combination reduced K. pneumoniae-induced IL-6 and IL-8 but not TNF-α expression. The reduction in cytokine expression was greater with polymyxin B than fosfomycin alone, and combinations showed significantly greater reductions compared to monotherapies. Our findings suggest that further research is needed to understand immune-mediated killing to identify a strategy which harnesses the power of the immune response against these hard to treat bacteria in an in vivo system.

Pharmacodynamic and immunomodulatory effects of polymyxin B in combination with fosfomycin against KPC-2-producing Klebsiella pneumoniae.

Determining the role of the immune response in preventing antimicrobial resistance and optimising antibiotic regimens against carbapenemase-producing Klebsiella pneumoniae is a research gap that exists and needs to be further explored. The objective of this study was to determine the pharmacodynamic and immunomodulatory effects of fosfomycin alone and in combination with polymyxin B against KPC-2-producing K. pneumoniae clinical isolates. Six K. pneumoniae isolates were selected (polymyxin B MIC, 0.5-64 mg/L; fosfomycin MIC, 16-128 mg/L) to evaluate the pharmacodynamics of monotherapy and combination therapies in static time-kill studies. A mechanism-based model was used to characterise the joint activity of polymyxin B and fosfomycin. A549 human airway epithelial cells were infected with four isolates to evaluate the immunomodulatory effects of treatment. Our mechanism-based model indicated greater bacterial killing efficacy of fosfomycin with polymyxin B compared with monotherapy. In combination, polymyxin B was assumed to exert an outer membrane effect that resulted in an increase in the ability of fosfomycin to reach its target site. The mechanism-based model described the data well across all six strains, with R2 values ranging from 0.705-0.935. Combination therapy reduced K. pneumoniae-induced IL-6 and IL-8 but not TNFα expression. The reduction in cytokine expression was greater with polymyxin B than fosfomycin alone; combination therapy showed significantly greater reduction compared to either monotherapy. Our findings suggest that further research is needed to better understand immune-mediated killing in order to identify a strategy which harnesses the power of the immune response against these hard-to-treat bacteria.

Feasibility and Safety of Contrast-Enhanced Ultrasound of the Neonatal Brain: A Prospective Study Using MRI as the Reference Standard.

BACKGROUND. MRI is the reference standard for neonatal brain imaging, but it is expensive, time-consuming, potentially limited by availability and accessibility, and contraindicated in some patients. Transfontanelle neonatal head ultrasound is an excellent alternative but may be less sensitive and specific than MRI. Contrast-enhanced ultrasound (CEUS) has the potential to improve the capabilities of ultrasound. OBJECTIVE. The purpose of this study is to prospectively evaluate the feasibility, safety, and diagnostic performance of transfontanelle neonatal brain CEUS, with MRI used as the reference standard. METHODS. Neonates in the institutional neonatal ICU who were undergoing MRI as part of their clinical care were prospectively recruited to undergo portable brain ultrasound and CEUS for research purposes. Brain ultrasound and CEUS were performed portably without moving the patient from the isolette or crib in the neonatal ICU. Adverse events were recorded. Two radiologists independently evaluated ultrasound and CEUS images for abnormalities and then reached consensus regarding discrepancies. A separate radiologist reviewed MRI examinations. Sensitivity, specificity, and interreader agreement were evaluated, with MRI used as the reference. Qualitative post hoc image review was performed. RESULTS. Twenty-six neonates (nine boys and 17 girls; mean [± SD] age, 15.2 ± 14.0 days) were included. No significant alteration in patient vital signs or adverse reaction to the ultrasound contrast agent (UCA) occurred. The mean duration of the examination was significantly shorter for combined ultrasound and CEUS than for MRI (21.1 ± 4.7 vs 74.2 ± 34.8 minutes; p < .001). Interrater agreement for any abnormality was almost perfect for both ultrasound and CEUS (κ = 0.92 and 0.85, respectively). Sensitivity for any abnormality was 86.7% for ultrasound and 93.3% for CEUS; specificity was 100.0% for both. CEUS had sensitivity of 87.5% for acute or subacute ischemia and 100.0% for chronic ischemia; its specificity was 100.0% for acute or subacute ischemia and chronic ischemia. For both ultrasound and CEUS, sensitivity for subdural and intraparenchymal hemorrhage was poor (22.2-50.0%). On CEUS but not on MRI, post hoc review showed a case of postischemic hyperperfusion, which was confirmed by subsequently performed contrast-enhanced CT. CONCLUSION. The use of portable brain CEUS in neonates is feasible, safe, and more rapid than MRI. CLINICAL IMPACT. The potential diagnostic utility of brain neonatal CEUS relative to conventional ultrasound, particularly for ischemia, warrants further investigation.

A Series Registration Framework to Recover Resting-State Functional Magnetic Resonance Data Degraded By Motion.

Data retention is a significant problem in the medical imaging domain. For example, resting-state functional magnetic resonance images (rs-fMRIs) are invaluable for studying neurodevelopment but are highly susceptible to corruption due to patient motion. The effects of patient motion can be reduced through post-acquisition techniques such as volume registration. Traditional volume registration minimizes the global differences between all volumes in the rs-fMRI sequence and a designated reference volume. We suggest using the spatiotemporal relationships between subsequent image volumes to inform the registration: they are used initialize each volume registration to reduce local differences between volumes while minimizing global differences. We apply both the traditional and novel registration methods to a set of healthy human neonatal rs-fMRIs with significant motion artifacts (N=17). Both methods impacted the mean and standard deviation of the image sequences' correlation ratio matrices similarly; however, the novel framework was more effective in meeting gold standard motion thresholds.

Association between Subcortical Morphology and Cerebral White Matter Energy Metabolism in Neonates with Congenital Heart Disease.

Complex congenital heart disease (CHD) is associated with neurodevelopmental impairment, the mechanism of which is unknown. Cerebral cortical dysmaturation in CHD is linked to white matter abnormalities, including developmental vulnerability of the subplate, in relation to oxygen delivery and metabolism deficits. In this study, we report associations between subcortical morphology and white matter metabolism in neonates with CHD using quantitative magnetic resonance imaging (MRI) and spectroscopy (MRS). Multi-modal brain imaging was performed in three groups of neonates close to term-equivalent age: (1) term CHD (n = 56); (2) preterm CHD (n = 37) and (3) preterm control group (n = 22). Thalamic volume and cerebellar transverse diameter were obtained in relation to cerebral metrics and white matter metabolism. Short echo single-voxel MRS of parietal and frontal white matter was used to quantitate metabolites related to brain maturation (n-acetyl aspartate [NAA], choline, myo-inositol), neurotransmitter (glutamate), and energy metabolism (glutamine, citrate, creatine and lactate). Multi-variate regression was performed to delineate associations between subcortical morphological measurements and white matter metabolism controlling for age and white matter injury. Reduced thalamic volume, most pronounced in the preterm control group, was associated with increased citrate levels in all three group in the parietal white matter. In contrast, reduced cerebellar volume, most pronounced in the preterm CHD group, was associated with reduced glutamine in parietal grey matter in both CHD groups. Single ventricle anatomy, aortic arch obstruction, and cyanotic lesion were predictive of the relationship between reduced subcortical morphometry and reduced GLX (particularly glutamine) in both CHD cohorts (frontal white matter and parietal grey matter). Subcortical morphological associations with brain metabolism were also distinct within each of the three groups, suggesting these relationships in the CHD groups were not directly related to prematurity or white matter injury alone. Taken together, these findings suggest that subplate vulnerability in CHD is likely relevant to understanding the mechanism of both cortical and subcortical dysmaturation in CHD infants. Future work is needed to link this potential pattern of encephalopathy of CHD (including the constellation of grey matter, white matter and brain metabolism deficits) to not only abnormal fetal substrate delivery and oxygen conformance, but also regional deficits in cerebral energy metabolism.

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.

Clinical Factors Associated with Cerebral Metabolism in Term Neonates with Congenital Heart Disease.

OBJECTIVE: To determine associations between patient and clinical factors with postnatal brain metabolism in term neonates with congenital heart disease (CHD) via the use of quantitative magnetic resonance spectroscopy. STUDY DESIGN: Neonates with CHD were enrolled prospectively to undergo pre- and postoperative 3T brain magnetic resonance imaging. Short-echo single-voxel magnetic resonance spectroscopy of parietal white matter was used to quantify metabolites related to brain maturation (n-acetyl aspartate, choline, myo- inositol), neurotransmitters (glutamate and gamma-aminobutyric acid), energy metabolism (glutamine, citrate, glucose, and phosphocreatine), and injury/apoptosis (lactate and lipids). Multivariable regression was performed to search for associations between (1) patient-specific/prenatal/preoperative factors with concurrent brain metabolism and (2) intraoperative and postoperative factors with postoperative brain metabolism. RESULTS: A total of 83 magnetic resonance images were obtained on 55 subjects. No patient-specific, prenatal, or preoperative factors associated with concurrent metabolic brain dysmaturation or elevated lactate could be identified. Chromosome 22q11 microdeletion and age at surgery were predictive of altered concurrent white matter phosphocreatine (P < .0055). The only significant intraoperative association found was increased deep hypothermic circulatory arrest time with reduced postoperative white matter glutamate and gamma-aminobutyric acid (P < .0072). Multiple postoperative factors, including increased number of extracorporeal membrane oxygenation days (P < .0067), intensive care unit, length of stay (P < .0047), seizures in the intensive care unit (P < .0009), and home antiepileptic use (P < .0002), were associated with reduced postoperative white matter n-acetyl aspartate. CONCLUSION: Multiple postoperative factors were found to be associated with altered brain metabolism in term infants with CHD, but not patient-specific, preoperative, or intraoperative factors.

The Correlation Between a Short-term Conventional Electroencephalography in the First Day of Life and Brain Magnetic Resonance Imaging in Newborns Undergoing Hypothermia for Hypoxic-Ischemic Encephalopathy.

OBJECTIVE: Electroencephalograph recorded in the first day of life in newborns treated with hypothermia for hypoxic-ischemic encephalopathy could be utilized as a predictive tool for the severity of brain injury on magnetic resonance imaging and mortality. STUDY DESIGN: We analyzed newborns who were admitted for therapeutic hypothermia due to hypoxic-ischemic encephalopathy. All enrolled infants underwent encephalography within the first 24 hours of life and underwent brain magnetic resonance imaging after rewarming. All encephalographs were independently reviewed for background amplitude, continuity, and variability. Brain injury determined by magnetic resonance imaging was scored using methods described by Bonifacio et al. RESULTS: Forty-one newborns were included in the study. Each encephalograph variable correlated significantly with the severity of injury on brain magnetic resonance imaging (P < 0.001 for each). The overall encephalograph severity estimated as mild, moderate, and severe also correlated with injury (P < 0.001). Each encephalograph variable correlated with mortality (P < 0.001 for each) and also the overall encephalograph severity (P < 0.001). CONCLUSION: Severity of electrographic findings on encephalograph in the first day of life during therapeutic hypothermia for hypoxic-ischemic encephalopathy correlated with the extent of injury on brain magnetic resonance imaging. This information may be useful for families and aid guide clinical decision making.

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.

Global and Regional Derangements of Cerebral Blood Flow and Diffusion Magnetic Resonance Imaging after Pediatric Cardiac Arrest.

OBJECTIVE: To quantify and examine the relationship between global and regional cerebral blood flow (CBF) and water diffusion on brain magnetic resonance imaging (MRI) in children after cardiac arrest. STUDY DESIGN: Children admitted to a tertiary care children's hospital from July 2011 to April 2013 who received a brain MRI within 2 weeks after cardiac arrest that included arterial spin labeling and apparent diffusion coefficient (ADC) sequences were studied. CBF and ADC values were calculated globally and in 19 regions of interest. Outcome variables included survival and favorable neurologic outcome, which was defined as Pediatric Cerebral Performance Category ≤3 at 6 months. We examined global and regional relationships between CBF and ADC and their association with outcome. RESULTS: This sample included 14 pediatric patients (mean time to MRI 6 ± 4 days), 9 of whom survived and 6 who survived with favorable outcome. Global ADC was significantly decreased in patients with unfavorable outcome (P = .02). Increased CBF and decreased ADC often were colocalized in the same region, especially in children who had unfavorable outcomes. CONCLUSIONS: In this exploratory study, global restricted water diffusion on ADC after pediatric cardiac arrest was associated with unfavorable outcome. MRI assessments of perfusion and diffusion may have prognostic value after pediatric cardiac arrest.