Postnatal Brain Trajectories and Maternal Intelligence Predict Childhood Outcomes in Complex CHD.

Objective: To determine whether early structural brain trajectories predict early childhood neurodevelopmental deficits in complex CHD patients and to assess relative cumulative risk profiles of clinical, genetic, and demographic risk factors across early development. Study Design: Term neonates with complex CHDs were recruited at Texas Children's Hospital from 2005-2011. Ninety-five participants underwent three structural MRI scans and three neurodevelopmental assessments. Brain region volumes and white matter tract fractional anisotropy and radial diffusivity were used to calculate trajectories: perioperative, postsurgical, and overall. Gross cognitive, language, and visuo-motor outcomes were assessed with the Bayley Scales of Infant and Toddler Development and with the Wechsler Preschool and Primary Scale of Intelligence and Beery-Buktenica Developmental Test of Visual-Motor Integration. Multi-variable models incorporated risk factors. Results: Reduced overall period volumetric trajectories predicted poor language outcomes: brainstem ((ß, 95% CI) 0.0977, 0.0382-0.1571; p = 0.0022) and white matter (0.0023, 0.0001-0.0046; p = 0.0397) at 5 years; brainstem (0.0711, 0.0157-0.1265; p = 0.0134) and deep grey matter (0.0085, 0.0011-0.0160; p = 0.0258) at 3 years. Maternal IQ was the strongest contributor to language variance, increasing from 37% at 1 year, 62% at 3 years, and 81% at 5 years. Genetic abnormality's contribution to variance decreased from 41% at 1 year to 25% at 3 years and was insignificant at 5 years. Conclusion: Reduced postnatal subcortical-cerebral white matter trajectories predicted poor early childhood neurodevelopmental outcomes, despite high contribution of maternal IQ. Maternal IQ was cumulative over time, exceeding the influence of known cardiac and genetic factors in complex CHD, underscoring the importance of heritable and parent-based environmental factors.

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.

Quantitative Magnetic Resonance Cerebral Spinal Fluid Flow Properties and Executive Function Cognitive Outcomes in Congenital Heart Disease.

Cerebrospinal fluid (CSF) circulation has recently been shown to be important in nutrient distribution, waste removal, and neurogenesis. Increased CSF volumes are frequently observed in congenital heart disease (CHD) and are associated with neurodevelopmental deficits. This suggests prolonged perturbation to the CSF system and possible interference to its homeostatic function, which may contribute to the neurodevelopmental deficits in CHD. CSF flow has yet to be studied in CHD patients, but the pulsatile flow of CSF throughout the brain is driven mainly by cardiopulmonary circulation. Given the underlying heart defects in CHD, the cardiopulmonary circulatory mechanisms in CHD might be impaired with resultant perturbation on the CSF circulation. In this study, we determine whether CSF flow, using MRI measurements of static and dynamic pulsatile flow, is abnormal in youths with CHD compared to healthy controls in relation to executive cognitive function. CSF flow measurements were obtained on a total of 58 child and young adult participants (CHD=20, healthy controls = 38). The CSF flow was measured across the lumen of the Aqueduct of Sylvius using cardiac-gated phase-contrast MRI at 3.0T. Static pulsatility was characterized as anterograde and retrograde peak velocities, mean velocity, velocity variance measurements, and dynamic pulsatility calculated as each participant's CSF flow deviation from the study cohort's consensus flow measured with root mean squared deviation (RMSD) were obtained. The participants had neurocognitive assessments for executive function with focus on inhibition, cognitive flexibility, and working memory domains. The CHD group demonstrated greater dynamic pulsatility (higher overall flow RMSD over the entire CSF flow cycle) compared to controls (p=0.0353), with no difference detected in static pulsatility measures. However, lower static CSF flow pulsatility (anterograde peak velocity: p=0.0323) and lower dynamic CSF flow pulsatility (RMSD: p=0.0181) predicted poor inhibitory executive function outcome. Taken together, while the whole CHD group exhibited higher dynamic CSF flow pulsatility compared to controls, the subset of CHD subjects with relatively reduced static and dynamic CSF flow pulsatility had the worst executive functioning, specifically the inhibition domain. These findings suggest that altered CSF flow pulsatility may be central to not only brain compensatory mechanisms but can also drive cognitive impairment in CHD. Further studies are needed to investigate possible mechanistic etiologies of aberrant CSF pulsatility (i.e. primary cardiac hemodynamic disturbances, intrinsic brain vascular stiffness, altered visco-elastic properties of tissue, or glial-lymphatic disturbances), which can result in acquired small vessel brain injury (including microbleeds and white matter hyperintensities).

Functional network organization is locally atypical in children and adolescents with congenital heart disease.

Children and adolescents with congenital heart disease (CHD) frequently experience neurodevelopmental impairments that can impact academic performance, memory, attention, and behavioral function, ultimately affecting overall quality of life. This study aims to investigate the impact of CHD on functional brain network connectivity and cognitive function. Using resting-state fMRI data, we examined several network metrics across various brain regions utilizing weighted networks and binarized networks with both absolute and proportional thresholds. Regression models were fitted to patient neurocognitive exam scores using various metrics obtained from all three methods. Our results unveil significant differences in network connectivity patterns, particularly in temporal, occipital, and subcortical regions, across both weighted and binarized networks. Furthermore, we identified distinct correlations between network metrics and cognitive performance, suggesting potential compensatory mechanisms within specific brain regions.

Early Infant Prefrontal Cortical Microstructure Predicts Present and Future Emotionality.

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

Mitotic Block and Epigenetic Repression Underlie Neurodevelopmental Defects and Neurobehavioral Deficits in Congenital Heart Disease.

Poor neurodevelopment is often observed with congenital heart disease (CHD), especially with mutations in chromatin modifiers. Here analysis of mice with hypoplastic left heart syndrome (HLHS) arising from mutations in Sin3A associated chromatin modifier Sap130 , and adhesion protein Pcdha9, revealed neurodevelopmental and neurobehavioral deficits reminiscent of those in HLHS patients. Microcephaly was associated with impaired cortical neurogenesis, mitotic block, and increased apoptosis. Transcriptional profiling indicated dysregulated neurogenesis by REST, altered CREB signaling regulating memory and synaptic plasticity, and impaired neurovascular coupling modulating cerebral blood flow. Many neurodevelopmental/neurobehavioral disease pathways were recovered, including autism and cognitive impairment. These same pathways emerged from genome-wide DNA methylation and Sap130 chromatin immunoprecipitation sequencing analyses, suggesting epigenetic perturbation. Mice with Pcdha9 mutation or forebrain-specific Sap130 deletion without CHD showed learning/memory deficits and autism-like behavior. These novel findings provide mechanistic insights indicating the adverse neurodevelopment in HLHS may involve cell autonomous/nonautonomous defects and epigenetic dysregulation and suggest new avenues for therapy.

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.

Multivariate and regional age-related change in basal ganglia iron in neonates.

In the perinatal period, reward and cognitive systems begin trajectories, influencing later psychiatric risk. The basal ganglia is important for reward and cognitive processing but early development has not been fully characterized. To assess age-related development, we used a measure of basal ganglia physiology, specifically brain tissue iron, obtained from nT2* signal in resting-state functional magnetic resonance imaging (rsfMRI), associated with dopaminergic processing. We used data from the Developing Human Connectome Project (n = 464) to assess how moving from the prenatal to the postnatal environment affects rsfMRI nT2*, modeling gestational and postnatal age separately for basal ganglia subregions in linear models. We did not find associations with tissue iron and gestational age [range: 24.29-42.29] but found positive associations with postnatal age [range:0-17.14] in the pallidum and putamen, but not the caudate. We tested if there was an interaction between preterm birth and postnatal age, finding early preterm infants (GA < 35 wk) had higher iron levels and changed less over time. To assess multivariate change, we used support vector regression to predict age from voxel-wise-nT2* maps. We could predict postnatal but not gestational age when maps were residualized for the other age term. This provides evidence subregions differentially change with postnatal experience and preterm birth may disrupt trajectories.

The use of sodium MRI in the diagnosis of an anaplastic astrocytoma during immunotherapy: a case report.

Gliomas in the pediatric population are targeted with immune-modulating therapies. The gold standard imaging modality for diagnosis and monitoring treatment response is magnetic resonance imaging (MRI); however, the complex post-therapy-induced changes can make treatment response assessment difficult. These include radiation necrosis, pseudoresponse, and pseudoprogression, as well as more complex responses in the setting of immunotherapy. We report a case of an 11-year-old male with a supratentorial astrocytoma (WHO grade 3) that underwent treatment with immunotherapy. There was a clinical concern for progression due to increased fluid-attenuated inversion recovery (FLAIR) hyperintensity at the site of the primary neoplasm during immunotherapy. However, the Sodium (23Na) MRI continued demonstrating decreased total sodium concentrations, supporting pseudoprogression over true progression, which was confirmed clinicaly. This case reports the capability of 23Na MRI to differentiate between progression, recurrence, and other posttreatment changes.

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.

Gestational and postnatal age associations for striatal tissue iron deposition in early infancy.

Striatal development is crucial for later motor, cognitive, and reward behavior, but age-related change in striatal physiology during the neonatal period remains understudied. An MRI-based measure of tissue iron deposition, T2*, is a non-invasive way to probe striatal physiology neonatally, linked to dopaminergic processing and cognition in children and adults. Striatal subregions have distinct functions that may come online at different time periods in early life. To identify if there are critical periods before or after birth, we measured if striatal iron accrued with gestational age at birth [range= 34.57-41.85 weeks] or postnatal age at scan [range= 5-64 days], using MRI to probe the T2* signal in N = 83 neonates in three striatal subregions. We found iron increased with postnatal age in the pallidum and putamen but not the caudate. No significant relationship between iron and gestational age was observed. Using a subset of infants scanned at preschool age (N = 26), we show distributions of iron shift between time points. In infants, the pallidum had the least iron of the three regions but had the most by preschool age. Together, this provides evidence of distinct change for striatal subregions, a possible differentiation between motor and cognitive systems, identifying a mechanism that may impact future trajectories.

Gestational and postnatal age associations for striatal tissue iron deposition in early infancy.

Striatal development is crucial for later motor, cognitive, and reward behavior, but age-related change in striatal physiology during the neonatal period remains understudied. An MRI-based measure of tissue iron deposition, T2*, is a non-invasive way to probe striatal physiology neonatally, linked to dopaminergic processing and cognition in children and adults. Striatal subregions have distinct functions that may come online at different time periods in early life. To identify if there are critical periods before or after birth, we measured if striatal iron accrued with gestational age at birth [range=34.57-41.85 weeks] or postnatal age at scan [range=5-64 days], using MRI to probe the T2* signal in N=83 neonates in three striatal subregions. We found iron increased with postnatal age in the pallidum and putamen but not the caudate. No significant relationship between iron and gestational age was observed. Using a subset of infants scanned at preschool age (N=26), we show distributions of iron shift between timepoints. In infants, the pallidum had the least iron of the three regions but had the most by preschool age. Together, this provides evidence of distinct change for striatal subregions, a possible differentiation between motor and cognitive systems, identifying a mechanism that may impact future trajectories. Highlights: Neonatal striatal tissue iron can be measured using the T2* signal from rsfMRInT2* changed with postnatal age in the pallidum and putamen but not in the caudatenT2* did not change with gestational age in any of the three regionsPatterns of iron deposition (nT2*) among regions shift from infancy to preschool.

Immuno-PET Imaging of CD69 Visualizes T-Cell Activation and Predicts Survival Following Immunotherapy in Murine Glioblastoma.

Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. Immunotherapy may be promising for the treatment of some patients with GBM; however, there is a need for noninvasive neuroimaging techniques to predict immunotherapeutic responses. The effectiveness of most immunotherapeutic strategies requires T-cell activation. Therefore, we aimed to evaluate an early marker of T-cell activation, CD69, for its use as an imaging biomarker of response to immunotherapy for GBM. Herein, we performed CD69 immunostaining on human and mouse T cells following in vitro activation and post immune checkpoint inhibitors (ICI) in an orthotopic syngeneic mouse glioma model. CD69 expression on tumor-infiltrating leukocytes was assessed using single-cell RNA sequencing (scRNA-seq) data from patients with recurrent GBM receiving ICI. Radiolabeled CD69 Ab PET/CT imaging (CD69 immuno-PET) was performed on GBM-bearing mice longitudinally to quantify CD69 and its association with survival following immunotherapy. We show CD69 expression is upregulated upon T-cell activation and on tumor-infiltrating lymphocytes (TIL) in response to immunotherapy. Similarly, scRNA-seq data demonstrated elevated CD69 on TILs from patients with ICI-treated recurrent GBM as compared with TILs from control cohorts. CD69 immuno-PET studies showed a significantly higher tracer uptake in the tumors of ICI-treated mice compared with controls. Importantly, we observed a positive correlation between survival and CD69 immuno-PET signals in immunotherapy-treated animals and established a trajectory of T-cell activation by virtue of CD69-immuno-PET measurements. Our study supports the potential use of CD69 immuno-PET as an immunotherapy response assessment imaging tool for patients with GBM. Significance: Immunotherapy may hold promise for the treatment of some patients with GBM. There is a need to assess therapy responsiveness to allow the continuation of effective treatment in responders and to avoid ineffective treatment with potential adverse effects in the nonresponders. We demonstrate that noninvasive PET/CT imaging of CD69 may allow early detection of immunotherapy responsiveness in patients with GBM.

Maternal perceived stress and infant behavior during the COVID-19 pandemic.

BACKGROUND: Maternal stress has negative consequences on infant behavioral development, and COVID-19 presented uniquely stressful situations to mothers of infants born during the pandemic. We hypothesized that mothers with higher levels of perceived stress during the pandemic would report higher levels of infant regulatory problems including crying and interrupted sleep patterns. METHODS: As part 6 sites of a longitudinal study, mothers of infants born during the pandemic completed the Perceived Stress Scale, the Brief Infant Sleep Questionnaire, and an Infant Crying survey at 6 (n = 433) and 12 (n = 344) months of infant age. RESULTS: Maternal perceived stress, which remained consistent at 6 and 12 months of infant age, was significantly positively correlated with time taken to settle infants. Although maternal perceived stress was not correlated with uninterrupted sleep length, time taken to put the infant to sleep was correlated. Perceived stress was also correlated with the amount of infant crying and fussiness reported at 6 months. CONCLUSIONS: Mothers who reported higher levels of perceived stress during the pandemic reported higher levels of regulatory problems, specifically at 6 months. Examining how varying levels of maternal stress and infant behaviors relate to overall infant developmental status over time is an important next step. IMPACT: Women giving birth during the COVID-19 pandemic who reported higher levels of stress on the Perceived Stress Scale also reported higher levels of infant fussiness and crying at 6 months old, and more disruptive sleep patterns in their infants at 6 months and 12 months old. Sleeping problems and excessive crying in infancy are two regulatory problems that are known risk factors for emotional and behavioral issues in later childhood. This paper is one of the first studies highlighting the associations between maternal stress and infant behaviors during the COVID-19 pandemic.

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.

Acquisition and Analysis of Excised Neocortex from Pediatric Patients with Focal Cortical Dysplasia Using Mesoscale Diffusion MRI.

Non-invasive classification of focal cortical dysplasia (FCD) subtypes remains challenging from a radiology perspective. Quantitative imaging biomarkers (QIBs) have the potential to distinguish subtypes that lack pathognomonic features and might help in defining the extent of abnormal connectivity associated with each FCD subtype. A key motivation of diagnostic imaging is to improve the localization of a "lesion" that can guide the surgical resection of affected tissue, which is thought to cause seizures. Conversely, surgical resections to eliminate or reduce seizures provided unique opportunities to develop magnetic resonance imaging (MRI)-based QIBs by affording long scan times to evaluate multiple contrast mechanisms at the mesoscale (0.5 mm isotropic voxel dimensions). Using ex vivo hybrid diffusion tensor imaging on a 9.4 T MRI scanner, the grey to white matter ratio of scalar indices was lower in the resected middle temporal gyrus (MTG) of two neuropathologically confirmed cases of FCD compared to non-diseased control postmortem fixed temporal lobes. In contrast, fractional anisotropy was increased within FCD and also adjacent white matter tracts. Connectivity (streamlines/mm3) in the MTG was higher in FCD, suggesting that an altered connectivity at the lesion locus can potentially provide a tangible QIB to distinguish and characterize FCD abnormalities. However, as illustrated here, a major challenge for a robust tractographical comparison lies in the considerable differences in the ex vivo processing of bioptic and postmortem samples. Mesoscale diffusion MRI has the potential to better define and characterize epileptic tissues obtained from surgical resection to advance our understanding of disease etiology and treatment.