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Use of magnetic resonance imaging (MRI) as a tool to aid in neuroprognostication after cardiac arrest (CA) has been described, yet details of specific indications, timing, and sequences are unknown. We aim to define the current practices in use of brain MRI in prognostication after pediatric CA.A survey was distributed to pediatric institutions participating in three international studies. Survey questions related to center demographics, clinical practice patterns of MRI after CA, neuroimaging resources, and details regarding MRI decision support.Response rate was 31% (44 of 143). Thirty-four percent (15 of 44) of centers have a clinical pathway informing the use of MRI after CA. Fifty percent (22 of 44) of respondents reported that an MRI is obtained in nearly all patients with CA, and 32% (14 of 44) obtain an MRI in those who do not return to baseline neurological status. Poor neurological examination was reported as the most common factor (91% [40 of 44]) determining the timing of the MRI. Conventional sequences (T1, T2, fluid-attenuated inversion recovery, and diffusion-weighted imaging/apparent diffusion coefficient) are routinely used at greater than 97% of centers. Use of advanced imaging techniques (magnetic resonance spectroscopy, diffusion tensor imaging, and functional MRI) were reported by less than half of centers.Conventional brain MRI is a common practice for prognostication after CA. Advanced imaging techniques are used infrequently. The lack of standardized clinical pathways and variability in reported practices support a need for higher-quality evidence regarding the indications, timing, and acquisition protocols of clinical MRI studies.

Background In newborns with hypoxic-ischemic encephalopathy (HIE), the correlation between neonatal neuroimaging and the degree of neurodevelopmental impairment (NDI) is unclear. Methods Infants with HIE enrolled in a randomized controlled trial underwent neonatal MRI/MR spectroscopy (MRS) using a harmonized protocol at 4–6 days of age. The severity of brain injury was measured with a validated scoring system. Using proportional odds regression, we calculated adjusted odds ratios (aOR) for the associations between MRI/MRS measures of injury and primary ordinal outcome (i.e., normal, mild NDI, moderate NDI, severe NDI, or death) at age 2 years. Results Of 451 infants with MRI/MRS at a median age of 5 days (IQR 4.5–5.8), outcomes were normal (51%); mild (12%), moderate (14%), severe NDI (13%); or death (9%). MRI injury score (aOR 1.06, 95% CI 1.05, 1.07), severe brain injury (aOR 39.6, 95% CI 16.4, 95.6), and MRS lactate/n-acetylaspartate (NAA) ratio (aOR 1.6, 95% CI 1.4,1.8) were associated with worse primary outcomes. Infants with mild/moderate MRI brain injury had similar BSID-III cognitive, language, and motor scores as infants with no injury. Conclusion In the absence of severe injury, brain MRI/MRS does not accurately discriminate the degree of NDI. Given diagnostic uncertainty, families need to be counseled regarding a range of possible neurodevelopmental outcomes. Impact Half of all infants with hypoxic-ischemic encephalopathy (HIE) enrolled in a large clinical trial either died or had neurodevelopmental impairment at age 2 years despite receiving therapeutic hypothermia. Severe brain injury and a global pattern of brain injury on MRI were both strongly associated with death or neurodevelopmental impairment. Infants with mild or moderate brain injury had similar mean BSID-III cognitive, language, and motor scores as infants with no brain injury on MRI. Given the prognostic uncertainty of brain MRI among infants with less severe degrees of brain injury, families should be counseled regarding a range of possible neurodevelopmental outcomes.

Magnetic resonance spectroscopy (MRS) is a valuable adjunct to structural brain imaging. State-of-the-art MRS has benefited greatly from recent technical advancements. Neurometabolic alterations in pediatric brain diseases have implications for diagnosis, prognosis, and therapy. Herein, the authors discuss MRS technical considerations and applications in the setting of various pediatric disease processes including tumors, metabolic diseases, hypoxic/ischemic encephalopathy/stroke, epilepsy, demyelinating disease, and infection.

Many patients with dementia may have comorbid or misdiagnosed normal pressure hydrocephalus, a treatable neurologic disorder. The callosal angle is a validated biomarker for normal pressure hydrocephalus with 93% diagnostic accuracy. Our purpose was to develop and evaluate an algorithm for automatically computing callosal angles from MR images of the brain.This article reports the results of analyzing callosal angles from 1856 subjects with 5264 MR images from the Open Access Series of Imaging Studies and the Alzheimer's Disease Neuroimaging Initiative databases. Measurement variability was examined between 2 neuroradiologists (The algorithm identified that 12.4% of subjects from these carefully screened cohorts had callosal angles of90°, a published threshold for possible normal pressure hydrocephalus. The intraclass correlation coefficient was 0.97 for agreement between neuroradiologists and 0.90 for agreement between manual and automatic measurement. The method was robust to different head orientations. The median coefficient of variation for repeat examinations was 4.2% (Q1 = 3.1%, Q3 = 5.8%). The simulated classification of normal pressure hydrocephalus versus Alzheimer using the automatic callosal angle had an accuracy, sensitivity, and specificity of 0.87 each.In even the most pristine research databases, analyses of the callosal angle indicate that some patients may have normal pressure hydrocephalus. The automatic callosal angle measurement can rapidly and objectively screen for normal pressure hydrocephalus in patients who would otherwise be misdiagnosed.

Neonatal hypoxic-ischemic encephalopathy is an important cause of death as well as long-term disability in survivors. Erythropoietin has been hypothesized to have neuroprotective effects in infants with hypoxic-ischemic encephalopathy, but its effects on neurodevelopmental outcomes when given in conjunction with therapeutic hypothermia are unknown.In a multicenter, double-blind, randomized, placebo-controlled trial, we assigned 501 infants born at 36 weeks or more of gestation with moderate or severe hypoxic-ischemic encephalopathy to receive erythropoietin or placebo, in conjunction with standard therapeutic hypothermia. Erythropoietin (1000 U per kilogram of body weight) or saline placebo was administered intravenously within 26 hours after birth, as well as at 2, 3, 4, and 7 days of age. The primary outcome was death or neurodevelopmental impairment at 22 to 36 months of age. Neurodevelopmental impairment was defined as cerebral palsy, a Gross Motor Function Classification System level of at least 1 (on a scale of 0 [normal] to 5 [most impaired]), or a cognitive score of less than 90 (which corresponds to 0.67 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition.Of 500 infants in the modified intention-to-treat analysis, 257 received erythropoietin and 243 received placebo. The incidence of death or neurodevelopmental impairment was 52.5% in the erythropoietin group and 49.5% in the placebo group (relative risk, 1.03; 95% confidence interval [CI], 0.86 to 1.24; P = 0.74). The mean number of serious adverse events per child was higher in the erythropoietin group than in the placebo group (0.86 vs. 0.67; relative risk, 1.26; 95% CI, 1.01 to 1.57).The administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy did not result in a lower risk of death or neurodevelopmental impairment than placebo and was associated with a higher rate of serious adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT02811263.).

Background and Purpose: Ketogenic diet (KD) improves seizure control in patients with drug-resistant forms of epilepsy; however, the mechanism of action remains poorly understood. Increased mitochondrial levels of glutathione (GSH) might contribute to a change in seizure susceptibility suggestive of possible anticonvulsant role for GSH. Our goals were to quantify changes of absolute GSH levels in the brain by in vivo MR spectroscopy and correlate that with degree of seizure control in patients on KD. Methods: Five cognitively normal adult patients with drug-resistant epilepsy were initially included and 2 completed the study. Each patient was evaluated by a neurologist and registered dietitian at baseline, 1, 3, and 6 months for seizure status and diet adherence. Each patient received a baseline short TE single-voxel water-suppressed point-resolved spectroscopy (PRESS) 1 H MRS in parieto/occipital grey matter and parietal white matter on a 3 Tesla General Electric magnet prior to starting the ketogenic diet and a follow-up stury at 6 months. Multiple metabolites, including GSH, were quantified using LCModel.Results: After being on ketogenic diet for 6 months, both patients (42-years-old male and 35-years-old female) demonstrated marked increases in absolute GSH level in both gray matter (0.1 to 1.4 and 0.1 to 0.7 IU) and white matter (0.65 to 1.5 and 0.8 to 2 IU), as well as 50% improvements in seizure duration and frequency. Other metabolites including ketone bodies, Acetone (Acn), Beta hydroxybutyrate (βHB), and acetoacetate (AcAC), did not demonstrate consistent changes. Conclusion: Markedly increased levels of GSH (7-fold and 14-fold) were observed in longitudinal prospective study of two adult patients with intractable epilepsy with 50% seizure improvement after initiation of ketogenic diets. This pilot study supports the possible anticonvulsant role of GSH in the brain.

Purpose: Diffuse intrinsic pontine gliomas (DIPG) are highly aggressive tumors with no currently available curative therapy. This study evaluated whether measurements of in vivo cell metabolites using magnetic resonance spectroscopy (MRS) may serve as biomarkers of response to therapy, including progression. Methods: Single-voxel MR spectra were serially acquired in two cohorts of patients with DIPG treated with radiation therapy (RT) with or without concurrent chemotherapy and prior to progression: 14 participants were enrolled in a clinical trial of adjuvant glioma-associated antigen peptide vaccines and 32 patients were enrolled who did not receive adjuvant vaccine therapy. Spearman correlations measured overall survival associations with absolute metabolite concentrations of myo-inositol (mI), creatine (Cr), and n-acetyl-aspartate (NAA) and their ratios relative to choline (Cho) during three specified time periods following completion of RT. Linear mixed-effects regression models evaluated the longitudinal associations between metabolite ratios and time from death (terminal decline). Results: Overall survival was not associated with metabolite ratios obtained shortly after RT (1.9–3.8 months post-diagnosis) in either cohort. In the vaccine cohort, an elevated mI/Cho ratio after 2–3 doses (3.9–5.2 months post-diagnosis) was associated with longer survival (rho = 0.92, 95% CI 0.67–0.98). Scans performed up to 6 months before death showed a terminal decline in the mI/Cho ratio, with an average of 0.37 ratio/month in vaccine patients (95% CI 0.11–0.63) and 0.26 (0.04–0.48) in the non-vaccine cohort. Conclusion: Higher mI/Cho ratios following RT, consistent with less proliferate tumors and decreased cell turnover, were associated with longer survival, suggesting that this ratio can serve as a biomarker of prognosis following RT. This finding was seen in both cohorts, although the association with OS was detected earlier in the vaccine cohort. Increased mI/Cho (possibly reflecting immune-effector cell influx into the tumor as a mechanism of tumor response) requires further study.

Childhood posterior fossa group A ependymomas (PFAs) have limited treatment options and bear dismal prognoses compared to group B ependymomas (PFBs). PFAs overexpress the oncohistone-like protein EZHIP (enhancer of Zeste homologs inhibitory protein), causing global reduction of repressive histone H3 lysine 27 trimethylation (H3K27me3), similar to the oncohistone H3K27M. Integrated metabolic analyses in patient-derived cells and tumors, single-cell RNA sequencing of tumors, and noninvasive metabolic imaging in patients demonstrated enhanced glycolysis and tricarboxylic acid (TCA) cycle metabolism in PFAs. Furthermore, high glycolytic gene expression in PFAs was associated with a poor outcome. PFAs demonstrated high EZHIP expression associated with poor prognosis and elevated activating mark histone H3 lysine 27 acetylation (H3K27ac). Genomic H3K27ac was enriched in PFAs at key glycolytic and TCA cycle–related genes including hexokinase-2 and pyruvate dehydrogenase. Similarly, mouse neuronal stem cells (NSCs) expressing wild-type EZHIP (EZHIP-WT) versus catalytically attenuated EZHIP-M406K demonstrated H3K27ac enrichment at hexokinase-2 and pyruvate dehydrogenase, accompanied by enhanced glycolysis and TCA cycle metabolism. AMPKα-2, a key component of the metabolic regulator AMP-activated protein kinase (AMPK), also showed H3K27ac enrichment in PFAs and EZHIP-WT NSCs. The AMPK activator metformin lowered EZHIP protein concentrations, increased H3K27me3, suppressed TCA cycle metabolism, and showed therapeutic efficacy in vitro and in vivo in patient-derived PFA xenografts in mice. Our data indicate that PFAs and EZHIP-WT–expressing NSCs are characterized by enhanced glycolysis and TCA cycle metabolism. Repurposing the antidiabetic drug metformin lowered pathogenic EZHIP, increased H3K27me3, and suppressed tumor growth, suggesting that targeting integrated metabolic/epigenetic pathways is a potential therapeutic strategy for treating childhood ependymomas.

International audience; With contributions from the global natural product (NP) research community, and continuing the Raw Data Initiative, this review collects a comprehensive demonstration of the immense scientific value of disseminating raw nuclear magnetic resonance (NMR) data, independently of, and in parallel with, classical publishing outlets. A comprehensive compilation of historic to present-day cases as well as contemporary and future applications show that addressing the urgent need for a repository of publicly accessible raw NMR data has the potential to transform natural products (NPs) and associated fields of chemical and biomedical research. The call for advancing open sharing mechanisms for raw data is intended to enhance the transparency of experimental protocols, augment the reproducibility of reported outcomes, including biological studies, become a regular component of responsible research, and thereby enrich the integrity of NP research and related fields.

Purpose: To evaluate six cerebral arterial segmentation algorithms in a set of patients with a wide range of hemodynamic characteristics to determine real-world performance. Approach: Time-of-flight magnetic resonance angiograms were acquired from 33 subjects: normal controls ([Formula: see text]), sickle cell disease ([Formula: see text]), and non-sickle anemia ([Formula: see text]) using a 3 Tesla Philips Achieva scanner. Six segmentation algorithms were tested: (1) Otsu’s method, (2) K-means, (3) region growing, (4) active contours, (5) minimum cost path, and (6) U-net machine learning. Segmentation algorithms were tested with two region-selection methods: global, which selects the entire volume; and local, which iteratively tracks the arteries. Five slices were manually segmented from each patient by two readers. Agreement between manual and automatic segmentation was measured using Matthew’s correlation coefficient (MCC). Results: Median algorithm segmentation times ranged from 0.1 to 172.9 s for a single angiogram versus 10 h for manual segmentation. Algorithms had inferior performance to inter-observer vessel-based ([Formula: see text] , [Formula: see text]) and voxel-based ([Formula: see text] , [Formula: see text]) measurements. There were significant differences between algorithms ([Formula: see text]) and between patients ([Formula: see text]). Post-hoc analyses indicated (1) local minimum cost path performed best with vessel-based ([Formula: see text] , [Formula: see text]) and voxel-based ([Formula: see text] , [Formula: see text]) analyses; and (2) higher vessel-based performance in non-sickle anemia ([Formula: see text]) and lower voxel-based performance in sickle cell ([Formula: see text]) compared with normal controls. All reported MCCs are medians. Conclusions: The best-performing algorithm (local minimum cost path, voxel-based) had 9.59% worse performance than inter-observer agreement but was 3 orders of magnitude faster. Automatic segmentation was non-inferior in patients with sickle cell disease and superior in non-sickle anemia.

Background Fetal magnetic resonance imaging (MRI) and spectroscopy (MRS) provide a unique opportunity to non-invasively measure markers of neurodevelopment in survivors of twin-twin transfusion syndrome (TTTS). Objective To characterize fetal brain maturation after laser surgery for TTTS by measuring brain volumes and cerebral metabolite concentrations using fetal MRI + MRS. Study design Prospective study of dual surviving fetuses treated with laser surgery for TTTS. At 4-5 postoperative weeks, fetal MRI was used together with novel image analysis to automatically extract major brain tissue volumes. Fetal MRS was used to measure major metabolite concentrations in the fetal brain. Results Twenty-one twin pairs were studied. The average (±SD) gestational age at MRI was 25.89 (±2.37) weeks. Total brain volume (TBV) was lower in the donors, although cerebral volumes were not different between twin pairs. Recipients showed lower proportions of cortical and cerebellar volumes, normalized to TBV and cerebral volumes. MRS data showed that biochemical differences between twin brains were related to discrepancy in their brain volumes. Conclusion Although donors have a smaller TBV compared to recipients, proportionality of brain tissue volumes are preserved in donors. MRS maturational markers of fetal brain development show that recovery in donors persists 4 weeks after surgery.

Background: Low Grade Gliomas(LGG) account for about 50% of childhood brain tumors. Elevated citrate levels have previously been shown to be markers for aggressive behavior in LGGs and the H3K27M and G34R/V mutations have emerged as molecular drivers for pediatric high-grade gliomas(HGG). Procedure: We retrospectively analyzed data from 25 patients with midline gliomas to determine whether citrate levels measured through magnetic resonance spectroscopy(MRS) were associated with histone mutations identified by immunohistochemistry. Results: Median age was 6 years (range:0-16 years) with 13 males and 12 females. Most of the patients 14(56%) had a LGG with the most common locations being the thalamus 13(52%) and brainstem 7(28%). The majority had undergone a biopsy 16(65%) or a partial resection 8(32%). Gross total resection was achieved in only one patient(4%). The majority of the patients received adjuvant chemotherapy and/or radiotherapy. Median citrate levels trended higher in patients with HGG compared to those with LGG (1.49vs0.93mmol/kg, p-value=0.16) and in patients with the H3K27M mutation compared to those without (2.30vs0.80mmol/kg, p-value 0.26). Histological grading (LGGvsHGG) (OR: 3.96, 95% confidence interval (CI):1.32-11.94), H3K27M mutation (OR:3.77, 95% CI:1.05-13.61), and age (OR:1.12, 95%CI:1.00-1.25) were significant adverse prognostic factors in univariate analysis but only the histological grading remained significant in multivariate analysis. Conclusion: We determined that H3K27M mutations and elevated citrate levels were adverse prognostic factors in both patients with LGG and HGG. Exploring the relation between these two markers in larger studies could lead to a noninvasive way of predicting high risk behavior prior to biopsy.

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.

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 pre-operatively (N = 61) and post-operatively (N = 50) compared to 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-operative and post-operative period compared to controls, related to microstructural differences. Controlling for cost, we show the presence of increased small-worldness (hierarchical fiber organization) in CHD infants pre-operatively, that persists in the post-operative period compared to 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.

Abnormal cerebrospinal fluid (CSF) dynamics can produce a number of significant clinical problems to include hydrocephalus, loculated areas within the ventricles or subarachnoid spaces as well as impairment of normal CSF movement between the cranial and spinal compartments that can result in a cerebellar ectopia and hydrosyringomyelia. Thus, assessing the patency of fluid flow between adjacent CSF compartments non-invasively by magnetic resonance imaging (MRI) has definite clinical value. Our objective was to demonstrate that a novel tag-based CSF imaging methodology offers improved contrast when compared with a commercially available application. In a prospective study, ten normal healthy adult subjects were examined on 3T magnets with time-spatial labeling inversion pulse (Time-SLIP) and a new tag-based flow technique—time static tagging and mono-contrast preservation (Time-STAMP). The image contrast was calculated for dark-untagged CSF and bright-flowing CSF. We tested the results with the D’Agostino and Pearson normality test and Friedman’s test with Dunn’s multiple comparison correction for significance. Separately 96 pediatric patients were evaluated using the Time-STAMP method. In healthy adults, contrasts were consistently higher with Time-STAMP than Time-SLIP (p

The picture archiving and communication system (PACS) replaced the old film archiving mechanism that stored and moved the data produced by different image-acquisition devices within hospitals. Usin...

A review of pediatric pineal region tumors is provided with emphasis on advanced imaging techniques. The 3 major categories of pineal region tumors include germ cell tumors, pineal parenchymal tumors, and tumors arising from adjacent structures such as tectal astrocytomas. The clinical presentation, biochemical markers, and imaging of these types of tumors are reviewed.

The potential benefits of peptide-based immunotherapy for pediatric brain tumors are under investigation. Treatment-related heterogeneity has resulted in radiographic challenges, including pseudoprogression. Conventional MR imaging has limitations in assessment of different forms of treatment-related heterogeneity, particularly regarding distinguishing true tumor progression from efficacious treatment responses. Advanced neuroimaging techniques, including diffusion magnetic resonance (MR), perfusion MR, and MR spectroscopy, may add value in the assessment of treatment-related heterogeneity. Observations suggest that recent delineation of specific response criteria for immunotherapy of adult brain tumors is likely relevant to the pediatric population and further validation in multicenter pediatric brain tumor peptide-based vaccine studies is warranted.

BACKGROUND AND PURPOSE: Atypical teratoid/rhabdoid tumors are rare, aggressive central nervous system tumors that are predominantly encountered in very young children. Our aim was to determine whether in vivo metabolic profiles correlate with molecular features of central nervous system pediatric atypical teratoid/rhabdoid tumors. MATERIALS AND METHODS: Twenty confirmed patients with atypical teratoid/rhabdoid tumors who underwent MR spectroscopy were included in this study. In vivo metabolite levels of atypical teratoid/rhabdoid tumors were compared with molecular subtypes assessed by achaete-scute homolog 1 expression. Additionally, brain-specific creatine kinase levels were determined in tissue samples. RESULTS: In vivo creatine concentrations were higher in tumors that demonstrated achaete-scute homolog 1 expression compared with those without achaete-scute homolog 1 expression (3.42 ± 1.1 versus 1.8 ± 0.8 IU, P < .01). Additionally, levels of myo-inositol (mI) (9.0 ± 1.5 versus 4.7 ± 3.6 IU, P < .05) were significantly different, whereas lipids approached significance (44 ± 20 versus 80 ± 30 IU, P = .07) in these 2 cohorts. Higher brain-specific creatine kinase levels were observed in the cohort with achaete-scute homolog 1 expression (P < .05). Pearson correlation analysis showed a significant positive correlation of brain-specific creatine kinase with absolute creatine (P < .05) and myo-inositol (P < .05) concentrations. CONCLUSIONS: In vivo MR spectroscopy may predict key molecular features of atypical teratoid/rhabdoid tumors at initial diagnosis, leading to timely patient risk stratification and accelerating the development of targeted therapies.

H3K27M-midline gliomas are fatal tumors that mainly harbor H3.3K27M mutations resulting in global H3K27me3 reduction that impacts neuroglial-differentiation. However, the exact mechanisms by which H3.3K27M mutations promote cancer are poorly understood. Metabolic reprogramming is a hallmark of cancer and we hypothesized that H3.3K27M mutations can reprogram metabolism to support uncontrolled growth. We demonstrate that H3.3K27M-mutant cells show elevated levels of critical enzymes related to glycolysis and TCA cycle metabolism including hexokinase-2, isocitrate dehydrogenase (IDH)-1 and glutamate dehydrogenase. H3.3K27M cells also demonstrated enhanced glycolysis, glutamine and TCA-cycle metabolism accompanied by increased alpha-ketoglutarate (α-KG) production. Mutant IDH (mIDH)1/2 converts α-KG to D-2-hydroxyglutarate (D-2HG). D-2HG increases H3K27me3 by inhibiting α-KG’s function to drive H3K27-demethylases. We discovered that H3.3K27M cells use α-KG in an opposing manner to maintain low H3K27me3. Inhibiting enzymes related to α-KG generation including hexokinase-2, glutamate-dehydrogenase and wild type-IDH1 increased global H3K27me3, altered chromatin accessibility at neuroglial-differentiation factors, lowered tumor cell proliferation, and increased overall survival in vivo in two independent H3.3K27M animal models (p< 0.0001). H3K27M and mIDH1 were mutually exclusive in-patient tumor samples and D-2HG treatment or forced-mIDH1 expression in H3.3K27M cells increased global H3K27me3 and cell death. Finally, H3.3K27M and mIDH1 were synthetic lethal in vitro. Our data suggest that H3.3K27M and mIDH1 hijack a critical and conserved metabolic pathway in opposing manners to regulate global H3K27me3. These results have implications for understanding the pathogenesis of fatal H3K27M-gliomas and for developing therapeutic strategies by disruption of an integrated metabolic/epigenetic-axis. Citation Format: Chan Chung, Stefan Sweha, Drew Pratt, Benita Tamrazi, Pooja Panwalkar, Adam Banda, Jill Bayliss, Debra Hawes, Fusheng Yang, Ho-Joon Lee, Mengrou Shan, Marcin Cieslik, Tingting Qin, Christian Werner, Daniel Wahl, Costas Lyssiotis, Viveka Nand Yadav, Carl Koschmann, Arul Chinnaiyan, Stefan Blüml, Alexander Judkins, Sriram Venneti. Integrated metabolic and epigenomic reprograming by H3K27M mutations in diffuse intrinsic pontine gliomas [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PR02.

Purpose To determine whether the chemical shift of residual N-acetylaspartate (NAA) signal in pilocytic astrocytomas (PA) is consistent with the position of the NAA peak in controls. Methods MR spectra from 27 pediatric World Health Organization (WHO) grade I pilocytic astrocytoma patients, fifteen patients with WHO grade II and high-grade (III–IV) astrocytomas, and 36 controls were analyzed. All spectra were acquired with a short echo time (35 ms), single voxel point-resolved spectroscopy sequence on clinical 3 tesla scanners. Fully automated LCModel software was used for processing, which included the fitting of peak positions for NAA and creatine (Cr). Results The chemical shift difference between the NAA and Cr peaks was significantly smaller (by 0.016 ± 0.005 parts per million, P

Summary H3K27M diffuse intrinsic pontine gliomas (DIPGs) are fatal and lack treatments. They mainly harbor H3.3K27M mutations resulting in H3K27me3 reduction. Integrated analysis in H3.3K27M cells, tumors, and in vivo imaging in patients showed enhanced glycolysis, glutaminolysis, and tricarboxylic acid cycle metabolism with high alpha-ketoglutarate (α-KG) production. Glucose and/or glutamine-derived α-KG maintained low H3K27me3 in H3.3K27M cells, and inhibition of key enzymes in glycolysis or glutaminolysis increased H3K27me3, altered chromatin accessibility, and prolonged survival in animal models. Previous studies have shown that mutant isocitrate-dehydrogenase (mIDH)1/2 glioma cells convert α-KG to D-2-hydroxyglutarate (D-2HG) to increase H3K27me3. Here, we show that H3K27M and IDH1 mutations are mutually exclusive and experimentally synthetic lethal. Overall, we demonstrate that H3.3K27M and mIDH1 hijack a conserved and critical metabolic pathway in opposing ways to maintain their preferred epigenetic state. Consequently, interruption of this metabolic/epigenetic pathway showed potent efficacy in preclinical models, suggesting key therapeutic targets for much needed treatments.

OBJECTIVE: To assess differences in regional brain temperatures during whole-body hypothermia and test the hypothesis that brain temperature profile is nonhomogenous in infants with hypoxic-ischemic encephalopathy. STUDY DESIGN: Infants with hypoxic-ischemic encephalopathy were enrolled prospectively in this observational study. Magnetic resonance (MR) spectra of basal ganglia, thalamus, cortical gray matter, and white matter (WM) were acquired during therapeutic hypothermia. Regional brain tissue temperatures were calculated from the chemical shift difference between water signal and metabolites in the MR spectra after performing calibration measurements. Overall difference in regional temperature was analyzed by mixed-effects model; temperature among different patterns and severity of injury on MR imaging also was analyzed. Correlation between temperature and depth of brain structure was analyzed using repeated-measures correlation. RESULTS: In total, 53 infants were enrolled (31 girls, mean gestational age: 38.6 ± 2 weeks; mean birth weight: 3243 ± 613 g). MR spectroscopy was acquired at mean age of 2.2 ± 0.6 days. A total of 201 MR spectra were included in the analysis. The thalamus, the deepest structure (36.4 ± 2.3 mm from skull surface), was lowest in temperature (33.2 ± 0.8°C, compared with basal ganglia: 33.5 ± 0.9°C; gray matter: 33.6 ± 0.7°C; WM: 33.8 ± 0.9°C, all P < .001). Temperatures in more superficial gray matter and WM regions (depth: 21.9 ±2.4 and 21.5 ± 2.2 mm) were greater than the rectal temperatures (33.4 ± 0.4°C, P < .03). There was a negative correlation between temperature and depth of brain structure (r(rm) = −0.36, P < .001). CONCLUSIONS: Whole-body hypothermia was effective in cooling deep brain structures, whereas superficial structures were warmer, with temperatures significantly greater than rectal temperatures.

With contributions from the global natural product (NP) research community, and continuing the Raw Data Initiative, this review collects a comprehensive demonstration of the immense scientific value of disseminating raw nuclear magnetic resonance (NMR) data, independently of, and in parallel with, classical publishing outlets., Covering: up to 2018 With contributions from the global natural product (NP) research community, and continuing the Raw Data Initiative, this review collects a comprehensive demonstration of the immense scientific value of disseminating raw nuclear magnetic resonance (NMR) data, independently of, and in parallel with, classical publishing outlets. A comprehensive compilation of historic to present-day cases as well as contemporary and future applications show that addressing the urgent need for a repository of publicly accessible raw NMR data has the potential to transform natural products (NPs) and associated fields of chemical and biomedical research. The call for advancing open sharing mechanisms for raw data is intended to enhance the transparency of experimental protocols, augment the reproducibility of reported outcomes, including biological studies, become a regular component of responsible research, and thereby enrich the integrity of NP research and related fields.

Therapeutic hypothermia has emerged as the first empirically supported therapy for neuroprotection in neonates with hypoxic-ischemic encephalopathy (HIE). We used magnetic resonance spectroscopy (1H-MRS) to characterize the effects of hypothermia on energy metabolites, neurotransmitters, and antioxidants. Thirty-one neonates with HIE were studied during hypothermia and after rewarming. Metabolite concentrations (mmol/kg) were determined from the thalamus, basal ganglia, cortical grey matter, and cerebral white matter. In the thalamus, phosphocreatine concentrations were increased by 20% during hypothermia when compared to after rewarming (3.49 ± 0.88 vs. 2.90 ± 0.65, p

Citrate, a tricarboxylic acid cycle intermediate, is present in high concentrations in pediatric diffuse intrinsic pontine gliomas (DIPG). Since citrate increases during hypoxia in animal studies, we hypothesized that it accumulates in DIPG when hypoperfused. Relative tumor blood volumes (rTBV) were determined, using dynamic susceptibility contrast-enhanced magnetic resonance imaging, in twelve children [median age 8.2 (range 3.2-14.5) years] with DIPG and compared to citrate concentrations measured with in vivo proton magnetic resonance spectroscopy ((1)H MRS). Tissue perfusion and metabolite concentration were assessed at initial presentation and over the clinical course, yielding 36 and 46 perfusion and MR spectroscopy datasets, respectively. At presentation, DIPG blood volume was 60 ± 27 % of that measured for normal cerebellum. Citrate, which is not detectable in normal brain tissue, was present in DIPG at concentrations of 3.81 ± 1.44 mmol/kg tissue. Over the course of the disease and treatment, rTBV increased and citrate decreased (both p < 0.05) with an inverse correlation (p = 0.028). Citrate accumulation is associated with tissue hypoperfusion in DIPG.

Preterm birth is associated with alteration in corticothalamic development, which underlies poor neurodevelopmental outcomes. Our hypothesis was that preterm neonates with CHD would demonstrate abnormal thalamic microstructure when compared to critically ill neonates without CHD. A secondary aim was to identify any association between thalamic microstructural abnormalities and perioperative clinical variables. We compared thalamic DTI measurements in 21 preterm neonates with CHD to two cohorts of neonates without CHD: 28 term and 27 preterm neonates, identified from the same neonatal intensive care unit. Comparison was made with three other selected white matter regions using ROI manual-based measurements. Correlation was made with post-conceptional age and perioperative clinical variables. In preterm neonates with CHD, there were age-related differences in thalamic diffusivity (axial and radial) compared to the preterm and term non-CHD group, in contrast to no differences in anisotropy. Contrary to our hypothesis, abnormal thalamic and optic radiation microstructure was most strongly associated with an elevated first arterial blood gas pO2 and elevated preoperative arterial blood gas pH (p < 0.05). Age-related thalamic microstructural abnormalities were observed in preterm neonates with CHD. Perinatal hyperoxemia and increased perioperative serum pH were associated with abnormal thalamic microstructure in preterm neonates with CHD. This study emphasizes the vulnerability of thalamocortical development in the preterm neonate with CHD.

Thalamic structural co-variation with cortical regions has been demonstrated in preterm infants, but its relationship to cortical function and severity of non-cystic white matter injury (non-cystic WMI) is unclear. The relationship between thalamic morphology and both cortical network synchronization and cortical structural connectivity has not been established. We tested the hypothesis that in preterm neonates, thalamic volume would correlate with primary cortical visual function and microstructural integrity of cortico-cortical visual association pathways. A total of 80 term-equivalent preterm and 44 term-born infants underwent high-resolution structural imaging coupled with visual functional magnetic resonance imaging or diffusion tensor imaging. There was a strong correlation between thalamic volume and primary visual cortical activation in preterms with non-cystic WMI (r = 0.81, p-value = 0.001). Thalamic volume also correlated strongly with interhemispheric cortico-cortical connectivity (splenium) in preterm neonates with a relatively higher severity of non-cystic WMI (p-value, Highlights • Thalamic volume correlates with primary visual activation in preterm infants. • Thalamic volume correlates with interhemispheric connectivity in preterms infants. • Disruption of thalamic and callosal connectivity co-exists in preterm infants.

BACKGROUND Determination of cardiac output requires measurement of both heart rate and stroke volume. Techniques for measuring heart rate are widespread, and 1 technique for bedside monitoring of stroke volume is electrical impedance cardiography. OBJECTIVES To determine the accuracy and precision of stroke volume measured via impedance cardiography and whether the technique can be used to detect trends. METHODS Eleven healthy research participants (22-52 years old) were examined with simultaneous impedance cardiography and phase-contrast magnetic resonance imaging at rest and during exercise. Bland-Altman analysis with repeated-measures correction was used to compare stroke volumes determined with the 2 methods. The suitability of impedance cardiography for detecting trends in stroke volume was analyzed by using the Critchley radial limits of agreement method. RESULTS Phase-contrast magnetic resonance imaging indicated a mean stroke volume of 87 (SD, 16) mL at rest; in 9 volunteers, it changed during exercise (P = .04 to P < .001); in 2 volunteers, it did not (P = .32, P = .06). For the range of stroke-volume measurements (60-122 mL), impedance cardiography yielded underestimates of stroke volumes at the low end (bias, -17 mL) and overestimates at the high end (bias, +17 mL; P < .001). Corresponding 95% limits of agreement were 64 mL, a 73% overestimate or underestimate of stroke volume at rest. Critchley radial limits of agreement indicated poor concordance of stroke-volume trends. CONCLUSIONS Impedance cardiography had low accuracy and precision in measuring absolute stroke volume and was a poor detector of stroke-volume trends.

The posteromedial cortex (PMC) including the posterior cingulate, retrosplenial cortex, and medial parietal cortex/precuneus is an epicenter of cortical interactions in a wide spectrum of neural activity. Anatomic connections between PMC and thalamic components have been established in animal studies, but similar studies do not exist for the fetal and neonatal period. Magnetic resonance spectroscopy (MRS) allows for noninvasive measurement of metabolites in early development. Using single-voxel 3-T MRS, healthy term neonates (n 5 31, mean postconception age 41.5 weeks ± 3.8 weeks) were compared with control children (n 5 23, mean age 9.4 years ± 5.1 years) and young adults (n 5 10, mean age 24.1 years ± 2.6 years). LCModel-based calculations compared metabolites within medial parietal gray matter (colocalizing to the PMC), posterior thalamus, and parietal white matter voxels. Common metabolic changes existed for neuronal–axonal maturation and structural markers in the PMC, thalamus, and parietal white matter with increasing NAA and glutamate and decreasing myoinositol and choline with age. Key differences in creatine and glucose metabolism were noted in the PMC, in contrast to the thalamic and parietal white matter locations, suggesting a unique role of energy metabolism. Significant parallel metabolite developmental changes of multiple other metabolites including aspartate, glutamine, and glutathione with age were present between PMC and parietal white matter but not between PMC and thalamus. These findings offer insight into the metabolic architecture of the interface between structural and functional topology of brain networks. Further investigation unifying metabolic changes with functional and anatomic pathways may further enhance the understanding of the PMC in posterior default mode network development.

INTRODUCTION: Punctate white matter lesions (pWMLs) and diffuse excessive high signal intensity (DEHSI) are commonly observed signal abnormalities on MRI scans of high-risk preterm infants near term-equivalent age. To establish whether these features are indicative abnormalities in axonal development or astroglia, we compared pWMLs and DEHSI to markers of axons and astrogliosis, derived from magnetic resonance spectroscopy (MRS). METHODS: Data from 108 preterm infants (gestational age at birth 31.0 weeks±4.3; age at scan 41.2 weeks±6.0) who underwent MR examinations under clinical indications were included in this study. Linear regression analyses were used to test the effects of pWMLs and DEHSI on N-acetyl-aspartate (NAA) and myoinositol concentrations, respectively. RESULTS: Across the full sample, pWMLs were associated with a reduction in NAA whereas moderate to severe DEHSI altered the normal age-dependent changes in myoinositol such that myoinositol levels were lower at younger ages with no change during the perinatal period. Subgroup analyses indicated that the above associations were driven by the subgroup of neonates with both pWMLs and moderate to severe DEHSI. CONCLUSION: Overall, these findings suggest that pWMLs in conjunction with moderate/severe DEHSI may signify a population of infants at risk for long-term adverse neurodevelopmental outcome due to white matter injury and associated axonopathy. The loss of normal age-associated changes in myoinositol further suggests disrupted astroglial function and/or osmotic dysregulation.

Gliofibroma is a rare central nervous system (CNS) tumor with yet-undescribed molecular characteristics. We describe a 20-month-old boy presenting with a large infiltrative gliofibroma arising in the left midbrain. The tumor was partially resected and the pathology was consistent with gliofibroma with low proliferation. Magnetic resonance spectroscopy of the remaining mass was consistent with a high-grade tumor. Molecular findings were significant for a BRAF(V600E) mutation and homozygous deletion of CDKN2A. The patient was treated with targeted therapy using a combination of the BRAF(V600E) inhibitor vemurafenib and the MEK inhibitor, trametinib, with rapid clinical response. Tumor shrinkage was sustained for at least 12 months. Routine MRI at 15 months revealed marked tumor regrowth with pathology from subsequent resection demonstrating areas of low-grade morphology as well as areas with high-grade features. Molecular findings on the initial recurrence were notable for new PDGFRA (Asp842Tyr) and PTPN11 (Ala72Val) mutations in addition to the original genetic alterations. The patient received radiation therapy, but became symptomatic shortly prior to completion. MRI demonstrated new infiltrative tumor anterior to the lateral ventricle, outside the radiation field and extensive subependymal infiltration. Resection of the new mass revealed two new mutations in TP53 (Arg196Gln) and PIK3CA (His1047Arg), in addition to the four previous alterations. To our knowledge, this is the first report on gliofibroma with extensive molecular characterization and the first reported high-grade glioma with molecular data from three successive biopsies. The observed serial acquisition of new mutations on subsequent recurrent specimens is consistent with clonal evolution of disease. The availability of three sets of molecular results on repeat biopsies is unique even to the broader diagnosis of high-grade glioma and sheds light on the biology of recurrence.

Diffuse intrinsic pontine gliomas (DIPG) are inoperable and highly resistant tumors to chemotherapy and irradiation. DIPG has the worst prognosis among all pediatric brain tumors and the overwhelming majority of patients die within 6-18 months after diagnosis.We retrospectively reviewed the charts of six DIPG patients treated with chemoradiotherapy (daily carboplatin and oral etoposide in five patients and temozolomide in one patient) followed by maintenance chemotherapy consisting of irinotecan, temozolomide, and bevacizumab at our institution between January 2007 until December 2007.Event-free survival (EFS) and overall survival (OS) were 10.4 ± 3.08 and 14.6 ± 3.55 months, respectively. Side effects in the patients included hypertension in two, abdominal cramping and diarrhea in four, and neutropenia in five patients.This augmented regimen was associated with increased but tolerable toxicity and a modest increase in EFS and OS when compared with published literature in patients with DIPG (median EFS and OS of 6.1 and 9.6 months, respectively). More effective therapies are desperately needed.

Equations fitting the normative values for gender-specific brain size changes are available. However, these equations do not fit for all age ranges across the human lifespan and particularly have failed to examine the fit across the continuum of prenatal and postnatal human life. We sought to develop a parametric equation that best describes the changes in gender-specific brain size as a function of age across the continuum of prenatal and postnatal human life. Brain weight and brain volume data retrieved from the literature were combined to perform a meta-analysis. Additions to previously published findings included collecting a dataset that spanned the continuum of human lifespan, logarithmic transformation of the data and utilization of the Birch equation. We used Akaike's Information Criterion (AIC) for quantitative evaluation of the new equations. A total of 2,011 brain weight data points spanning from 10 weeks of fetal gestation to over 90 years of age were retrieved. Using our approach, we developed equations with improved fits and lower or similar AIC values compared to the published equations. The new equations are modifications of the basic Birch model. These equations are the first to describe the gender-specific brain weight changes through the continuum of both prenatal and postnatal human life while achieving a level of accuracy similar to or better than the previous, more age-restricted models. The new equations are improved compared to previously used equations and may be useful to those who study brain development, particularly researchers interested in prenatal and postnatal brain size.

Background Extracorporeal membrane oxygenation (ECMO) is an effective therapy for supporting infants with reversible cardiopulmonary failure. Still, survivors are at risk for long-term neurodevelopmental impairments, the cause of which is not fully understood. Objective To elucidate the effects of ECMO on the newborn brain. We hypothesized that the cerebral metabolic profile of neonates who received ECMO would differ from neonates who did not receive ECMO. To address this, we used magnetic resonance spectroscopy (1H-MRS) to investigate the effects of venoarterial and venovenous ECMO on cerebral metabolism. Methods 41 neonates treated with ECMO were contrasted to 38 age-matched neonates. Results All 1H-MRS data were acquired from standardized grey matter and white matter regions of interest using a short-echo (TE = 35 milliseconds), point-resolved spectroscopy sequence (PRESS) and quantitated using LCModel. Metabolite concentrations (mmol/kg) were compared across groups using multivariate analysis of covariance. Elevated creatine (p = 0.002) and choline (p = 0.005) concentrations were observed in the grey matter among neonates treated with ECMO relative to the reference group. Likewise, choline concentrations were elevated in the white matter (p = 0.003) while glutamate was reduced (p = 0.03). Contrasts between ECMO groups revealed lower osmolite concentrations (e.g. myoinositol) among the venovenous ECMO group. Conclusion Neonates who underwent ECMO were found to have an abnormal cerebral metabolic profile, with the pattern of abnormalities suggestive of an underlying inflammatory process. Additionally, neonates who underwent venovenous ECMO had low cerebral osmolite concentrations as seen in vasogenic edema.

The purpose of this study was to explore the feasibility of assessing quality of diffusion tensor imaging (DTI) from multiple sites and vendors using American College of Radiology (ACR) phantom. Participating sites (Siemens (n=2), GE (n=2), and Philips (n=4)) reached consensus on parameters for DTI and used the widely available ACR phantom. Tensor data were processed at one site. B0 and eddy current distortions were assessed using grid line displacement on phantom Slice 5; signal‐to‐noise ratio (SNR) was measured at the center and periphery of the b=0 image; fractional anisotropy (FA) and mean diffusivity (MD) were assessed using phantom Slice 7. Variations of acquisition parameters and deviations from specified sequence parameters were recorded. Nonlinear grid line distortion was higher with linear shimming and could be corrected using the 2nd order shimming. Following image registration, eddy current distortion was consistently smaller than acquisition voxel size. SNR was consistently higher in the image periphery than center by a factor of 1.3–2.0. ROI‐based FA ranged from 0.007 to 0.024. ROI‐based MD ranged from 1.90×10−3 to 2.33×10−3mm2/s(median=2.04×10−3mm2/s). Two sites had image void artifacts. The ACR phantom can be used to compare key quality measures of diffusion images acquired from multiple vendors at multiple sites. PACS number(s): 87.57.‐s, 87.19.lf

Between birth and late adolescence, the human brain undergoes exponential maturational changes. Using in vivo magnetic resonance spectroscopy, we determined the developmental profile for 6 metabolites in 5 distinct brain regions based on spectra from 309 children from 0 to 18 years of age. The concentrations of N-acetyl-aspartate (an indicator for adult-type neurons and axons), creatine (energy metabolite), and glutamate (excitatory neurotransmitter) increased rapidly between birth and 3 months, a period of rapid axonal growth and synapse formation. Myo-inositol, implicated in cell signaling and a precursor of membrane phospholipid, as well as an osmolyte and astrocyte marker, declined rapidly during this period. Choline, a membrane metabolite and indicator for de novo myelin and cell membrane synthesis, peaked from birth until approximately 3 months, and then declined gradually, reaching a plateau at early childhood. Similarly, taurine, involved in neuronal excitability, synaptic potentiation, and osmoregulation, was high until approximately 3 months and thereafter declined. These data indicate that the first 3 months of postnatal life are a critical period of rapid metabolic changes in the development of the human brain. This study of the developmental profiles of the major brain metabolites provides essential baseline information for future analyses of the pediatric health and disease.

For typically developing infants, the last trimester of fetal development extending into the first post-natal months is a period of rapid brain development. Infants who are born premature face significant risk of brain injury (e.g., intraventricular or germinal matrix hemorrhage and periventricular leukomalacia) from complications in the perinatal period and also potential long-term neurodevelopmental disabilities because these early injuries can interrupt normal brain maturation. Neuroimaging has played an important role in the diagnosis and management of the preterm infant. Both cranial US and conventional MRI techniques are useful in diagnostic and prognostic evaluation of preterm brain development and injury. Cranial US is highly sensitive for intraventricular hemorrhage (IVH) and provides prognostic information regarding cerebral palsy. Data are limited regarding the utility of MRI as a routine screening instrument for brain injury for all preterm infants. However, MRI might provide diagnostic or prognostic information regarding PVL and other types of preterm brain injury in the setting of specific clinical indications and risk factors. Further development of advanced MR techniques like volumetric MR imaging, diffusion tensor imaging, metabolic imaging (MR spectroscopy) and functional connectivity are necessary to provide additional insight into the molecular, cellular and systems processes that underlie brain development and outcome in the preterm infant. The adult concept of the "connectome" is also relevant in understanding brain networks that underlie the preterm brain. Knowledge of the preterm connectome will provide a framework for understanding preterm brain function and dysfunction, and potentially even a roadmap for brain plasticity. By combining conventional imaging techniques with more advanced techniques, neuroimaging findings will likely be used not only as diagnostic and prognostic tools, but also as biomarkers for long-term neurodevelopmental outcomes, instruments to assess the efficacy of neuroprotective agents and maneuvers in the NICU, and as screening instruments to appropriately select infants for longitudinal developmental interventions.

The neuroanatomic substrate of cognitive deficits in long-term survivors of prematurity with PVL is poorly understood. The thalamus is critically involved in cognition via extensive interconnections with the cerebral cortex. We hypothesized that the thalamus is atrophic (reduced in volume) in childhood survivors of prematurity with neuroimaging evidence of PVL and that the atrophy is associated with selective microstructural abnormalities within its subdivisions.We performed quantitative volumetric and DTI measurements of the thalamus in 17 children with neuroimaging evidence of PVL (mean postconceptional age, 5.6 ± 4.0 years) who were born prematurely and compared these with 74 term control children (5.7 ± 3.4 years).The major findings were the following: 1) a significant reduction in the overall volume of the thalamus in patients with PVL compared with controls (P.0001), which also correlated with the severity of PVL (P = .001); 2) significantly decreased FA (P = .003) and increased λ(⊥) (P = .02) in the thalamus overall and increased axial, radial, and mean diffusivities in the pulvinar (P.03), suggesting injury to afferent and efferent myelinated axons; and 3) a positive correlation of pulvinar abnormalities with those of the parieto-occipital white matter in periventricular leukomalacia, suggesting that the pulvinar abnormalities reflect secondary effects of damaged interconnections between the pulvinar and parieto-occipital cortices in the cognitive visual network.There are volumetric and microstructural abnormalities of the thalamus in preterm children with PVL, very likely reflecting neuronal loss and myelinated axonal injury. The selective microstructural damage in the pulvinar very likely contributes to abnormal cognitive visual processing known to occur in such survivors.

BACKGROUND AND PURPOSE: DIBSGs have the worst prognosis among pediatric brain tumors with no improvement of outcome for several decades. In this study, we determined whether diffusion imaging could improve patient stratification and our understanding of the impact of therapies. MATERIALS AND METHODS: Nine baseline and 24 follow-up DTI studies performed in 9 patients on a 1.5T clinical MR imaging scanner were reviewed. ADC and FA were measured for the whole lesion and at 5 anatomic levels: the rostral medulla, caudal pons, midpons, rostral pons, and caudal midbrain. Reference data were obtained from 8 controls with normal brain stem, 6 patients with medulloblastoma, and 7 patients with pilocytic astrocytoma. RESULTS: ADC was higher in untreated DIBSG than in normal brain stem and medulloblastoma (1.14 ± 0.18 [×10(−3) mm(2)/s] versus 0.75 ± 0.06 and 0.56 ± 0.05, both P < .001). FA was lower in DIBSG than in normal brain stem (0.24 ± 0.04 versus 0.43 ± 0.02, P < .001) but was higher than that in pilocytic astrocytoma (0.17 ± 0.05, P < .05). Lower baseline ADC and higher FA correlated with a worse clinical course. Correlations were more significant at the caudal midbrain than in other regions. ADC decreased and FA increased after RT. Changes of FA after RT at the caudal midbrain correlated with event-free survival. CONCLUSIONS: Baseline ADC and FA of DIBSG revealed hypocellular tumors with extensive edema. Diffusion changes after therapy implied reduced edema but did not support a significant response to therapy. The significance of diffusion properties varied with anatomic locations, the caudal midbrain being particularly important.

Identification of abnormalities in the contralateral hemisphere in patients with hemimegalencephaly is critical in their management. In this report, we present a 5-day-old neonate with hemimegalencephaly who demonstrated an enlarged ipsilateral cerebral hemisphere and diffuse volume loss in the contralateral hemisphere on conventional MR imaging sequences. The ipsilateral frontal white matter demonstrated relatively increased NAA, fractional anistropy, and cerebral blood volume values compared to published normative data. In addition, the white matter of the contralateral hemisphere demonstrated elevated lactate and increased mean diffusivity compared to published normative data, supporting the abnormal conventional MR findings. Advanced MR neuroimaging techniques may help further confirm and characterize abnormalities in the smaller contralateral hemisphere in neonatal hemimegalencephaly.

Over the last decade, magnetic resonance (MR) imaging has become an essential tool in the evaluation of both in vivo human brain development and perinatal brain injury. Recent technology including MR-compatible neonatal incubators, neonatal head coils, advanced MR pulse sequences, and 3-T field strength magnets allow high-quality MR imaging studies to be performed on sick neonates. This article will review basic principles and concepts underlying recent advances in MR spectroscopy, diffusion, perfusion, and volumetric MR imaging. These techniques provide quantitative assessment and novel insight of both brain development and brain injury in the immature brain. Knowledge of normal developmental changes in quantitative MR values is also essential to interpret pathologic cases.

Molecular imaging with positron emitting tomography (PET) is widely accepted as an essential part of the diagnosis and evaluation of neoplastic and non-neoplastic disease processes. PET has expanded its role from the research domain into clinical application for oncology, cardiology and neuropsychiatry. More recently, PET is being used as a clinical molecular imaging tool in pediatric neuroimaging. PET is considered an accurate and noninvasive method to study brain activity and to understand pediatric neurological disease processes. In this review, specific examples of the clinical use of PET are given with respect to pediatric neuroimaging. The current use of co-registration of PET with MR imaging is exemplified in regard to pediatric epilepsy. The current use of PET/CT in the evaluation of head and neck lymphoma and pediatric brain tumors is also reviewed. Emerging technologies including PET/MRI and neuroreceptor imaging are discussed.