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BackgroundBrain injury is common in neonates with complex neonatal congenital heart disease (CHD) and affects neurodevelopmental outcomes.ObjectivesGiven advancements in perioperative care, we sought to determine if the rate of preoperative and postoperative brain injury detected by using brain magnetic resonance imaging (MRI) and associated clinical risk factors have changed over time in complex CHD.MethodsA total of 270 term newborns with complex CHD were prospectively enrolled for preoperative and postoperative brain MRIs between 2001 and 2021 with a total of 466 MRI scans. Brain injuries in the form of white matter injury (WMI) or focal stroke and clinical factors were compared across 4 epochs of 5-year intervals with logistic regression.ResultsRates of preoperative WMI and stroke did not change over time. After adjusting for timing of the postoperative MRI, site, and cardiac group, the odds of newly acquired postoperative WMI were significantly lower in Epoch 4 compared with Epoch 1 (OR: 0.29; 95% CI: 0.09-1.00; P = 0.05). The adjusted probability of postoperative WMI declined significantly by 18.7% from Epoch 1 (24%) to Epoch 4 (6%). Among clinical risk factors, lowest systolic, mean, and diastolic blood pressures in the first 24 hours after surgery were significantly higher in the most recent epoch.ConclusionsThe prevalence of postoperative WMI has declined, whereas preoperative WMI rates remain constant. More robust postoperative blood pressures may explain these findings by minimizing periods of ischemia and supporting cerebral perfusion. These results suggest potential modifiable clinical targets in the postoperative time period to minimize the burden of WMI.

Poor and asymmetric fetal growth have been associated with neonatal brain injury (BI) and worse neurodevelopmental outcomes (NDO) in the growth-restricted population due to placental insufficiency. We tested the hypothesis that postnatal markers of fetal growth (birthweight (BW), head circumference (HC), and head to body symmetry) are associated with preoperative white matter injury (WMI) and NDO in infants with single ventricle physiology (SVP) and d-transposition of great arteries (TGA). 173 term newborns (106 TGA; 67 SVP) at two sites had pre-operative brain MRI to assess for WMI and measures of microstructural brain development. NDO was assessed at 30 months with the Bayley Scale of Infant Development-II (n = 69). We tested the association between growth parameters at birth with the primary outcome of WMI on the pre-operative brain MRI. Secondary outcomes included measures of NDO. Newborns with TGA were more likely to have growth asymmetry with smaller heads relative to weight while SVP newborns were symmetrically small. There was no association between BW, HC or asymmetry and WMI on preoperative brain MRI or with measures of microstructural brain development. Similarly, growth parameters at birth were not associated with NDO at 30 months. In a multivariable model only cardiac lesion and site were associated with NDO. Unlike other high-risk infant populations, postnatal markers of fetal growth including head to body asymmetry that is common in TGA is not associated with brain injury or NDO. Lesion type appears to play a more important role in NDO in CHD.

ObjectiveTo evaluate the association of therapeutic hypothermia with magnetic resonance imaging (MRI) findings and 30-month neurodevelopment in term neonatal encephalopathy.Study designCross-sectional analysis of 30-month neurodevelopment (IQR 19.0-31.4) in a prospective cohort of mild-to-severe neonatal encephalopathy imaged on day 4 (1993-2017 with institutional implementation of therapeutic hypothermia in 2007). MRI injury was classified as normal, watershed, or basal ganglia/thalamus. Abnormal motor outcome was defined as Bayley-II psychomotor developmental index

Neuroimaging is widely used to aid in the diagnosis and clinical management of neonates with neonatal encephalopathy (NE). Yet, despite widespread use clinically, there are few published guidelines on neuroimaging for neonates with NE. This review outlines the primary patterns of brain injury associated with hypoxic-ischemic injury in neonates with NE and their frequency, associated neuropathological features, and risk factors. In addition, it provides an overview of neuroimaging methods, including the most widely used scoring systems used to characterize brain injury in these neonates and their utility as predictive biomarkers. Last, recommendations for neuroimaging in neonates with NE are presented.

ObjectiveTo test the hypothesis that delayed brain development in fetuses with d-transposition of the great arteries or hypoplastic left heart syndrome heightens their postnatal susceptibility to acquired white matter injury.MethodsThis is a cohort study across 3 sites. Subjects underwent fetal (third trimester) and neonatal preoperative magnetic resonance imaging of the brain to measure total brain volume as a measure of brain maturity and the presence of acquired white matter injury after birth. White matter injury was categorized as no-mild or moderate-severe based on validated grading criteria. Comparisons were made between the injury groups.ResultsA total of 63 subjects were enrolled (d-transposition of the great arteries: 37; hypoplastic left heart syndrome: 26). White matter injury was present in 32.4% (n = 12) of d-transposition of the great arteries and 34.6% (n = 8) of those with hypoplastic left heart syndrome. Overall total brain volume (taking into account fetal and neonatal scan) was significantly lower in those with postnatal moderate-severe white matter injury compared with no-mild white matter injury after adjusting for age at scan and site in d-transposition of the great arteries (coefficient: 14.8 mL, 95% confidence interval, -28.8 to -0.73, P = .04). The rate of change in total brain volume from fetal to postnatal life did not differ by injury group. In hypoplastic left heart syndrome, no association was noted between overall total brain volume and change in total brain volume with postnatal white matter injury.ConclusionsLower total brain volume beginning in late gestation is associated with increased risk of postnatal moderate-severe white matter injury in d-transposition of the great arteries but not hypoplastic left heart syndrome. Rate of brain growth was not a risk factor for white matter injury. The underlying fetal and perinatal physiology has different implications for postnatal risk of white matter injury.

BackgroundCumulative supplemental oxygen (CSO) and cumulative mean airway pressure (CMAP) are associated with bronchopulmonary dysplasia (BPD) in preterm infants, but their relationships to white matter injury (WMI) and neurodevelopment have not been evaluated.MethodsPreterm infants

Osmotic equilibrium and membrane potential in animal cells depend on concentration gradients of sodium (Na+) and potassium (K+) ions across the plasma membrane, a function catalyzed by the Na+,K+-ATPase α-subunit. Here, we describe ATP1A3 variants encoding dysfunctional α3-subunits in children affected by polymicrogyria, a developmental malformation of the cerebral cortex characterized by abnormal folding and laminar organization. To gain cell-biological insights into the spatiotemporal dynamics of prenatal ATP1A3 expression, we built an ATP1A3 transcriptional atlas of fetal cortical development using mRNA in situ hybridization and transcriptomic profiling of ∼125,000 individual cells with single-cell RNA sequencing (Drop-seq) from 11 areas of the midgestational human neocortex. We found that fetal expression of ATP1A3 is most abundant to a subset of excitatory neurons carrying transcriptional signatures of the developing subplate, yet also maintains expression in nonneuronal cell populations. Moving forward a year in human development, we profiled ∼52,000 nuclei from four areas of an infant neocortex and show that ATP1A3 expression persists throughout early postnatal development, most predominantly in inhibitory neurons, including parvalbumin interneurons in the frontal cortex. Finally, we discovered the heteromeric Na+,K+-ATPase pump complex may form nonredundant cell-type-specific α-β isoform combinations, including α3-β1 in excitatory neurons and α3-β2 in inhibitory neurons. Together, the developmental malformation phenotype of affected individuals and single-cell ATP1A3 expression patterns point to a key role for α3 in human cortex development, as well as a cell-type basis for pre- and postnatal ATP1A3-associated diseases.

Background Impairments in fetal oxygen delivery have been implicated in brain dysmaturation seen in congenital heart disease (CHD), suggesting a role for in utero transplacental oxygen therapy. We applied a novel imaging tool to quantify fetal cerebral oxygenation by measuring T2* decay. We compared T2* in fetuses with CHD with controls with a focus on cardiovascular physiologies (transposition or left-sided obstruction) and described the effect of brief administration of maternal hyperoxia on T2* decay. Methods and Results This is a prospective study performed on pregnant mothers with a prenatal diagnosis of CHD compared with controls in the third trimester. Participants underwent a fetal brain magnetic resonance imaging scan including a T2* sequence before and after maternal hyperoxia. Comparisons were made between control and CHD fetuses including subgroup analyses by cardiac physiology. Forty-four mothers (CHD=24, control=20) participated. Fetuses with CHD had lower total brain volume (238.2 mm3, 95% CI, 224.6-251.9) compared with controls (262.4 mm3, 95% CI, 245.0-279.8, P=0.04). T2* decay time was faster in CHD compared with controls (beta=-14.4, 95% CI, -23.3 to -5.6, P=0.002). The magnitude of change in T2* with maternal hyperoxia was higher in fetuses with transposition compared with controls (increase of 8.4 ms, 95% CI, 0.5-14.3, P=0.01), though between-subject variability was noted. Conclusions Cerebral tissue oxygenation is lower in fetuses with complex CHD. There was variability in the response to maternal hyperoxia by CHD subgroup that can be tested in future larger studies. Cardiovascular physiology is critical when designing neuroprotective clinical trials in the fetus with CHD.

IntroductionWhole-exome sequencing (WES) has identified de novo variants in chromatin remodelling genes in patients with neurodevelopmental disorders (NDD). We report on a novel genetic discovery in chromatin remodelling in patients with NDD who also have corpus callosum (CC) anomalies.ObjectiveTo discover novel genes linked to both CC anomalies and NDD.MethodsClinical WES was performed for evaluation of NDD, identifying five patients with de novo variants in SUPT16H, a subunit of the FACT (facilitates chromatin transcription) complex. The clinical phenotypes, genetic results and brain MRIs were obtained and systematically reviewed. In silico protein function predictions were assessed and allele frequencies in control populations were compared.ResultsWe identified four patients with de novo missense variants in SUPT16H and one patient with a de novo deletion including SUPT16H. These variants were not reported in the updated Genome Aggregation Database. When assayable, all protein products were predicted to be damaging. Symptoms included intellectual disability, autistic features, minor dysmorphic features and seizures. Anomalies of the CC were seen in all three patients with available brain imaging.ConclusionOur findings implicate the gene SUPT16H in a novel disorder characterised by neurodevelopmental deficits and CC anomalies.

PurposeThe exocyst complex is a conserved protein complex that mediates fusion of intracellular vesicles to the plasma membrane and is implicated in processes including cell polarity, cell migration, ciliogenesis, cytokinesis, autophagy, and fusion of secretory vesicles. The essential role of these genes in human genetic disorders, however, is unknown.MethodsWe performed homozygosity mapping and exome sequencing of consanguineous families with recessively inherited brain development disorders. We modeled an EXOC7 splice variant in vitro and examined EXOC7 messenger RNA (mRNA) expression in developing mouse and human cortex. We modeled exoc7 loss-of-function in a zebrafish knockout.ResultsWe report variants in exocyst complex members, EXOC7 and EXOC8, in a novel disorder of cerebral cortex development. In EXOC7, we identified four independent partial loss-of-function (LOF) variants in a recessively inherited disorder characterized by brain atrophy, seizures, and developmental delay, and in severe cases, microcephaly and infantile death. In EXOC8, we found a homozygous truncating variant in a family with a similar clinical disorder. We modeled exoc7 deficiency in zebrafish and found the absence of exoc7 causes microcephaly.ConclusionOur results highlight the essential role of the exocyst pathway in normal cortical development and how its perturbation causes complex brain disorders.

BackgroundHyperpolarized 13C spectroscopic magnetic resonance spectroscopy (MRS) is an advanced imaging tool that may provide important real-time information about brain metabolism.MethodsMice underwent unilateral hypoxia-ischemia (HI) on postnatal day (P)10. Injured and sham mice were scanned at P10, P17, and P31. We used hyperpolarized 13C MRS to investigate the metabolic exchange of pyruvate to lactate in real time during brain development following HI. 13C-1-labeled pyruvate was hyperpolarized and injected into the tail vein through a tail-vein catheter. Chemical-shift imaging was performed to acquire spectral-spatial information of the metabolites in the brain. A voxel placed on each of the injured and contralateral hemispheres was chosen for comparison. The difference in pyruvate delivery and lactate to pyruvate ratio was calculated for each of the voxels at each time point. The normalized lactate level of the injured hemisphere was also calculated for each mouse at each of the scanning time points.ResultsThere was a significant reduction in pyruvate delivery and a higher lactate to pyruvate ratio in the ipsilateral (HI) hemisphere at P10. The differences decreased at P17 and disappeared at P31. The normalized lactate level in the injured hemisphere increased from P10 to P31 in both sham and HI mice without brain injury.ConclusionWe describe a method for detecting and monitoring the evolution of HI injury during brain maturation which could prove to be an excellent biomarker of injury.

BackgroundNeonatal seizures are associated with adverse neurologic sequelae including epilepsy in childhood. Here we aim to determine whether levels of cytokines in neonates with brain injury are associated with acute symptomatic seizures or remote epilepsy.MethodsThis is a cohort study of term newborns with encephalopathy at UCSF between 10/1993 and 1/2000 who had dried blood spots. Maternal, perinatal/postnatal, neuroimaging, and epilepsy variables were abstracted by chart review. Logistic regression was used to compare levels of cytokines with acute seizures and the development of epilepsy.ResultsIn a cohort of 26 newborns with neonatal encephalopathy at risk for hypoxic ischemic encephalopathy with blood spots for analysis, diffuse alterations in both pro- and anti-inflammatory cytokine levels were observed between those with (11/28, 39%) and without acute symptomatic seizures. Seventeen of the 26 (63%) patients had >2 years of follow-up and 4/17 (24%) developed epilepsy. Higher levels of pro-inflammatory cytokines IL-6 and TNF-α within the IL-1β pathway were significantly associated with epilepsy.ConclusionsElevations in pro-inflammatory cytokines in the IL-1β pathway were associated with later onset of epilepsy. Larger cohort studies are needed to confirm the predictive value of these circulating biomarkers.

ObjectiveTo better evaluate the imaging spectrum of subcortical heterotopic gray matter brain malformations (subcortical heterotopia [SUBH]), we systematically reviewed neuroimaging and clinical data of 107 affected individuals.MethodsSUBH is defined as heterotopic gray matter, located within the white matter between the cortex and lateral ventricles. Four large brain malformation databases were searched for individuals with these malformations; data on imaging, clinical outcomes, and results of molecular testing were systematically reviewed and integrated with all previously published subtypes to create a single classification system.ResultsReview of the databases revealed 107 patients with SUBH, the large majority scanned during childhood (84%), including more than half before 4 years (59%). Although most individuals had cognitive or motor disability, 19% had normal development. Epilepsy was documented in 69%. Additional brain malformations were common and included abnormalities of the corpus callosum (65/102 [64%]), and, often, brainstem or cerebellum (47/106 [44%]). Extent of the heterotopic gray matter brain malformations (unilateral or bilateral) did not influence the presence or age at onset of seizures. Although genetic testing was not systematically performed in this group, the sporadic occurrence and frequent asymmetry suggests either postzygotic mutations or prenatal disruptive events. Several rare, bilateral forms are caused by mutations in genes associated with cell proliferation and polarity (EML1, TUBB, KATNB1, CENPJ, GPSM2).ConclusionThis study reveals a broad clinical and imaging spectrum of heterotopic malformations and provides a framework for their classification.

Four boys with Pelizaeus-Merzbacher disease, an X-linked leukodystrophy, underwent transplantation with human allogeneic central nervous system stem cells (HuCNS-SC). Subsequently, all subjects were followed for an additional 4 years in this separate follow-up study to evaluate safety, neurologic function, magnetic resonance imaging (MRI) data, and immunologic response. The neurosurgical procedure, immunosuppression, and HuCNS-SC transplantation were well tolerated and all four subjects were alive at the conclusion of the study period. At year 2, all subjects exhibited diffusion MRI changes at the implantation sites as well as in more distant brain regions. There were persistent, increased signal changes in the three patients who were studied up to year 5. Two of four subjects developed donor-specific HLA alloantibodies, demonstrating that neural stem cells can elicit an immune response when injected into the CNS, and suggesting the importance of monitoring immunologic parameters and identifying markers of engraftment in future studies.

Background Tube-assisted feeding in infancy is common in patients with single-ventricle physiology ( SVP ). Postnatal brain development is delayed, and injury is common, in patients with SVP . The role of brain findings in feeding outcomes remains unclear. We sought to determine the association between neonatal perioperative brain injury and postnatal brain maturation with feeding-tube dependency in patients with SVP at neonatal discharge and just before the stage-2 palliation. Methods and Results We evaluated a cohort of 48 term neonates with SVP who underwent pre- and postoperative brain magnetic resonance imaging. Perioperative brain injury and microstructural brain development were measured with diffusion tensor imaging including fractional anisotropy in white matter and apparent diffusion coefficient in gray matter. The primary outcome was defined as being 100% orally fed (binary). Of the patients 79% (38/48) were tube fed at hospital discharge, and 27% (12/45) were tube fed before stage-2 palliation. Perioperative brain injury did not differ by group. Orally fed patients had a faster rate of decrease in apparent diffusion coefficient (3%, 95% CI 1.7% to 4.6%, P

BackgroundTo assess whether postnatal plasma cholesterol levels are associated with microstructural and macrostructural regional brain development in preterm newborns.MethodsSixty preterm newborns (born 24-32 weeks gestational age) were assessed using MRI studies soon after birth and again at term-equivalent age. Blood samples were obtained within 7 days of each MRI scan to analyze for plasma cholesterol and lathosterol (a marker of endogenous cholesterol synthesis) levels. Outcomes were assessed at 3 years using the Bayley Scales of Infant Development, Third Edition.ResultsEarly plasma lathosterol levels were associated with increased axial and radial diffusivities and increased volume of the subcortical white matter. Early plasma cholesterol levels were associated with increased volume of the cerebellum. Early plasma lathosterol levels were associated with a 2-point decrease in motor scores at 3 years.ConclusionsHigher early endogenous cholesterol synthesis is associated with worse microstructural measures and larger volumes in the subcortical white matter that may signify regional edema and worse motor outcomes. Higher early cholesterol is associated with improved cerebellar volumes. Further work is needed to better understand how the balance of cholesterol supply and endogenous synthesis impacts preterm brain development, especially if these may be modifiable factors to improve outcomes.

Pediatric neuroimaging is challenging due the rapid structural, metabolic, and functional changes that occur in the developing brain. A specially trained team is needed to produce high quality diagnostic images in children, due to their small physical size and immaturity. Patient motion, cooperation and medical condition dictate the methods and equipment used. A customized approach tailored to each child's age and functional status with the appropriate combination of dedicated staff, imaging hardware, and software is key; these range from low-tech techniques, such as feed and swaddle, to specialized small bore MRI scanners, MRI compatible incubators and neonatal head coils. New pre-and post-processing techniques can also compensate for the motion artifacts and low signal that often degrade neonatal scans.

BackgroundNeonates with congenital heart disease (CHD) are at high risk of punctate white matter injury (WMI) and impaired brain development. We hypothesized that WMI in CHD neonates occurs in a characteristic distribution that shares topology with preterm WMI and that lower birth gestational age (GA) is associated with larger WMI volume.Objective(1) To quantitatively assess the volume and location of WMI in CHD neonates across three centres. (2) To compare the volume and spatial distribution of WMI between term CHD neonates and preterm neonates using lesion mapping.MethodsIn 216 term born CHD neonates from three prospective cohorts (mean birth GA: 39 weeks), WMI was identified in 86 neonates (UBC: 29; UCSF: 43; UCZ: 14) on pre- and/or post-operative T1 weighted MRI. WMI was manually segmented and volumes were calculated. A standard brain template was generated. Probabilistic WMI maps (total, pre- and post-operative) were developed in this common space. Using these maps, WMI in the term CHD neonates was compared with that in preterm neonates: 58 at early-in-life (mean postmenstrual age at scan 32.2 weeks); 41 at term-equivalent age (mean postmenstrual age at scan 40.1 weeks).ResultsThe total WMI volumes of CHD neonates across centres did not differ (p = 0.068): UBC (median = 84.6 mm3, IQR = 26-174.7 mm3); UCSF (median = 104 mm3, IQR = 44-243 mm3); UCZ (median = 121 mm3, IQR = 68-200.8 mm3). The spatial distribution of WMI in CHD neonates showed strong concordance across centres with predilection for anterior and posterior rather than central lesions. Predominance of anterior lesions was apparent on the post-operative WMI map relative to the pre-operative map. Lower GA at birth predicted an increasing volume of WMI across the full cohort (41.1 mm3 increase of WMI per week decrease in gestational age; 95% CI 11.5-70.8; p = 0.007), when accounting for centre and heart lesion. While WMI in term CHD and preterm neonates occurs most commonly in the intermediate zone/outer subventricular zone there is a paucity of central lesions in the CHD neonates relative to preterms.ConclusionsWMI in term neonates with CHD occurs in a characteristic topology. The spatial distribution of WMI in term neonates with CHD reflects the expected maturation of pre-oligodendrocytes such that the central regions are less vulnerable than in the preterm neonates.

Acute chorioamnionitis refers to the neutrophilic inflammation of the placental tissues thought to result from an ascending bacterial infection. It is considered a major factor associated with pretermbirth and has been estimated to occur in 40%to 80% of preterm deliveries. Chorioamnionitis is associated with several adverse neonatal outcomes, including respiratory distress syndrome, sepsis, bronchopulmonary dysplasia, and death. Clinical studies examining brain injury and neurodevelopmental outcomes among infants with chorioamnionitis have yielded inconsistent results. Most of these studies have focused on intraventricular hemorrhage (IVH) and cystic periventricular leukomalacia. Because the incidence of cystic periventricular leukomalacia has greatly decreased during the past decades concurrent with improvements in neonatal intensive care, punctate white matter injury (WMI) is increasingly recognized as the most prevalent pattern of brain injury among preterm neonates. The researchers performed a prospective cohort study conducted across 3 academic centers in Canada, the Netherlands, and the United States. Children who were born preterm (24-32 weeks' gestation) and who had undergone a placental pathologic evaluation, magnetic resonance imaging (MRI) as soon as clinically stable, and Bayley Scales of Infant and Toddler Development, 3rd Edition (Bayley III) assessments between 18 and 24 months' corrected age (CA) were included. Magnetic resonance imaging scans were assessed for grade of IVH and volume of punctate WMI. Data analysis occurred between December 2016 and January 2018. Final multivariable analyses examining the association of chorioamnionitis with motor and cognitive outcomes accounted for academic center and perinatal and postnatal factors. PunctateWMI volume and IVH detected on neonatalMRI scans were used tomeasure the results,withmotor and cognitive outcomes defined using Bayley III assessments conducted among these children between 18 and 24 months' CA. There were 448 preterm infants (24-32 weeks' gestation) in the total cohort. Infants were included in the analysis if they had undergone placental pathologic assessments, early brainMRI, and 18 to 24 months of follow-up.Among the cohorts fromthe 3 academic centers, infants with evidence of a congenital infection, genetic syndrome, or large parenchymal hemorrhagic infarction (>2 cm) were excluded. Each placenta was sent fresh for macroscopic and microscopic analyses, which were conducted using the same clinical protocols at each center. Histologic chorioamnionitis was defined by clinical pathologists using strict criteria and the degree of placental inflammation was scored.

BackgroundNeurocutaneous melanosis is a rare disorder in which children with large cutaneous melanotic nevi have associated melanosis in the brain. Although many affected children have structurally normal brains, some have associated developmental disorders or brain anomalies.ObjectivesTo determine the range of extent of brain melanosis as assessed by magnetic resonance imaging (MRI) and to investigate the frequency and types of associated brain anomalies.Materials and methodsWe retrospectively reviewed brain and spine MRIs of 80 patients with congenital melanocytic nevi (range: 1 day to 22 years of age) affiliated with Nevus Outreach Inc. from 1998 to 2017. Central nervous system (CNS) melanosis was diagnosed when a mass with abnormal parenchymal T1 hyperintensity was seen. The locations of abnormal signal, associated malformations, the presence of contrast enhancement and, in patients with more than one MRI, changes over time were recorded. Associations among findings were analyzed using chi-square test or Fisher exact test.ResultsBrain abnormalities were identified in 33 patients. The most common finding was melanosis in the amygdala, which was found in 31 patients (an isolated finding in 14 patients). Nineteen patients had melanosis in the brainstem, cerebellum, cerebral cortex or thalamus. Cerebral and/or spinal leptomeningeal enhancement was uncommon (five patients). Hindbrain melanosis was associated with cerebellar and pontine hypoplasia (P=0.012). Brain melanosis was most easily seen on T1 images prior to myelination; reduced/loss of visibility was noted as the CNS matured.ConclusionBrain melanosis is a common manifestation in children with large cutaneous melanotic nevi, most commonly found in the anterior temporal lobes (amygdala), brainstem, cerebellum and cerebral cortex. Hindbrain melanosis is associated with hypoplasia of the affected structures. Early imaging is optimal to provide the greatest sensitivity for diagnosis and to guide proper management.

Purpose To evaluate whether patients with neurofibromatosis type 1 (NF1)-a multisystem neurodevelopmental disorder with myriad imaging manifestations, including focal transient myelin vacuolization within the deep gray nuclei, brainstem, and cerebellum-exhibit differences in cortical and subcortical structures, particularly in subcortical regions where these abnormalities manifest. Materials and Methods In this retrospective study, by using clinically obtained three-dimensional T1-weighted MR images and established image analysis methods, 10 intracranial volume-corrected subcortical and 34 cortical regions of interest (ROIs) were quantitatively assessed in 32 patients with NF1 and 245 age- and sex-matched healthy control subjects. By using linear models, ROI cortical thicknesses and volumes were compared between patients with NF1 and control subjects, as a function of age. With hierarchic cluster analysis and partial correlations, differences in the pattern of association between cortical and subcortical ROI volumes in patients with NF1 and control subjects were also evaluated. Results Patients with NF1 exhibited larger subcortical volumes and thicker cortices of select regions, particularly the hippocampi, amygdalae, cerebellar white matter, ventral diencephalon, thalami, and occipital cortices. For the thalami and pallida and 22 cortical ROIs in patients with NF1, a significant inverse association between volume and age was found, suggesting that volumes decrease with increasing age. Moreover, compared with those in control subjects, ROIs in patients with NF1 exhibited a distinct pattern of clustering and partial correlations. Discussion Neurofibromatosis type 1 is characterized by larger subcortical volumes and thicker cortices of select structures. Most apparent within the hippocampi, amygdalae, cerebellar white matter, ventral diencephalon, thalami and occipital cortices, these neurofibromatosis type 1-associated volumetric changes may, in part, be age dependent. © RSNA, 2018 Online supplemental material is available for this article.

Tuberous sclerosis complex (TSC), a heritable neurodevelopmental disorder, is caused by mutations in the TSC1 or TSC2 genes. To date, there has been little work to elucidate regional TSC1 and TSC2 gene expression within the human brain, how it changes with age, and how it may influence disease. Using a publicly available microarray dataset, we found that TSC1 and TSC2 gene expression was highest within the adult neo-cerebellum and that this pattern of increased cerebellar expression was maintained throughout postnatal development. During mid-gestational fetal development, however, TSC1 and TSC2 expression was highest in the cortical plate. Using a bioinformatics approach to explore protein and genetic interactions, we confirmed extensive connections between TSC1/TSC2 and the other genes that comprise the mammalian target of rapamycin (mTOR) pathway, and show that the mTOR pathway genes with the highest connectivity are also selectively expressed within the cerebellum. Finally, compared to age-matched controls, we found increased cerebellar volumes in pediatric TSC patients without current exposure to antiepileptic drugs. Considered together, these findings suggest that the cerebellum may play a central role in TSC pathogenesis and may contribute to the cognitive impairment, including the high incidence of autism spectrum disorder, observed in the TSC population.

Channelopathies are disorders caused by abnormal ion channel function in differentiated excitable tissues. We discovered a unique neurodevelopmental channelopathy resulting from pathogenic variants in SCN3A, a gene encoding the voltage-gated sodium channel NaV1.3. Pathogenic NaV1.3 channels showed altered biophysical properties including increased persistent current. Remarkably, affected individuals showed disrupted folding (polymicrogyria) of the perisylvian cortex of the brain but did not typically exhibit epilepsy; they presented with prominent speech and oral motor dysfunction, implicating SCN3A in prenatal development of human cortical language areas. The development of this disorder parallels SCN3A expression, which we observed to be highest early in fetal cortical development in progenitor cells of the outer subventricular zone and cortical plate neurons and decreased postnatally, when SCN1A (NaV1.1) expression increased. Disrupted cerebral cortical folding and neuronal migration were recapitulated in ferrets expressing the mutant channel, underscoring the unexpected role of SCN3A in progenitor cells and migrating neurons.

BackgroundBrain injury (BI) is reported in 60% of newborns with critical congenital heart disease as white matter injury (WMI) or stroke. Neurodevelopmental (ND) impairments are reported in these patients. The relationship between neonatal BI and ND outcome has not been established.ObjectivesThis study sought to determine the association between peri-operative BI and ND outcomes in infants with single ventricle physiology (SVP) and d-transposition of the great arteries (d-TGA).MethodsTerm newborns with d-TGA and SVP had pre-operative and post-operative brain magnetic resonance imaging and ND outcomes assessed at 12 and 30 months with the Bayley Scales of Infant Development-II. BI was categorized by the brain injury severity score and WMI was quantified by volumetric analysis.ResultsA total of 104 infants had follow-up at 12 months and 70 had follow-up at 30 months. At 12 months, only clinical variables were associated with ND outcome. At 30 months, subjects with moderate-to-severe WMI had significantly lower Psychomotor Development Index (PDI) scores (13 points lower) as compared with those with none or minimal WMI for d-TGA and SVP (p = 0.03 and p = 0.05, respectively) after adjusting for various factors. Quantitative WMI volume was likewise associated. Stroke was not associated with outcome. The Bland-Altman limits of agreement for PDI scores at 12 and 30 months were wide (-40.3 to 31.2) across the range of mean PDI values.ConclusionsIncreasing burden of WMI is associated with worse motor outcomes at 30 months for infants with critical congenital heart disease, whereas no adverse association was seen between small strokes and outcome. These results support the utility of neonatal brain magnetic resonance imaging in this population to aid in predicting later outcomes and the importance of ND follow-up beyond 1 year of age.

Neurodegenerative diseases likely share common underlying pathobiology. Although prior work has identified susceptibility loci associated with various dementias, few, if any, studies have systematically evaluated shared genetic risk across several neurodegenerative diseases. Using genome-wide association data from large studies (total n = 82,337 cases and controls), we utilized a previously validated approach to identify genetic overlap and reveal common pathways between progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), Parkinson's disease (PD) and Alzheimer's disease (AD). In addition to the MAPT H1 haplotype, we identified a variant near the chemokine receptor CXCR4 that was jointly associated with increased risk for PSP and PD. Using bioinformatics tools, we found strong physical interactions between CXCR4 and four microglia related genes, namely CXCL12, TLR2, RALB, and CCR5. Evaluating gene expression from post-mortem brain tissue, we found that expression of CXCR4 and microglial genes functionally related to CXCR4 was dysregulated across a number of neurodegenerative diseases. Furthermore, in a mouse model of tauopathy, expression of CXCR4 and functionally associated genes was significantly altered in regions of the mouse brain that accumulate neurofibrillary tangles most robustly. Beyond MAPT, we show dysregulation of CXCR4 expression in PSP, PD, and FTD brains, and mouse models of tau pathology. Our multi-modal findings suggest that abnormal signaling across a 'network' of microglial genes may contribute to neurodegeneration and may have potential implications for clinical trials targeting immune dysfunction in patients with neurodegenerative diseases.

ObjectiveFocal cortical dysplasias (FCDs) often cause pharmacoresistant epilepsy, and surgical resection can lead to seizure-freedom. Magnetic resonance imaging (MRI) and positron emission tomography (PET) play complementary roles in FCD identification/localization; nevertheless, many FCDs are small or subtle, and difficult to find on routine radiological inspection. We aimed to automatically detect subtle or visually-unidentifiable FCDs by building a classifier based on an optimized cortical surface sampling of combined MRI and PET features.MethodsCortical surfaces of 28 patients with histopathologically-proven FCDs were extracted. Morphology and intensity-based features characterizing FCD lesions were calculated vertex-wise on each cortical surface, and fed to a 2-step (Support Vector Machine and patch-based) classifier. Classifier performance was assessed compared to manual lesion labels.ResultsOur classifier using combined feature selections from MRI and PET outperformed both quantitative MRI and multimodal visual analysis in FCD detection (93% vs 82% vs 68%). No false positives were identified in the controls, whereas 3.4% of the vertices outside FCD lesions were also classified to be lesional ("extralesional clusters"). Patients with type I or IIa FCDs displayed a higher prevalence of extralesional clusters at an intermediate distance to the FCD lesions compared to type IIb FCDs (p

Magnetic resonance imaging (MRI) is the workhorse modality in pediatric neuroimaging because it provides excellent soft-tissue contrast without ionizing radiation. Until recently, studies were uninterpretable without sedation; however, given development of shorter sequences, sequences that correct for motion, and studies showing the potentially deleterious effects of sedation on immature laboratory animals, it is prudent to minimize sedation when possible. This manuscript provides basic guidelines for performing pediatric neuro MRI without sedation by both modifying technical factors to reduce scan time and noise, and using a multi-disciplinary team to coordinate imaging with the patient's biorhythms.

ObjectiveTo assess the trajectory of perioperative brain growth in relationship to cardiac diagnosis and acquired brain injuries.MethodsThis was a cohort study of term neonates with hypoplastic left heart syndrome (HLHS) and d-transposition of the great arteries (d-TGA). Subjects underwent magnetic resonance imaging of the brain pre- and postoperatively to determine the severity of brain injury and total and regional brain volumes by the use of automated morphometry. Comparisons were made by cardiac lesion and injury status.ResultsA total of 79 subjects were included (49, d-TGA; 30, HLHS). Subjects with HLHS had more postoperative brain injury (55.6% vs 30.4%, P = .03) and more severe brain injury (moderate-to-severe white matter [WM] injury, P = .01). Total and regional perioperative brain growth was not different by brain injury status (either pre- or postoperative). However, subjects with moderate-to-severe WM injury had a slower rate of brain growth in WM and gray matter compared with those with no injury. Subjects with HLHS had a slower rate of growth globally and in WM and deep gray matter as compared with d-TGA (total brain volume: 12 cm3/wk vs 7 cm3; WM: 2.1 cm3/wk vs 0.6 cm3; deep gray matter: 1.5 cm3/wk vs 0.7 cm3; P

BackgroundHuman studies investigating the link between postnatal polyunsaturated fatty acids and preterm brain growth are limited, despite emerging evidence of potential effects on outcomes.MethodsSixty preterm neonates

Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) are epileptogenic neurodevelopmental malformations caused by mutations in mTOR pathway genes. Deep sequencing of these genes in FCD/HME brain tissue identified an etiology in 27 of 66 cases (41%). Radiographically indistinguishable lesions are caused by somatic activating mutations in AKT3, MTOR, and PIK3CA and germline loss-of-function mutations in DEPDC5, NPRL2, and TSC1/2, including TSC2 mutations in isolated HME demonstrating a "two-hit" model. Mutations in the same gene cause a disease continuum from FCD to HME to bilateral brain overgrowth, reflecting the progenitor cell and developmental time when the mutation occurred. Single-cell sequencing demonstrated mTOR activation in neurons in all lesions. Conditional Pik3ca activation in the mouse cortex showed that mTOR activation in excitatory neurons and glia, but not interneurons, is sufficient for abnormal cortical overgrowth. These data suggest that mTOR activation in dorsal telencephalic progenitors, in some cases specifically the excitatory neuron lineage, causes cortical dysplasia.

Posterior pituitary ectopia has been reported previously in association with optic nerve hypoplasia, as a variant of septo-optic dysplasia. We describe a 14-year-old boy with posterior pituitary ectopia and bilateral optic disc pits. He had hypopituitarism and a reduction in visual acuity to 20/40 in each eye, owing to loss of foveal ganglion cells. Optic pits and posterior pituitary ectopia may have occurred together in the same subject by chance, but the rarity of both conditions suggests a possible association.

Arthrogryposis multiplex congenital, the occurrence of multiple joint contractures at birth, can in some cases be accompanied by insufficient myelination of peripheral nerves, muscular hypotonia, reduced tendon reflexes, and respiratory insufficiency. Recently mutations in the CASPR/CNTN1 complex have been associated with similar severe phenotypes and CNTNAP1 gene mutations, causing loss of the CASPR protein, were shown to cause severe, prenatal onset arthrogryposis multiplex congenita in four unrelated families. Here we report a consanguineous Arab family from Qatar with three children having an early lethal form of arthrogryposis multiplex congenita and a novel frameshift mutation in CNTNAP1. We further expand the existing CNTNAP1-associated phenotype to include profound cerebral and cerebellar atrophy.

Motor, sensory, and integrative activities of the brain are coordinated by a series of midline-bridging neuronal commissures whose development is tightly regulated. Here we report a new human syndrome in which these commissures are widely disrupted, thus causing clinical manifestations of horizontal gaze palsy, scoliosis, and intellectual disability. Affected individuals were found to possess biallelic loss-of-function mutations in the gene encoding the axon-guidance receptor 'deleted in colorectal carcinoma' (DCC), which has been implicated in congenital mirror movements when it is mutated in the heterozygous state but whose biallelic loss-of-function human phenotype has not been reported. Structural MRI and diffusion tractography demonstrated broad disorganization of white-matter tracts throughout the human central nervous system (CNS), including loss of all commissural tracts at multiple levels of the neuraxis. Combined with data from animal models, these findings show that DCC is a master regulator of midline crossing and development of white-matter projections throughout the human CNS.

This study aimed to characterize the circumstances of death in encephalopathic neonates treated with therapeutic hypothermia. Patients who died after or during treatment with therapeutic hypothermia between 2007-2014 were identified. Patient circumstance of death was characterized using an established paradigm. Thirty-one of 229 patients died (14%) at a median of 3 days of life. Most who died were severely encephalopathic on examination (90%) and had severely abnormal electroencephalographic (EEG) findings (87%). All those who had magnetic resonance images (n = 13) had evidence of moderate-severe brain injury; 6 had near-total brain injury. Cooling was discontinued prematurely in 61% of patients. Most patients (90%) were physiologically stable at the time of death; 81% died following elective extubation for quality of life considerations. Three patients (10%) died following withholding or removal of artificial hydration and nutrition. Characterization of death in additional cohorts is needed to identify differences in decision making practices over time and between centers.

Global patterns of brain injury correlate with motor, cognitive, and language outcomes in survivors of neonatal encephalopathy (NE). However, it is still unclear whether local changes in brain structure predict specific deficits. We therefore examined whether differences in brain structure at 6 months of age are associated with neurodevelopmental outcomes in this population. We enrolled 32 children with NE, performed structural brain MR imaging at 6 months, and assessed neurodevelopmental outcomes at 30 months. All subjects underwent T1-weighted imaging at 3 T using a 3D IR-SPGR sequence. Images were normalized in intensity and nonlinearly registered to a template constructed specifically for this population, creating a deformation field map. We then used deformation based morphometry (DBM) to correlate variation in the local volume of gray and white matter with composite scores on the Bayley Scales of Infant and Toddler Development (Bayley-III) at 30 months. Our general linear model included gestational age, sex, birth weight, and treatment with hypothermia as covariates. Regional brain volume was significantly associated with language scores, particularly in perisylvian cortical regions including the left supramarginal gyrus, posterior superior and middle temporal gyri, and right insula, as well as inferior frontoparietal subcortical white matter. We did not find significant correlations between regional brain volume and motor or cognitive scale scores. We conclude that, in children with a history of NE, local changes in the volume of perisylvian gray and white matter at 6 months are correlated with language outcome at 30 months. Quantitative measures of brain volume on early MRI may help identify infants at risk for poor language outcomes.