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Background We previously reported that increasing severity of watershed (WS) injury in neonatal magnetic resonance imaging (MRI) is associated with worse language outcomes in early childhood. In the present study, we investigated the relationship between neonatal injury patterns and cognitive profile in adolescents with neonatal encephalopathy. Methods Term neonates with encephalopathy were prospectively enrolled and imaged using brain MRI from 1999 to 2008. Neonatal brain injury was scored according to the degree of injury in WS and basal ganglia/thalamus (BG/T) areas. The children underwent a neurocognitive assessment and follow-up brain MRI at the age of 10–16 years. The relationship between neonatal brain injury patterns and adolescent cognitive outcomes was assessed. Results In a cohort of 16 children, neonatal MRI showed WS injury in 7, BG/T injury in 2, and normal imaging in 7. Children with WS injury had lower estimated overall cognitive ability than those with normal imaging. Increasing WS injury score was associated with decreasing estimated overall cognitive ability, Perceptual Reasoning Index, and digit span score. Conclusions Children with the WS injury are at an increased risk of having problems in long-term intellectual ability. These cognitive outcomes may underlie early language difficulties seen in children with neonatal WS injury. Impact Adolescents with a history of neonatal encephalopathy and watershed pattern of injury on neonatal brain magnetic resonance imaging (MRI) had lower overall cognitive ability, perceptual reasoning skills, and auditory working memory than those with normal neonatal imaging. Children with post-neonatal epilepsy and cerebral palsy had the worst cognitive outcomes. Watershed pattern of injury confers high long-term differences in intellectual ability.

Background and purpose The diagnosis of childhood arteriopathy is complex. We present a Web-based, evidence-backed classification system to return the most likely cause(s) of a pediatric arterial ischemic stroke. This tool incorporates a decision-making algorithm that considers a patient's clinical and imaging features before returning a differential diagnosis, including the likelihood of various arteriopathy subtypes. Methods The Vascular Effects of Infection in Pediatric Stroke study prospectively enrolled 355 children with arterial ischemic stroke (2010-2014). Previously, a central panel of experts classified the stroke etiology. To create this tool, we used the 174 patients with definite arteriopathy and spontaneous cardioembolic stroke as the "derivation cohort" and the 34 with "possible" arteriopathy as the "test cohort." Using logistic regression models of clinical and imaging characteristics associated with each arteriopathy subtype in the derivation cohort, we built a decision framework that we integrated into a Web interface specifically designed to create a probabilistic differential diagnosis. We applied the Web-based tool to the "test cohort." Results The differential diagnosis returned by our tool was in complete agreement with the experts' opinions in 20.6% of patients. We observed a partial agreement in 41.2% of patients and an overlap in 29.4% of patients. The tool disagreed with the experts on the diagnoses of 3 patients (8.8%). Conclusions Our tool yielded an overlapping differential diagnosis in most patients that defied definitive classification by experts. Although it needs to be validated in an independent cohort, it helps facilitate high-quality, and timely diagnoses of arteriopathy in pediatric patients.

Purpose The endoplasmic reticulum membrane complex (EMC) is a highly conserved, multifunctional 10-protein complex related to membrane protein biology. In seven families, we identified 13 individuals with highly overlapping phenotypes who harbor a single identical homozygous frameshift variant in EMC10. Methods Using exome, genome, and Sanger sequencing, a recurrent frameshift EMC10 variant was identified in affected individuals in an international cohort of consanguineous families. Multiple families were independently identified and connected via Matchmaker Exchange and internal databases. We assessed the effect of the frameshift variant on EMC10 RNA and protein expression and evaluated EMC10 expression in normal human brain tissue using immunohistochemistry. Results A homozygous variant EMC10 c.287delG (Refseq NM_206538.3, p.Gly96Alafs*9) segregated with affected individuals in each family, who exhibited a phenotypic spectrum of intellectual disability (ID) and global developmental delay (GDD), variable seizures and variable dysmorphic features (elongated face, curly hair, cubitus valgus, and arachnodactyly). The variant arose on two founder haplotypes and results in significantly reduced EMC10 RNA expression and an unstable truncated EMC10 protein. Conclusion We propose that a homozygous loss-of-function variant in EMC10 causes a novel syndromic neurodevelopmental phenotype. Remarkably, the recurrent variant is likely the result of a hypermutable site and arose on distinct founder haplotypes.

Background Cerebral palsy (CP) is the most common motor disability of childhood. Its early identification is an important priority for parents and is critical for access to early intervention resources, which may optimize function. Methods A prospective cohort of term neonates at high risk for CP was assessed by neonatal magnetic resonance imaging (MRI) to determine myelination of the posterior limb of the internal capsule, General Movements Assessment to assess typical fidgety movements at age three months, and followed to at least age two years to determine diagnosis of CP based on neurological examination. Results Seven of 58 children developed CP (12%), two with moderate/severe CP. Sensitivity and specificity for abnormal myelination of the posterior limb of the internal capsule were (PLIC) was 29% and 94%, and for absent fidgety movements, 29% and 98%, respectively. Negative predictive value of both absent myelination of the PLIC and absent fidgety movements was 90% (79% to 96%) for any CP and 98% (90% to 100%) for moderate/severe CP cerebral palsy. None of the children with both normal PLIC and normal fidgety movements had moderate/severe CP. Conclusion Normal neonatal MRI and General Movements Assessment at age three months are reassuring that a high-risk term-born child is at low risk for moderate/severe CP. These results are important for counseling parents and individualizing therapy resources in the community.

A healthy, asymptomatic woman was referred after incidental discovery of a right superior incongruous hemianopia. Magnetic resonance imaging disclosed a schizencephalic cleft passing through Meyer’s loop of the left optic radiation. The lesion may have resulted from a focal vascular accident or disruption of cortical neurogenesis during gestation.

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.

Background: Hyperpolarized 13C spectroscopic magnetic resonance spectroscopy (MRS) is an advanced imaging tool that may provide important real-time information about brain metabolism. Methods: Mice 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. Results: There 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. Conclusion: We 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.

Malformations of cortical development are a group of rare disorders commonly manifesting with developmental delay, cerebral palsy or seizures. The neurological outcome is extremely variable depending on the type, extent and severity of the malformation and the involved genetic pathways of brain development. Neuroimaging plays an essential role in the diagnosis of these malformations, but several issues regarding malformations of cortical development definitions and classification remain unclear. The purpose of this consensus statement is to provide standardized malformations of cortical development terminology and classification for neuroradiological pattern interpretation. A committee of international experts in paediatric neuroradiology prepared systematic literature reviews and formulated neuroimaging recommendations in collaboration with geneticists, paediatric neurologists and pathologists during consensus meetings in the context of the European Network Neuro-MIG initiative on Brain Malformations (https://www.neuro-mig.org/). Malformations of cortical development neuroimaging features and practical recommendations are provided to aid both expert and non-expert radiologists and neurologists who may encounter patients with malformations of cortical development in their practice, with the aim of improving malformations of cortical development diagnosis and imaging interpretation worldwide.

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.

Background Anti-NMDA receptor encephalitis is an immune-mediated disorder characterized by antibodies against the GluN1 subunit of the NMDA receptor that is increasingly recognized as a treatable cause of childhood epileptic encephalopathy. In adults, the disorder has been associated with reversible changes in brain volume over the course of treatment and recovery, but in children, little is known about its time course and associated imaging manifestations. Case presentation A previously healthy 20-month-old boy presented with first-time unprovoked seizures, dysautonomia, and dyskinesia. Paraneoplastic workup was negative, but CSF was positive for anti-NMDAR antibodies. The patient’s clinical condition waxed and waned over a 14-month course of treatment with first- and second-line immunotherapies (including steroids, IVIG, rituximab, and cyclophosphamide). Serial brain MRIs scans obtained at 5 time points spanning this same period showed no abnormal signal or enhancement but were remarkable for cycles of reversible regional cortical volume loss. All scans included identical 1-mm resolution 3D T1-weighted sequences obtained on the same 3 T scanner. Using a novel longitudinal processing stream in FreeSurfer6 (Reuter M, et. al, Neuroimage 61:1402–18, 2012) we quantified the rate of change in cortical volume at each vertex (% volume change per month) between consecutive scans and correlated these changes with the time course of the patient’s treatment and clinical response. We found regionally specific changes in cortical volume (up to 7% per month) that preferentially affected the frontal and occipital lobes and paralleled the patient’s clinical course, with clinical decline associated with volume loss and clinical improvement associated with volume gain. Conclusions Our results suggest that reversible cortical volume loss in anti-NMDA encephalitis has a regional specificity that mirrors many of the clinical symptoms associated with the disorder and tracks the dynamics of disease severity over time. This case illustrates how quantitative morphometric techniques can be applied to clinical imaging data to reveal patterns of brain change that may provide insight into disease pathophysiology. More widespread application of this approach might reveal regional and temporal patterns specific to different types of autoimmune encephalitis, providing a tool for diagnosis and a surrogate marker for monitoring treatment response.

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: 14.8mL, 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

Although seizures in neonates are common and often due to acute brain injury, 10-15% are unprovoked from congenital brain malformations. A better understanding of the risk of neonatal-onset epilepsy by the type of brain malformation is essential for counseling and monitoring. In this retrospective cohort study, we evaluated 132 neonates with congenital brain malformations and their risk of neonatal-onset epilepsy. Malformations were classified into one of five categories based on imaging patterns on prenatal or postnatal imaging. Infants were monitored with continuous video EEG (cEEG) for encephalopathy and paroxysmal events in addition to abnormal neuroimaging. Seventy-four of 132 (56%) neonates underwent EEG monitoring, and 18 of 132 (14%) were diagnosed with neonatal-onset epilepsy. The highest prevalence of epilepsy was in neonates with disorders of neuronal migration/organization (9/34, 26%; 95% confidence interval [CI] = 13-44%), followed by disorders of early prosencephalic development (6/38, 16%; 95% CI = 6-31%), complex total brain malformations (2/16, 13%; 95% CI = 2-38%), and disorders of midbrain/hindbrain malformations (1/30, 3%; 95% CI = 0-17%). Of neonates with epilepsy, 5 of 18 (28%) had only electrographic seizures, 13 of 18 (72%) required treatment with two or more antiseizure medicines (ASMs), and 7 of 18 (39%) died within the neonatal period. Our results demonstrate that disorders of neuronal migration/organization represent the highest-risk group for early-onset epilepsy. Seizures are frequently electrographic only, require treatment with multiple ASMs, and portend a high mortality rate. These results support American Clinical Neurophysiology Society recommendations for EEG monitoring during the neonatal period for infants with congenital brain malformations.

Cerebellar malformations are diverse congenital anomalies frequently associated with developmental disability. Although genetic and prenatal non-genetic causes have been described, no systematic analysis has been performed. Here, we present a large-exome sequencing study of Dandy-Walker malformation (DWM) and cerebellar hypoplasia (CBLH). We performed exome sequencing in 282 individuals from 100 families with DWM or CBLH, and we established a molecular diagnosis in 36 of 100 families, with a significantly higher yield for CBLH (51%) than for DWM (16%). The 41 variants impact 27 neurodevelopmental-disorder-associated genes, thus demonstrating that CBLH and DWM are often features of monogenic neurodevelopmental disorders. Though only seven monogenic causes (19%) were identified in more than one individual, neuroimaging review of 131 additional individuals confirmed cerebellar abnormalities in 23 of 27 genetic disorders (85%). Prenatal risk factors were frequently found among individuals without a genetic diagnosis (30 of 64 individuals [47%]). Single-cell RNA sequencing of prenatal human cerebellar tissue revealed gene enrichment in neuronal and vascular cell types; this suggests that defective vasculogenesis may disrupt cerebellar development. Further, de novo gain-of-function variants in PDGFRB, a tyrosine kinase receptor essential for vascular progenitor signaling, were associated with CBLH, and this discovery links genetic and non-genetic etiologies. Our results suggest that genetic defects impact specific cerebellar cell types and implicate abnormal vascular development as a mechanism for cerebellar malformations. We also confirmed a major contribution for non-genetic prenatal factors in individuals with cerebellar abnormalities, substantially influencing diagnostic evaluation and counseling regarding recurrence risk and prognosis.

Summary 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., Highlights • Neural stem cell transplantation has a safe long-term safety profile • Donor-specific alloantibodies develop after stem cell transplantation into the CNS • Diffusion MR imaging is a potential surrogate for CNS myelination, Gupta and colleagues show that transplantation with allogeneic central nervous system stem cells can be performed safely in humans with minimal morbidity. Immunologic data, however, show that neural stem cells can elicit an immune response following transplantation, suggesting the importance of monitoring immunologic parameters.

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.

Author(s): Bach, Ashley M; Fang, Annie Y; Bonifacio, Sonia; Rogers, Elizabeth E; Scheffler, Aaron; Partridge, J Colin; Xu, Duan; Barkovich, A James; Ferriero, Donna M; Glass, Hannah C; Gano, Dawn | Abstract: 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 l70, Bayley-III motor score l85 or functional motor deficit. Abnormal cognitive outcome was defined as Bayley-II mental developmental index l70 or Bayley-III cognitive score l85. Abnormal composite outcome was defined as abnormal motor and/or cognitive outcome, or death. The association of therapeutic hypothermia with MRI and outcomes was evaluated with multivariable logistic regression adjusted for propensity to receive therapeutic hypothermia.ResultsFollow-up was available in 317 (78%) surviving children, of whom 155 (49%) received therapeutic hypothermia. Adjusting for propensity, therapeutic hypothermia was independently associated with decreased odds of abnormal motor (OR 0.15, 95% CI 0.06-0.40, Pnln.001) and cognitive (OR 0.11, 95% CI 0.04-0.33, Pnln.001) outcomes. This association remained statistically significant after adjustment for injury pattern. The predictive accuracy of MRI pattern for abnormal composite outcome was unchanged between therapeutic hypothermia-treated (area under the receiver operating curve 0.76; 95% CI 0.61-0.91) and untreated (area under the receiver operating curve 0.74; 95% CI 0.67-0.81) infants. The negative predictive value of normal MRI was high in therapeutic hypothermia-treated and untreated infants (motor 96% vs 90%; cognitive 99% vs 95%).ConclusionsTherapeutic hypothermia is associated with lower rates of brain injury and adverse 30-month outcomes after neonatal encephalopathy. The predictive accuracy of MRI in the first week of life is unchanged by therapeutic hypothermia. Normal MRI remains reassuring for normal 30-month outcome after therapeutic hypothermia.

ObjectiveWe aimed to identify pathogenic variants in a girl with epilepsy, developmental delay, cerebellar ataxia, oral motor difficulty, and structural brain abnormalities with the use of whole-exome sequencing.MethodsWhole-exome trio analysis and molecular functional studies were performed in addition to the clinical findings and neuroimaging studies.ResultsBrain MRI showed mild pachygyria, hypoplasia of the cerebellar vermis, and abnormal foliation of the cerebellar vermis, suspected for a variant in one of the genes of the Reelin pathway. Trio whole-exome sequencing and additional functional studies were performed to identify the pathogenic variants. Trio whole-exome sequencing revealed compound heterozygous splice variants in DAB1, both affecting the highly conserved functional phosphotyrosine-binding domain. Expression studies in patient-derived cells showed loss of normal transcripts, confirming pathogenicity.ConclusionsWe conclude that these variants are very likely causally related to the cerebral phenotype and propose to consider loss-of-function DAB1 variants in patients with RELN-like cortical malformations.

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.

The human brain grows the most dramatically during the perinatal and early post-natal periods, during which pre-term birth or perinatal injury that may alter brain structure and lead to developmental anomalies. Thus, characterizing cortical thickness of developing brains remains an important goal. However, this task is often complicated by inaccurate cortical surface extraction due to small-size brains. Here, we propose a novel complex framework for the reconstruction of neonatal WM and pial surfaces, accounting for large partial volumes due to small-size brains. The proposed approach relies only on T1-weighted images unlike previous T2-weighted image-based approaches while only T1-weighted images are sometimes available under the different clinical/research setting. Deep neural networks are first introduced to the neonatal magnetic resonance imaging (MRI) pipeline to address the mis-segmentation of brain tissues. Furthermore, this pipeline enhances cortical boundary delineation using combined models of the cerebrospinal fluid (CSF)/GM boundary detection with edge gradient information and a new skeletonization of sulcal folding where no CSF voxels are seen due to the limited resolution. We also proposed a systematic evaluation using three independent datasets comprising 736 pre-term and 97 term neonates. Qualitative assessment for reconstructed cortical surfaces shows that 86.9% are rated as accurate across the three site datasets. In addition, our landmark-based evaluation shows that the mean displacement of the cortical surfaces from the true boundaries was less than a voxel size (0.532 ± 0.035 mm). Evaluating the proposed pipeline (namely NEOCIVET 2.0) shows the robustness and reproducibility across different sites and different age-groups. The mean cortical thickness measured positively correlated with post-menstrual age (PMA) at scan (p < 0.0001); Cingulate cortical areas grew the most rapidly whereas the inferior temporal cortex grew the least rapidly. The range of the cortical thickness measured was biologically congruent (1.3 mm at 28 weeks of PMA to 1.8 mm at term equivalent). Cortical thickness measured on T1 MRI using NEOCIVET 2.0 was compared with that on T2 using the established dHCP pipeline. It was difficult to conclude that either T1 or T2 imaging is more ideal to construct cortical surfaces. NEOCIVET 2.0 has been open to the public through CBRAIN (https://mcin-cnim.ca/technology/cbrain/), a web-based platform for processing brain imaging data.

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 mm 3 , 95% CI, 224.6–251.9) compared with controls (262.4 mm 3 , 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.

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 that is catalyzed by the Na,K-ATPase alpha subunit. In vertebrates, four paralogous genes, ATP1A1-4, encode distinct alpha subunit isoforms (a1-a4), three of which (a1, a2, a3) are expressed in the brain, and two (a1, a3) predominantly in neurons. The a3 isoform, encoded by ATP1A3, is critical to neuronal physiology, and a growing spectrum of neurological diseases are associated with ATP1A3 pathogenic variants, with ages of onset ranging from early childhood to adulthood. Here, we describe ATP1A3 variants encoding dysfunctional a3 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 established a transcriptional atlas of ATP1A3 expression during cortical development using mRNA in situ hybridization and transcriptomic profiling of ~125,000 individual cells with single-cell RNA sequencing (Drop-Seq) from various areas of the midgestational human neocortex. We find that fetal expression of ATP1A3 is restricted to a subset of excitatory neurons carrying transcriptional signatures of neuronal activity and maturation characteristic of the developing subplate. Furthermore, by performing Drop-Seq on ~52,000 nuclei from four different areas of an infant human neocortex, we show that ATP1A3 expression persists throughout early postnatal development, not only within excitatory neurons across all cortical layers, but also and more predominantly in inhibitory neurons, with specific enrichment in fast-spiking basket cells. In addition, we show that ATP1A3 expression, both in fetal and postnatal neurons, tends to be higher in frontal cortical areas than in occipital areas, in a pattern consistent with the rostro-caudal maturation gradient of the human neocortex. Finally, we discover distinct co-expression patterns linking catalytic α subunit isoforms (ATP1A1,2,3) and auxiliary isoforms (ATP1B1,2,3), suggesting the ATPase pump may form non-redundant, cell-type specific α-β combinations. Together, the importance of the developmental phenotypes and dynamic expression patterns of ATP1A3 point to a key role for a3 in the development and function of human cortex.

Purpose The 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. Methods We 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. Results We 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. Conclusion Our results highlight the essential role of the exocyst pathway in normal cortical development and how its perturbation causes complex brain disorders.

We investigated the ability of graph convolutional network (GCN) that takes into account the mesh topology as a sparse graph to predict brain age for preterm neonates using cortical surface morphometrics, i.e. cortical thickness and sulcal depth. Compared to machine learning and deep learning methods that did not use the surface topological information, the GCN better predicted the ages for preterm neonates with none/mild perinatal brain injuries (NMI). We then tested the GCN trained using NMI brains to predict the age of neonates with severe brain injuries (SI). Results also displayed good accuracy ( $\text{MAE}=1.43$ weeks), while the analysis of the interaction term (true age × group) showed that the slope of the predicted brain age relative to the true age for the SI group was significantly less steep than the NMI group ( $\mathrm{p} ), indicating that SI can decelerate early postnatal growth. To understand regional contributions to age prediction, we applied GCNs separately to the vertices within each cortical parcellation. The middle cingulate cortex that is known to be one of the thickest cortical regions in the neonatal period showed the best accuracy in age prediction ( $\text{MAE}=1.24$ weeks). Furthermore, we found that the regional brain ages computed using GCN models in several frontal cortices significantly correlated with cognitive abilities at 3 years of age. Furthermore, the brain predicted age in part of the superior temporal cortex, which is the auditory and language processing locus, was related to language functional scores at 3 years. Our results demonstrate the potential of the GCN models for predicting brain age as well as localizing brain regions contributing to the prediction of age and future cognitive outcome.

Perinatal brain injuries in preterm neonates are associated with alterations in structural neurodevelopment, leading to impaired cognition, motor coordination, and behavior. However, it remains unknown how such injuries affect postnatal cortical folding and structural covariance networks, which indicate functional parcellation and reciprocal brain connectivity. Studying 229 magnetic resonance scans from 158 preterm neonates (n = 158, mean age = 28.2), we found that severe injuries including intraventricular hemorrhage, periventricular leukomalacia, and ventriculomegaly lead to significantly reduced cortical folding and increased covariance (hyper-covariance) in only the early (35 weeks) of the third trimester. The aberrant hyper-covariance may drive acceleration of cortical folding as a compensatory mechanism to “catch-up” with normal development. By 40 weeks, preterm neonates with/without severe brain injuries exhibited no difference in cortical folding and covariance compared with healthy term neonates. However, graph theory-based analysis showed that even after recovery, severely injured brains exhibit a more segregated, less integrated, and overall inefficient network system with reduced integration strength in the dorsal attention, frontoparietal, limbic, and visual network systems. Ultimately, severe perinatal injuries cause network-level deviations that persist until the late stage of the third trimester and may contribute to neurofunctional impairment.

Genes mutated in human neuronal migration disorders encode tubulin proteins and a variety of tubulin-binding and -regulating proteins, but it is very poorly understood how these proteins function together to coordinate migration. Additionally, the way in which regional differences in neocortical migration are controlled is completely unknown. Here we describe a new syndrome with remarkably region-specific effects on neuronal migration in the posterior cortex, reflecting de novo variants in CEP85L. We show that CEP85L is required cell autonomously in vivo and in vitro for migration, that it localizes to the maternal centriole, and that it forms a complex with many other proteins required for migration, including CDK5, LIS1, NDE1, KIF2A, and DYNC1H1. Loss of CEP85L disrupts CDK5 localization and activation, leading to centrosome disorganization and disrupted microtubule cytoskeleton organization. Together, our findings suggest that CEP85L highlights a complex that controls CDK5 activity to promote neuronal migration. Refereed/Peer-reviewed

Author(s): Kamino, Daphne; Chau, Vann; Studholme, Colin; Liu, Mengyuan; Xu, Duan; Barkovich, A James; Ferriero, Donna M; Miller, Steven P; Brant, Rollin; Tam, Emily WY | Abstract: 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.

Protein homeostasis is tightly regulated by the ubiquitin proteasome pathway. Disruption of this pathway gives rise to a host of neurological disorders. Through whole exome sequencing (WES) in families with neurodevelopmental disorders, we identified mutations in PSMD12, a core component of the proteasome, underlying a neurodevelopmental disorder with intellectual disability (ID) and features of autism spectrum disorder (ASD). We performed WES on six affected siblings from a multiplex family with ID and autistic features, the affected father, and two unaffected mothers, and a trio from a simplex family with one affected child with ID and periventricular nodular heterotopia. We identified an inherited heterozygous nonsense mutation in PSMD12 (NM_002816: c.367C>T: p.R123X) in the multiplex family and a de novo nonsense mutation in the same gene (NM_002816: c.601C>T: p.R201X) in the simplex family. PSMD12 encodes a non-ATPase regulatory subunit of the 26S proteasome. We confirm the association of PSMD12 with ID, present the first cases of inherited PSMD12 mutation, and demonstrate the heterogeneity of phenotypes associated with PSMD12 mutations.

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.

BACKGROUND:Brain 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. OBJECTIVES:This 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). METHODS:Term newborns with d-TGA and SVP had pre-operative and post-operative brain magnetic resonance imaging and ND outcomes assessed at 12 and 30months with the Bayley Scales of Infant Development-II. BI was categorized by the brain injury severity score and WMI was quantified by volumetric analysis. RESULTS:A total of 104 infants had follow-up at 12months and 70 had follow-up at 30months. At 12months, only clinical variables were associated with ND outcome. At 30months, 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 30months were wide (-40.3 to 31.2) across the range of mean PDI values. CONCLUSIONS:Increasing burden of WMI is associated with worse motor outcomes at 30months for infants with criticalcongenital heart disease, whereas no adverse association was seen between small strokes and outcome. Theseresults support the utility of neonatal brain magnetic resonance imaging in this population to aid in predictinglateroutcomes and the importance of ND follow-up beyond 1 year of age.

MR imaging of premature neonates is challenging due to their small size, need for temperature support and monitoring, and immature central nervous system. Use of MR compatible incubators and MR compatible monitoring apparatus, careful selection of imaging protocols, and real time review of images by a radiologist can streamline the imaging process and improve image quality. Imaging should be focused upon (1) the child's biorhythms (imaging during sleep cycles), (2) minimizing delays during transport and (3) delaying noisy MR sequences until the end of an examination. Successful imaging of premature neonates requires teamwork: advanced planning, careful communication among neonatologists, nurses, and radiologists, established imaging protocols, and coordination among team members during all aspects of the process.

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

Aminoacyl-transfer RNA (tRNA) synthetases ligate amino acids to specific tRNAs and are essential for protein synthesis. Although alanyl-tRNA synthetase (AARS) is a synthetase implicated in a wide range of neurological disorders from Charcot-Marie-Tooth (CMT) disease to infantile epileptic encephalopathy, there have been limited data on their pathogenesis. Here we report loss-of-function mutations in AARS in two siblings with progressive microcephaly with hypomyelination, intractable epilepsy and spasticity. Whole exome sequencing identified that the affected individuals were compound heterozygous for mutations in AARS gene, c.2067dupC (p.Tyr690Leufs*3) and c.2738G>A (p.Gly913Asp). A lymphoblastoid cell line developed from one of the affected individuals showed a strong reduction in AARS abundance. The mutations decrease aminoacylation efficiency by 70–90%. The p.Tyr690Leufs*3 mutation also abolished editing activity required for hydrolyzing misacylated tRNAs, thereby increasing errors during aminoacylation. Our study has extended potential mechanisms underlying AARS-related disorders to include destabilization of the protein, aminoacylation dysfunction, and defective editing activity. This article is protected by copyright. All rights reserved

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.

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.

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.

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., Highlights • Global volume loss after neonatal brain injury results in poorer language outcome. • Variability in language correlates specifically with left perisylvian brain volume. • Changes in regional brain volume are not correlated with motor or cognitive outcome.

Neuroimaging enables the evaluation of many aspects of brain maturation, and detection of abnormalities such as malformation and injury. MRI is integral to the diagnostic work-up of congenital and acquired disorders of the central nervous system in newborns, and imaging findings are central to prognostication. This paper reviews techniques to optimize assessment of maturity of the neonatal brain, as well as abnormalities and injuries of the newborn brain that are associated with abnormal neurocognitive development.

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 CI 0.6% to 2.2%, P =0.001) at the time of stage‐2 palliation compared with tube‐fed patients, denoting more robust brain development. Conclusions Slower rate of postnatal brain maturation but not perioperative brain injury is associated with feeding modality in infancy. These results support the importance of brain health in optimizing feeding outcomes in patients with SVP .

Though quantification of cortical thickness characterizes a main aspect of morphology in developing brains, it is challenged in the analysis of neonatal brain MRI due to inaccurate pial surface extraction. In this study, we propose a pial surface reconstruction method to address for the relatively large partial volume (PV) within the sulcal basin. The new approach leverages the benefits of using new skeletonization and the deformation models with a new gradient feature. The proposed skeletonization method combines the voxels representing the skeleton of cerebrospinal fluid partial volume (CSF-PV) with the voxels of the medial plane of the gray matter (GM) volume of the sulcus where no CSF-PV is estimated due to the squashed sulcal bank and the limited resolution. Subsequently, the outer cortical boundary is identified by first deforming the initial surface to the skeleton, then refining it using the gradient model characterizing the subtle edges representing the “ground truth” of the GM/CSF boundary. Our landmark-based evaluation showed that the initial boundary identified by the skeletonization was already close to the “ground truth” of the GM/CSF boundary (0.4 mm distant). Furthermore, this was significantly improved by the reconstruction of the final pial surface $( \lt 0.1$ mm; $\mathrm {p}\lt 0.0001)$. The mean cortical thickness measured through our pipeline positively correlated with postmenstrual age (PMA) at scan $( \mathrm {p}\lt 0.0001)$. The range of the measurement was biologically reasonable (1.4 mm at 28 weeks of PMA to 2.2 mm at term equivalent $vs$. young adults: 2.5–3.5 mm) and was quite close to past reports (2.1 mm at term).

Author(s): Numis, Adam L; Foster-Barber, Audrey; Deng, Xutao; Rogers, Elizabeth E; Barkovich, A James; Ferriero, Donna M; Glass, Hannah C | Abstract: 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 g2 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.

Background Neonates 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. Methods In 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). Results The 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. Conclusions WMI 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.

As magnetic resonance imaging has been increasingly used to study brain injury and brain development in premature newborns, the prevalence of cerebellar abnormalities is increasingly recognized. The preterm cerebellum is highly vulnerable to a number of insults during its critical phase of growth and development throughout the period of prematurity and beyond. Direct cerebellar injury and additional factors such as supratentorial brain injury and glucocorticoid exposure adversely impact cerebellar growth and, consequently, increase the risk of neurodevelopmental disabilities. In this chapter the causes and consequences of cerebellar hypoplasia of prematurity are reviewed.

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.

Objective Recent reports have described single individuals with neurodevelopmental disability (NDD) harboring heterozygous KCNQ3 de novo variants (DNVs). We sought to assess whether pathogenic variants in KCNQ3 cause NDD and to elucidate the associated phenotype and molecular mechanisms. Methods Patients with NDD and KCNQ3 DNVs were identified through an international collaboration. Phenotypes were characterized by clinical assessment, review of charts, electroencephalographic (EEG) recordings, and parental interview. Functional consequences of variants were analyzed in vitro by patch-clamp recording. Results Eleven patients were assessed. They had recurrent heterozygous DNVs in KCNQ3 affecting residues R230 (R230C, R230H, R230S) and R227 (R227Q). All patients exhibited global developmental delay within the first 2 years of life. Most (8/11, 73%) were nonverbal or had a few words only. All patients had autistic features, and autism spectrum disorder (ASD) was diagnosed in 5 of 11 (45%). EEGs performed before 10 years of age revealed frequent sleep-activated multifocal epileptiform discharges in 8 of 11 (73%). For 6 of 9 (67%) recorded between 1.5 and 6 years of age, spikes became near-continuous during sleep. Interestingly, most patients (9/11, 82%) did not have seizures, and no patient had seizures in the neonatal period. Voltage-clamp recordings of the mutant KCNQ3 channels revealed gain-of-function (GoF) effects. Interpretation Specific GoF variants in KCNQ3 cause NDD, ASD, and abundant sleep-activated spikes. This new phenotype contrasts both with self-limited neonatal epilepsy due to KCNQ3 partial loss of function, and with the neonatal or infantile onset epileptic encephalopathies due to KCNQ2 GoF. ANN NEUROL 2019;86:181-192

Malformations of cortical development (MCDs) compose a diverse range of disorders that are common causes of neurodevelopmental delay and epilepsy. With improved imaging and genetic methodologies, the underlying molecular and pathobiological characteristics of several MCDs have been recently elucidated. In this review, we discuss genetic and molecular alterations that disrupt normal cortical development, with emphasis on recent discoveries, and provide detailed radiological features of the most common and important MCDs. Ann Neurol 2016;80:797-810.

In recent years, the concept of hypomyelinating disorders has been proposed as a group of disorders with varying systemic manifestations that are identified by MR findings of absence or near absence of the T2 hypointensity that develops in white matter as a result of myelination. Initially proposed as a separate group because they were the largest single category of undiagnosed leukodystrophies, their separation as a distinct group that can be recognized by looking for a specific MRI feature has resulted in a marked increase in their diagnosis and a better understanding of the different causes of hypomyelination. This review will discuss the clinical presentations, imaging findings on standard MRI, and new MRI-related techniques that allow a better understanding of these disorders and proposed methods for quantifying the myelination as a potential means of assessing disease course and the effects of proposed treatments. Disorders with hypomyelination of white matter, or hypomyelinating disorders (HMDs), represent the single largest category among undiagnosed genetic leukoencephalopathies (Schiffmann and van der Knaap, 2009; Steenweg et al., 2010). This group of inborn errors of metabolism is characterized by a magnetic resonance imaging (MRI) appearance of reduced or absent myelin development: delay in the development of T2 hypointensity and, often, T1 hyperintensity in the white matter of the brain. The concept of hypomyelination was first conceptualized by (Schiffmann and van der Knaap, 2009; Steenweg et al., 2010; Schiffmann et al., 1994) in a series of papers that showed that these MRI characteristics were easily recognized, were different from the MRI characteristics of dysmyelinating and demyelinating disorders, and that the combination of these imaging findings with specific other clinical and imaging features could be used to make diagnoses with some confidence. In this manuscript, we will discuss the physiologic and genetic bases of hypomyelinating disorders, as well as their classification, clinical manifestations and imaging characteristics.

In recent years, the concept of hypomyelinating disorders has been proposed as a group of disorders with varying systemic manifestations that are identified by MR findings of absence or near absence of the T2 hypointensity that develops in white matter as a result of myelination. Initially proposed as a separate group because they were the largest single category of undiagnosed leukodystrophies, their separation as a distinct group that can be recognized by looking for a specific MRI feature has resulted in a marked increase in their diagnosis and a better understanding of the different causes of hypomyelination. This review will discuss the clinical presentations, imaging findings on standard MRI, and new MRI-related techniques that allow a better understanding of these disorders and proposed methods for quantifying the myelination as a potential means of assessing disease course and the effects of proposed treatments. Disorders with hypomyelination of white matter, or hypomyelinating disorders (HMDs), represent the single largest category among undiagnosed genetic leukoencephalopathies (Schiffmann and van der Knaap, 2009; Steenweg et al., 2010). This group of inborn errors of metabolism is characterized by a magnetic resonance imaging (MRI) appearance of reduced or absent myelin development: delay in the development of T2 hypointensity and, often, T1 hyperintensity in the white matter of the brain. The concept of hypomyelination was first conceptualized by (Schiffmann and van der Knaap, 2009; Steenweg et al., 2010; Schiffmann et al., 1994) in a series of papers that showed that these MRI characteristics were easily recognized, were different from the MRI characteristics of dysmyelinating and demyelinating disorders, and that the combination of these imaging findings with specific other clinical and imaging features could be used to make diagnoses with some confidence. In this manuscript, we will discuss the physiologic and genetic bases of hypomyelinating disorders, as well as their classification, clinical manifestations and imaging characteristics.

Preterm birth has a dramatic impact on polyunsaturated fatty acid exposures for the developing brain. This study examined the association between postnatal fatty acid levels and measures of brain injury and development, as well as outcomes. A cohort of 60 preterm newborns (24–32 wk gestational age) was assessed using early and near-term magnetic resonance imaging (MRI) studies. Red blood cell fatty acid composition was analyzed coordinated with each scan. Outcome at a mean of 33 mo corrected age was assessed using the Bayley Scales of Infant Development, 3rd edition. Adjusting for confounders, a 1% increase in postnatal docosahexaenoic acid (DHA) levels at early MRI was associated with 4.3-fold decreased odds of intraventricular hemorrhage, but was not associated with white matter injury or cerebellar haemorrhage. Higher DHA and lower linoleic acid (LA) levels at early MRI were associated with lower diffusivity in white matter tracts and corresponding improved developmental scores in follow-up. Higher DHA and lower LA levels in the first few weeks of life are associated with decreased intraventricular haemorrhage, improved microstructural brain development, and improved outcomes in preterm born children. Early and possibly antenatal interventions in high-risk pregnancies need to be studied for potential benefits in preterm developmental outcomes.