Transient Focal Neurologic Symptoms Correspond to Regional Cerebral Hypoperfusion by MRI: A Stroke Mimic in Children.

Children who present with acute transient focal neurologic symptoms raise concern for stroke or transient ischemic attack. We present a series of 16 children who presented with transient focal neurologic symptoms that raised concern for acute stroke but who had no evidence of infarction and had unilateral, potentially reversible imaging features on vascular and perfusion-sensitive brain MR imaging. Patients were examined with routine brain MR imaging, MRA, perfusion-sensitive sequences, and DWI. Fourteen (88%) children had lateralized MRA evidence of arterial tree pruning without occlusion, all had negative DWI findings, and all showed evidence of hemispheric hypoperfusion by susceptibility-weighted imaging or arterial spin-labeling perfusion imaging at presentation. These findings normalized following resolution of symptoms in all children who had follow-up imaging (6/16, 38%). The use of MR imaging with perfusion-sensitive sequences, DWI, and MRA can help to rapidly distinguish children with conditions mimicking stroke from those with acute stroke.

Developmental fMRI study of episodic verbal memory encoding in children.

BACKGROUND: Understanding the maturation and organization of cognitive function in the brain is a central objective of both child neurology and developmental cognitive neuroscience. This study focuses on episodic memory encoding of verbal information by children, a cognitive domain not previously studied using fMRI. METHODS: Children from 7 to 19 years of age were scanned at 1.5-T field strength using event-related fMRI while performing a novel verbal memory encoding paradigm in which words were incidentally encoded. A subsequent memory analysis was performed. SPM2 was utilized for whole brain and region-of-interest analyses of data. Both whole-sample intragroup analyses and intergroup analyses of the sample divided into 2 subgroups by age were conducted. RESULTS: Importantly, behavioral memory performance was equal across the age range of children studied. Encoding-related activation in the left hippocampus and bilateral basal ganglia declined as age increased. In addition, while robust blood oxygen level-dependent signal was found in left prefrontal cortex with task performance, no encoding-related age-modulated prefrontal activation was observed in either hemisphere. CONCLUSION: These data are consistent with a developmental pattern of verbal memory encoding function in which left hippocampal and bilateral basal ganglionic activations are more robust earlier in childhood but then decline with age. No encoding-related activation was found in prefrontal cortex which may relate to this region's recognized delay in biologic maturation in humans. These data represent the first fMRI demonstration of verbal encoding function in children and are relevant developmentally and clinically.

The NIH MRI study of normal brain development (Objective-2): newborns, infants, toddlers, and preschoolers.

The Magn. Reson. Imaging (MRI) study of normal brain development currently conducted by the Brain Development Cooperative Group represents the most extensive MRI study of brain and behavioral development from birth through young adulthood ever conducted. This multi-center project, sponsored by four Institutes of the National Institutes of Health, uses a combined longitudinal and cross-sectional design to characterize normal, healthy brain and behavioral development. Children, ages newborn through 18-plus years of age, receive comprehensive behavioral, neurological and multimodal MRI evaluations via Objective-2 (birth through 4-years 5-months of age) and Objective-1 (4-years 6-months through 18 years of age and older). This report presents methods (e.g., neurobehavioral assessment, brain scan) and representative preliminary results (e.g., growth, behavior, brain development) for children from newborn through 4-years 5-months of age. To date, 75 participants from birth through 4-years 5-months have been successfully brain scanned during natural sleep (i.e., without sedation); most with multiple longitudinal scans (i.e., 45 children completing at least three scans, 22 completing four or more scans). Results from this younger age range will increase our knowledge and understanding of healthy brain and neurobehavioral development throughout an important, dynamic, and rapid growth period within the human life span; determine developmental associations among measures of brain, other physical characteristics, and behavior; and facilitate the development of automated, quantitative MR image analyses for neonates, infants and young children. The correlated brain MRI and neurobehavioral database will be released for use by the research and clinical communities at a future date.

Prolonged T*2 values in newborn versus adult brain: Implications for fMRI studies of newborns.

The neonatal brain possesses higher water content, lower macromolecular concentration, and reduced synaptic density than is found in the brain of a 1-year-old child. Changes in MRI characteristics of brain such as relaxation times accompany rapid changes in brain during early postnatal development. It was hypothesized that T(*)(2) values found in newborns would be significantly higher than those found in 9-month-old children and adults as measured at 1.5 T. Spoiled gradient echo measurements of T(*)(2) within the brains of newborns, 9-month-olds, and adults confirmed this hypothesis. The results have implications with regard to functional MRI studies in newborns since, in general, BOLD signal optimization is achieved when echo times TE are set equal to the T(*)(2) values of the tissue of interest. Since significantly longer T(*)(2) values are found in newborns, it is suggested that the TE values employed for fMRI studies of newborns should be increased to maximize BOLD signal intensity changes and improve the overall reliability of fMRI results in newborns.

Biexponential apparent diffusion coefficient parametrization in adult vs newborn brain.

The decay of brain water signal with b-factor in adult and newborn brains has been measured over an extended b-factor range. Measurements of the apparent diffusion coefficient (ADC) decay curves were made at 16 b-factors from 100 to 5000 s/mm(2) along three orthogonal directions using a line scan diffusion imaging (LSDI) sequence to acquire data from 0.09 ml voxels in a mid-brain axial slice. Regions-of-interest (ROIs) in cortical gray (CG) and white matter in the internal capsule (IC) were selected for ADC decay curve analyses using a biexponential fitting model over this extended b-factor range. Measures of the fast and slow ADC component amplitudes and the traces of the fast and slow diffusion coefficients were obtained from CG and IC ROIs in both adults and newborns. The ADC decay curves from the newborn brain regions were found to have a significantly higher fraction of the fast diffusion ADC component than corresponding regions in the adult brain. The results demonstrate that post-natal brain development has a profound affect on the biexponential parameters which characterize the decay of water signal over an extended b-factor range in both gray and white matter.

Developmental neuroimaging of children using magnetic resonance techniques.

Cognitive and motor development in children remain fascinating processes that are uniquely human. Progress has been made in recent years in elucidating the prenatal process of human brain development. In addition, much information exists regarding the behavioral aspects of postnatal human development. However, little is known about the relationship between anatomic postnatal central nervous system development and the accretion of functional milestones observed in children from the neonatal period through adolescence. Recently, powerful qualitative and quantitative magnetic resonance techniques have been developed that will permit detailed inquiry into the connection between the developing brain and the developing mind. In this review, first, the steps of prenatal and postnatal brain development are reviewed briefly. Subsequently, recent magnetic resonance imaging data related to human brain development during the fetal, neonatal, and later childhood periods are presented. Finally, functional magnetic resonance imaging (fMRI) is discussed. Specific examples of its usefulness are provided. Magnetic resonance imaging techniques such as quantitative MRI, volumetric MRI, diffusion tensor imaging, and functional magnetic resonance imaging (fMRI) when combined with neurologic and neuropsychologic evaluation, will provide new insights into the cognitive development of children. MRDD Research Reviews 6:68-80, 2000.

MR line-scan diffusion-weighted imaging of term neonates with perinatal brain ischemia.

BACKGROUND AND PURPOSE: MR diffusion-weighted imaging provides early demonstration of neonatal brain infarction. The evolution and limitations of diffusion-weighted imaging findings in newborns, however, have not been evaluated. Using line-scan diffusion imaging (LSDI), we investigated perinatal ischemic brain injury. METHODS: Nineteen term newborns (age, 9 hours to 8 days; mean age, 2.6 days) with perinatal brain ischemia were evaluated using LSDI (1520/62.5/1 [TR/TE/excitations]) (b maximum = 750 s/mm2) and T1- and T2-weighted spin-echo (conventional) MR imaging. Follow-up examinations were performed in seven patients and autopsy in one. Apparent diffusion coefficients (ADCs) were measured in deep gray matter, white matter, the cortex, and focal lesions. RESULTS: Based on conventional MR imaging or pathologic findings, patients were divided into two groups. Group 1 (n = 12) had symmetric/diffuse injury consistent with global hypoperfusion. Group 2 (n = 7) had focal/multifocal injury suggesting cerebrovascular occlusion. ADCs were abnormal at initial examination in 10 newborns in group 1 and in all newborns in group 2. The results of LSDI were abnormal before conventional MR imaging was performed in three newborns in group 1. ADCs were maximally decreased between days 1 and 3 in deep gray matter, perirolandic white matter, and focal lesions. Delayed decreases in ADCs were observed in subcortical white matter from days 4 through 10 in three patients in group 1. CONCLUSION: After global hypoperfusion, LSDI showed deep gray matter and perirolandic white matter lesions before conventional MR imaging. LSDI may underestimate the extent of injury, however, possibly because of variations in the compartmentalization of edema, selective vulnerability, and delayed cell death. Differences in LSDI of symmetric/diffuse and focal/multifocal lesions may reflect differences in pathophysiology or timing of the injury. These findings may have implications for acute interventions.

Exclusion of the gastrin-releasing peptide receptor (GRPR) locus as a candidate gene for Rett syndrome.

The gene for the gastrin-releasing peptide receptor (GRPR) has been mapped to a candidate region for Rett syndrome (RTT) on the short arm of the X chromosome. The recent report of a translocation that disrupted the gene in an individual with mental retardation and autistic behavior prompted us to examine GRPR as a possible locus for RTT. Genomic polymerase chain reaction amplification of exons followed by single-strand conformation analysis screening in 25 unrelated RTT-affected individuals and by direct sequencing in 12 others has failed to detect any mutation. No gross structural rearrangements were found by Southern analysis of DNA from six unrelated RTT-affected individuals. A high-frequency biallelic polymorphism caused by two single nucleotide substitutions in exon 2 was discovered. The allele frequencies were identical in the RTT population as compared to 100 normal control X chromosomes. This polymorphism will enable future evaluation of the GRPR locus as a candidate for other X-linked mental retardation or neurobehavioral syndromes.

Hypoxic-ischemic brain injury in the term newborn. Neuropathology, clinical aspects, and neuroimaging.

Hypoxic-ischemic cerebral injury in the full-term infant results in a variety of neurologic manifestations. The pathogenetic events resulting in this central nervous system injury may occur throughout the prenatal period. Several clinical patterns of signs and symptoms of hypoxic-ischemic cerebral injury have been identified in the term infant. Further, characteristic neuroradiologic patterns of this injury can be discerned. Information derived from the term infant's clinical course and neuroimaging data convey useful neurodevelopmental prognostic information. Several potential and promising therapeutic agents exist may attenuate the sequelae of hypoxic-ischemic cerebral injury to the term infant.

Oligodendroglial development in human fetal cerebrum.

We have successfully established mixed glial cell primary cultures prepared from individual fetal human brains (15-18 weeks' gestation in age). Cultures were maintained for as long as 3 months in either 10% fetal calf serum (FCS) or serum-free chemically defined medium (CDM). By morphological and immunohistochemical criteria, the precursor cell for human oligodendrocytes (O-2A cell) was identified. This cell exhibited the bipolar morphology and A2B5-positive (A2B5+) immunoreactivity typical of the O-2A precursor cell. With time in culture, cells possessing a stellate morphology appeared, some of which stained with the O4 antibody, indicative of cell differentiation in the oligodendroglial lineage. At yet older culture age, arborized cells bearing the O1 (galactocerebroside, GC) immunohistochemical marker and displaying the morphological characteristics typical of more mature oligodendrocytes were found, confirming their oligodendroglial identity. Oligodendroglial differentiation was supported best by CDM rather than FCS. To complement these observations, double immunofluorescent studies were performed on parietal sections from human fetal brains at 20 to 22 weeks of gestation. Bipolar A2B5+, multipolar A2B5+/O4+, and arborized A2B5-/O1+ cells were found, thus confirming the presence of oligodendrocytes in human fetal brain at this stage of prenatal development and consistent with the observations made in cell culture.

Neonatal idiopathic cerebral venous thrombosis: an unrecognized cause of transient seizures or lethargy.

Seven neonates who presented with either lethargy (four infants) or seizures (three infants) were found by magnetic resonance (MR) phase imaging to have idiopathic cerebral venous thrombosis (CVT). Examination showed only hypotonia or hyperreflexia. The presence of CVT was suggested by unenhanced cranial computed tomographic (CT) scans. Conventional MR T1- and T2-weighted images often indicated more extensive thromboses than were suggested by cranial CT. In all infants, MR phase imaging confirmed thromboses by establishing absence of blood flow in cerebral veins or sinuses. No infant received anticoagulation. Lethargy slowly resolved and seizures did not recur. Normal development has been observed thus far in brief follow-up. The occurrence of seven infants with idiopathic neonatal CVT within a 3-month period indicates that CVT may be a cause of neonatal seizures or lethargy of unclear cause. MR phase imaging provides a powerful, noninvasive means of confirming the diagnosis. Treatment with anticoagulants does not appear necessary.

A search for X-chromosome uniparental disomy and DNA rearrangements in the Rett syndrome.

The cause of the Rett syndrome remains unknown but is thought to be related to X-chromosome abnormalities. Restriction fragment length polymorphism analysis was employed to search for X-chromosome DNA rearrangements and uniparental disomy in 16 probands and their families. Eighteen different probes, each specific for an area on either the long or the short arm of the X-chromosome, were used. DNA rearrangements were not detected at any of the tested loci. In addition, at each informative locus evidence of both maternal and paternal contributions was found in all probands. Thus, no evidence of either chromosomal abnormality or uniparental disomy was found in the population studied. If uniparental disomy is indeed a causative genetic mechanism for the Rett syndrome, its occurrence may only be infrequent.

Primary structure of influenza virus genome regions coding for polypeptides from the major antigenic sites of H3 hemagglutinin.

Nucleotide sequences for some regions of the hemagglutinin (HA) gene of influenza virus A/Leningrad/385/80 (H3N2) were analyzed. A double-stranded complementary DNA was synthesized on the influenza genome RNA in the presence of synthetic oligodeoxyribonucleotides A GCAAAAGCAGG and A GTAGAAACAAG and inserted into the Pst I-site of the pBR322 plasmid through G-C-tailing. Nucleotide sequences were determined by a solid phase modification of the Maxam and Gilbert procedure. A comparison of our data with those for influenza virus A/Bangkok/1/79, which is the nearest sequenced prototype of the strain investigated, revealed only two base changes in the variable region of the HA gene. One of them was accompanied by a change in the coded amino acid (Asp53----Tyr) located in the antigenic site E of the HA glycoprotein. There also were some point mutations in the constant region of the gene. The results obtained are discussed in terms of the evolution of "Hong Kong" influenza viruses during their circulation.