Neonatal encephalopathy represents a heterogeneous group of conditions associated with life-long developmental disabilities and neurological deficits. Clinical measures and current anatomic brain imaging remain inadequate predictors of outcome in children with neonatal encephalopathy. Some studies have suggested that brain development and, therefore, brain connectivity may be altered in the subgroup of patients who subsequently go on to develop clinically significant neurological abnormalities. Large-scale structural brain connectivity networks constructed using diffusion tractography have been posited to reflect organizational differences in white matter architecture at the mesoscale, and thus offer a unique tool for characterizing brain development in patients with neonatal encephalopathy. In this manuscript we use diffusion tractography to construct structural networks for a cohort of patients with neonatal encephalopathy. We systematically map these networks to a high-dimensional space and then apply standard machine learning algorithms to predict neurological outcome in the cohort. Using nested cross-validation we demonstrate high prediction accuracy that is both statistically significant and robust over a broad range of thresholds. Our algorithm offers a novel tool to evaluate neonates at risk for developing neurological deficit. The described approach can be applied to any brain pathology that affects structural connectivity.
Background and Purpose
Primary microcephalies are incompletely understood malformations that are often associated with developmental brain anomalies, yet it is not understood if the associated anomalies result from the microcephaly itself or from associated developmental/genetic mishaps. This study reviewed and analyzed a large number of MRI scans of children with microcephaly to determine the frequency of associated morphological findings and to assess whether these findings were associated with the severity of the microcephaly.
Materials and Methods
MRIs of 119 patients with clinically diagnosed microcephaly were retrospectively reviewed, focusing on the degree of microcephaly, simplification of gyri, white matter volume, abnormalities of corpus callosum, size and structure of posterior fossa contents, and myelination. Associations among the findings were evaluated using the Spearman correlation coefficient and the Fisher exact test.
Among 7 patients with mild, 42 with moderate, and 70 with extreme microcephaly, a significant correlation was identified between a greater degree of microcephaly and both a greater degree of simplified gyration and decreased white matter volume. The severity of callosal anomaly showed a lower, but still significant, correlation with the severity of microcephaly. Degree of hypoplasia of posterior fossa structures, delay in myelination, and abnormality of basal ganglia did not correlate with the degree of microcephaly.
A strong correlation was found between the degree of microcephaly, the volume of white matter, and the presence of a simplified gyral pattern. These associations should be considered when attempting to use neuroimaging for segregation and classification of patients with microcephaly.
Polymicrogyria; cerebral cortex; magnetic resonance imaging; brain malformation
Tensor based morphometry (TBM) is a powerful approach to analyze local structural changes in brain anatomy. However, conventional scalar TBM methods do not completely capture all direction specific volume changes required to model complex changes such as those during brain growth. In this paper, we describe novel TBM descriptors for studying direction-specific changes in a subject population which can be used in conjunction with scalar TBM to analyze local patterns in directionality of volume change during brain development. We also extend the methodology to provide a new approach to mapping directional asymmetry in deformation tensors associated with the emergence of structural asymmetry in the developing brain. We illustrate the use of these methods by studying developmental patterns in the human fetal brain, in vivo. Results show that fetal brain development exhibits a distinct spatial pattern of anisotropic growth. The most significant changes in the directionality of growth occurs in the cortical plate at major sulci. Our analysis also detected directional growth asymmetry in the peri-sylvian region and the medial frontal lobe of the fetal brain.
Structural MRI; Fetal imaging; tensor based morphometry; directional growth modeling; brain development
Background and purpose
Changes of the major forebrain commissures in lissencephaly have not been systematically studied. This study investigated the developmental differences of the commissures in patients with varying types of lissencephaly to determine whether specific commissural features may help in distinguishing among lissencephaly phenotypes.
Materials and methods
MRI of 124 patients were retrospectively reviewed. Patients were classified as classic(cLIS), variant(vLIS) and Cobblestone lissencephaly(CBSC) according to cortical phenotype; few patients had genetic diagnoses. Abnormalities of the corpus callosum, anterior (AC), and hippocampal commissures (HC) were recorded, and the overall shape was regarded as hypogenetic, hypoplastic, dysmorphic, angled splenium and convex corpus compared with ge matched controls. Correlations between commissural characteristics and cortical patterns were analyzed using Monte Carlo simulation of chi-square, ‘extention to mxn table’, and Fisher’s exact tests as appropriate (p<0.05).
Patients were classified as cLIS (57.4%), vLIS (38.4%) or CBSC (4.2%). The most common callosal developmental anomaly was hypogenesis with absent rostrum, small inferior genu and small splenium. An angled (90°) splenium was found to be significantly associated with cLIS; and excessively convex corpus callosum with VLDLR mutations. ACC with enlarged anterior commissure was found in all ARX mutations.
Specific patterns of the commissure anomalies were associated with certain types of lissencephaly. Callosal anomalies were more common than those of AC or HC. Developmental differences of commissures may be useful as an imaging criterion in differentiating the groups of lissencephalies and may give insight into the processes causing these malformations.
Agenesis of the corpus callosum (ACC), cerebellar hypoplasia (CBLH), and polymicrogyria (PMG) are severe congenital brain malformations with largely undiscovered causes. We conducted a large-scale chromosomal copy number variation (CNV) discovery effort in 255 ACC, 220 CBLH, and 147 PMG patients, and 2,349 controls. Compared to controls, significantly more ACC, but unexpectedly not CBLH or PMG patients, had rare genic CNVs over one megabase (p = 1.48×10−3; odds ratio [OR] = 3.19; 95% confidence interval [CI] = 1.89–5.39). Rare genic CNVs were those that impacted at least one gene in less than 1% of the combined population of patients and controls. Compared to controls, significantly more ACC but not CBLH or PMG patients had rare CNVs impacting over 20 genes (p = 0.01; OR = 2.95; 95% CI = 1.69–5.18). Independent qPCR confirmation showed that 9.4% of ACC patients had de novo CNVs. These, in comparison to inherited CNVs, preferentially overlapped de novo CNVs previously observed in patients with autism spectrum disorders (p = 3.06×10−4; OR = 7.55; 95% CI = 2.40–23.72). Interestingly, numerous reports have shown a reduced corpus callosum area in autistic patients, and diminished social and executive function in many ACC patients. We also confirmed and refined previously known CNVs, including significantly narrowing the 8p23.1-p11.1 duplication present in 2% of our current ACC cohort. We found six novel CNVs, each in a single patient, that are likely deleterious: deletions of 1p31.3-p31.1, 1q31.2-q31.3, 5q23.1, and 15q11.2-q13.1; and duplications of 2q11.2-q13 and 11p14.3-p14.2. One ACC patient with microcephaly had a paternally inherited deletion of 16p13.11 that included NDE1. Exome sequencing identified a recessive maternally inherited nonsense mutation in the non-deleted allele of NDE1, revealing the complexity of ACC genetics. This is the first systematic study of CNVs in congenital brain malformations, and shows a much higher prevalence of large gene-rich CNVs in ACC than in CBLH and PMG.
Here, we systematically test the genetic etiology of three common developmental brain malformations: agenesis of the corpus callosum (ACC), cerebellar hypoplasia (CBLH), and polymicrogyria (PMG) by copy number variation (CNV) analysis in a large cohort of brain malformation patients and controls. We found significantly more ACC but not CBLH or PMG patients with rare genic CNVs over one megabase and with rare CNVs impacting over 20 genes when compared with controls. De novo CNVs were found in 9.4% of ACC patients, and interestingly many such CNVs overlapped with de novo CNVs observed in autism. Notably, numerous studies have demonstrated a reduction in the corpus callosum area in autistic brains. Our analysis also refined previously known large CNVs that cause these malformations, and identified six novel CNVs that are likely deleterious. One ACC patient had inherited a deletion from the father which, through exome sequencing, was found to uncover a recessive nonsense mutation in NDE1 on the non-deleted allele inherited from the mother. Our study is the first to systematically evaluate the burden of rare genic CNVs in congenital brain malformations and shows that large gene-rich CNVs are more common in ACC than in CBLH and PMG.
To describe a homogeneous subtype of periventricular nodular heterotopia (PNH) as part of a newly defined malformation complex.
Observational study including review of brain MRI and clinical findings of a cohort of 50 patients with PNH in the temporo-occipital horns and trigones, mutation analysis of the FLNA gene, and anatomopathologic study of a fetal brain.
There were 28 females and 22 males. All were sporadic with the exception of an affected mother and son. Epilepsy occurred in 62%, cerebellar signs in 56%, cognitive impairment in 56%, and autism in 12%. Seventy percent were referred within the 3rd year of life. Imaging revealed a normal cerebral cortex in 76% and abnormal cortical folding in 24%. In all patients the hippocampi were under-rotated and in 10% they merged with the heterotopia. Cerebellar dysgenesis was observed in 84% and a hypoplastic corpus callosum in 60%. There was no gender bias or uneven gender distribution of clinical and anatomic severity. No mutations of FLNA occurred in 33 individuals examined. Heterotopia in the fetal brain revealed cytoarchitectonic characteristics similar to those associated with FLNA mutations; cortical pathology was not typical of polymicrogyria. Cerebellar involvement was more severe and the hippocampi appeared simple and under-rotated.
This series delineates a malformation complex in which PNH in the trigones and occipito-temporal horns is associated with hippocampal, corpus callosum, and cerebellar dysgenesis. This subtype of PNH is distinct from classic PNH caused by FLNA mutations.
To date, growth of the human fetal cerebellum has been estimated primarily from linear measurements from ultrasound and 2D magnetic resonance imaging (MRI). In this study, we use 3D analytical methods to develop normative growth trajectories for the cerebellum in utero. We measured cerebellar volume, linear dimensions, and local surface curvature from 3D reconstructed MRI of the human fetal brain (N = 46). We found that cerebellar volume increased approximately 7-fold from 20 to 31 gestational weeks. The better fit of the exponential curve (R2 = 0.96) compared to the linear curve (R2 = 0.92) indicated acceleration in growth. Within-subject cerebellar and cerebral volumes were highly correlated (R2 = 0.94), though the cerebellar percentage of total brain volume increased from approximately 2.4% to 3.7% (R2 = 0.63). Right and left hemispheric volumes did not significantly differ. Transcerebellar diameter, vermal height, and vermal anterior to posterior diameter increased significantly at constant rates. From the local curvature analysis, we found that expansion along the inferior and superior aspects of the hemispheres resulted in decreased convexity, which is likely due to the physical constraints of the dura surrounding the cerebellum and the adjacent brainstem. The paired decrease in convexity along the inferior vermis and increased convexity of the medial hemisphere represents development of the paravermian fissure, which becomes more visible during this period. In this 3D morphometric analysis of the human fetal cerebellum, we have shown that cerebellar growth is accelerating at a greater pace than the cerebrum and described how cerebellar growth impacts the shape of the structure.
Cerebellum; Fetal MRI; Brain development; Posterior fossa; Vermis
We describe six cases from three unrelated consanguineous Egyptian families with a novel characteristic brain malformation at the level of the diencephalic–mesencephalic junction. Brain magnetic resonance imaging demonstrated a dysplasia of the diencephalic–mesencephalic junction with a characteristic ‘butterfly’-like contour of the midbrain on axial sections. Additional imaging features included variable degrees of supratentorial ventricular dilatation and hypoplasia to complete agenesis of the corpus callosum. Diffusion tensor imaging showed diffuse hypomyelination and lack of an identifiable corticospinal tract. All patients displayed severe cognitive impairment, post-natal progressive microcephaly, axial hypotonia, spastic quadriparesis and seizures. Autistic features were noted in older cases. Talipes equinovarus, non-obstructive cardiomyopathy and persistent hyperplastic primary vitreous were additional findings in two families. One of the patients required shunting for hydrocephalus; however, this yielded no change in ventricular size suggestive of dysplasia rather than obstruction. We propose the term ‘diencephalic–mesencephalic junction dysplasia’ to characterize this autosomal recessive malformation.
diencephalon; mesencephalon; mental retardation; brainstem malformation; brain wiring
To investigate the contribution of hypoglycemia in the first 24 hours after birth to brain injury in term newborns at risk for neonatal encephalopathy.
A prospective cohort of 94 term neonates born between 1994 and 2010 with early postnatal brain MRI studies were analyzed for regions of brain injury. Neurodevelopmental outcome was assessed at one year of age.
Hypoglycemia (glucose <46mg/dL) in the first 24 hours after birth was detected in 16% of the cohort. Adjusting for potential confounders of early perinatal distress and need for resuscitation, neonatal hypoglycemia was associated with a 3.72-fold increased odds of corticospinal tract injury (P=0.047). Hypoglycemia was also associated with 4.82-fold increased odds of one-point worsened neuromotor score (P=0.038) and a 15-point lower cognitive and language score on the Bayley Scales of Infant Development (P=0.015).
Neonatal hypoglycemia is associated with additional risks in the setting of neonatal encephalopathy with increased corticospinal tract injury and adverse motor and cognitive outcomes.
hypoglycemia; hypoxic-ischemic encephalopathy; neuroimaging; developmental outcome
With improving survival rates of preterm newborns, adverse cognitive outcomes are increasingly recognized. Adverse cognitive outcomes are associated with decreased cerebellar volumes, and modifiable risk factors for these adverse outcomes should be identified. Animal models demonstrate reduced preterm cerebellar growth after exposure to glucocorticoids. Preterm neonates were prospectively studied with serial MRI examinations near birth and again near term-equivalent age. Adjusting for associated clinical factors, antenatal bethamethasone was not associated with changes in cerebellar volume. Postnatal exposure to clinically routine doses of hydrocortisone or dexamethasone were associated with impaired cerebellar, but not cerebral, growth. Modifying postnatal risk factors for impaired cerebellar development, and particularly glucocorticoid exposure, may help to decrease risk for adverse neurological outcome after preterm birth.
The process of brain growth involves the expansion of tissue at different rates at different points within the brain. As the layers within the developing brain evolve they can thicken or increase in area as the brain surface begins to fold. In this work we propose a new spatiotemporal formulation of tensor based volume morphometry that is derived in relation to tissue boundaries. This allows the study of the directional properties of tissue growth by separately characterizing the changes in area and thickness of the adjacent layers. The approach uses temporally weighted, local regression across a population of anatomies with different ages to model changes in components of the growth radial and tangential to the boundary between tissue layers. The formulation is applied to the study of sulcal formation from in-utero MR imaging of human fetal brain anatomy. Results show that the method detects differential growth of tissue layers adjacent to the cortical surface, particularly at sulcal locations, as early as 22 gestational weeks.
Improved understanding of how the human brain is “wired” on a macroscale may now be possible due to the emerging field of MRI connectomics. However, mapping the rapidly developing infant brain networks poses challenges. In this study, we applied an automated template-free “baby connectome” framework using diffusion MRI to non-invasively map the structural brain networks in subjects of different ages, including premature neonates, term-born neonates, six-month-old infants, and adults. We observed increasing brain network integration and decreasing segregation with age in term-born subjects. We also explored how the equal area nodes can be grouped into modules without any prior anatomical information – an important step toward a fully network-driven registration and analysis of brain connectivity.
Early cortical folding and the emergence of structural brain asymmetries have been previously analyzed by neuropathology as well as qualitative analysis of magnetic resonance imaging (MRI) of fetuses and preterm neonates. In this study, we present a dedicated image analysis framework and its application for the detection of folding patterns during the critical period for the formation of many primary sulci (20–28 gestational weeks). Using structural information from in utero MRI, we perform morphometric analysis of cortical plate surface development and modeling of early folding in the normal fetal brain. First, we identify regions of the fetal brain surface that undergo significant folding changes during this developmental period and provide precise temporal staging of these changes for each region of interest. Then, we highlight the emergence of interhemispheric structural asymmetries that may be related to future functional specialization of cortical areas. Our findings complement previous descriptions of early sulcogenesis based on neuropathology and qualitative evaluation of 2D in utero MRI by accurate spatial and temporal mapping of the emergence of individual sulci as well as structural brain asymmetries. The study provides the missing starting point for their developmental trajectories and extends our understanding of normal cortical folding.
cortex; development; fetus; folding; lateralization
To describe the association between electrographic seizures and brain injury judged from magnetic resonance imaging (MRI) in newborns treated with hypothermia.
56 newborns treated with hypothermia were monitored using video-EEG through cooling and rewarming, and imaged at a median of 5 days. EEGs were reviewed for seizures and status epilepticus. Moderate-severe injury on MRI was measured using a classification similar to one predicting abnormal outcome in an analogous population.
Seizures were recorded in 17 newborns, five withstatus epilepticus. Moderate-severe injury was more common in newborns with seizures (RR 2.9; 95%CI 1.2-4.5; P=0.02), and present in all with status epilepticus. Children with moderate-severe injury had seizures that were multifocal, later onset, and more likely to have ongoing seizures following 20mg/kg phenobarbital. Newborns with only subclinical seizures were as likely to have injury as compared with those whose seizures had a clinical correlate (57% vs. 60%).
Seizures remain a risk factor for brain injury in the setting of therapeutic hypothermia, especially in neonates with status epilepticus, multifocal onset seizures, and need for multiple medications.However, 40% were spared from brain injury, suggesting that the outcome following seizures is not uniformly poor in children treated with therapeutic hypothermia.
Intensive care; Infant, newborn; Hypothermia, induced; Seizures; Electroencephalography; Magnetic resonance imaging
We examined neonatal predictors of epilepsy in term newborns with neonatal encephalopathy (NE) by studying children enrolled in a longitudinal, single center cohort study. Clinical data were obtained through chart review, and MRI was performed in the neonatal period. We administered a seizure questionnaire to parents of children aged ≥12 months (range 12 months–16.5 years) to determine the outcome of epilepsy. The association between clinical predictors and time to onset of epilepsy was assessed using Cox proportional hazards regression. Thirteen of 129 children developed epilepsy: all had neonatal seizures and brain injury on neonatal MRI. Of the newborns with neonatal seizures, 25% (15.8/1000 person-years) developed epilepsy, with the highest hazard ratios (HR) in the newborns with status epilepticus (HR 35.8, 95% CI 6.5 –196.5). Children with severe or near-total brain injury were more likely to develop epilepsy compared with those with only mild or moderate injury (HR 5.5, 95% CI 1.8–16.8). In a multivariable analysis adjusting for degree of encephalopathy and severe/near total brain injury, status epilepticus was independently associated with epilepsy. These data add to information regarding epilepsy pathogenesis, and further aid clinicians to counsel parents regarding the likelihood that a newborn with NE will develop epilepsy.
Hemimegalencephaly (HMG) is a developmental brain disorder characterized by an enlarged, malformed cerebral hemisphere, typically causing epilepsy that requires surgical resection. We studied resected HMG tissue to test whether the condition might reflect somatic mutations affecting genes critical to brain development. We found that 2/8 HMG samples showed trisomy of chromosome 1q, encompassing many genes, including AKT3, which is known to regulate brain size. A third case showed a known activating mutation in AKT3 (c.49G→A, creating p.E17K) that was not present in the patient’s blood cells. Remarkably, the E17K mutation in AKT3 is exactly paralogous to E17K mutations in AKT1 and AKT2 recently discovered in somatic overgrowth syndromes. We show that AKT3 is the most abundant AKT paralogue in brain during neurogenesis and that phosphorylated AKT is abundant in cortical progenitor cells. Our data suggest that somatic mutations limited to brain could represent an important cause of complex neurogenetic disease.
More than 60 percent of newborns with severe congenital heart disease develop perioperative brain injuries. Known risk factors include: preoperative hypoxemia, cardiopulmonary bypass characteristics, and postoperative hypotension. Infection is an established risk factor for white matter injury in premature newborns. In this study, we examined term infants with congenital heart disease requiring surgical repair to determine whether infection is associated with white matter injury. Acquired infection was specified by site (bloodstream, pneumonia, or surgical site infection) according to strict definitions. Infection was present in 23/127. Pre and post-operative imaging was evaluated for acquired injury by a pediatric neuroradiologist. Overall, there was no difference in newly acquired postoperative white matter injury in infants with infection (30 percent), compared to those without (31 percent). When stratified by anatomy, infants with transposition of the great arteries and bloodstream infection had an estimated doubling of risk of white matter injury that was not significant, whereas those with single ventricle anatomy had no apparent added risk. When considering only infants without stroke, the estimated association was higher, and became significant after adjusting for duration of inotrope therapy. In this study, nosocomial infection was not associated with white matter injury. Nonetheless, when controlling for risk factors, there was an association between bloodstream infection and white matter injury in selected sub-populations. Infection prevention may have the potential to mitigate long-term neurologic impairment as a consequence of white matter injury, which underscores the importance of attention to infection control for these patients.
Heart defects, congenital; Sepsis; Magnetic resonance imaging; Leukomalacia, periventricular; Pneumonia, ventilator acquired
This study reports a large case series of children with Aicardi syndrome. A new severity scoring system is established to assess sidedness of ocular and brain lesions. Thirty-five children were recruited from Aicardi syndrome family conferences. All children received dilated ophthalmologic exams, and brain MRI’s were reviewed. Ocular and brain MRI Aicardi lesion severity scores were devised. A linear mixed model was used to compare each side for the ocular and brain MRI severity scores of Aicardi associated disease. Twenty-six children met inclusion criteria for the study. All subjects were female, ages 3 months to 19 years. Rates per child of optic nerve coloboma, severe lacunae, and microphthalmos in one or both eyes (among those with complete fundus exams available) were 10/24 (42%), 8/22 (36%), and 7/26 (27%), respectively. Ocular and brain MRI asymmetry was found in 18% (4/22) and 58% (15/26) of subjects, respectively, with more right sided brain lesions than left (V=52, P=0.028). A significant correlation between sidedness of brain disease and microphthalmos was seen (T = 2.54, P = 0.02). This study substantiates the range and severity of Aicardi syndrome associated ophthalmologic and brain MRI lesions from prior smaller case series.
The most common cause of arterial ischemic stroke (AIS) in a previously healthy child is a large vessel cerebral arteriopathy. Varicella zoster virus is an established etiology, and recent data implicate a non-specific effect of additional common viral infections on cerebral vessels. The Vascular effects of Infection in Pediatric Stroke (VIPS) study is a multicenter cohort study that will test the hypotheses that (1) infection can lead to childhood AIS by causing vascular injury, and (2) the resultant arteriopathy, and inflammatory markers, predict recurrent stroke.
We are prospectively enrolling 480 children (aged 1 month through 18 years) with AIS and collecting (1) extensive infectious histories (through parental interview), (2) blood and serum samples (and CSF, when clinically obtained), and (3) clinically obtained but standardized brain and cerebrovascular imaging studies. Imaging studies are being centrally reviewed and adjudicated. Centralized laboratory assays will include serologies (acute and convalescent) and molecular assays for herpes viruses, and levels of inflammatory markers. Subjects are followed prospectively for recurrent ischemic events for the duration of the study (minimum of 1 year). We are banking biological specimens (including DNA) for future studies of specific infectious agents and mediators of inflammation relevant to thrombosis and vascular injury.
In a cross-sectional analysis, we will use logistic regression techniques to measure the association between markers of infection (from the clinical history and laboratory assays) and cerebral arteriopathy. In a prospective cohort analysis, we will use survival analysis techniques to determine whether cerebral arteriopathy and inflammatory markers predict recurrent stroke.
VIPS will shed light on the vascular effects of infection in childhood stroke. Because arteriopathy is likely the major predictor of recurrent stroke in children, a better understanding of the vascular injury pathway is critical for the development of rational strategies for secondary stroke prevention in children.
The corpus callosum is hypothesized to play a fundamental role in integrating information and mediating complex behaviors. Here, we demonstrate that lack of normal callosal development can lead to deficits in functional connectivity that are related to impairments in specific cognitive domains. We examined resting-state functional connectivity in individuals with agenesis of the corpus callosum (AgCC) and matched controls using magnetoencephalographic imaging (MEG-I) of coherence in the alpha (8–12 Hz), beta (12–30 Hz) and gamma (30–55 Hz) bands. Global connectivity (GC) was defined as synchronization between a region and the rest of the brain. In AgCC individuals, alpha band GC was significantly reduced in the dorsolateral pre-frontal (DLPFC), posterior parietal (PPC) and parieto-occipital cortices (PO). No significant differences in GC were seen in either the beta or gamma bands. We also explored the hypothesis that, in AgCC, this regional reduction in functional connectivity is explained primarily by a specific reduction in interhemispheric connectivity. However, our data suggest that reduced connectivity in these regions is driven by faulty coupling in both inter- and intrahemispheric connectivity. We also assessed whether the degree of connectivity correlated with behavioral performance, focusing on cognitive measures known to be impaired in AgCC individuals. Neuropsychological measures of verbal processing speed were significantly correlated with resting-state functional connectivity of the left medial and superior temporal lobe in AgCC participants. Connectivity of DLPFC correlated strongly with performance on the Tower of London in the AgCC cohort. These findings indicate that the abnormal callosal development produces salient but selective (alpha band only) resting-state functional connectivity disruptions that correlate with cognitive impairment. Understanding the relationship between impoverished functional connectivity and cognition is a key step in identifying the neural mechanisms of language and executive dysfunction in common neurodevelopmental and psychiatric disorders where disruptions of callosal development are consistently identified.
In the latter half of gestation (20 to 40 gestational weeks), human brain growth accelerates in conjunction with cortical folding and the deceleration of ventricular zone progenitor cell proliferation. These processes are reflected in changes in the volume of respective fetal tissue zones. Thus far, growth trajectories of the fetal tissue zones have been extracted primarily from 2D measurements on histological sections and magnetic resonance imaging (MRI). In this study, the volumes of major fetal zones—cortical plate (CP), subplate and intermediate zone (SP+IZ), germinal matrix (GMAT), deep gray nuclei (DG), and ventricles (VENT)—are calculated from automatic segmentation of motion-corrected, 3D reconstructed MRI. We analyzed 48 T2-weighted MRI scans from 39 normally developing fetuses in utero between 20.57 and 31.14 gestational weeks (GW). The supratentorial volume (STV) increased linearly at a rate of 15.22% per week. The SP+IZ (14.75% per week) and DG (15.56% per week) volumes increased at similar rates. The CP increased at a greater relative rate (18.00% per week), while the VENT (9.18% per week) changed more slowly. Therefore, CP increased as a fraction of STV and the VENT fraction declined. The total GMAT volume slightly increased then decreased after 25 GW. We did not detect volumetric sexual dimorphisms or total hemispheric volume asymmetries, which may emerge later in gestation. Further application of the automated fetal brain segmentation to later gestational ages will bridge the gap between volumetric studies of premature brain development and normal brain development in utero.
brain development; magnetic resonance imaging; growth rate; prenatal; cortex; probabilistic atlas
To establish normative metabolite ratios throughout the newborn brain using 3D MR Spectroscopic Imaging.
Materials and Methods
MRI and MRSI have been valuable tools for assessing normal and abnormal neuronal maturation for newborns. In this study, we performed whole brain 3D MRSI in addition to comprehensive anatomic and other functional imaging methods to examine maturation. 55 newborn subjects (28.4 ± 2.6 weeks post-conceptional age at birth, 34.1 ± 3.1 weeks post-conception age at scan, 32 males and 23 females) had high quality MRSI studies (104 exams) and normal neurodevelopmental outcome (NMS=0, MDI>85) at age 12 months.
The NAA to Cho ratio increased significantly with age for all regions. Lac to NAA ratio decreased significantly with age in the regions of thalamus, basal ganglia, cortical spinal tract, and parietal white matter, and showed a decreasing trend in the other regions.
Brain metabolites can be obtained through in vivo 3D MRSI and used to monitor newborn brain maturation.
newborn; brain; spectroscopy; mrsi
Recently developed techniques for reconstruction of high-resolution 3D images from fetal MR scans allows us to study the morphometry of developing brain tissues in utero. However, existing adult brain analysis methods cannot be directly applied as the anatomy of the fetal brain is significantly different in terms of geometry and tissue morphology. We describe an approach to atlas-based segmentation of the fetal brain with particular focus on the delineation of the germinal matrix, a transient structure related to brain growth. We segment 3D images reconstructed from in utero clinical MR scans and measure volumes of different brain tissue classes for a group of fetal subjects at gestational age 20.5–22.5 weeks. We also include a partial validation of the approach using manual tracing of the germinal matrix at different gestational ages.