Early exit from neonatal therapeutic hypothermia: A single institution experience using MRI to guide decision-making.

BACKGROUND: To evaluate the feasibility of a protocol using combined magnetic resonance imaging (MRI), clinical data, and electroencephalogram (EEG) to identify neonates with mild neonatal encephalopathy (NE) treated with therapeutic hypothermia (TH) who are eligible for "early exit". METHODS: Retrospective chart review of TH cases at a single Level III NICU over a 5-year period was used to describe the demographic, clinical, and outcome data in neonates that received early exit in contrast to 72 hour TH treatment. RESULTS: Two hundred and eight TH cases, including 18 early exit cases (9%) and 9 cases (4%) evaluated for early exit with MRI but continued on 72 hours of TH, were identified. Early exit and 72 hour treatment groups did not differ in demographics or cord gas measures, although early exit neonates had a shorter length of stay (p < 0.05). Consistent with the early exit protocol, no early exit infants had evidence of moderate or severe encephalopathy on EEG or evidence of hypoxic ischemic injury on MRI at 24 hours of life. Neurology follow up between age 1 and 18 months was available for 10 early exit infants, 8 of whom had a normal examination. CONCLUSIONS: Early MRI at 24 hours of age, alongside clinical and EEG criteria, is feasible as part of a protocol to identify neonates eligible for early exit from therapeutic hypothermia.

Comparison of CBF Measured with Combined Velocity-Selective Arterial Spin-Labeling and Pulsed Arterial Spin-Labeling to Blood Flow Patterns Assessed by Conventional Angiography in Pediatric Moyamoya.

BACKGROUND AND PURPOSE: Imaging CBF is important for managing pediatric moyamoya. Traditional arterial spin-labeling MR imaging detects delayed transit thorough diseased arteries but is inaccurate for measuring perfusion because of these delays. Velocity-selective arterial spin-labeling is insensitive to transit delay and well-suited for imaging Moyamoya perfusion. This study assesses the accuracy of a combined velocity-selective arterial spin-labeling and traditional pulsed arterial spin-labeling CBF approach in pediatric moyamoya, with comparison to blood flow patterns on conventional angiography. MATERIALS AND METHODS: Twenty-two neurologically stable pediatric patients with moyamoya and 5 asymptomatic siblings without frank moyamoya were imaged with velocity-selective arterial spin-labeling, pulsed arterial spin-labeling, and DSA (patients). Qualitative comparison was performed, followed by a systematic comparison using ASPECTS-based scoring. Quantitative pulsed arterial spin-labeling CBF and velocity-selective arterial spin-labeling CBF for the middle cerebral artery, anterior cerebral artery, and posterior cerebral artery territories were also compared. RESULTS: Qualitatively, velocity-selective arterial spin-labeling perfusion maps reflect the DSA parenchymal phase, regardless of postinjection timing. Conversely, pulsed arterial spin-labeling maps reflect the DSA appearance at postinjection times closer to the arterial spin-labeling postlabeling delay, regardless of vascular phase. ASPECTS comparison showed excellent agreement (88%, κ = 0.77, P < .001) between arterial spin-labeling and DSA, suggesting velocity-selective arterial spin-labeling and pulsed arterial spin-labeling capture key perfusion and transit delay information, respectively. CBF coefficient of variation, a marker of perfusion variability, was similar for velocity-selective arterial spin-labeling in patient regions of delayed-but-preserved perfusion compared to healthy asymptomatic sibling regions (coefficient of variation = 0.30 versus 0.26, respectively, Δcoefficient of variation = 0.04), but it was significantly different for pulsed arterial spin-labeling (coefficient of variation = 0.64 versus 0.34, Δcoefficient of variation = 0.30, P < .001). CONCLUSIONS: Velocity-selective arterial spin-labeling offers a powerful approach to image perfusion in pediatric moyamoya due to transit delay insensitivity. Coupled with pulsed arterial spin-labeling for transit delay information, a volumetric MR imaging approach capturing key DSA information is introduced.

Advanced diffusion imaging for assessing normal white matter development in neonates and characterizing aberrant development in congenital heart disease.

Background: Elucidating developmental trajectories of white matter (WM) microstructure is critically important for understanding normal development and regional vulnerabilities in several brain disorders. Diffusion Weighted Imaging (DWI) is currently the method of choice for in-vivo white matter assessment. A majority of neonatal studies use the standard Diffusion Tensor Imaging (DTI) model although more advanced models such as the Neurite Orientation Dispersion and Density Imaging (NODDI) model and the Gaussian Mixture Model (GMM) have been used in adult population. In this study, we compare the ability of these three diffusion models to detect regional white matter maturation in typically developing control (TDC) neonates and regional abnormalities in neonates with congenital heart disease (CHD). Methods: Multiple b-value diffusion Magnetic Resonance Imaging (dMRI) data were acquired from TDC neonates (N = 16) at 38 to 47 gestational weeks (GW) and CHD neonates (N = 19) aged 37 weeks to 41 weeks. Measures calculated from the diffusion signal included not only Mean Diffusivity (MD) and Fractional Anisotropy (FA) derived from the standard DTI model, but also three advanced diffusion measures, namely, the fiber Orientation Dispersion Index (ODI), the isotropic volume fraction (Viso), and the intracellular volume fraction (Vic) derived from the NODDI model. Further, we used two novel measures from a non-parametric GMM, namely the Return-to-Origin Probability (RTOP) and Return-to-Axis Probability (RTAP), which are sensitive to axonal/cellular volume and density respectively. Using atlas-based registration, 22 white matter regions (6 projection, 4 association, and 1 callosal pathways bilaterally in each hemisphere) were selected and the mean value of all 7 measures were calculated in each region. These values were used as dependent variables, with GW as the independent variable in a linear regression model. Finally, we compared CHD and TDC groups on these measures in each ROI after removing age-related trends from both the groups. Results: Linear analysis in the TDC population revealed significant correlations with GW (age) in 12 projection pathways for MD, Vic, RTAP, and 11 pathways for RTOP. Several association pathways were also significantly correlated with GW for MD, Vic, RTAP, and RTOP. The right callosal pathway was significantly correlated with GW for Vic. Consistent with the pathophysiology of altered development in CHD, diffusion measures demonstrated differences in the association pathways involved in language systems, namely the Uncinate Fasciculus (UF), the Inferior Fronto-occipital Fasciculus (IFOF), and the Superior Longitudinal Fasciculus (SLF). Overall, the group comparison between CHD and TDC revealed lower FA, Vic, RTAP, and RTOP for CHD bilaterally in the a) UF, b) Corpus Callosum (CC), and c) Superior Fronto-Occipital Fasciculus (SFOF). Moreover, FA was lower for CHD in the a) left SLF, b) bilateral Anterior Corona Radiata (ACR) and left Retrolenticular part of the Internal Capsule (RIC). Vic was also lower for CHD in the left Posterior Limb of the Internal Capsule (PLIC). ODI was higher for CHD in the left CC. RTAP was lower for CHD in the left IFOF, while RTOP was lower in CHD in the: a) left ACR, b) left IFOF and c) right Anterior Limb of the Internal Capsule (ALIC). Conclusion: In this study, all three methods revealed the expected changes in the WM regions during the early postnatal weeks; however, GMM outperformed DTI and NODDI as it showed significantly larger effect sizes while detecting differences between the TDC and CHD neonates. Future studies based on a larger sample are needed to confirm these results and to explore clinical correlates.

Quantitative Folding Pattern Analysis of Early Primary Sulci in Human Fetuses with Brain Abnormalities.

BACKGROUND AND PURPOSE: Aberrant gyral folding is a key feature in the diagnosis of many cerebral malformations. However, in fetal life, it is particularly challenging to confidently diagnose aberrant folding because of the rapid spatiotemporal changes of gyral development. Currently, there is no resource to measure how an individual fetal brain compares with normal spatiotemporal variations. In this study, we assessed the potential for automatic analysis of early sulcal patterns to detect individual fetal brains with cerebral abnormalities. MATERIALS AND METHODS: Triplane MR images were aligned to create a motion-corrected volume for each individual fetal brain, and cortical plate surfaces were extracted. Sulcal basins were automatically identified on the cortical plate surface and compared with a combined set generated from 9 normal fetal brain templates. Sulcal pattern similarities to the templates were quantified by using multivariate geometric features and intersulcal relationships for 14 normal fetal brains and 5 fetal brains that were proved to be abnormal on postnatal MR imaging. Results were compared with the gyrification index. RESULTS: Significantly reduced sulcal pattern similarities to normal templates were found in all abnormal individual fetuses compared with normal fetuses (mean similarity [normal, abnormal], left: 0.818, 0.752; P < .001; right: 0.810, 0.753; P < .01). Altered location and depth patterns of sulcal basins were the primary distinguishing features. The gyrification index was not significantly different between the normal and abnormal groups. CONCLUSIONS: Automated analysis of interrelated patterning of early primary sulci could outperform the traditional gyrification index and has the potential to quantitatively detect individual fetuses with emerging abnormal sulcal patterns.

Multi-shell diffusion signal recovery from sparse measurements.

For accurate estimation of the ensemble average diffusion propagator (EAP), traditional multi-shell diffusion imaging (MSDI) approaches require acquisition of diffusion signals for a range of b-values. However, this makes the acquisition time too long for several types of patients, making it difficult to use in a clinical setting. In this work, we propose a new method for the reconstruction of diffusion signals in the entire q-space from highly undersampled sets of MSDI data, thus reducing the scan time significantly. In particular, to sparsely represent the diffusion signal over multiple q-shells, we propose a novel extension to the framework of spherical ridgelets by accurately modeling the monotonically decreasing radial component of the diffusion signal. Further, we enforce the reconstructed signal to have smooth spatial regularity in the brain, by minimizing the total variation (TV) norm. We combine these requirements into a novel cost function and derive an optimal solution using the Alternating Directions Method of Multipliers (ADMM) algorithm. We use a physical phantom data set with known fiber crossing angle of 45° to determine the optimal number of measurements (gradient directions and b-values) needed for accurate signal recovery. We compare our technique with a state-of-the-art sparse reconstruction method (i.e., the SHORE method of Cheng et al. (2010)) in terms of angular error in estimating the crossing angle, incorrect number of peaks detected, normalized mean squared error in signal recovery as well as error in estimating the return-to-origin probability (RTOP). Finally, we also demonstrate the behavior of the proposed technique on human in vivo data sets. Based on these experiments, we conclude that using the proposed algorithm, at least 60 measurements (spread over three b-value shells) are needed for proper recovery of MSDI data in the entire q-space.

Sex and the migraine brain.

The brain responds differently to environmental and internal signals that relate to the stage of development of neural systems. While genetic and epigenetic factors contribute to a premorbid state, hormonal fluctuations in women may alter the set point of migraine. The cyclic surges of gonadal hormones may directly alter neuronal, glial and astrocyte function throughout the brain. Estrogen is mainly excitatory and progesterone inhibitory on brain neuronal systems. These changes contribute to the allostatic load of the migraine condition that most notably starts at puberty in girls.

Diffusion tensor analysis of pediatric multiple sclerosis and clinically isolated syndromes.

BACKGROUND AND PURPOSE: DTI has shown focal and diffuse white matter abnormalities in adults and children with MS. Here we explore whether DTI abnormalities are present at the time of a first attack or CIS in children and whether early DTI features can predict the development of MS. MATERIALS AND METHODS: We assessed region-of-interest and tract-based mean ADC and mean FA values for 3 major white matter pathways and NAWM in 20 children with MS, 27 children with forms of CIS, and controls. Tracts were selected by using standard region-of-interest placements on color FA maps. Identical ROIs were placed in the NAWM on b = 0 T2-weighted images to ensure that both ROIs and resulting tracts passed through NAWM. Conventional MR imaging characteristics were assessed by visual inspection. Statistical analysis compared FA and ADC values between groups by a t test. Logistic regression assessed the predictive value of DTI measures and published conventional MR imaging measures for conversion from CIS to MS. RESULTS: In pediatric patients with MS, all white matter pathways and analysis confined to the NAWM demonstrated higher mean ADC values and lower mean FA than in controls. In contrast, there were no significant differences in mean ADC and mean FA of white matter pathways in all CIS cohorts compared with controls. In the CIS cohort, none of the DTI measures in white matter pathways or in NAWM were significantly associated with conversion to RRMS in univariate or multivariate models (P > .05 in all models). CONCLUSIONS: There are significant anisotropic abnormalities in the NAWM of major tracts in children with MS. In contrast, there were no significant changes in pediatric patients with CIS compared with controls at baseline. DTI measures did not predict conversion to MS. The period between CIS and conversion to pediatric MS may represent a window of opportunity for the prevention of diffuse damage in the CNS and potentially progressive disability.

Bilateral subcortical heterotopia with partial callosal agenesis in a mouse mutant.

Cognition and behavior depend on the precise placement and interconnection of complex ensembles of neurons in cerebral cortex. Mutations that disrupt migration of immature neurons from the ventricular zone to the cortical plate have provided major insight into mechanisms of brain development and disease. We have discovered a new and highly penetrant spontaneous mutation that leads to large nodular bilateral subcortical heterotopias with partial callosal agenesis. The mutant phenotype was first detected in a colony of fully inbred BXD29 mice already known to harbor a mutation in Tlr4. Neurons confined to the heterotopias are mainly born in midgestation to late gestation and would normally have migrated into layers 2-4 of overlying neocortex. Callosal cross-sectional area and fiber number are reduced up to 50% compared with coisogenic wildtype BXD29 substrain controls. Mutants have a pronounced and highly selective defect in rapid auditory processing. The segregation pattern of the mutant phenotype is most consistent with a two-locus autosomal recessive model, and selective genotyping definitively rules out the Tlr4 mutation as a cause. The discovery of a novel mutation with strong pleiotropic anatomical and behavioral effects provides an important new resource for dissecting molecular mechanisms and functional consequences of errors of neuronal migration.

Altered fetal cerebral and cerebellar development in twin-twin transfusion syndrome.

BACKGROUND AND PURPOSE: Neurodevelopmental disability is common in twins with TTTS in utero; however, the responsible neuropathology remains uncertain. We proposed to document the frequency of brain abnormalities on clinical fetal MR images and to determine if quantitative fetal brain biometric analysis in twin fetuses with TTTS was different from those in healthy control fetuses. MATERIALS AND METHODS: We reviewed the fetal brain MR images of 33 twin pairs with TTTS clinically evaluated in our institution. Eighteen fetal MR images of "healthy" twins with TTTS were further studied with biometric analysis in comparison with GA-matched singleton fetuses to detect quantitative differences in brain growth and development. RESULTS: A higher incidence of anomalies (11/33, 33.3%) was found than previously reported. The most frequent abnormality was ventriculomegaly (7/11, 63%) in both donor and recipient. In "healthy" twins with TTTS, biometric analysis revealed persistently small measurements (cBTD, CMT, TCD, and VAPD) in the donor cerebrum and cerebellum in comparison with their recipient cotwin and healthy control fetuses. These differences were preserved when normalized by cBTD. CONCLUSIONS: Our findings show that significant brain abnormalities are common in TTTS. In addition, diffuse subtle abnormalities are also present in normal-appearing donor fetal brains that cannot be solely explained by overall growth restriction. Such subtle fetal brain anomalies may explain the high incidence of poor long-term neurodevelopmental outcomes of survivors, and they need to be further investigated with more sophisticated quantitative fetal imaging methodologies.

Multimodal imaging of spike propagation: a technical case report.

We report an 11-year-old boy with intractable epilepsy, who had cortical dysplasia in the right superior frontal gyrus. Spatiotemporal source analysis of MEG and EEG spikes demonstrated a similar time course of spike propagation from the superior to inferior frontal gyri, as observed on intracranial EEG. The tractography reconstructed from DTI showed a fiber connection between these areas. Our multimodal approach demonstrates spike propagation and a white matter tract guiding the propagation.

Fetal MR imaging evidence of prolonged apparent diffusion coefficient decrease in fetal death.

We report 2 fetal MR imaging cases at 22 wkGA with cerebral bright DWI and low ADC, 8 and 19 days after documented fetal death. These observations illustrate that decreased diffusion can be present weeks after injury onset, and its presence cannot be used to time injury onset within 1 week, which could significantly impact determination of the proximate cause of fetal brain injury in future cases.

White matter maturation reshapes structural connectivity in the late developing human brain.

From toddler to late teenager, the macroscopic pattern of axonal projections in the human brain remains largely unchanged while undergoing dramatic functional modifications that lead to network refinement. These functional modifications are mediated by increasing myelination and changes in axonal diameter and synaptic density, as well as changes in neurochemical mediators. Here we explore the contribution of white matter maturation to the development of connectivity between ages 2 and 18 y using high b-value diffusion MRI tractography and connectivity analysis. We measured changes in connection efficacy as the inverse of the average diffusivity along a fiber tract. We observed significant refinement in specific metrics of network topology, including a significant increase in node strength and efficiency along with a decrease in clustering. Major structural modules and hubs were in place by 2 y of age, and they continued to strengthen their profile during subsequent development. Recording resting-state functional MRI from a subset of subjects, we confirmed a positive correlation between structural and functional connectivity, and in addition observed that this relationship strengthened with age. Continuously increasing integration and decreasing segregation of structural connectivity with age suggests that network refinement mediated by white matter maturation promotes increased global efficiency. In addition, the strengthening of the correlation between structural and functional connectivity with age suggests that white matter connectivity in combination with other factors, such as differential modulation of axonal diameter and myelin thickness, that are partially captured by inverse average diffusivity, play an increasingly important role in creating brain-wide coherence and synchrony.

Tract-based analysis of callosal, projection, and association pathways in pediatric patients with multiple sclerosis: a preliminary study.

BACKGROUND AND PURPOSE: Region-of-interest (ROI) and tract-based diffusion tensor imaging (DTI) analyses have detected increased apparent diffusion coefficients (ADCs) and decreased fractional anisotropy (FA) in callosal and projection systems of adult patients with multiple sclerosis (MS). We explored whether similar changes occur in pediatric patients with MS, assessing 3 major white matter pathways (interhemispheric, projection, and intrahemispheric) in both visibly involved and normal-appearing white matter (NAWM). MATERIALS AND METHODS: DTI datasets from 10 patients with established pediatric MS and 10 age- sex-, and imaging technique-matched controls were analyzed. Tracts were reconstructed by using a fiber assignment by continuous tracking algorithm with a diffusion-weighted imaging mask and a 35 degrees angular threshold. Tracts were selected by using standard ROI placements on color FA maps cross-referenced to b = 0 T2-weighted images for studying white matter pathways. Ten identical ROIs were placed in NAWM on b = 0 T2-weighted images to ensure that both ROIs and resulting tracts passed through NAWM. RESULTS: In pediatric MS, all tracts had higher mean ADC values (P = .002 to P < .04) and lower mean FA (P = .009 to P < .02) than those in healthy controls. Even when the tracts were confined to NAWM, the mean ADC was higher (P < .004 to P < .05) and the mean FA was lower (P = .002 to P < .02). T2 lesion burden correlated with tract-based mean ADC. ROI mean ADC increased, and both tract and ROI mean FA decreased with increasing T2 lesion burden, however with a statistically nonsignificant correlation. CONCLUSIONS: Increased mean ADC and decreased mean FA occur in all 3 major white matter pathways, both in visibly involved white matter and NAWM in pediatric MS.

A METHODOLOGY FOR ANALYZING CURVATURE IN THE DEVELOPING BRAIN FROM PRETERM TO ADULT.

The character and timing of gyral development is one manifestation of the complex orchestration of human brain development. The ability to quantify these changes would not only allow for deeper understanding of cortical development, but also conceivably allow for improved detection of pathologies. This paper describes a FreeSurfer based image-processing analysis "pipeline" or methodology that inputs an MRI volume, corrects possible contrast defects, creates surface reconstructions, and outputs various curvature-based function analyses. A technique of performing neonate reconstructions using FreeSurfer, which has not been possible previously due to inverted image contrast in pre-myelinated brains, is described. Once surfaces are reconstructed, the analysis component of the pipeline incorporates several surface-based curvature functions found in literature (principle curvatures, Gaussian, mean curvature, "curvedness", and Willmore Bending Energy). We consider the problem of analyzing curvatures from different sized brains by introducing a Gaussian-curvature based variable-radius filter. Segmented volume data is also analyzed for folding measures: a gyral folding index (gyrification-white index GWI), and a gray-white matter junction folding index (WMF). A very simple curvature-based classifier is proposed that has the potential to discriminate between certain classes of subjects. We also present preliminary results of this curvature analysis pipeline on nine neonate subjects (30.4 weeks through 40.3 weeks Corrected Gestational Age), 3 children (2, 3, and 7 years) and 3 adults (33, 37, and 39 years). Initial results demonstrate that curvature measures and functions across our subjects peaked at term, with a gradual decline through early childhood and further decline continuing through to adults. We can also discriminate older neonates, children, and adults based on curvature analysis. Using a variable radius Gaussian-curvature filter, we also observed that the per-unit bending energy of neonate brain surfaces was also much higher than the children and adults.

Magnetoencephalographic mapping of interictal spike propagation: a technical and clinical report.

Distinguishing propagated epileptic activity from primary epileptic foci is of critical importance in presurgical evaluation of patients with medically intractable focal epilepsy. We studied an 11-year-old patient with complex partial epilepsy by using simultaneous magnetoencephalography (MEG) and electroencephalography (EEG). In EEG, bilateral interictal discharges appeared synchronous, whereas MEG source analysis suggested propagation of spikes from the right to the left frontal lobe.

The value of multichannel MEG and EEG in the presurgical evaluation of 70 epilepsy patients.

OBJECTIVE: To evaluate the sensitivity of a simultaneous whole-head 306-channel magnetoencephalography (MEG)/70-electrode EEG recording to detect interictal epileptiform activity (IED) in a prospective, consecutive cohort of patients with medically refractory epilepsy that were considered candidates for epilepsy surgery. METHODS: Seventy patients were prospectively evaluated by simultaneously recorded MEG/EEG. All patients were surgical candidates or were considered for invasive EEG monitoring and had undergone an extensive presurgical evaluation at a tertiary epilepsy center. MEG and EEG raw traces were analysed individually by two independent reviewers. RESULTS: MEG data could not be evaluated due to excessive magnetic artefacts in three patients (4%). In the remaining 67 patients, the overall sensitivity to detect IED was 72% (48/67 patients) for MEG and 61% for EEG (41/67 patients) analysing the raw data. In 13% (9/67 patients), MEG-only IED were recorded, whereas in 3% (2/67 patients) EEG-only IED were recorded. The combined sensitivity was 75% (50/67 patients). CONCLUSION: Three hundred and six-channel MEG has a similarly high sensitivity to record IED as EEG and appears to be complementary. In one-third of the EEG-negative patients, MEG can be expected to record IED, especially in the case of lateral neocortical epilepsy and/or cortical dysplasia.

3T phased array MRI improves the presurgical evaluation in focal epilepsies: a prospective study.

BACKGROUND: Although detection of concordant lesions on MRI significantly improves postsurgical outcomes in focal epilepsy (FE), many conventional MR studies remain negative. The authors evaluated the role of phased array surface coil studies performed at 3 Tesla (3T PA MRI). METHODS: Forty patients with medically intractable focal epilepsies were prospectively imaged with 3T PA-MRI including high matrix TSE T2, fluid attenuated inversion recovery, and magnetization prepared rapid gradient echo. All patients were considered candidates for epilepsy surgery. 3T PA-MRIs were reviewed by a neuroradiologist experienced in epilepsy imaging with access to clinical information. Findings were compared to reports of prior standard 1.5T MRI epilepsy studies performed at tertiary care centers. RESULTS: Experienced, unblinded review of 3T PA-MRI studies yielded additional diagnostic information in 48% (19/40) compared to routine clinical reads at 1.5T. In 37.5% (15/40), this additional information motivated a change in clinical management. In the subgroup of patients with prior 1.5T MRIs interpreted as normal, 3T PA-MRI resulted in the detection of a new lesion in 65% (15/23). In the subgroup of 15 patients with known lesions, 3T PA-MRI better defined the lesion in 33% (5/15). CONCLUSION: Phased array surface coil studies performed at 3 Tesla read by an experienced unblinded neuroradiologist can improve the presurgical evaluation of patients with focal epilepsy when compared to routine clinical 1.5T studies read at tertiary care centers.