A Neonatal Bimodal MR-CT Head Template.

Neonatal MR templates are appropriate for brain structural analysis and spatial normalization. However, they do not provide the essential accurate details of cranial bones and fontanels-sutures. Distinctly, CT images provide the best contrast for bone definition and fontanels-sutures. In this paper, we present, for the first time, an approach to create a fully registered bimodal MR-CT head template for neonates with a gestational age of 39 to 42 weeks. Such a template is essential for structural and functional brain studies, which require precise geometry of the head including cranial bones and fontanels-sutures. Due to the special characteristics of the problem (which requires inter-subject inter-modality registration), a two-step intensity-based registration method is proposed to globally and locally align CT images with an available MR template. By applying groupwise registration, the new neonatal CT template is then created in full alignment with the MR template to build a bimodal MR-CT template. The mutual information value between the CT and the MR template is 1.17 which shows their perfect correspondence in the bimodal template. Moreover, the average mutual information value between normalized images and the CT template proposed in this study is 1.24±0.07. Comparing this value with the one reported in a previously published approach (0.63±0.07) demonstrates the better generalization properties of the new created template and the superiority of the proposed method for the creation of CT template in the standard space provided by MR neonatal head template. The neonatal bimodal MR-CT head template is freely downloadable from https://www.u-picardie.fr/labo/GRAMFC.

Skull Segmentation and Reconstruction From Newborn CT Images Using Coupled Level Sets.

This study presents a new approach for segmentation and reconstruction of newborn's skull including bones, fontanels, and sutures from computed tomography (CT) images. The segmentation approach relies on propagation of a pair of interacting smooth surfaces based on geodesic active regions. These surfaces evolve in opposite directions; the exterior surface moves inward while the interior one moves in outward direction. The moving surfaces are forced to stop when arriving at the outer or the inner surface of the cranial bones using edge information. Since fontanels and sutures are not directly detectable in CT images, this method imposes specific propagation constraints for coupled interfaces to prevent the moving surfaces from intersecting each other and penetrating into the opposite region. Finally, an algorithm for level set initialization is introduced which enforces the evolving surfaces to conform to the shape of the head. The proposed method was evaluated using 18 neonatal CT images. The segmentation results achieved by the suggested method have been compared with manual segmentations by two different raters, performed to establish a reliable reference. The comparison of the two segmentation results using the Dice similarity coefficient and modified Hausdorff distance shows that the proposed approach provides satisfactory results.

Temporal resolvability analysis of macroscopic morphological development in neonatal cerebral magnetic resonance images.

OBJECTIVES: Reliable gradation of neonatal brain development is important for clinical investigation of neurological disorders. A prerequisite for such quantification of development is knowledge about temporal resolvability. METHODS: We hypothesized 2-week interval as the temporal resolvability of age-related templates to study macroscopic morphological brain development in the early weeks after birth. Therefore, we constructed two templates for the gestational age (GA) ranges of 39 to 40 and 41 to 42 weeks using T1-weighted magnetic resonance (MR) images. Then, we compared the spatial variation of anatomical landmarks and the average and the maximal length of spatial deformation in 30 subjects normalized to the two templates along x, y, and z directions. RESULTS: Multivariate analysis of variance (MANOVA) revealed significant difference between spatial variations of the above macroscopic features in the two age ranges. Furthermore, quantitative analysis of feature scattering yielded the same result even in features for which the null hypothesis was not rejected by MANOVA. Moreover, the same procedure was reiterated on two sets of subjects with the closer age range of 1 week (40 and 41 week's GA) and no significant difference could be detected. CONCLUSIONS: The results strengthen the hypothesis that 2-week is the temporal resolvability of age-related templates for macroscopic morphological studies of the developing brain in the early weeks after birth.

Syllabic discrimination in premature human infants prior to complete formation of cortical layers.

The ontogeny of linguistic functions in the human brain remains elusive. Although some auditory capacities are described before term, whether and how such immature cortical circuits might process speech are unknown. Here we used functional optical imaging to evaluate the cerebral responses to syllables at the earliest age at which cortical responses to external stimuli can be recorded in humans (28- to 32-wk gestational age). At this age, the cortical organization in layers is not completed. Many neurons are still located in the subplate and in the process of migrating to their final location. Nevertheless, we observed several points of similarity with the adult linguistic network. First, whereas syllables elicited larger right than left responses, the posterior temporal region escaped this general pattern, showing faster and more sustained responses over the left than over the right hemisphere. Second, discrimination responses to a change of phoneme (ba vs. ga) and a change of human voice (male vs. female) were already present and involved inferior frontal areas, even in the youngest infants (29-wk gestational age). Third, whereas both types of changes elicited responses in the right frontal region, the left frontal region only reacted to a change of phoneme. These results demonstrate a sophisticated organization of perisylvian areas at the very onset of cortical circuitry, 3 mo before term. They emphasize the influence of innate factors on regions involved in linguistic processing and social communication in humans.

Quantitative effect of the neonatal fontanel on synthetic near infrared spectroscopy measurements.

Near infrared spectroscopy (NIRS) is a functional imaging technique allowing measurement of local cerebral oxygenation. This modality is particularly adapted to critically ill neonates, as it can be used at the bedside and is a suitable and noninvasive tool for carrying out longitudinal studies. However, NIRS is sensitive to the imaged medium and consequently to the optical properties of biological tissues in which photons propagate. In this study, the effect of the neonatal fontanel was investigated by predicting photon propagation using a probabilistic Monte Carlo approach. Two anatomical newborn head models were created from computed tomography and magnetic resonance images: (1) a realistic model including the fontanel tissue and (2) a model in which the fontanel was replaced by skull tissue. Quantitative change in absorption due to simulated activation was compared for the two models for specific regions of activation and optical arrays simulated in the temporal area. A correction factor was computed to quantify the effect of the fontanel and defined by the ratio between the true and recovered change. The results show that recovered changes in absorption were more precise when determined with the anatomical model including the fontanel. The results suggest that the fontanel should be taken into account in quantification of NIRS responses to avoid misinterpretation in experiments involving temporal areas, such as language or auditory studies.

A tool to investigate symmetry properties of newborns brain: the newborns' symmetric brain atlas.

It is well established that the two hemispheres of the human brain exhibit a certain degree of asymmetry. Postmortem studies of developing brains of pre- and postpartum infants have shown that already in this early stage of development Heschl gyrus, planum temporale and superior temporal sulcus (STS) exhibit pronounced asymmetry. Advances in acquisition and computational evaluation of high-resolution magnetic resonance images provide enhanced tools for noninvasive studies of brain asymmetry in newborns. Until now most atlases used for image processing contain themselves asymmetry and may thus introduce and/or increase asymmetry already contained in the original data of brain structural or functional images. So, it is preferable to avoid the application of these asymmetric atlases. Thus, in this paper we present our framework to create a symmetric brain atlas from a group of newborns aged between 39 and 42 weeks after gestation. The resulting atlas demonstrates no difference between its original and its flipped version as should be the case for an asymmetric atlas. Consequently, the resulting symmetric atlas can be used for applications such as analysis of development of brain asymmetry in the context of language development.

Realistic head model design and 3D brain imaging of NIRS signals using audio stimuli on preterm neonates for intra-ventricular hemorrhage diagnosis.

In this paper we propose an auditory stimulation and near infra-red spectroscopy (NIRS) hemodynamic changes acquisition protocol for preterm neonates. This study is designed to assess the specific characteristics of neurovascular coupling to auditory stimuli in healthy and ill neonate brains. The method could lead to clinical application in intra-ventricular hemorrhage (IVH) diagnosis along with other techniques such as EEG. We propose a realistic head model creation with all useful head structures and brain tissues including the neonate fontanel for more accurate results from NIRS signals modeling. We also design a 3D imaging tool for dynamic mapping and analysis of brain activation onto the cortex surface. Results show significant differences in oxy-hemoglobin between healthy neonates and subjects with IVH.

Experimental investigation of NIRS spatial sensitivity.

Near infrared spectroscopy (NIRS) is regarded as a potential medical diagnostic technique for investigation of hemodynamic changes. However, uncertainties pertaining to the origin of NIRS signals have hampered its clinical interpretation. The uncertainities in NIRS measurements especially in case of living tissues are due to lack of rigorous combined theoretical-experimental studies resulting in clear understanding of the origin of NIRS signals. For their reliable interpretation it is important to understand the relationship between spatial changes in optical properties and corresponding changes in the NIRS signal. We investigated spatial sensitivity of near infrared optical measurements using an experimental approach. It uses a liquid optical phantom as tissue equivalent, which is explored under robot-control by a small, approximately point like perturbation of desired optical properties, and a NIRS instrument for trans-illumination/reflection measurements. The experimentally obtained sensitivity has been analyzed and compared with numerical simulations. In preliminary experiments we investigated the influence of various optical properties of the medium and of source/detector distances on the spatial sensitivity distribution. The acquired sensitivity maps can be used to define characteristic parameters. As an example, we used a 25% threshold to define a penetration depth measure which provides values in good accordance with published ones. To the best of our knowledge this is the first experimental study of NIRS spatial sensitivity. The presented method will allow in depth experimental investigation of the influence of various conditions pertaining to medium such as optical properties of tissue (scattering and absorption) and of the source/detector configuration.

Quantitative investigation of the effect of the extra-cerebral vasculature in diffuse optical imaging: a simulation study.

Diffuse optical imaging (DOI) is a non invasive technique allowing the recovery of hemodynamic changes in the brain. Due to the diffusive nature of photon propagation in turbid media and the fact that cerebral tissues are located around 1.5 cm under the adult human scalp, DOI measurements are subject to partial volume errors. DOI measurements are also sensitive to large pial vessels because oxygenated and deoxygenated hemoglobin are the dominant chromophores in the near infrared window. In this study, the effect of the extra-cerebral vasculature in proximity of the sagittal sinus was investigated for its impact on DOI measurements simulated over the human adult visual cortex. Numerical Monte Carlo simulations were performed on two specific models of the human head derived from magnetic resonance imaging (MRI) scans. The first model included the extra-cerebral vasculature in which constant hemoglobin concentrations were assumed while the second did not. The screening effect of the vasculature was quantified by comparing recovered hemoglobin changes from each model for different optical arrays and regions of activation. A correction factor accounting for the difference between the recovered and the simulated hemoglobin changes was computed in each case. The results show that changes in hemoglobin concentration are better estimated when the extra-cerebral vasculature is modeled and the correction factors obtained in this case were at least 1.4-fold lower. The effect of the vasculature was also examined in a high-density diffuse optical tomography configuration. In this case, the difference between changes in hemoglobin concentration recovered with each model was reduced down to 10%.

Design and construction of a brain phantom to simulate neonatal MR images.

This paper presents the design and construction of a 3D digital neonatal neurocranial phantom and its application for the simulation of brain magnetic resonance (MR) images. Commonly used digital brain phantoms (e.g. BrainWeb) are based on the adult brain. With the growing interest in computer-aided methods for neonatal MR image processing, there is a growing demand a digital phantom and brain MR image simulator especially for the neonatal brains. This is due to the pronounced differences between adult and neonatal brains not only in terms of size but also, more importantly, in terms of geometrical proportions and the need to subdivide white matter into two different tissue types in neonates. Therefore the neonatal brain phantom created in the here presented work consists of 9 different tissue types: skin, fat, muscle, skull, dura mater, gray matter, myelinated white matter, nonmyelinated white matter and cerebrospinal fluid. Each voxel has a vector consisting of 9 components, one for each of these nine tissue types. This digital phantom can be used to map simulated magnetic resonance signal intensities resulting in simulated MR images of the newborns head. These images with controlled degradation of the image data present a representative, reproducible data set ideal for development and evaluation of neonatal MRI analysis methods, e.g. segmentation and registration algorithms.

NIRS-measured oxy- and deoxyhemoglobin changes associated with EEG spike-and-wave discharges in a genetic model of absence epilepsy: the GAERS.

PURPOSE: Absence epilepsy may be severe and is frequently accompanied by cognitive delay, yet its metabolic/hemodynamic aspects have not been established. The Genetic Absence Epilepsy Rats from Strasbourg (GAERS) are an isomorphic, predictive, and homologous model of human absence epilepsy. We studied hemodynamic changes related to generalized spike-and-wave discharges (GSWDs) in GAERS by using a technique with high temporal resolution: near-infrared spectroscopy (NIRS). We hypothesized that conflicting results from other techniques might be due to the averaging of a biphasic response such as the one we described in children. METHODS: NIRS is particularly suitable for monitoring changes in the concentrations of oxy-, deoxy-, and total hemoglobin (HbO2, HHb, and HbT), using the specific absorption properties of living tissues in the near infrared range. We obtained concomitant high quality electroencephalography (EEG)-NIRS recordings in six GAERS (total of 444 seizures), and tested whether the discharges were related to changes in cardiac or respiration rates. RESULTS: The onset of GSWDs was preceded by a deactivation, followed by an activation that was possibly due to seizure-suppression mechanisms. The end was marked by a deactivation. The onset of GSWDs was associated with a decrease and the end with a brief increase in respiratory rate. DISCUSSION: Our results differ partially from those of previous studies on hemodynamic aspects of GSWDs (many of which describe a simple deactivation), probably due to differences in temporal resolution and data processing; however, they are consistent with metabolic studies, functional magnetic resonance imaging (fMRI) studies on WAG/Rij rats, and some results in children with absence epilepsy.

Vagus nerve stimulation induces changes in respiratory sinus arrhythmia of epileptic children during sleep.

PURPOSE: This study analyzed the direct short-term effect of vagus nerve stimulation (VNS) on respiratory sinus arrhythmia (RSA) in children with pharmacoresistant epilepsy. METHODS: RSA magnitude is calculated as the ratio between maximum and minimum heart rate for each respiratory cycle-before, during, and after the actual VNS period. In 10 children, changes in RSA magnitude were evaluated on polysomnographic recordings, including electrocardiography (ECG), electroencephalography (EEG), thoracoabdominal distension, nasal airflow, and VNS artifacts. Measurements during stimulation were compared with those at baseline, immediately preceding the VNS periods and individually for each patient. RESULT: During VNS, respiratory frequency increased and respiratory amplitude decreased with a variable effect on cardiac activity. The coupling between heart rate and respiratory rate was disturbed and RSA magnitude decreased significantly in 6 of 10 children during VNS. These changes in RSA magnitude varied from one child to another. The observed changes for respiratory and cardiac activity were concomitant with changes in RSA but were not correlated. CONCLUSION: Together with disorders of respiration, cardiac activity, and oxygen saturation (SaO(2)) described previously. VNS also modifies synchronization between cardiac and respiratory activity, resulting in poor optimization of oxygen delivery to tissues that can be regarded as an additive side effect, which should be considered in patients with already altered brain function. This interaction between the effects of VNS and potential autonomic nervous system (ANS) dysfunction already reported in epileptic patients should be considered to be potentially life-threatening. In addition, evaluation of changes in respiratory parameters can also provide reliable markers for further evaluation of the effectiveness of VNS.

Detection of EEG transients in neonates and older children using a system based on dynamic time-warping template matching and spatial dipole clustering.

We present a novel system for detecting electroencephalographic transient events in neonates and older children. The detection system consists of three major elements: (i) a preprocessing stage for filtering EEG and detecting artifacts, (ii) a hierarchical course-to-fine temporal event detection stage and (iii) a hierarchical course-to-fine spatial event selection stage to incorporate spatial contextual information for rejection of spurious events. The output consists of homogeneous EEG events and their corresponding dipole clusters. The system was evaluated on EEG signals recorded in four neonates and six older children. There was a high degree of correlation between system-detected and expert-marked events for all patients. Mean sensitivities of 84.9% and 91.9% and mean selectivities of 86.3% and 90.6% were obtained for the neonates and the older children, respectively. This tool is appropriate for the detection and selection of homogeneous EEG events prior to source localization. Quantitative spatial analysis of dipoles may facilitate the physician's assessment of patients' brain dysfunction.

Animal model of the short-term cardiorespiratory effects of intermittent vagus nerve stimulation.

PURPOSE: To develop an animal model of the effects of vagus nerve stimulation (VNS) on heart rate and respiration in studies of seizure treatment. METHODS: Nine rats implanted with ECG, EMG, and VNS electrodes and pulse generator were stimulated with 81 different sets of parameters while they slept in a plethysmographic box. RESULT: From cardiorespiratory effects of VNS, an index (alpha) was found to distinguish between weak and strong VNS doses. Weak VNS dose induced an increase in respiratory frequency and no significant change in heart rate. The effect of VNS on respiration, similar to that observed in children, can be divided into 3 phases. Strong VNS dose induced a decrease in respiratory frequency concomitant with a decrease in heart rate. Increasing the intensity of the VNS induced a proportional increase in the maximal inspiratory strength. CONCLUSION: Various VNS parameter settings induce different and concomitant cardiorespiratory variations in conscious sleeping rats. These effects correlate with the intensity of the VNS parameters. Understanding the effects of the intensity of VNS parameters may allow for further optimization of VNS parameters in patients receiving VNS.

Inverse coupling between respiratory and cardiac oscillators in a life-threatening event in a neonate.

The authors report the case of a baby boy born at a gestational age of 32 weeks who experienced a life-threatening event triggered by vagal overactivity, associated with a transient phase of inverse coupling with a 1:1 phase ratio between ECG and respiration, resulting in respiratory arrest. This case report highlights the vital importance of coupling between cardiac and respiratory oscillators, especially in premature infants or neonates.

NIRS-measured oxy- and deoxyhemoglobin changes associated with EEG spike-and-wave discharges in children.

PURPOSE: Absence epilepsy is characterized by 3-Hz generalized spike-and-wave discharges (GSWD) on the electroencephalogram, associated with behavioral arrest. It may be severe, and even in childhood benign absence epilepsy cognitive delay is frequent, yet the metabolic/hemodynamic aspects of this kind of epilepsy have not been established. We aimed to determine if the GSWD were related to hemodynamic changes by using a new technique with high temporal resolution: near infrared spectroscopy (NIRS). METHODS: NIRS is gaining acceptance as a technique particularly suitable for routine follow-up in children, using the specific absorption properties of living tissues in the near infrared range to measure changes in the concentrations of oxy-, deoxy- and total hemoglobin (HbO(2), HHb, and HbT, respectively). We performed simultaneous electroencephalography (EEG) and left frontal NIRS recordings in six children with GSWD. We also tested if the discharges were related to changes in cardiac or respiratory rates. RESULTS: GSWD were associated in the frontal area with an oxygenation (beginning 10 s before the GSWD) followed by strong deoxygenation, then oxygenation again with [HbT] increase, and a return to baseline. We did not identify any relationship between the onset of the GSWD and heart or respiratory rates. DISCUSSION: Our results partially differ from previous studies on GSWD hemodynamic aspects (many of which described a simple deactivation), probably due to differences in temporal resolution and data processing. Simultaneous acquisition of EEG and NIRS can optimize the use of both techniques and help shed light on the mechanisms underlying spike-and-wave discharges.

High-resolution electroencephalography and source localization in neonates.

Although Electroencephalography (EEG) source localization is being widely used in adults, this promising technique has not yet been applied to newborns because of technical difficulties, such as lack of data concerning the newborn skull conductivity, thickness, and homogeneity. Using a new type of EEG headcap molded on each baby's head, we aimed to determine whether this technique could be adapted to neonates, and to evaluate the importance of these technical difficulties. We carried out EEG source reconstruction of the recordings of five neonates using dipole fit algorithm. We used four different head models for each neonate, obtained from individual MRI scans: normal skull thickness and conductivity of 0.0042 S/m; normal thickness and conductivity of 0.33 S/m; increased thickness and conductivity of 0.0042 S/m; and normal thickness and conductivity with a modeled bregma fontanel. Dipole locations were consistent with MRI and clinical data. The mean difference between the dipole locations in the 0.0042 and the 0.33 S/m skull layer models was 11.6 +/- 2.5 mm, with an average 29.7% decrease in magnitude for the 0.33 S/m model but no significant changes for the dipoles orientation. Skull layer thickness had a large influence on magnitude, but no significant effect on position and orientation. The mean difference between the dipole locations induced by the modeled fontanel was 2.0 +/- 2.1 mm, with an average 2.1% increase in magnitude. Our results show that EEG source localization is feasible in neonates. With further development, the technique may prove useful for neurological evaluation of neonates.

Does spatiotemporal synchronization of EEG change prior to absence seizures?

We applied linear and nonlinear synchronization measures to characterize the synchrony between cortical regions and detect cerebral epileptic states in scalp EEG recordings recorded prior and during typical absence seizures. An overall rapid increase in the synchronization level between different cerebral regions was observed during the ictal state. During the interictal state, the degree of interdependence between EEG channels was significantly less than that observed in the ictal state (p<0.05). In 63% of the 35 seizures analyzed, a preictal state was identified by a significant decrease in the synchronization level with respect to the interictal state. However, in 31% of the seizures, the synchronization level in the preictal state was higher than that of the interictal state. In the remaining 6% of the seizures, no significant changes were found in the synchronization values in the interictal state prior to the seizures onset. In all the seizures analyzed, the interchannel synchrony persisted in the postictal state with synchronization level significantly higher than that observed in the interictal state. This study supports the hypothesis of having a focal susceptibility of the cerebral cortex prior to absence seizures and further underlines that this susceptibility is reproducible and patient-specific.

A multistage knowledge-based system for EEG seizure detection in newborn infants.

OBJECTIVE: Automatic seizure detection has attracted attention as a method to obtain valuable information concerning the duration, timing, and frequency of seizures. Methods currently used to detect EEG seizures in adults show high false detection rates in neonates because they lack information about specific age-dependent features of normal and pathological EEG and artifacts. This paper describes a novel multistage knowledge-based seizure detection system for newborn infants to identify and classify normal and pathological newborn EEGs as well as seizures with a reduced false detection rate. METHODS: We developed the system in a way to make comprehensive use of spatial and temporal contextual information obtained from multichannel EEGs. The system development consists of six major stages: (i) EEG data collection and bandpass filtering; (ii) automatic artifact detection; (iii) feature extraction from segments of non-seizure and seizure activities; (iv) feature selection via the relevance and redundancy analysis; (v) EEG classification and pattern recognition using a trained multilayer back-propagation neural network; and (v) knowledge-based decision-making to examine each of possible EEG patterns from a multi-channel perspective. The system was developed and tested with the EEG recordings of 10 newborns aged between 39 and 42 weeks. RESULTS: The overall sensitivity, selectivity, and average detection rate of the system were 74%, 70.1%, and 79.7%, respectively. The average false detection of 1.55/h was also achieved by the system with a feature reduction up to 80%. CONCLUSIONS: The expert rule-based decision-making subsystem accompanying the classifier helped to reduce the false detection rate, reject a wide variety of artifacts, and discriminate various patterns of EEG. SIGNIFICANCE: This paper may serve as a guide for the selection of discriminative features to improve the accuracy of conventional seizure detection systems for routine clinical EEG interpretation and brain activity monitoring in newborns especially those hospitalized in the neonatal intensive care units.

A neonatal atlas template for spatial normalization of whole-brain magnetic resonance images of newborns: preliminary results.

Commonly used brain templates are based on adults' or children's brains. In this study, we create a neonatal brain template. This becomes necessary because of the pronounced differences not only in size but even more importantly in geometrical proportions of the brains of adults and children as compared to the ones of newborns. The template is created based on high resolution T1 magnetic resonance images of 7 individuals with gestational ages between 39 and 42 weeks at the dates of examination. As usual, the created template presents two characteristics in a single image: an average intensity and an average shape. The normalization process to map subjects to the same space is done using SPM2 (Statistical Parametric Mapping) and its deformation toolbox. It consists of two steps: an affine and a nonlinear registration for global and local alignments, respectively. The template was evaluated by (i) study of anatomical local deviations and (ii) amount of local deformations of brain tissues in normalized neonatal images. The extracted results were compared with the ones obtained by normalization using adult and pediatric templates. It was shown that the application of our neonatal brain template for alignment of neonatal images results in a pronounced increase in performance of the normalization procedure as indicated by reduction of deviation of anatomical equivalent structures. The neonatal atlas template is freely downloadable from http://www.u-picardie.fr/labo/GRAMFC.