Brain Connectivity Analysis in Children. Effects of Prematurity. and Prenatal Growth Restriction

Introduction: Survival of children born prematurely or with very low birth weight has increased dramatically, but the long term developmental outcome remains unknown. Many children have deficits in cognitive capacities, in particular involving executive domains and those disabilities are likely to involve a central nervous system deficit. To understand their neurostructural origin, we use DTI. Structurally segregated and functionally regions of the cerebral cortex are interconnected by a dense network of axonal pathways. We noninvasively map these pathways across cortical hemispheres and construct normalized structural connection matrices derived from DTI MR tractography. Group comparisons of brain connectivity reveal significant changes in fiber density in case of children with poor intrauterine grown and extremely premature children (gestational age<28 weeks at birth) compared to control subjects. This changes suggest a link between cortico-axonal pathways and the central nervous system deficit. Methods: Sixty premature born infants (5-6 years old) were scanned on clinical 3T scanner (Magnetom Trio, Siemens Medical Solutions, Erlangen, Germany) at two hospitals (HUG, Geneva and CHUV, Lausanne). For each subject, T1-weighted MPRAGE images (TR/TE=2500/2.91,TI=1100, resolution=1x1x1mm, matrix=256x154) and DTI images (30 directions, TR/TE=10200/107, in-plane resolution=1.8x1.8x2mm, 64 axial, matrix=112x112) were acquired. Parent(s) provided written consent on prior ethical board approval. The extraction of the Whole Brain Structural Connectivity Matrix was performed following (Cammoun, 2009 and Hagmann, 2008). The MPARGE images were registered using an affine registration to the non-weighted-DTI and WM-GM segmentation performed on it. In order to have equal anatomical localization among subjects, 66 cortical regions with anatomical landmarks were created using the curvature information, i.e. sulcus and gyrus (Cammoun et al, 2007; Fischl et al, 2004; Desikan et al, 2006) with freesurfer software (http://surfer.nmr.mgh.harvard.edu/). Tractography was performed in WM using an algorithm especially designed for DTI/DSI data (Hagmann et al., 2007) and both information were then combined in a matrix. Each row and column of the matrix corresponds to a particular ROI. Each cell of index (i,j) represents the fiber density of the bundle connecting the ROIs i and j. Subdividing each cortical region, we obtained 4 Connectivity Matrices of different resolution (33, 66, 125 and 250 ROI/hemisphere) for each subject . Subjects were sorted in 3 different groups, namely (1) control, (2) Intrauterine Growth Restriction (IUGR), (3) Extreme Prematurity (EP), depending on their gestational age, weight and percentile-weight score at birth. Group-to-group comparisons were performed between groups (1)-(2) and (1)-(3). The mean age at examination of the three groups were similar. Results: Quantitative analysis were performed between groups to determine fibers density differences. For each group, a mean connectivity matrix with 33ROI/hemisphere resolution was computed. On the other hand, for all matrix resolutions (33,66,125,250 ROI/hemisphere), the number of bundles were computed and averaged. As seen in figure 1, EP and IUGR subjects present an overall reduction of fibers density in both interhemispherical and intrahemispherical connections. This is given quantitatively in table 1. IUGR subjects presents a higher percentage of missing fiber bundles than EP when compared to control subjects (~16% against 11%). When comparing both groups to control subjects, for the EP subjects, the occipito-parietal regions seem less interhemispherically connected whilst the intrahemispherical networks present lack of fiber density in the lymbic system. Children born with IUGR, have similar reductions in interhemispherical connections than the EP. However, the cuneus and precuneus connections with the precentral and paracentral lobe are even lower than in the case of the EP. For the intrahemispherical connections the IUGR group preset a loss of fiber density between the deep gray matter structures (striatum) and the frontal and middlefrontal poles, connections typically involved in the control of executive functions. For the qualitative analysis, a t-test comparing number of bundles (p-value<0.05) gave some preliminary significant results (figure 2). Again, even if both IUGR and EP appear to have significantly less connections comparing to the control subjects, the IUGR cohort seems to present a higher lack of fiber density specially relying the cuneus, precuneus and parietal areas. In terms of fiber density, preliminary Wilcoxon tests seem to validate the hypothesis set by the previous analysis. Conclusions: The goal of this study was to determine the effect of extreme prematurity and poor intrauterine growth on neurostructural development at the age of 6 years-old. This data indicates that differences in connectivity may well be the basis for the neurostructural and neuropsychological deficit described in these populations in the absence of overt brain lesions (Inder TE, 2005; Borradori-Tolsa, 2004; Dubois, 2008). Indeed, we suggest that IUGR and prematurity leads to alteration of connectivity between brain structures, especially in occipito-parietal and frontal lobes for EP and frontal and middletemporal poles for IUGR. Overall, IUGR children have a higher loss of connectivity in the overall connectivity matrix than EP children. In both cases, the localized alteration of connectivity suggests a direct link between cortico-axonal pathways and the central nervous system deficit. Our next step is to link these connectivity alterations to the performance in executive function tests.

The brain tracks the energetic value in food images.

Do our brains implicitly track the energetic content of the foods we see? Using electrical neuroimaging of visual evoked potentials (VEPs) we show that the human brain can rapidly discern food's energetic value, vis à vis its fat content, solely from its visual presentation. Responses to images of high-energy and low-energy food differed over two distinct time periods. The first period, starting at approximately 165 ms post-stimulus onset, followed from modulations in VEP topography and by extension in the configuration of the underlying brain network. Statistical comparison of source estimations identified differences distributed across a wide network including both posterior occipital regions and temporo-parietal cortices typically associated with object processing, and also inferior frontal cortices typically associated with decision-making. During a successive processing stage (starting at approximately 300 ms), responses differed both topographically and in terms of strength, with source estimations differing predominantly within prefrontal cortical regions implicated in reward assessment and decision-making. These effects occur orthogonally to the task that is actually being performed and suggest that reward properties such as a food's energetic content are treated rapidly and in parallel by a distributed network of brain regions involved in object categorization, reward assessment, and decision-making.

The geometric structure of the brain fiber pathways.

The structure of the brain as a product of morphogenesis is difficult to reconcile with the observed complexity of cerebral connectivity. We therefore analyzed relationships of adjacency and crossing between cerebral fiber pathways in four nonhuman primate species and in humans by using diffusion magnetic resonance imaging. The cerebral fiber pathways formed a rectilinear three-dimensional grid continuous with the three principal axes of development. Cortico-cortical pathways formed parallel sheets of interwoven paths in the longitudinal and medio-lateral axes, in which major pathways were local condensations. Cross-species homology was strong and showed emergence of complex gyral connectivity by continuous elaboration of this grid structure. This architecture naturally supports functional spatio-temporal coherence, developmental path-finding, and incremental rewiring with correlated adaptation of structure and function in cerebral plasticity and evolution.

Use of anisotropic modelling in electrical impedance tomography: description of method and preliminary assessment of utility in imaging brain function in the adult human head.

Electrical Impedance Tomography (EIT) is an imaging method which enables a volume conductivity map of a subject to be produced from multiple impedance measurements. It has the potential to become a portable non-invasive imaging technique of particular use in imaging brain function. Accurate numerical forward models may be used to improve image reconstruction but, until now, have employed an assumption of isotropic tissue conductivity. This may be expected to introduce inaccuracy, as body tissues, especially those such as white matter and the skull in head imaging, are highly anisotropic. The purpose of this study was, for the first time, to develop a method for incorporating anisotropy in a forward numerical model for EIT of the head and assess the resulting improvement in image quality in the case of linear reconstruction of one example of the human head. A realistic Finite Element Model (FEM) of an adult human head with segments for the scalp, skull, CSF, and brain was produced from a structural MRI. Anisotropy of the brain was estimated from a diffusion tensor-MRI of the same subject and anisotropy of the skull was approximated from the structural information. A method for incorporation of anisotropy in the forward model and its use in image reconstruction was produced. The improvement in reconstructed image quality was assessed in computer simulation by producing forward data, and then linear reconstruction using a sensitivity matrix approach. The mean boundary data difference between anisotropic and isotropic forward models for a reference conductivity was 50%. Use of the correct anisotropic FEM in image reconstruction, as opposed to an isotropic one, corrected an error of 24 mm in imaging a 10% conductivity decrease located in the hippocampus, improved localisation for conductivity changes deep in the brain and due to epilepsy by 4-17 mm, and, overall, led to a substantial improvement on image quality. This suggests that incorporation of anisotropy in numerical models used for image reconstruction is likely to improve EIT image quality.

Brain surface non-rigid registration in auditory processing

Résumé: Le développement rapide de nouvelles technologies comme l'imagerie médicale a permis l'expansion des études sur les fonctions cérébrales. Le rôle principal des études fonctionnelles cérébrales est de comparer l'activation neuronale entre différents individus. Dans ce contexte, la variabilité anatomique de la taille et de la forme du cerveau pose un problème majeur. Les méthodes actuelles permettent les comparaisons interindividuelles par la normalisation des cerveaux en utilisant un cerveau standard. Les cerveaux standards les plus utilisés actuellement sont le cerveau de Talairach et le cerveau de l'Institut Neurologique de Montréal (MNI) (SPM99). Les méthodes de recalage qui utilisent le cerveau de Talairach, ou celui de MNI, ne sont pas suffisamment précises pour superposer les parties plus variables d'un cortex cérébral (p.ex., le néocortex ou la zone perisylvienne), ainsi que les régions qui ont une asymétrie très importante entre les deux hémisphères. Le but de ce projet est d'évaluer une nouvelle technique de traitement d'images basée sur le recalage non-rigide et utilisant les repères anatomiques. Tout d'abord, nous devons identifier et extraire les structures anatomiques (les repères anatomiques) dans le cerveau à déformer et celui de référence. La correspondance entre ces deux jeux de repères nous permet de déterminer en 3D la déformation appropriée. Pour les repères anatomiques, nous utilisons six points de contrôle qui sont situés : un sur le gyrus de Heschl, un sur la zone motrice de la main et le dernier sur la fissure sylvienne, bilatéralement. Evaluation de notre programme de recalage est accomplie sur les images d'IRM et d'IRMf de neuf sujets parmi dix-huit qui ont participés dans une étude précédente de Maeder et al. Le résultat sur les images anatomiques, IRM, montre le déplacement des repères anatomiques du cerveau à déformer à la position des repères anatomiques de cerveau de référence. La distance du cerveau à déformer par rapport au cerveau de référence diminue après le recalage. Le recalage des images fonctionnelles, IRMf, ne montre pas de variation significative. Le petit nombre de repères, six points de contrôle, n'est pas suffisant pour produire les modifications des cartes statistiques. Cette thèse ouvre la voie à une nouvelle technique de recalage du cortex cérébral dont la direction principale est le recalage de plusieurs points représentant un sillon cérébral. Abstract : The fast development of new technologies such as digital medical imaging brought to the expansion of brain functional studies. One of the methodolgical key issue in brain functional studies is to compare neuronal activation between individuals. In this context, the great variability of brain size and shape is a major problem. Current methods allow inter-individual comparisions by means of normalisation of subjects' brains in relation to a standard brain. A largerly used standard brains are the proportional grid of Talairach and Tournoux and the Montreal Neurological Insititute standard brain (SPM99). However, there is a lack of more precise methods for the superposition of more variable portions of the cerebral cortex (e.g, neocrotex and perisyvlian zone) and in brain regions highly asymmetric between the two cerebral hemipsheres (e.g. planum termporale). The aim of this thesis is to evaluate a new image processing technique based on non-linear model-based registration. Contrary to the intensity-based, model-based registration uses spatial and not intensitiy information to fit one image to another. We extract identifiable anatomical features (point landmarks) in both deforming and target images and by their correspondence we determine the appropriate deformation in 3D. As landmarks, we use six control points that are situated: one on the Heschl'y Gyrus, one on the motor hand area, and one on the sylvian fissure, bilaterally. The evaluation of this model-based approach is performed on MRI and fMRI images of nine of eighteen subjects participating in the Maeder et al. study. Results on anatomical, i.e. MRI, images, show the mouvement of the deforming brain control points to the location of the reference brain control points. The distance of the deforming brain to the reference brain is smallest after the registration compared to the distance before the registration. Registration of functional images, i.e fMRI, doesn't show a significant variation. The small number of registration landmarks, i.e. six, is obvious not sufficient to produce significant modification on the fMRI statistical maps. This thesis opens the way to a new computation technique for cortex registration in which the main directions will be improvement of the registation algorithm, using not only one point as landmark, but many points, representing one particular sulcus.

Task-induced deactivation from rest extends beyond the default mode brain network

Activity decreases, or deactivations, of midline and parietal cortical brain regions are routinely observed in human functional neuroimaging studies that compare periods of task-based cognitive performance with passive states, such as rest. It is now widely held that such task-induced deactivations index a highly organized"default-mode network" (DMN): a large-scale brain system whose discovery has had broad implications in the study of human brain function and behavior. In this work, we show that common task-induced deactivations from rest also occur outside of the DMN as a function of increased task demand. Fifty healthy adult subjects performed two distinct functional magnetic resonance imaging tasks that were designed to reliably map deactivations from a resting baseline. As primary findings, increases in task demand consistently modulated the regional anatomy of DMN deactivation. At high levels of task demand, robust deactivation was observed in non-DMN regions, most notably, the posterior insular cortex. Deactivation of this region was directly implicated in a performance-based analysis of experienced task difficulty. Together, these findings suggest that task-induced deactivations from rest are not limited to the DMN and extend to brain regions typically associated with integrative sensory and interoceptive processes.

Tangential migration of neuronal precursors of glutamatergic neurons in the adult mammalian brain.

In a classic model of mammalian brain formation, precursors of principal glutamatergic neurons migrate radially along radial glia fibers whereas GABAergic interneuron precursors migrate tangentially. These migration modes have significant implications for brain function. Here we used clonal lineage tracing of active radial glia-like neural stem cells in the adult mouse dentate gyrus and made the surprising discovery that proliferating neuronal precursors of glutamatergic granule neurons exhibit significant tangential migration along blood vessels, followed by limited radial migration. Genetic birthdating and morphological and molecular analyses pinpointed the neuroblast stage as the main developmental window when tangential migration occurs. We also developed a partial "whole-mount" dentate gyrus preparation and observed a dense plexus of capillaries, with which only neuroblasts, among the entire population of progenitors, are directly associated. Together, these results provide insight into neuronal migration in the adult mammalian nervous system.

Cortical mapping with navigated transcranial magnetic stimulation in low-grade glioma surgery

Transcranial magnetic stimulation (TMS) is a promising method for both investigation and therapeutic treatment of psychiatric and neurologic disorders and, more recently, for brain mapping. This study describes the application of navigated TMS for motor cortex mapping in patients with a brain tumor located close to the precentral gyrus. Materials and methods: In this prospective study, six patients with low-grade gliomas in or near the precentral gyrus underwent TMS, and their motor responses were correlated to locations in the cortex around the lesion, generating a functional map overlaid on three-dimensional magnetic resonance imaging (MRI) scans of the brain. To determine the accuracy of this new method, we compared TMS mapping with the gold standard mapping with direct cortical electrical stimulation in surgery. The same navigation system and TMS-generated map were used during the surgical resection procedure. Results: The motor cortex could be clearly mapped using both methods. The locations corresponding to the hand and forearm, found during intraoperative mapping, showed a close spatial relationship to the homotopic areas identified by TMS mapping. The mean distance between TMS and direct cortical electrical stimulation (DES) was 4.16 +/- 1.02 mm (range: 2.56-5.27 mm). Conclusion: Preoperative mapping of the motor cortex with navigated TMS prior to brain tumor resection is a useful presurgical planning tool with good accuracy.

Comparison of brain PrPd distribution in ovine BSE and scrapie

Scrapie and bovine spongiform encephalopathy (BSE) are both prion diseases affecting ruminants, and these diseases do not share the same public health concerns. Surveillance of the BSE agent in small ruminants has been a great challenge, and the recent identification of diverse prion diseases in ruminants has led to the development of new methods for strain typing. In our study, using immunohistochemistry (IHC), we assessed the distribution of PrP(d) in the brains of 2 experimentally BSE-infected sheep with the ARQ/ARQ genotype. Distribution of PrP(d) in the brain, from the spinal cord to the frontal cortex, was remarkably similar in the 2 sheep despite different inoculation routes and incubation periods. Comparatively, overall PrP(d) brain distribution, evaluated by IHC, in 19 scrapie cases with the ARQ/ARQ, ARQ/VRQ, and VRQ/VRQ genotypes, in some cases showed similarities to the experimentally BSE-infected sheep. There was no exclusive neuroanatomical site with a characteristic and specific PrP(d) type of accumulation induced by the BSE agent. However, a detailed analysis of the topography, types, and intensity of PrP(d) deposits in the frontal cortex, striatum, piriform cortex, hippocampus, mesencephalon, and cerebellum allowed the BSE-affected sheep group to be distinguished from the 19 scrapie cases analyzed in our study. These results strengthen and emphasize the potential interest of PrP(d) brain mapping to help in identifying prion strains in small ruminants.

Brain areas involved in medial temporal lobe seizures: a principal component analysis of ictal SPECT data

The study describes brain areas involved in medial temporal lobe (mTL) seizures of 12 patients. All patients showed so-called oro-alimentary behavior within the first 20 s of clinical seizure manifestation characteristic of mTL seizures. Single photon emission computed tomography (SPECT) images of regional cerebral blood flow (rCBF) were acquired from the patients in ictal and interictal phases and from normal volunteers. Image analysis employed categorical comparisons with statistical parametric mapping and principal component analysis (PCA) to assess functional connectivity. PCA supplemented the findings of the categorical analysis by decomposing the covariance matrix containing images of patients and healthy subjects into distinct component images of independent variance, including areas not identified by the categorical analysis. Two principal components (PCs) discriminated the subject groups: patients with right or left mTL seizures and normal volunteers, indicating distinct neuronal networks implicated by the seizure. Both PCs were correlated with seizure duration, one positively and the other negatively, confirming their physiological significance. The independence of the two PCs yielded a clear clustering of subject groups. The local pattern within the temporal lobe describes critical relay nodes which are the counterpart of oro-alimentary behavior: (1) right mesial temporal zone and ipsilateral anterior insula in right mTL seizures, and (2) temporal poles on both sides that are densely interconnected by the anterior commissure. Regions remote from the temporal lobe may be related to seizure propagation and include positively and negatively loaded areas. These patterns, the covarying areas of the temporal pole and occipito-basal visual association cortices, for example, are related to known anatomic paths.

Brain responses to auditory and visual stimulus offset: Shared representations of temporal edges

Edges are crucial for the formation of coherent objects from sequential sensory inputs within a single modality. Moreover, temporally coincident boundaries of perceptual objects across different sensory modalities facilitate crossmodal integration. Here, we used functional magnetic resonance imaging in order to examine the neural basis of temporal edge detection across modalities. Onsets of sensory inputs are not only related to the detection of an edge but also to the processing of novel sensory inputs. Thus, we used transitions from input to rest (offsets) as convenient stimuli for studying the neural underpinnings of visual and acoustic edge detection per se. We found, besides modality-specific patterns, shared visual and auditory offset-related activity in the superior temporal sulcus and insula of the right hemisphere. Our data suggest that right hemispheric regions known to be involved in multisensory processing are crucial for detection of edges in the temporal domain across both visual and auditory modalities. This operation is likely to facilitate cross-modal object feature binding based on temporal coincidence. Hum Brain Mapp, 2008. (c) 2008 Wiley-Liss, Inc.

BrainMaps.org - Interactive High-Resolution Digital Brain Atlases and Virtual Microscopy

BrainMaps.org is an interactive high-resolution digital brain atlas and virtual microscope that is based on over 20 million megapixels of scanned images of serial sections of both primate and non-primate brains and that is integrated with a high-speed database for querying and retrieving data about brain structure and function over the internet. Complete brain datasets for various species, including Homo sapiens, Macaca mulatta, Chlorocebus aethiops, Felis catus, Mus musculus, Rattus norvegicus, and Tyto alba, are accessible online. The methods and tools we describe are useful for both research and teaching, and can be replicated by labs seeking to increase accessibility and sharing of neuroanatomical data. These tools offer the possibility of visualizing and exploring completely digitized sections of brains at a sub-neuronal level, and can facilitate large-scale connectional tracing, histochemical and stereological analyses.

Perfusion in rat brain at 7 T with arterial spin labeling using FAIR-TrueFISP and QUIPSS.

Measurement of perfusion in longitudinal studies allows for the assessment of tissue integrity and the detection of subtle pathologies. In this work, the feasibility of measuring brain perfusion in rats with high spatial resolution using arterial spin labeling is reported. A flow-sensitive alternating recovery sequence, coupled with a balanced gradient fast imaging with steady-state precession readout section was used to minimize ghosting and geometric distortions, while achieving high signal-to-noise ratio. The quantitative imaging of perfusion using a single subtraction method was implemented to address the effects of variable transit delays between the labeling of spins and their arrival at the imaging slice. Studies in six rats at 7 T showed good perfusion contrast with minimal geometric distortion. The measured blood flow values of 152.5+/-6.3 ml/100 g per minute in gray matter and 72.3+/-14.0 ml/100 g per minute in white matter are in good agreement with previously reported values based on autoradiography, considered to be the gold standard.

Functional brain network efficiency predicts intelligence

The neuronal causes of individual differences in mental abilities such as intelligence are complex and profoundly important. Understanding these abilities has the potential to facilitate their enhancement. The purpose of this study was to identify the functional brain network characteristics and their relation to psychometric intelligence. In particular, we examined whether the functional network exhibits efficient small-world network attributes (high clustering and short path length) and whether these small-world network parameters are associated with intellectual performance. High-density resting state electroencephalography (EEG) was recorded in 74 healthy subjects to analyze graph-theoretical functional network characteristics at an intracortical level. Ravens advanced progressive matrices were used to assess intelligence. We found that the clustering coefficient and path length of the functional network are strongly related to intelligence. Thus, the more intelligent the subjects are the more the functional brain network resembles a small-world network. We further identified the parietal cortex as a main hub of this resting state network as indicated by increased degree centrality that is associated with higher intelligence. Taken together, this is the first study that substantiates the neural efficiency hypothesis as well as the Parieto-Frontal Integration Theory (P-FIT) of intelligence in the context of functional brain network characteristics. These theories are currently the most established intelligence theories in neuroscience. Our findings revealed robust evidence of an efficiently organized resting state functional brain network for highly productive cognitions.