Subplate subpopulations in the hypoxic-ischemic neonatal rat brain

Subplate neurons are among the earliest born cells of the neocortex and play a fundamental role in cortical development, in particular in the formation of thalamocortical connections. Subplate abnormalities have been described in several neuropathological disorders including schizophrenia, autism and periventricular eukomalacia (Eastwood and Harrison, Schizophr Res, 79, 2005; McQuillen and Ferriero, Brain Pathol, 15, 2005). We have identified and confirmed a range of specific markers for murine subplate using a microarray based approach and found that different subplate subpopulations are characterized by distinct expression patterns of these genes (Hoerder-Suabedissen et al., Cereb Cortex, 19, 2009). In this current study, we are making use of these markers to investigate neuropathological changes of the subplate after cerebral hypoxia-ischemia (HI) in the neonatal rat. First, we characterized the expression of a number of murine subplate markers in the postnatal rat using immunohistochemistry and in situ hybridization. While several genes (Nurr1, Cplx3, Ctgf and Tmem163) presented very similar expression patterns as in the mouse, others (Ddc, MoxD1 and TRH) were completely absent in the rat cortex. This finding suggests important differences in the subplate populations of these two rodent species. In a neonatal rat model of HI, selective vulnerability of subplate has been suggested using BrdU birthdating methods (McQuillen et al., J Neurosci, 15, 2003). We hypothesized that certain subplate subpopulations could be more susceptible than others and analyzed the above subplate markers in a similar yet slightly milder HI model. Two-day old male rat pups underwent permanent occlusion of the right common carotid artery followed by a period of hypoxia (6% O2, 1.5h or 2h) and were analyzed six days later. Preliminary counts on three subplate subpopulations (Nurr1+, Cplx3+ and Ctgf+ cells, respectively) showed similar reductions in cell numbers for all three groups. In addition, we found that the majority of cases which show changes in the subplate also exhibit lesions in the deep cortical layers VI (identified by FoxP2 expression) and sometimes even layer V (revealed by Er81 immunoreactivity), which questions the selective susceptibility of subplate over other cortical layers under the conditions we used in our model. Supported by MRC, FMO holds a Berrow Scholarship, Lincoln College, Oxford.

A pipeline approach with spatial information for segmenting multiple sclerosis lesions on brain magnetic resonance imaging

Background: Conventional magnetic resonance imaging (MRI) techniques are highly sensitive to detect multiple sclerosis (MS) plaques, enabling a quantitative assessment of inflammatory activity and lesion load. In quantitative analyses of focal lesions, manual or semi-automated segmentations have been widely used to compute the total number of lesions and the total lesion volume. These techniques, however, are both challenging and time-consuming, being also prone to intra-observer and inter-observer variability.Aim: To develop an automated approach to segment brain tissues and MS lesions from brain MRI images. The goal is to reduce the user interaction and to provide an objective tool that eliminates the inter- and intra-observer variability.Methods: Based on the recent methods developed by Souplet et al. and de Boer et al., we propose a novel pipeline which includes the following steps: bias correction, skull stripping, atlas registration, tissue classification, and lesion segmentation. After the initial pre-processing steps, a MRI scan is automatically segmented into 4 classes: white matter (WM), grey matter (GM), cerebrospinal fluid (CSF) and partial volume. An expectation maximisation method which fits a multivariate Gaussian mixture model to T1-w, T2-w and PD-w images is used for this purpose. Based on the obtained tissue masks and using the estimated GM mean and variance, we apply an intensity threshold to the FLAIR image, which provides the lesion segmentation. With the aim of improving this initial result, spatial information coming from the neighbouring tissue labels is used to refine the final lesion segmentation.Results:The experimental evaluation was performed using real data sets of 1.5T and the corresponding ground truth annotations provided by expert radiologists. The following values were obtained: 64% of true positive (TP) fraction, 80% of false positive (FP) fraction, and an average surface distance of 7.89 mm. The results of our approach were quantitatively compared to our implementations of the works of Souplet et al. and de Boer et al., obtaining higher TP and lower FP values.Conclusion: Promising MS lesion segmentation results have been obtained in terms of TP. However, the high number of FP which is still a well-known problem of all the automated MS lesion segmentation approaches has to be improved in order to use them for the standard clinical practice. Our future work will focus on tackling this issue.

Normal variation in fronto-occipital circuitry and cerebellar structure with an autism-associated polymorphism of CNTNAP2.

Recent genetic studies have implicated a number of candidate genes in the pathogenesis of Autism Spectrum Disorder (ASD). Polymorphisms of CNTNAP2 (contactin-associated like protein-2), a member of the neurexin family, have already been implicated as a susceptibility gene for autism by at least 3 separate studies. We investigated variation in white and grey matter morphology using structural MRI and diffusion tensor imaging. We compared volumetric differences in white and grey matter and fractional anisotropy values in control subjects characterised by genotype at rs7794745, a single nucleotide polymorphism in CNTNAP2. Homozygotes for the risk allele showed significant reductions in grey and white matter volume and fractional anisotropy in several regions that have already been implicated in ASD, including the cerebellum, fusiform gyrus, occipital and frontal cortices. Male homozygotes for the risk alleles showed greater reductions in grey matter in the right frontal pole and in FA in the right rostral fronto-occipital fasciculus compared to their female counterparts who showed greater reductions in FA of the anterior thalamic radiation. Thus a risk allele for autism results in significant cerebral morphological variation, despite the absence of overt symptoms or behavioural abnormalities. The results are consistent with accumulating evidence of CNTNAP2's function in neuronal development. The finding suggests the possibility that the heterogeneous manifestations of ASD can be aetiologically characterised into distinct subtypes through genetic-morphological analysis.

The costs of disorders of the brain in Switzerland: an update from the European Brain Council Study for 2010.

BACKGROUND: In 2005, findings of the first "cost of disorders of the brain in Europe" study of the European Brain Council (EBC) showed that these costs cause a substantial economic burden to the Swiss society. In 2010 an improved update with a broader range of disorders has been analysed. This report shows the new findings for Switzerland and discusses changes. METHODS: Data are derived from the EBC 2010 census study that estimates 12-month prevalence of 12 groups of disorders of the brain and calculates costs (direct health-care costs, direct non-medical costs and indirect costs) by combining top-down and bottom up cost approaches using existing data. RESULTS: The most frequent disorder was headache (2.3 million). Anxiety disorders were found in 1 million persons and sleep disorders in 700,000 persons. Annual costs for all assessed disorders total to 14.5 billion Euro corresponding to about 1,900 EUR per inhabitant per year. Mood, psychotic disorders and dementias (appr. 2 billion EUR each) were most costly. Costs per person were highest for neurological/neurosurgery-relevant disorders, e.g. neuromuscular disorders, brain tumour and multiple sclerosis (38,000 to 24,000 EUR). CONCLUSION: The estimates of the EBC 2010 study for Switzerland provide a basis for health care planning. Increase in size and costs compared to 2005 are mostly due to the inclusion of new disorders (e.g., sleep disorders), or the re-definition of others (e.g., headache) and to an increase in younger cohorts. We suggest coordinated research and preventive measures coordinated between governmental bodies, private health-care and pharmaceutical companies.

G Protein-Coupled Receptor heterodimerization in the brain

G protein-coupled receptors (GPCRs) play critical roles in cellular processes and signaling and have been shown to form heteromers with diverge biochemical and/or pharmacological activities that are different from those of the corresponding monomers or homomers. However, despite extensive experimental results supporting the formation of GPCR heteromers in heterologous systems, the existence of such receptor heterocomplexes in the brain remains largely unknown, mostly because of the lack of appropriate methodology. Herein, we describe the in situ proximity ligation assay procedure underlining its high selectivity and sensitivity to image GPCR heteromers with confocal microscopy in brain sections. We describe here how the assay is performed and discuss advantages and disadvantages of this method compared with other available techniques.

Extrasynaptic neurotransmission in the modulation of brain function. Focus on the striatal neuronal glial networks

Extrasynaptic neurotransmission is an important short distance form of volume transmission (VT) and describes the extracellular diffusion of transmitters and modulators after synaptic spillover or extrasynaptic release in the local circuit regions binding to and activating mainly extrasynaptic neuronal and glial receptors in the neuroglial networks of the brain. Receptor-receptor interactions in G protein-coupled receptor (GPCR) heteromers play a major role, on dendritic spines and nerve terminals including glutamate synapses, in the integrative processes of the extrasynaptic signaling. Heteromeric complexes between GPCR and ion-channel receptors play a special role in the integration of the synaptic and extrasynaptic signals. Changes in extracellular concentrations of the classical synaptic neurotransmitters glutamate and GABA found with microdialysis is likely an expression of the activity of the neuron-astrocyte unit of the brain and can be used as an index of VT-mediated actions of these two neurotransmitters in the brain. Thus, the activity of neurons may be functionally linked to the activity of astrocytes, which may release glutamate and GABA to the extracellular space where extrasynaptic glutamate and GABA receptors do exist. Wiring transmission (WT) and VT are fundamental properties of all neurons of the CNS but the balance between WT and VT varies from one nerve cell population to the other. The focus is on the striatal cellular networks, and the WT and VT and their integration via receptor heteromers are described in the GABA projection neurons, the glutamate, dopamine, 5-hydroxytryptamine (5-HT) and histamine striatal afferents, the cholinergic interneurons, and different types of GABA interneurons. In addition, the role in these networks of VT signaling of the energy-dependent modulator adenosine and of endocannabinoids mainly formed in the striatal projection neurons will be underlined to understand the communication in the striatal cellular networks

A review of atlas-based segmentation for magnetic resonance brain images.

Normal and abnormal brains can be segmented by registering the target image with an atlas. Here, an atlas is defined as the combination of an intensity image (template) and its segmented image (the atlas labels). After registering the atlas template and the target image, the atlas labels are propagated to the target image. We define this process as atlas-based segmentation. In recent years, researchers have investigated registration algorithms to match atlases to query subjects and also strategies for atlas construction. In this paper we present a review of the automated approaches for atlas-based segmentation of magnetic resonance brain images. We aim to point out the strengths and weaknesses of atlas-based methods and suggest new research directions. We use two different criteria to present the methods. First, we refer to the algorithms according to their atlas-based strategy: label propagation, multi-atlas methods, and probabilistic techniques. Subsequently, we classify the methods according to their medical target: the brain and its internal structures, tissue segmentation in healthy subjects, tissue segmentation in fetus, neonates and elderly subjects, and segmentation of damaged brains. A quantitative comparison of the results reported in the literature is also presented.

Evolution of the neurochemical profile after transient focal cerebral ischemia in the mouse brain.

Evolution of the neurochemical profile consisting of 19 metabolites after 30 mins of middle cerebral artery occlusion was longitudinally assessed at 3, 8 and 24 h in 6 to 8 microL volumes in the striatum using localized 1H-magnetic resonance spectroscopy at 14.1 T. Profound changes were detected as early as 3 h after ischemia, which include elevated lactate levels in the presence of significant glucose concentrations, decreases in glutamate and a transient twofold glutamine increase, likely to be linked to the excitotoxic release of glutamate and conversion into glial glutamine. Interestingly, decreases in N-acetyl-aspartate (NAA), as well as in taurine, exceeded those in neuronal glutamate, suggesting that the putative neuronal marker NAA is rather a sensitive marker of neuronal viability. With further ischemia evolution, additional, more profound concentration decreases were detected, reflecting a disruption of cellular functions. We conclude that early changes in markers of energy metabolism, glutamate excitotoxicity and neuronal viability can be detected with high precision non-invasively in mice after stroke. Such investigations should lead to a better understanding and insight into the sequential early changes in the brain parenchyma after ischemia, which could be used for identifying new targets for neuroprotection.

MR connectomics: a conceptual framework for studying the developing brain.

THE COMBINATION OF ADVANCED NEUROIMAGING TECHNIQUES AND MAJOR DEVELOPMENTS IN COMPLEX NETWORK SCIENCE, HAVE GIVEN BIRTH TO A NEW FRAMEWORK FOR STUDYING THE BRAIN: "connectomics." This framework provides the ability to describe and study the brain as a dynamic network and to explore how the coordination and integration of information processing may occur. In recent years this framework has been used to investigate the developing brain and has shed light on many dynamic changes occurring from infancy through adulthood. The aim of this article is to review this work and to discuss what we have learned from it. We will also use this body of work to highlight key technical aspects that are necessary in general for successful connectome analysis using today's advanced neuroimaging techniques. We look to identify current limitations of such approaches, what can be improved, and how these points generalize to other topics in connectome research.

Schizotypal perceptual aberrations of time: correlation between score, behavior and brain activity.

A fundamental trait of the human self is its continuum experience of space and time. Perceptual aberrations of this spatial and temporal continuity is a major characteristic of schizophrenia spectrum disturbances--including schizophrenia, schizotypal personality disorder and schizotypy. We have previously found the classical Perceptual Aberration Scale (PAS) scores, related to body and space, to be positively correlated with both behavior and temporo-parietal activation in healthy participants performing a task involving self-projection in space. However, not much is known about the relationship between temporal perceptual aberration, behavior and brain activity. To this aim, we composed a temporal Perceptual Aberration Scale (tPAS) similar to the traditional PAS. Testing on 170 participants suggested similar performance for PAS and tPAS. We then correlated tPAS and PAS scores to participants' performance and neural activity in a task of self-projection in time. tPAS scores correlated positively with reaction times across task conditions, as did PAS scores. Evoked potential mapping and electrical neuroimaging showed self-projection in time to recruit a network of brain regions at the left anterior temporal cortex, right temporo-parietal junction, and occipito-temporal cortex, and duration of activation in this network positively correlated with tPAS and PAS scores. These data demonstrate that schizotypal perceptual aberrations of both time and space, as reflected by tPAS and PAS scores, are positively correlated with performance and brain activation during self-projection in time in healthy individuals along the schizophrenia spectrum.

Differences of Functional Connectivity Brain Network in Emotional Judgment

Using combined emotional stimuli, combining photos of faces and recording of voices, we investigated the neural dynamics of emotional judgment using scalp EEG recordings. Stimuli could be either combioned in a congruent, or a non-congruent way.. As many evidences show the major role of alpha in emotional processing, the alpha band was subjected to be analyzed. Analysis was performed by computing the synchronization of the EEGs and the conditions congruent vs. non-congruent were compared using statistical tools. The obtained results demonstrate that scalp EEG ccould be used as a tool to investigate the neural dynamics of emotional valence and discriminate various emotions (angry, happy and neutral stimuli).