External awareness and GABA--a multimodal imaging study combining fMRI and [18F]flumazenil-PET.

Awareness is an essential feature of the human mind that can be directed internally, that is, toward our self, or externally, that is, toward the environment. The combination of internal and external information is crucial to constitute our sense of self. Although the underlying neuronal networks, the so-called intrinsic and extrinsic systems, have been well-defined, the associated biochemical mechanisms still remain unclear. We used a well-established functional magnetic resonance imaging (fMRI) paradigm for internal (heartbeat counting) and external (tone counting) awareness and combined this technique with [(18)F]FMZ-PET imaging in the same healthy subjects. Focusing on cortical midline regions, the results showed that both stimuli types induce negative BOLD responses in the mPFC and the precuneus. Carefully controlling for structured noise in fMRI data, these results were also confirmed in an independent data sample using the same paradigm. Moreover, the degree of the GABAA receptor binding potential within these regions was correlated with the neuronal activity changes associated with external, rather than internal awareness when compared to fixation. These data support evidence that the inhibitory neurotransmitter GABA is an influencing factor in the differential processing of internally and externally guided awareness. This in turn has implications for our understanding of the biochemical mechanisms underlying awareness in general and its potential impact on psychiatric disorders.

Multi-level bootstrap analysis of stable clusters in resting-state fMRI.

A variety of methods have been developed to identify brain networks with spontaneous, coherent activity in resting-state functional magnetic resonance imaging (fMRI). We propose here a generic statistical framework to quantify the stability of such resting-state networks (RSNs), which was implemented with k-means clustering. The core of the method consists in bootstrapping the available datasets to replicate the clustering process a large number of times and quantify the stable features across all replications. This bootstrap analysis of stable clusters (BASC) has several benefits: (1) it can be implemented in a multi-level fashion to investigate stable RSNs at the level of individual subjects and at the level of a group; (2) it provides a principled measure of RSN stability; and (3) the maximization of the stability measure can be used as a natural criterion to select the number of RSNs. A simulation study validated the good performance of the multi-level BASC on purely synthetic data. Stable networks were also derived from a real resting-state study for 43 subjects. At the group level, seven RSNs were identified which exhibited a good agreement with the previous findings from the literature. The comparison between the individual and group-level stability maps demonstrated the capacity of BASC to establish successful correspondences between these two levels of analysis and at the same time retain some interesting subject-specific characteristics, e.g. the specific involvement of subcortical regions in the visual and fronto-parietal networks for some subjects.

Positional and surface area asymmetry of the human cerebral cortex.

Previous studies of cortical asymmetry have relied mainly on voxel-based morphometry (VBM), or manual segmentation of regions of interest. This study uses fully automated, surface-based techniques to analyse position and surface area asymmetry for the mid-surfaces of 112 right-handed subjects' cortical hemispheres from a cohort of young adults. Native space measurements of local surface area asymmetry and vertex position asymmetry were calculated from surfaces registered to a previously validated hemisphere-unbiased surface-based template. Our analysis confirms previously identified hemispheric asymmetries (Yakovlevian torque, frontal and occipital petalia) in enhanced detail. It does not support previous findings of gender/asymmetry interactions or rightward planum parietale areal increase. It reveals several new findings, including a striking leftward increase in surface area of the supramarginal gyrus (peak effect 18%), compared with a smaller areal increase in the left Heschl's gyrus and planum temporale region (peak effect 8%). A second finding was rightward increase in surface area (peak effect 10%) in a band around the medial junction between the occipital lobe, and parietal and temporal lobes. By clearly separating out the effects of structural translocation and surface area change from those of thickness and curvature, this study resolves the confound of these variables inherent in VBM studies.

Brain size and cortical structure in the adult human brain.

We investigated the scale relationship between size and cortical structure of human brains in a large sample of magnetic resonance imaging data. Cortical structure was estimated with several measures (cortical volume, surface area, and thickness, sulcal depth, and absolute mean curvature in sulcal regions and sulcal walls) using three-dimensional surface-based methods in 148 normal subjects (n [men/women]: 83/65, age [mean +/- standard deviation]: 25.0 +/- 4.9 years). We found significantly larger scaling exponents than geometrically predicted for cortical surface area, absolute mean curvature in sulcal regions and in sulcal walls, and smaller ones for cortical volume and thickness. As brain size increases, the cortex thickens only slightly, but the degree of sulcal convolution increases dramatically, indicating that human cortices are not simply scaled versions of one another. Our results are consistent with previous hypotheses that greater local clustering of interneuronal connections would be required in a larger brain, and fiber tension between local cortical areas would induce cortical folds. We suggest that sex effects are explained by brain size effects in cortical structure at a macroscopic and lobar regional level, and that it is necessary to consider true relationships between cortical measures and brain size due to the limitations of linear stereotaxic normalization.

GABA(A) receptors in visual and auditory cortex and neural activity changes during basic visual stimulation.

Recent imaging studies have demonstrated that levels of resting γ-aminobutyric acid (GABA) in the visual cortex predict the degree of stimulus-induced activity in the same region. These studies have used the presentation of discrete visual stimulus; the change from closed eyes to open also represents a simple visual stimulus, however, and has been shown to induce changes in local brain activity and in functional connectivity between regions. We thus aimed to investigate the role of the GABA system, specifically GABA(A) receptors, in the changes in brain activity between the eyes closed (EC) and eyes open (EO) state in order to provide detail at the receptor level to complement previous studies of GABA concentrations. We conducted an fMRI study involving two different modes of the change from EC to EO: an EO and EC block design, allowing the modeling of the haemodynamic response, followed by longer periods of EC and EO to allow the measuring of functional connectivity. The same subjects also underwent [(18)F]Flumazenil PET to measure GABA(A) receptor binding potentials. It was demonstrated that the local-to-global ratio of GABA(A) receptor binding potential in the visual cortex predicted the degree of changes in neural activity from EC to EO. This same relationship was also shown in the auditory cortex. Furthermore, the local-to-global ratio of GABA(A) receptor binding potential in the visual cortex also predicted the change in functional connectivity between the visual and auditory cortex from EC to EO. These findings contribute to our understanding of the role of GABA(A) receptors in stimulus-induced neural activity in local regions and in inter-regional functional connectivity.

Somatosensory-motor bodily representation cortical thinning in Tourette: effects of tic severity, age and gender.

INTRODUCTION: Tourette syndrome (TS) implicates the disinhibition of the cortico-striatal-thalamic-cortical circuitry (CSTC). Previous studies used a volumetric approach to investigate this circuitry with inconsistent findings. Cortical thickness may represent a more reliable measure than volume due to the low variability in the cytoarchitectural structure of the grey matter. METHODS: 66 magnetic resonance imaging scans were acquired from 34 TS subjects (age range 10-25, mean 17.19+/-4.1) and 32 normal controls (NC) (age range 10-20, mean 16.33+/-3.56). Brain morphology was assessed using the fully automated CIVET pipeline at the Montreal Neurological Institute. RESULTS: We report (1) significant cortical thinning in the fronto-parietal and somatosensory-motor cortices in TS relative to NC (p<.05); (2) TS boys showed thinner cortex relative to TS girls in the fronto-parietal cortical regions (p<.05); (3) significant decrease in the fronto-parietal mean cortical thickness in TS subjects with age relative to NC and in the pre-central cortex in TS boys relative to TS girls; (4) significant negative correlations between tic severity and the somatosensory-motor cortical thickness. CONCLUSIONS: TS revealed important thinning in brain regions particularly involved in the somatosensory/motor bodily representations which may play an important role in tics. Our findings are in agreement with Leckman et al. (1991) hypothesis stating that facial tics would be associated with dysfunction in an orofacial subset of the motor circuit, eye blinking with the occulo-motor circuit, whereas lack of inhibition to a dysfunction in the prefrontal cortex. Gender and age differences may reflect differential etiological factors, which have significant clinical relevance in TS and should be considered in developing and using diagnostic and therapeutic interventions.

An unbiased iterative group registration template for cortical surface analysis.

Accurate alignment of explicit surface representations of human cerebral cortices is necessary in order to compare local individual differences in cortical morphometric measurements (thickness, surface area, gyrification, etc.) in both normal and clinical populations. This paper presents a methodology for developing unbiased, high resolution iterative registration templates from a group of 222 subject hemispheres and shows that the resulting template provides better alignment of a separate set of test data than single-subject templates. It demonstrates that between 30 and 50 subjects are required to generate a stable iterative template. It also explores the way in which fold variants in registration templates affect the quality of registration. Finally, it shows that hemisphere-specific group registration templates systematically better register subject hemispheres of the same laterality, underlining the need to develop templates free of hemisphere bias for asymmetry analysis.