Altered structural network architecture is predictive of the presence of psychotic symptoms in patients with 22q11.2 deletion syndrome

22q11.2 deletion syndrome (22q11DS) represents a homogeneous model of schizophrenia particularly suitable for the search of neural biomarkers of psychosis. Impairments in structural connectivity related to the presence of psychotic symptoms have been reported in patients with 22q11DS. However, the relationships between connectivity changes in patients with different symptomatic profiles are still largely unknown and warrant further investigations. In this study, we used structural connectivity to discriminate patients with 22q11DS with (N = 31) and without (N = 31) attenuated positive psychotic symptoms. Different structural connectivity measures were used, including the number of streamlines connecting pairs of brain regions, graph theoretical measures, and diffusion measures. We used univariate group comparisons as well as predictive multivariate approaches. The univariate comparison of connectivity measures between patients with or without attenuated positive psychotic symptoms did not give significant results. However, the multivariate prediction revealed that altered structural network architecture discriminates patient subtypes (accuracy = 67.7%). Among the regions contributing to the classification we found the anterior cingulate cortex, which is known to be associated to the presence of psychotic symptoms in patients with 22q11DS. Furthermore, a significant discrimination (accuracy = 64%) was obtained with fractional anisotropy and radial diffusivity in the left inferior longitudinal fasciculus and the right cingulate gyrus. Our results point to alterations in structural network architecture and white matter microstructure in patients with 22q11DS with attenuated positive symptoms, mainly involving connections of the limbic system. These alterations may therefore represent a potential biomarker for an increased risk of psychosis that should be further tested in longitudinal studies

Adaptive Strategy for the Statistical Analysis of Connectomes

We study an adaptive statistical approach to analyze brain networks represented by brain connection matrices of interregional connectivity (connectomes). Our approach is at a middle level between a global analysis and single connections analysis by considering subnetworks of the global brain network. These subnetworks represent either the inter-connectivity between two brain anatomical regions or by the intra-connectivity within the same brain anatomical region. An appropriate summary statistic, that characterizes a meaningful feature of the subnetwork, is evaluated. Based on this summary statistic, a statistical test is performed to derive the corresponding p-value. The reformulation of the problem in this way reduces the number of statistical tests in an orderly fashion based on our understanding of the problem. Considering the global testing problem, the p-values are corrected to control the rate of false discoveries. Finally, the procedure is followed by a local investigation within the significant subnetworks. We contrast this strategy with the one based on the individual measures in terms of power. We show that this strategy has a great potential, in particular in cases where the subnetworks are well defined and the summary statistics are properly chosen. As an application example, we compare structural brain connection matrices of two groups of subjects with a 22q11.2 deletion syndrome, distinguished by their IQ scores

Regional cortical volumes and congenital heart disease: a MRI study in 22q11.2 deletion syndrome

Children with congenital heart disease (CHD) who survive surgery often present impaired neurodevelopment and qualitative brain anomalies. However, the impact of CHD on total or regional brain volumes only received little attention. We address this question in a sample of patients with 22q11.2 deletion syndrome (22q11DS), a neurogenetic condition frequently associated with CHD. Sixty-one children, adolescents, and young adults with confirmed 22q11.2 deletion were included, as well as 80 healthy participants matched for age and gender. Subsequent subdivision of the patients group according to CHD yielded a subgroup of 27 patients with normal cardiac status and a subgroup of 26 patients who underwent cardiac surgery during their first years of life (eight patients with unclear status were excluded). Regional cortical volumes were extracted using an automated method and the association between regional cortical volumes, and CHD was examined within a three-condition fixed factor. Robust protection against type I error used Bonferroni correction. Smaller total cerebral volumes were observed in patients with CHD compared to both patients without CHD and controls. The pattern of bilateral regional reductions associated with CHD encompassed the superior parietal region, the precuneus, the fusiform gyrus, and the anterior cingulate cortex. Within patients, a significant reduction in the left parahippocampal, the right middle temporal, and the left superior frontal gyri was associated with CHD. The present results of global and regional volumetric reductions suggest a role for disturbed hemodynamic in the pathophysiology of brain alterations in patients with neurodevelopmental disease and cardiac malformations

Analyzing quantitatively and topologically the white matter organization in 22Q11.2 deletion syndrome

At the convergence of neuroimaging, genetic polymorphism and psychiatry, this thesis highlights through two published articles the importance of genes in brain white matter (WM) development and organisation leading to schizophrenic symptoms. We investigate brain structure in a population with a high risk of developing schizophrenia due to a microdeletion in chromosome 22q11.2. We implement analytical tools for enhancing differences in their WM connections compared to typically developing individuals (TD). After exploring the limits of voxel-wise analysis via TBSS (Tract-Based Spatial Statistic), we used the Connectome Mapper (merging Diffusion and T1 images) to reconstruct the WM bundles linking pairs of cortical regions, creating the connectome, therefore the Network of the brain. Compared to TD connectomes, the 22q11.2DS connectivity reveals altered fronto-temporal connections. Network analysis shows specific dysconnected hubs compared to TD and lower efficiency of Broca and Wernike areas in 22q11.2DS with hallucinations compared to those without

Etude des spécificités du comportement d'exploration visuelle présentées par les personnes atteintes du syndrome vélo-cardio-facial et régions cérébrales associées

Individuals with 22q11.2 deletion syndrome (22q11DS) exhibit deficits in visuo-spatial reasoning, including impairments in spatial attention and visuo-spatial short-term memory. In the present study, we investigate specific mechanisms contributing to visuo-spatial impairments by recording gaze fixations using a Tobii 1750 eye-tracking machine. Fortyone participants with 22q11DS (aged 8-24, 18M 23F) and 38 healthy controls (aged 9-24, 20M 18F) completed a version of the Benton Visual Retention Test (BVRT) adapted for eye tracking. Participants studied each of the 10 geometric images from the BVRT for a period of 10 seconds. Each image was then followed by a multiple-choice slide containing the original image and three similar choices. Overall, individuals with 22q11DS demonstrated fewer (p=0.002) and shorter (p=0.012) fixations during their exploration of the 10 images compared to the control group. This was especially clear on images that had a lower level of complexity. Moreover, specific regions remained less explored than others in the 22q11DS group. For example, almost all peripheral figures were significantly less explored (from p<0.001to p<0.034) for 7 of the 8 images with a peripheral figure. Moreover, when multiple figures were presented centrally, the simplest of the figures remained significantly less explored (from p<0.004 to p<0.05) for 5 of the 7 images with multiple central figures. Main cortical aeras related to a deficits in visual exploration of peripheral figures is the Caudal Middle Frontal on both hemispheres and those related to a deficit in exploration of simple figures is the Left Anterior Cingulate While visuo-spatial impairments are frequently mentioned in relation to 22q11DS, the current study shows alterations to spontaneous exploration of complex geometrical images in affected individuals, which may be related as well to difficulties in attentional disengagement (Simon et al, 2005). These observations provide concrete mechanisms for improving visual scanpath in affected individuals

Hippocampal volume reduction in chromosome 22q11.2 deletion syndrome (22q11.2DS): a longitudinal study of morphometry and symptomatology

Recent studies observed an association between the structural integrity of the hippocampal structure and the manifestations of clinically significant psychotic symptoms in participants at high risk for psychosis. The present study sought to investigate the longitudinal trajectory of the hippocampal volume and its subregions among a sample of participants affected by 22q11.2 deletion syndrome (22q11.2DS), a neurogenetic disorder associated with elevated risk for psychosis. We specifically investigated possible correlations between hippocampal volumes, as measured by magnetic resonance imaging (MRI), and the manifestation of positive psychotic symptoms (hallucinations and delusions). Regional hippocampal volumes were measured twice with cerebral MRI obtained at 3-year intervals in 30 healthy participants and 31 gender-matched 22q11.2 microdeletion carriers aged 6 to 22. We examined potential associations between psychotic symptom manifestations and volumetric parameters at both time points. We found a hippocampal body-driven significant reduction in hippocampal volume among patients with 22q11DS compared to controls. No significant group by time interaction for the total or the subregional volumes were observed. In patients, larger hippocampal head at baseline was associated with the presence of hallucinations at follow-up. We first discuss the reduced hippocampal body finding in light of potentially abnormal mesiocortical circuits. We further discuss the association between baseline hippocampal head volume in participants with 22q11DS as a possible marker related to the later unfolding of psychotic symptoms

Decreased frontal gyrification correlates with altered connectivity in children with autism

The structural correlates of functional dysconnectivity in autism spectrum disorders (ASD) have been seldom explored, despite the fact that altered functional connectivity is one of the most frequent neuropathological observations in the disorder. We analyzed cerebral morphometry and structural connectivity using multi-modal imaging for 11 children/adolescents with ASD and 11 matched controls. We estimated regional cortical and white matter volumes, as well as vertex-wise measures of cortical thickness and local Gyrification Index (lGI). Diffusion Tensor Images (DTI) were used to measure Fractional Anisotropy (FA) and tractography estimates of short- and long-range connectivity. We observed four clusters of lGI reduction in patients with ASD, three were located in the right inferior frontal region extending to the inferior parietal lobe, and one was in the right medial parieto-occipital region. Reduced volume was found in the anterior corpus callosum, along with fewer inter-hemispheric frontal streamlines. Despite the spatial correspondence of decreased gyrification and reduced long connectivity, we did not observe any significant relationship between the two. However, a positive correlation between lGI and local connectivity was present in all four clusters in patients with ASD. Reduced gyrification in the inferior fronto-parietal and posterior medial cortical regions lends support for early-disrupted cortical growth in both the mirror neuron system and midline structures responsible for social cognition. Early impaired neurodevelopment in these regions may represent an initial substrate for altered maturation in the cerebral networks that support complex social skills. We also demonstrate that gyrification changes are related to connectivity. This supports the idea that an imbalance between short- and long-range white matter tracts not only impairs the integration of information from multiple neural systems, but also alters the shape of the brain early on in autism

Eye Gaze During Face Processing in Children and Adolescents With 22q11.2 Deletion Syndrome

OBJECTIVE: The 22q11.2 deletion syndrome (22q11DS) is a neurogenetic syndrome with high risk for the development of psychiatric disorder. There is interest in identifying reliable markers for measuring and monitoring socio-emotional impairments in 22q11DS during development. The current study investigated eye gaze as a potential marker during a face-processing task in children and young adolescents with 22q11DS. METHOD: Eye gaze and behavioral correlates were investigated in 26 subjects (aged 8 to 15 years) with 22q11DS during the Jane Task, which targets featural and configural face processing. Individuals with 22q11DS were compared with chronologically age-matched healthy controls and individuals with idiopathic developmental delay (DD). RESULTS: Few differences in accuracy were observed between patients with 22q11DS and DD controls; however individuals with 22q11DS spent less time on the eyes and more time on the mouths than both comparison groups. IQ predicted time on the eyes in subjects with 22q11DS, and anxiety predicted time on the eyes in DD and 22q11DS subjects. CONCLUSIONS: These results provide evidence for abnormal exploration of faces in the syndrome and suggest that time spent on the eyes may contribute to face processing difficulties and interact with anxiety levels to exacerbate socio-emotional dysfunction in affected individuals

Prefrontal Plasticity and Stress Inoculation-Induced Resilience

Coping with mild early life stress tends to make subsequent coping efforts more effective and therefore more likely to be used as a means of arousal regulation and resilience. Here we show that this developmental learning-like process of stress inoculation increases ventromedial prefrontal cortical volumes in peripubertal monkeys. Larger volumes do not reflect increased cortical thickness but instead represent surface area expansion of ventromedial prefrontal cortex. Expansion of ventromedial prefrontal cortex coincides with increased white matter myelination inferred from diffusion tensor magnetic resonance imaging. These findings suggest that the process of coping with early life stress increases prefrontal myelination and expands a region of cortex that broadly controls arousal regulation and resilience

Three-dimensional representations of the virtual fibers with significant differences between patients and controls.

<p>Inside the three-dimensional cortical view of each hemisphere in light grey, each segment of the fibers are represented with 3 canonical directional color gradients, green for anterior-posterior axis, blue for bottom-up axis and red for left-right axis. Virtual fibers have been regrouped in “Tube” shape by TrackVis Software (<a href="http://trackvis.org/" target="_blank">http://trackvis.org/</a>). Part A represents the decrease in the left fronto-temporal connections comprising the arcuate and the uncinate fasciculus (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058429#pone.0058429.s005" target="_blank">Video S5</a>). Part B represents the increase in the frontal lobe intra connections (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058429#pone.0058429.s001" target="_blank">Video S1</a>) and the decrease in the left occipital intra connections (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058429#pone.0058429.s008" target="_blank">Video S8</a>). Part C shows the increase in the right parietal intra connections (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058429#pone.0058429.s002" target="_blank">Video S2</a>) and parieto-occipital connections (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058429#pone.0058429.s003" target="_blank">Video S3</a>). Part D illustrates the decrease in bilateral limbic intra and inter connections (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058429#pone.0058429.s004" target="_blank">Video S4</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058429#pone.0058429.s007" target="_blank">S7</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058429#pone.0058429.s009" target="_blank">S9</a>) and the left parieto-limbic connections (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058429#pone.0058429.s006" target="_blank">Video S6</a>).</p