ENIGMA Epilepsy paper published in Brain!

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Jan 222018
 

The ENIGMA Epilepsy paper has been published in Brain today!

See also UCL’s press release here.

Whelan et al., 2018: “Structural brain abnormalities in the common epilepsies assessed in a worldwide ENIGMA study”

Abstract

Progressive functional decline in the epilepsies is largely unexplained. We formed the ENIGMA-Epilepsy consortium to understand factors that influence brain measures in epilepsy, pooling data from 24 research centres in 14 countries across Europe, North and South America, Asia, and Australia. Structural brain measures were extracted from MRI brain scans across 2149 individuals with epilepsy, divided into four epilepsy subgroups including idiopathic generalized epilepsies (n =367), mesial temporal lobe epilepsies with hippocampal sclerosis (MTLE; left, n = 415; right, n = 339), and all other epilepsies in aggregate (n = 1026), and compared to 1727 matched healthy controls. We ranked brain structures in order of greatest differences between patients and controls, by meta-analysing effect sizes across 16 subcortical and 68 cortical brain regions. We also tested effects of duration of disease, age at onset, and age-by-diagnosis interactions on structural measures. We observed widespread patterns of altered subcortical volume and reduced cortical grey matter thickness. Compared to controls, all epilepsy groups showed lower volume in the right thalamus (Cohen’s d = −0.24 to −0.73; P < 1.49 × 10−4), and lower thickness in the precentral gyri bilaterally (d = −0.34 to −0.52; P < 4.31 × 10−6). Both MTLE subgroups showed profound volume reduction in the ipsilateral hippocampus (d = −1.73 to −1.91, P < 1.4 × 10−19), and lower thickness in extrahippocampal cortical regions, including the precentral and paracentral gyri, compared to controls (d = −0.36 to −0.52; P < 1.49 × 10−4). Thickness differences of the ipsilateral temporopolar, parahippocampal, entorhinal, and fusiform gyri, contralateral pars triangularis, and bilateral precuneus, superior frontal and caudal middle frontal gyri were observed in left, but not right, MTLE (d = −0.29 to −0.54; P < 1.49 × 10−4). Contrastingly, thickness differences of the ipsilateral pars opercularis, and contralateral transverse temporal gyrus, were observed in right, but not left, MTLE (d = −0.27 to −0.51; P < 1.49 × 10−4). Lower subcortical volume and cortical thickness associated with a longer duration of epilepsy in the all-epilepsies, all-other-epilepsies, and right MTLE groups (beta, b < −0.0018; P < 1.49 × 10−4). In the largest neuroimaging study of epilepsy to date, we provide information on the common epilepsies that could not be realistically acquired in any other way. Our study provides a robust ranking of brain measures that can be further targeted for study in genetic and neuropathological studies. This worldwide initiative identifies patterns of shared grey matter reduction across epilepsy syndromes, and distinctive abnormalities between epilepsy syndromes, which inform our understanding of epilepsy as a network disorder, and indicate that certain epilepsy syndromes involve more widespread structural compromise than previously assumed.

 

 Posted by at 23:18

Paper available online at Journal of Neuroscience

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Sep 132017
 

Our paper with the title “Overdominant effect of a CHRNA4 polymorphism on cingulo-opercular network activity and cognitive control” is now available online at the Journal of Neuroscience.

Abstract:

The nicotinic system plays an important role in cognitive control, and is implicated in several neuropsychiatric conditions. Yet, the contributions of genetic variability in this system to individuals’ cognitive control abilities are poorly understood, and the brain processes that mediate such genetic contributions remain largely unidentified. In this first large-scale neuroimaging genetics study of the human nicotinic receptor system (two cohorts, males and females, fMRI total N=1586, behavioral total N=3650), we investigated a common polymorphism of the high-affinity nicotinic receptor α4β2 (rs1044396 on the CHRNA4 gene) previously implicated in behavioral and nicotine-related studies (albeit with inconsistent major/minor allele impacts). Based on our prior neuroimaging findings, we expected this polymorphism to impact neural activity in the cingulo-opercular network involved in core cognitive control processes including maintenance of alertness. Consistent across the cohorts, all cortical areas of the cingulo-opercular network showed higher activity in heterozygotes compared to both types of homozygotes during cognitive engagement. This inverted U-shaped relation reflects an overdominant effect, i.e. allelic interaction (cumulative evidence p=1.33*10-5). Furthermore, heterozygotes performed more accurately in behavioral tasks that primarily depend on sustained alertness. No effects were observed for haplotypes of the surrounding CHRNA4 region, supporting a true overdominant effect at rs1044396. As a possible mechanism, we observed that this polymorphism is an expression quantitative trait locus (eQTL) modulating CHRNA4 expression levels. This is the first report of overdominance in the nicotinic system. These findings connect CHRNA4 genotype, cingulo-opercular network activation and sustained alertness, providing insights into how genetics shapes individuals’ cognitive control abilities.

Significance statement:

The nicotinic acetylcholine system plays a central role in neuromodulatory regulation of cognitive control processes, and is dysregulated in several neuropsychiatric disorders. In spite of this functional importance, no large-scale neuroimaging genetics studies have targeted the contributions of genetic variability in this system to human brain activity. Here, we show impact of a common polymorphism of the high-affinity nicotinic receptor α4β2, consistent across brain activity and behavior in two large human cohorts. We report a hitherto unknown overdominant effect (allelic interaction) at this locus, where the heterozygotes show higher activity in the cingulo-opercular network underlying alertness maintenance, and higher behavioral alertness performance than both homozygous groups. This gene-brain-behavior relationship informs about the biological basis of inter-individual differences in cognitive control.

 Posted by at 08:55

Paper accepted in Journal of Neuroscience!

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Aug 232017
 

Our paper with the title “Overdominant effect of a CHRNA4 polymorphism on cingulo-opercular network activity and cognitive control” was accepted for publication in the Journal of Neuroscience.

 

 

 

 

Authors: Sepideh Sadaghiani, Bernard Ng, Andre Altmann, Jean-Baptiste Poline, Tobias Banaschewski, Arun Bokde, Uli Bromberg, Christian Büchel, Erin Burke Quinlan, Patricia Conrod, Sylvane Desrivières, Herta Flor, Vincent Frouin, Hugh Garavan, Penny Gowland, Juergen Gallinat, Andreas Heinz, Bernd Ittermann, Jean-Luc Martinot, Marie-Laure Martinot, Hervé Lemaitre, Frauke Nees, Dimitri Papadopoulos Orfanos, Tomas Paus, Luise Poustka, Sabina Millenet, Juliane Fröhner, Michael Smolka, Henrik Walter, Robert Whelan, Gunter Schumann, Valerio Napolioni, Michael Greicius

 Posted by at 11:26

Marzia Scelsi receives Merit Abstract Award for the 2017 OHBM Annual Meeting!

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Mar 092017
 

Our abstract “Multimodal Imaging Disease Progression Scores as Quantitative Traits in GWAS of the ADNI Cohort” was selected for an oral presentation at OHBM 2017, Vancouver, Canada!

On top of that lead author Marzia Scelsi received a Merit Abstract Award for the 2017 OHBM Annual Meeting. Congrats Marzia!

 

M. A. Scelsi, M. Lorenzi, J. M. Schott, S. Ourselin, A. Altmann, “Multimodal Imaging Disease Progression Scores as Quantitative Traits in GWAS of the ADNI Cohort”

Introduction

Quantitative trait genome-wide association studies (GWAS) in late-onset Alzheimer’s disease (AD) using imaging biomarkers focused either on cross-sectional or on longitudinal phenotypes derived from a single imaging modality. However, since clinical and imaging biomarkers in AD are highly interrelated, association studies based on single biomarkers may miss genetic factors influencing their joint variation. In order to account for their joint variability, in this work we propose to use two well-established AD biomarkers to define a disease progression score (DPS), and to subsequently perform a GWAS using this DPS as a novel quantitative phenotype.

 Posted by at 11:19

Paper accepted at SIPAIM 2016!

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Oct 102016
 

Our work on distributed partial least squares (PLS) has been accepted for an oral presentation at SIPAIM 2016. An earlier version of this paper was presented by Marco Lorenzi at MASAMB (Matematical and Statistical aspects of Molecular Biology) in Cambridge in early October.

Title: Secure multivariate large-scale multi-centric analysis through on-line learning: an imaging genetics case study

Authors: Marco Lorenzi, Boris Gutman, Paul M. Thompson, Daniel C. Alexander, Sebastien Ourselin, Andre Altmann

Abstract: State-of-the-art data analysis methods in genetics and related fields have advanced beyond massively univariate analyses. However, these methods suffer from the limited amount of data available at a single research site. Re- cent large-scale multi-centric imaging-genetic studies, such as ENIGMA, have to rely on meta-analysis of mass univariate models to achieve critical sample sizes for uncovering statistically significant associations. Indeed, model parameters, but not data, can be securely and anonymously shared between partners. We propose here partial least squares (PLS) as a multivariate imaging-genetics model in meta-studies. In particular, we propose an online estimation approach to partial least squares for the sequential estimation of the model parameters in data batches, based on an approximation of the singular value decomposition (SVD) of partitioned covariance matrices. We applied the proposed approach to the challenging problem of modeling the association between 1,167,117 genetic markers (SNPs, single nucleotide polymorphisms) and the brain cortical and sub-cortical atrophy (354,804 anatomical surface features) in a cohort of 639 individuals from the Alzheimer’s Disease Neuroimaging Initiative. We compared two different modeling strategies (sequential- and meta-PLS) to the classic non-distributed PLS. Both strategies exhibited only minimal approximation errors of model parameters. The proposed approaches pave the way to the application of multivariate models in large scale imaging-genetics meta-studies, and may lead to novel understandings of the complex brain phenotype-genotype interactions.

 Posted by at 22:12

Our work is highlighted at Alzforum

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Sep 022016
 

Two of our contributions to the recent AAIC in Toronto have been highlighted in an Alzforum news item. Click here to read the article.

Screenshot 2016-09-02 at 10.46.12 AM

 Posted by at 08:47

Re-Annotator annotation for the AIBS custom Agilent chip online

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Apr 102016
 

We just added the Re-Annotator annotation for the custom microarray chip from Agilent used by the Allen Institute for Brain Sciences. Get the annotation here. This annotation was also used for our recent paper in Science. We are also taking requests for frequently used chips to be added to the page, just email us! If you use Re-Annotator or the resulting annotations, please cite our paper.

 Posted by at 16:27

Paper accepted at ISBI 2016

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Mar 112016
 

Our paper with the title “Partial Least Squares Modeling for Imaging-Genetics in Alzheimer’s Disease: Plausibility and Generalization” was accepted for presentation at ISBI 2016.

Abstract: TBA


 

 Posted by at 23:11