Widespread white matter microstructural abnormalities in bipolar disorder: evidence from mega- and meta-analyses across 3033 individuals

Fronto-limbic white matter (WM) abnormalities are assumed to lie at the heart of the pathophysiology of bipolar disorder (BD); however, diffusion tensor imaging (DTI) studies have reported heterogeneous results and it is not clear how the clinical heterogeneity is related to the observed differences. This study aimed to identify WM abnormalities that differentiate patients with BD from healthy controls (HC) in the largest DTI dataset of patients with BD to date, collected via the ENIGMA network. We gathered individual tensor-derived regional metrics from 26 cohorts leading to a sample size of N = 3033 (1482 BD and 1551 HC). Mean fractional anisotropy (FA) from 43 regions of interest (ROI) and average whole-brain FA were entered into univariate mega- and meta-analyses to differentiate patients with BD from HC. Mega-analysis revealed significantly lower FA in patients with BD compared with HC in 29 regions, with the highest effect sizes observed within the corpus callosum (R2 = 0.041, Pcorr < 0.001) and cingulum (right: R2 = 0.041, left: R2 = 0.040, Pcorr < 0.001). Lithium medication, later onset and short disease duration were related to higher FA along multiple ROIs. Results of the meta-analysis showed similar effects. We demonstrated widespread WM abnormalities in BD and highlighted that altered WM connectivity within the corpus callosum and the cingulum are strongly associated with BD. These brain abnormalities could represent a biomarker for use in the diagnosis of BD. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org

Biomarqueurs du trouble bipolaire en imagerie par résonance magnétique

Le trouble bipolaire est une maladie fréquente et grave. Son diagnostic est souvent tardif et les traitements proposés ne sont que partiellement efficaces. La découverte de marqueurs biologiques pour cette pathologie est un enjeu important. Ces biomarqueurs pourraient permettre un diagnostic plus précoce et un meilleur pronostic.La neuroimagerie est un axe prometteur de potentiels biomarqueurs du trouble bipolaire. L'imagerie par résonance magnétique (IRM) a permis de mettre en évidence des différences cérébrales entre des groupes de patients bipolaires et de sujets sains. Cette phase exploratoire laisse espérer que certains de ces "biomarqueurs candidats" trouveront une application clinique.Ce travail de thèse fait la revue de l'état actuel des connaissances sur l'exploration de potentiels biomarqueurs pour le trouble bipolaire par trois techniques d'IRM particulièrement prometteuses : l IRM structurale, l IRM fonctionnelle et l IRM par tenseur de diffusion. Nous proposons également à travers deux travaux originaux un exemple de recherche de biomarqueurs pour le trouble bipolaire dans la substance blanche cérébrale : une méta-analyse des études en IRM par tenseur de diffusion et une étude en tractographie chez des patients bipolaires.PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocSudocFranceF

Cytomegalovirus seropositivity and serointensity are associated with hippocampal volume and verbal memory in schizophrenia and bipolar disorder.

International audienceINTRODUCTION: Cytomegalovirus (CMV) is a member of the herpesviridae family that has a limbic and temporal gray matter tropism. It is usually latent in humans but has been associated with schizophrenia, bipolar disorder and cognitive deficits in some populations. Hippocampal decreased volume and dysfunction play a critical role in these cognitive deficits. We hypothesized that CMV seropositivity and serointensity would be associated with hippocampal volume and cognitive functioning in patients with schizophrenia or bipolar disorder. METHODS: 102 healthy controls, 118 patients with bipolar disorder and 69 patients with schizophrenia performed the California Verbal Learning Test (CVLT) and had blood samples drawn to assess CMV IgG levels. A subgroup of 52 healthy controls, 31 patients with bipolar disorder and 27 patients with schizophrenia underwent T1 MRI for hippocampal volumetry. We analyzed the association between CMV serointensity and seropositivity with hippocampal volume. We also explored the correlation between CMV serointensity and seropositivity and CVLT scores. RESULTS: In both patient groups but not in controls, higher CMV serointensity was significantly associated with smaller right hippocampal volume. Further, in the group of patients with schizophrenia but not bipolar disorder, CMV serointensity was negatively correlated with CVLT scores. CONCLUSION: CMV IgG titers are associated with decreased hippocampal volume and poorer episodic verbal memory in patients with schizophrenia or bipolar disorder. The mechanism of this association warrants further exploration

A comprehensive tractography study of patients with bipolar disorder and their unaffected siblings.

BACKGROUND: Diffusion tensor imaging studies show reductions in fractional anisotropy (FA) in individuals with bipolar disorder and their unaffected siblings. However, the use of various analysis methods is an important source of between-study heterogeneity. Using tract-based spatial statistics, we previously demonstrated widespread FA reductions in patients and unaffected relatives. To better interpret the neuroanatomical pattern of this previous finding and to assess the influence of methodological heterogeneity, we here applied tractography to the same sample. METHODS: Diffusion-weighted images were acquired for 96 patients, 69 unaffected siblings and 56 controls. We applied TRACULA, an extension of a global probabilistic tractography algorithm, to automatically segment 18 major fiber tracts. Average FA within each tract and at each cross-section along each tract was compared between groups. RESULTS: Patients had reduced FA compared to healthy controls and their unaffected siblings in general, and in particular in the parietal part of the superior longitudinal fasciculus. In unaffected siblings, FA was nominally reduced compared to controls in the corpus callosum. Point-wise analyses indicated that similar effects were present along extended sections, but with variable effect sizes. Current symptom severity negatively correlated with FA in several fronto-limbic association tracts. CONCLUSIONS: The differential sensitivity of analysis techniques likely explains between-study heterogeneity in anatomical localization of FA reductions. The present tractography analysis confirms the presence of overall FA reductions in patients with bipolar disorder, which are most pronounced in the superior longitudinal fasciculus. Unaffected siblings may display similar, albeit more subtle and anatomically restricted FA reductions. Hum Brain Mapp 37:3474-3485, 2016. (c) 2016 Wiley Periodicals, Inc

Abnormal functional-structural cingulum connectivity in mania: combined functional magnetic resonance imaging-diffusion tensor imaging investigation in different phases of bipolar disorder.

Objective: The objective of the study was to investigate the relationship between structural connectivity (SC) and functional connectivity (FC) in the cingulum in bipolar disorder (BD) and its various phases. Method: We combined resting-state functional magnetic resonance imaging and probabilistic tractographic diffusion tensor imaging to investigate FC and SC of the cingulum and its portions, the SC-FC relationship, and their correlations with clinical and neurocognitive measures on sustained attention in manic (n = 21), depressed (n = 20), and euthymic (n = 20) bipolar patients and healthy controls (HC) (n = 42). Results: First, we found decreased FC between the anterior and posterior parts of the cingulum in manic patients when compared to depressed patients and HC. Second, we observed decreased SC of the cingulum bundle, particularly in its anterior part, in manic patients when compared to HC. Finally, alterations in the cingulum FC (but not SC) correlated with clinical severity scores while changes in the cingulum SC (but not FC) were related with neurocognitive deficits in sustained attention in BD. Conclusion: We demonstrate for the first time a reduction in FC and concomitantly in SC of the cingulum in mania, which correlated with psychopathological and neurocognitive parameters, respectively, in BD. This supports the central role of cingulum connectivity specifically in mania