Delphine Duclap

A Multicenter Tractography Study of Deep White Matter Tracts in Bipolar I Disorder: Psychotic Features and Interhemispheric Disconnectivity

IMPORTANCE Tractography studies investigating white matter (WM) abnormalities in patients with bipolar disorder have yielded heterogeneous results owing to small sample sizes. The small size limits their generalizability, a critical issue for neuroimaging studies of biomarkers of bipolar I disorder (BPI). OBJECTIVES To study WM abnormalities using whole-brain tractography in a large international multicenter sample of BPI patients and to compare these alterations between patients with or without a history of psychotic features during mood episodes. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional, multicenter, international, Q-ball imaging tractography study comparing 118 BPI patients and 86 healthy control individuals. In addition, among the patient group, we compared those with and without a history of psychotic features. University hospitals in France, Germany, and the United States contributed participants. INTERVENTIONS Participants underwent assessment using the Diagnostic Interview for Genetic Studies at the French sites or the Structured Clinical Interview for DSM-IV at the German and US sites. Diffusion-weighted magnetic resonance images were acquired using the same acquisition parameters and scanning hardware at each site. We reconstructed 22 known deep WM tracts using Q-ball imaging tractography and an automatized segmentation technique. MAIN OUTCOMES AND MEASURES Generalized fractional anisotropy values along each reconstructed WM tract. RESULTS Compared with controls, BPI patients had significant reductions in mean generalized fractional anisotropy values along the body and the splenium of the corpus callosum, the left cingulum, and the anterior part of the left arcuate fasciculus when controlling for age, sex, and acquisition site (corrected for multiple testing). Patients with a history of psychotic features had a lower mean generalized fractional anisotropy value than those without along the body of the corpus callosum (corrected for multiple testing). CONCLUSIONS AND RELEVANCE In this multicenter sample, BPI patients had reduced WM integrity in interhemispheric, limbic, and arcuate WM tracts. Interhemispheric pathways are more disrupted in patients with than in those without psychotic symptoms. Together these results highlight the existence of an anatomic disconnectivity in BPI and further underscore a role for interhemispheric disconnectivity in the pathophysiological features of psychosis in BPI.

Childhood trauma and the limbic network: a multimodal MRI study in patients with bipolar disorder and controls

BACKGROUND Childhood trauma (CT) is a major risk factor for psychiatric conditions. It is hypothesized that CT effects are mediated by the limbic system. Few multimodal neuroimaging studies allow an integrated perspective of this impact. Our goal was thus to study the effects of CT on the limbic network. METHODS We acquired multimodal MRI (T1, diffusion weighted, and resting state fMRI) data from 79 subjects (47 healthy controls and 32 patients with bipolar disorder, BD). We performed correlational analyses between Childhood Trauma Questionnaire (sub)scores (physical and emotional abuse/neglect and sexual abuse) and anatomo-functional measurements of the limbic network (hippocampal and amygdala volumes, prefronto-limbic functional connectivity, uncinate fractional anisotropy). RESULTS We found CTQ total scores to be negatively correlated with amygdala volume, prefronto-limbic functional connectivity (FC) and uncinate fractional anisotropy in our sample. Considering subscores, neglects (physical and emotional) were the only to affect neural parameters. The patients with BD drove most of the results. LIMITATIONS Small sample size and low level of trauma in controls. CONCLUSIONS Our multimodal approach enabled an integrated view of the long-term effects of CT on the limbic system.

Similar white matter but opposite grey matter changes in schizophrenia and high‐functioning autism

High‐functioning autism (HFA) and schizophrenia (SZ) are two of the main neurodevelopmental disorders, sharing several clinical dimensions and risk factors. Their exact relationship is poorly understood, and few studies have directly compared both disorders. Our aim was thus to directly compare neuroanatomy of HFA and SZ using a multimodal MRI design.

Dysfunctional decision-making related to white matter alterations in bipolar I disorder

OBJECTIVE This study investigated how frontal white matter (WM) alterations in patients with bipolar I disorder (BD-I) are linked to motivational dysregulation, often reported in the form of risk-taking and impulsivity, and whether structure-function relations in patients might differ from healthy subjects (HC). METHOD We acquired diffusion data from 24 euthymic BD-I patients and 24 controls, to evaluate WM integrity of selected frontal tracts. Risk-taking was assessed by the Cambridge Gambling Task and impulsivity by self-report with the Barratt-Impulsiveness Scale. RESULTS BD-I patients displayed significantly lower integrity in the right cingulum compared to HC. They also showed more risk-taking behavior and reported increased trait-impulsivity. Risk-taking was negatively associated with WM integrity in the right cingulum. Impulsivity was not related to WM integrity in investigated tracts. Together with age and sex, FA in the cingulum explained 25% of variance in risk-taking scores in all study participants. The left inferior fronto-occipital fasciculus (IFOF) was specifically predictive of risk-taking behavior in BD-I patients, but not in HC. LIMITATIONS The employed parameters did not allow us to specify the exact origin of WM changes, nor did the method allow the analysis of specific brain subregions. Also, sample size was moderate and the sample included patients with lifetime alcohol dependence/abuse, hence effects found need replication and have to be interpreted with caution. CONCLUSION Our results further strengthen recent models linking structural changes in frontal networks to behavioral markers of BD-I. They extend recent findings by showing that risk-taking is also linked to the cingulum in BD-I and HC, while other prefrontal tracts (IFOF) are specifically implicated in risk-taking behavior in BD-I patients. Meanwhile, self-reported impulsivity was not associated with WM integrity of the tracts investigated in our study.

Shape analysis of the cingulum, uncinate and arcuate fasciculi in patients with bipolar disorder

Background Abnormal maturation of brain connectivity is supposed to underlie the dysfunctional emotion regulation in patients with bipolar disorder (BD). To test this hypothesis, white matter integrity is usually investigated using measures of water diffusivity provided by MRI. Here we consider a more intuitive aspect of the morphometry of the white matter tracts: the shape of the fibre bundles, which is associated with neurodevelopment. We analyzed the shape of 3 tracts involved in BD: the cingulum (CG), uncinate fasciculus (UF) and arcuate fasciculus (AF). Methods We analyzed diffusion MRI data in patients with BD and healthy controls. The fibre bundles were reconstructed using Q-ball–based tractography and automated segmentation. Using Isomap, a manifold learning method, the differences in the shape of the reconstructed bundles were visualized and quantified. Results We included 112 patients and 82 controls in our analysis. We found the left AF of patients to be further extended toward the temporal pole, forming a tighter hook than in controls. We found no significant difference in terms of shape for the left UF, the left CG or the 3 right fasciculi. However, in patients compared with controls, the ventrolateral branch of the left UF in the orbitofrontal region had a tendency to be larger, and the left CG of patients had a tendency to be smaller in the frontal lobe and larger in the parietal lobe. Limitations This was a cross-sectional study. Conclusion Our results suggest neurodevelopmental abnormalities in the left AF in patients with BD. The statistical tendencies observed for the left UF and left CG deserve further study.

2793 – A multicenter tractography study of structural connectivity in bipolar disorder and effects of psychotic features

Introduction A number of studies have investigated white matter abnormalities in patients with bipolar disorder (BD) using diffusion tensor imaging. However, tractography studies yielded heterogeneous results partly due to small sample sizes. Aims In this work we aimed to study white matter abnormalities using whole-brain tractography in a large multicenter sample of patients with BD I with and without psychotic features. Objectives To compare mean generalized fractional anisotropy (GFA) along deep white matter tracts between patients with BD with a positive history of psychosis during illness phases, no such history and healthy controls. Methods We acquired diffusion-weighted MRI for 118 patients with BD I and 86 healthy controls using the same acquisition parameters and scanning hardware. We used Q-ball imaging tractography and an automatized segmentation technique to reconstruct 22 known deep white matter tracts and to obtain the mean GFA along each tract. Results Patients with BD had lower GFA values than controls along the corpus callosum (body and splenium), the left cingulum and the left arcuate fasciculus, when controlling for age, gender and acquisition site. All results with an exception for the long fibers of the left cingulum were driven by patients with a positive history of psychotic symptoms. Conclusions We demonstrated a reduced integrity of interhemispheric, limbic and arcuate white matter tracts in patients with BD I. Further, interhemispheric pathways were more disrupted in patients with psychotic symptoms, underscoring the role of interhemispheric connectivity in the pathophysiology of BD with psychosis.

Source localization of event-related potential effects differentiates between vascular dementia and Alzheimer's disease

Background: VaD and AD have different underlying pathogenic mechanisms, and may produce distinct signatures in brain activity that could aid in differential diagnosis. We investigate possible differential markers based on source localization of electrophysiological correlates of memory processing in VaD and AD. Methods: Advances in high resolution whole head EEG recordings, together with accurate conductivity models of head tissues, mean that reasonably accurate distributed source models can now be established. We used 128-channel EEG to measure amplitudes, latencies and topographies of the N2, P4, and P7 in AD and VaD patients and controls during an episodic memory task (all groups N = 8). We then used source localization methods (GeoSource; LAURA) to determine the cortical generators for the best performing ERP diagnostic markers. Results: The posterior N2 is prominent in controls and AD, but attenuated in VaD. This N2 effect localizes to the central occipital cortex in AD and controls, but not in VaD. The prefrontal P4 is prominent in controls, and evident in VaD, but attenuated in AD. The P4 localizes in all groups to the medial temporal region, but with varying intensity and timing. The right parietal P7 effect is prominent in controls, but attenuated in AD and VaD. The P7 localizes to prefrontal cortex in controls, but involves only right posterior cortex in VaD, and central posterior cortex in AD. Conclusions: Source localization analysis shows that scalp ERP differences between AD and VaD can be unambiguously attributed to different underlying generators within the brain. We hypothesize that these effects reflect disease-specific neuropathology, and offer new functional biomarkers to aid in differential diagnosis of AD and VaD.

Creation of a whole brain short association bundle atlas using a hybrid approach

The Human brain connection map is far from being complete. In particular the study of the superficial white matter (SWM) is an unachieved task. Its description is essential for the understanding of human brain function and the study of pathogenesis triggered by abnormal connectivity. In this work we expanded a previously developed method for the automatic creation of a whole brain SWM bundle atlas. The method is based on a hybrid approach. First a cortical parcellation is used to extract fibers connecting two regions. Then an intra-and inter-subject hierarchical clustering are applied to find well-defined SWM bundles reproducible across subjects. In addition to the fronto-parietal and insula regions of the left hemisphere, the analysis was extended to the temporal and occipital lobes, including all their internal regions, for both hemispheres. Validation steps are performed in order to test the robustness of the method and the reproducibility of the obtained bundles. First the method was applied to two independent groups of subjects, in order to discard bundles without match across the two independent atlases. Then, the resulting intersection atlas was projected on a third independent group of subjects in order to filter out bundles without reproducible and reliable projection. The final multi-subject U-fiber atlas is composed of 100 bundles in total, 50 per hemisphere, from which 35 are common to both hemispheres. The atlas can be used in clinical studies for segmentation of the SWM bundles in new subjects, and measure DW values or complement functional data.

Fronto-occipital Structural Disconnectivity as an Endophenotype of ASD

Introduction Autism spectrum disorders (ASD) are characterized by deficits in social interaction and behavioral impairments. Several studies have reported differences in white matter generalized Fractional Anisotropy (gFA) in ASD. Objectives We studied white matter microstructural integrity in individuals with ASD. Aims We conducted the first DWI-based whole brain tractography study to compare gFA in 22 deep white matter tracts in first-degree relatives of individuals with ASD to controls and individuals with ASD. Futhermore, we replicated our significants results in an independant sample. Methods Fifty-one first-degree relatives of individuals with ASD, 29 controls and 14 individuals with ASD participated. We performed q-ball imaging whole-brain tractography based on 1.5 T diffusion weighted MRI over 32 non-colinear directions. Then, we computed mean gFA along 22 main deep white matter tracts. A linear mixed model using group, gender, age and IQ as fixed effects and family as a random effect was used and Bonferroni correction applied. We also recruited a replication sample comprising 23 individuals with ASD and 32 controls. Results We demonstrated a significantly reduced mean gFA along the left IFOF in first-degree relatives of individuals with ASD and individuals with ASD compared with controls and replicated this finding in an independant sample of patients. A decrease in mean gFA was also observed in the left CST when we compared first-degree relatives of individuals with ASD to controls (no such decrease was present in patients). Conclusion Our work suggests that structural fronto-occipital disconnectivity may be an endophenotype of ASD.

Automatic diffusion-based fractional anisotropy measurements weighted by fiber density

IC-P-166 AUTOMATIC DIFFUSION-BASED FRACTIONAL ANISOTROPY MEASUREMENTS WEIGHTED BY FIBER DENSITY Adam Schwarz, Clarisse Longo dos Santos, Delphine Duclap, Cyril Poupon, Lea Marais, Derek Hill, Adam Schwarz, Jean-Francois Mangin, Eli Lilly and Company, Indianapolis, Indiana, United States; CEA, Gif-sur-Yvette, ~ A Zle-de-France, France; CEA IBM NeuroSpin, Gif-sur-Yvette, ~ A Zle-de-France, France; IXICO, London, United Kingdom; IXICO Ltd., London, United Kingdom; Eli Lilly, Indianapolis, Indiana, United States. Contact e-mail: a.schwarz@lilly.com