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Original Investigation |

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

Samuel Sarrazin, MSc1,2,3,4,5; Cyril Poupon, PhD5; Julia Linke, PhD6; Michèle Wessa, PhD6; Mary Phillips, MD, PhD7; Marine Delavest, MD8; Amelia Versace, MD, PhD7; Jorge Almeida, MD, PhD7; Pamela Guevara, PhD5,9; Delphine Duclap, MSc5; Edouard Duchesnay, PhD5; Jean-François Mangin, PhD5; Katia Le Dudal, MSc10; Claire Daban, PhD1,2,4; Nora Hamdani, MD, PhD1,2,4; Marc-Antoine D’Albis, MD1,2,3,4; Marion Leboyer, MD, PhD1,2,3,4; Josselin Houenou, MD, PhD1,2,4,5
[+] Author Affiliations
1Pôle de Psychiatrie, Assistance Publique–Hôpitaux de Paris (AP-HP), Hôpital Henri Mondor–Albert Chenevier, Créteil, France
2Institut National de la Santé et de la Recherche Médicale (INSERM), U955, Institut Mondor de Recherche Biomédicale, Psychiatrie Génétique, Créteil, France
3Faculté de Médecine, Universite Paris Est, Créteil, France
4Fondation Fondamental, Créteil, France
5NeuroSpin, CEA Seclay, Gif-sur-Yvette, France
6Section for Experimental Psychopathology and Neuroimaging, Department of General Psychiatry, Center for Psychosocial Medicine, Heidelberg University, Heidelberg, Germany
7Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
8Service de Psychiatrie, AP-HP, Hôpital Fernand Widal–Lariboisière, Paris, France
9Department of Electrical Engineering, Faculty of Engineering, University of Concepción, Concepción, Chile
10INSERM, Centre d’Investigation Clinique et Plateforme de Ressources Biologiques, Hôpitaux Henri Mondor, Créteil, France
JAMA Psychiatry. 2014;71(4):388-396. doi:10.1001/jamapsychiatry.2013.4513.
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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.

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Figure 1.
Reconstruction of the White Matter Processing Pipeline

A, Tractography mask. B, Whole-brain tractography. C, Segmentation based on fiber lengths. Colors represent different fiber length. Green indicates fibers ranging from 30 to 50 mm; light green, greater than 50 to 80 mm; dark green, greater than 80 to 95 mm; cyan blue, greater than 95 to 110 mm; dark olive green, greater than 110 to 130 mm; purple, greater than 130 to 150 mm; dark blue, greater than 150 to 175 mm; and dark purple, greater than 175 to 300 mm. D, Centroid tracts calculated from each fascicle. E, Final segmented bundles of the left hemisphere and of the interhemispheric region. Blue-green indicates the corpus callosum; light blue, the left cingulum; green, the left frontal thalamic radiations; purple, the left uncinate fasciculus; yellow, the left inferior frontal-occipital fasciculus; dark green, the left inferior longitudinal fasciculus; and red, the left arcuate fasciculus. F, Extraction of the mean generalized fractional anisotropy along the left inferior longitudinal fasciculus.

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Figure 2.
Mean Generalized Fractional Anisotropy (GFA) Along the Body of the Corpus Callosum for Patients and Controls

Individual GFA (an index of all the computed orientation distribution functions) values along the body of the corpus callosum for all patients with bipolar I disorder (BPI), those with psychotic features (PF), those without PF, and healthy controls. History of PF was not available for 1 BPI patient. A decreased GFA value is thought to indicate loss of integrity or loss of coherence of white matter.3aP < .05 corrected for multiple testing.

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