Abstract
Bipolar disorder (BD) is highly heritable. Thus, studies in first-degree relatives of individuals with BD could lead to the discovery of objective risk markers of BD. Abnormalities in white matter structure reported in at-risk individuals could play an important role in the pathophysiology of BD. Due to the lack of studies with other at-risk offspring, however, it remains unclear whether such abnormalities reflect BD-specific or generic risk markers for future psychopathology. Using a tract-profile approach, we examined 18 major white matter tracts in 38 offspring of BD parents, 36 offspring of comparison parents with non-BD psychopathology (depression, attention-deficit/hyperactivity disorder), and 41 offspring of healthy parents. Both at-risk groups showed significantly lower fractional anisotropy (FA) in left-sided tracts (cingulum, inferior longitudinal fasciculus, forceps minor), and significantly greater FA in right-sided tracts (uncinate fasciculus and inferior longitudinal fasciculus), relative to offspring of healthy parents (P < 0.05). These abnormalities were present in both healthy and affected youth in at-risk groups. Only offspring (particularly healthy offspring) of BD parents showed lower FA in the right superior longitudinal fasciculus relative to healthy offspring of healthy parents (P < 0.05). We show, for the first time, important similarities, and some differences, in white matter structure between offspring of BD and offspring of non-BD parents. Findings suggest that lower left-sided and higher right-sided FA in tracts important for emotional regulation may represent markers of risk for general, rather than BD-specific, psychopathology. Lower FA in the right superior longitudinal fasciculus may protect against development of BD in offspring of BD parents.
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Funding
The present study was supported by the National Institute of Mental Health grant R01 MH060952-16 (MPI: Drs. Birmaher and Phillips), by the National Institute of Health/National Center for Advancing Translational Sciences grant TL1 TR001858-01 (Dr. Wishwa Kapoor) and by the National Institute of Mental Health grants funding the LAMS study (2R01 MH73953-06A1, 2R01, MH73816-06A1, 2R01 MH73967-06A1, and 2R01 MH73801-06A1). These funding agencies were not involved in the design or conduct of the study, the collection, management, analysis, or interpretation of the data, or the preparation, review, or approval of the manuscript. We would like to acknowledge the participants and their families for their contributions to this study.
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V.A., L.C.D., A.H.E., L.A., Y.A., T.M.J., D.V.A., H.S.K., S.J.L., K.R.A., A.D., H.S.M., F.M.A., Y.E.A., G.B.I., and P.M.L., and G.S., M.K., B.L.K., and M.A. have no financial interests or potential conflicts of interest. A.L.E. has received research funding from CureMark, Forest, Lilly, and Shire, advisory board honoraria from Biomarin, Novartis, Noven, Otsuka, Roche, Seaside Therapeutics, and Shire, consulting fees from Tris Pharma, and travel support from Noven. F.T.W. has received federal funding or research support from, acted as a consultant to, received travel support from, and/or received a speaker’s honorarium from the Simons Foundation, Ingalls Foundation, Forest Laboratories, Ecoeos, IntegraGen, Shire Development, Bristol-Myers Squibb, National Institutes of Health, and the Brain and Behavior Research Foundation. F.R.L. receives or has received research support, acted as a consultant and/or served on a speaker’s bureau for Aevi, Akili, Alcobra, Amerex, American Academy of Child & Adolescent Psychiatry, American Psychiatric Press, Bracket, Epharma Solutions, Forest, Genentech, Guilford Press, Ironshore, Johns Hopkins University Press, KemPharm, Lundbeck, Merck, NIH, Neurim, Nuvelution, Otsuka, PCORI, Pfizer, Physicians Postgraduate Press, Purdue, Roche, Sage, Shire, Sunovion, Supernus Pharmaceuticals, Syneurx, Teva, Tris, TouchPoint, Validus, and WebMD. A.D. has served as a consultant for Janssen Research and received royalties from UpToDate. T.G. receives royalties from Guilford Press. B.B. receives or will receive royalties for publications from Random House, Inc. (New Hope for Children and Teens with Bipolar Disorder), Lippincott Williams & Wilkins (Treating Child and Adolescent Depression), and UpToDate. He is employed by the University of Pittsburgh and the University of Pittsburgh Medical Center/Western Psychiatric Institute and Clinic and receives research funding from NIMH.
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Versace, A., Ladouceur, C., Graur, S. et al. Diffusion imaging markers of bipolar versus general psychopathology risk in youth at-risk. Neuropsychopharmacol 43, 2212–2220 (2018). https://doi.org/10.1038/s41386-018-0083-z
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DOI: https://doi.org/10.1038/s41386-018-0083-z
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