This R01 renewal proposes multimodality magnetic resonance imaging (MRI) study of differences in age-related patterns of frontotemporal (FT) connectivity in adolescents and adults with and without bipolar disorder (BD) and the genetic factors that influence them. Despite severe consequences of BD in suffering for individuals, their families and communities, and the high associated rate of suicide, the biological mechanisms that underlie the development of BD and its effective treatment remain unclear. Currently, there is no biological marker to diagnose BD or to guide who might benefit from a specific treatment, though incorrect treatment can adversely affect prognosis and many with BD suffer from refractory symptoms. It is critical to understand how specific genetic predispositions lead to specific brain differences to improve detection, target treatments to those most likely to benefit based on their biology and discover new mechanisms to target for novel treatment development. Major challenges for the field also include presentations of BD that differ over the lifespan for reasons not understood, limiting ability to adapt detection and treatments for life phases. Progress of our research program includes identification of a FT neural system that subserves emotional processing as central in BD. Importantly, this system changes over the lifespan. Our current work supports progressive differences in FT gray matter between those with BD and healthy comparison (HC) individuals that emerge as significantly divergent in late adolescence/early adulthood and implicates neurotrophic genes (e.g. brain-derived neurotrophic factor, BDNF) in the neurodevelopmental differences. The white matter (WM) providing the connections within this FT neural system is increasingly implicated in BD. In progress towards our new aims, with a new focus on WM, preliminary diffusion tensor imaging (DTI) analyses suggest patterns of WM development in healthy individuals are characterized by increases in structural integrity of FT WM through the 4th decade of life, followed by decreases. Our preliminary data also support a divergent pattern for WM in adolescents and adults with BD that results in decreases in the structural integrity of WM in BD, with a peak in the decreases compared to HC individuals in the early 4th decade. This raises the important possibility of windows to prevent developmental progression of WM abnormalities in BD into adulthood. Moreover, the data implicate a gene associated with WM development, neuregulin 1 (NRG1), in influencing FT WM integrity in BD. In this renewal we therefore plan to extend our study of the FT neural system in BD using multimodality MRI to study WM with DTI, and associated FT functional connectivity with functional MRI methods, in a larger sample (including 150 new adolescents and adults with BD and 150 HCs) that will permit modeling of differences in age-related patterns and effects of NRG1 and other implicated genes. This program is devoted to a long-term goal of enhancing ability to treat individuals with BD more specifically, based on their genetic background and point in their lifespan, and development of more effective detection, treatment and prevention strategies.

Public Health Relevance

Bipolar Disorder (BD) causes immeasurable suffering for the millions of individuals worldwide with the disorder, their families, and their communities, and it is a leading cause of suicide; yet, its causes remain unknown and existing treatments are limited in effectiveness. Using combined brain scanning and genetics study in individuals with BD from adolescence through adulthood, we propose to build on exciting new leads from our ongoing work that show brain circuitry differences in BD that progress through adolescence into adulthood and identify genes that are related to this progression. This research could lead to new ways to halt illness progression in BD, enhance ability to detect BD and to treat individuals with it more specifically, based upon their genetic background and point in their lifespan, and someday prevent the disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH070902-10
Application #
8769164
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Meinecke, Douglas L
Project Start
2004-04-01
Project End
2015-11-30
Budget Start
2014-12-01
Budget End
2015-11-30
Support Year
10
Fiscal Year
2015
Total Cost
$599,848
Indirect Cost
$237,559
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06510
Weathers, Judah; Lippard, Elizabeth T C; Spencer, Linda et al. (2018) Longitudinal Diffusion Tensor Imaging Study of Adolescents and Young Adults With Bipolar Disorder. J Am Acad Child Adolesc Psychiatry 57:111-117
Lippard, Elizabeth T C; Mazure, Carolyn M; Johnston, Jennifer A Y et al. (2017) Brain circuitry associated with the development of substance use in bipolar disorder and preliminary evidence for sexual dimorphism in adolescents. J Neurosci Res 95:777-791
Johnston, Jennifer A Y; Wang, Fei; Liu, Jie et al. (2017) Multimodal Neuroimaging of Frontolimbic Structure and Function Associated With Suicide Attempts in Adolescents and Young Adults With Bipolar Disorder. Am J Psychiatry 174:667-675
Shaw, Philip; Blumberg, Hilary P (2017) Timely Research in Bipolar Disorder and Attention-Deficit/Hyperactivity Disorder. Biol Psychiatry 82:621-622
Lippard, E T C; Jensen, K P; Wang, F et al. (2017) Effects of ANK3 variation on gray and white matter in bipolar disorder. Mol Psychiatry 22:1345-1351
Najt, Pablo; Wang, Fei; Spencer, Linda et al. (2016) Anterior Cortical Development During Adolescence in Bipolar Disorder. Biol Psychiatry 79:303-10
Cox Lippard, Elizabeth T; Johnston, Jennifer A Y; Blumberg, Hilary P (2014) Neurobiological risk factors for suicide: insights from brain imaging. Am J Prev Med 47:S152-62
Blond, Benjamin N; Fredericks, Carolyn A; Blumberg, Hilary P (2012) Functional neuroanatomy of bipolar disorder: structure, function, and connectivity in an amygdala-anterior paralimbic neural system. Bipolar Disord 14:340-55
Liu, Jie; Blond, Benjamin N; van Dyck, Laura I et al. (2012) Trait and state corticostriatal dysfunction in bipolar disorder during emotional face processing. Bipolar Disord 14:432-41
Blumberg, Hilary P (2012) Euthymia, depression, and mania: what do we know about the switch? Biol Psychiatry 71:570-1

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