PROJECT SUMMARY/ABSTRACT: Bipolar Disorder (BD) is a common, serious medical disorder, affecting about 2% of individuals, which typically develops in adolescence. It causes suffering for affected individuals and their families, and difficulties in emotional, social, school and work function. It leads to lifelong risk for acute mood episodes, substance abuse and other medical illnesses (e.g. heart disease, diabetes), and early mortality owing to this morbidity and its suicide risk, the highest of psychiatric disorders. Suicide is a leading cause of death in adolescents; BD is a major risk factor. Early detection and treatment are critical, as earlier, untreated episodes worsen course and prognosis. Our findings in adolescents with BD of volume decreases in the amygdala (AMY), a brain region central to emotion processing, was replicated by other research groups and is one of the few potential early markers for BD. We then showed associations between AMY volume decreases and AMY activity excesses. Together with postmortem study evidence, this suggests early neurotoxic excesses in BD in the excitatory neurotransmitter glutamate (Glu) that could have detrimental effects on AMY structure and function. Data also support salutary effects on AMY structure and function of mood stabilizing medications that decrease Glu levels. Previous studies have primarily been of the AMY as a unitary structure; however, nuclei have different connectivity and functions and specific nuclei are increasingly implicated in BD. Identification of specific nuclei involved in BD is therefore important as the nuclei, their connected structures and their functions could be specific targets for detection, treatment and prevention of BD. Measurement of Glu and other neurochemicals could provide specific molecular targets. Previous magnetic resonance imaging (MRI) and MR spectroscopy (MRS) methods at lower magnetic field strengths did not permit morphological study of specific AMY nuclei and the relationship to Glu functioning. The Yale Magnetic Resonance Research Center has the expertise of Drs. Juchem, Mason and Rothman to perform 7T AMY MRI/MRS in vivo for unprecedented structural imaging of AMY nuclei and measures of AMY Glu levels in BD, with innovative methods to provide high image resolution, sensitivity and spectral resolution. Our collaborators Drs. Berretta (Harvard University) and Fudge (University of Rochester) are international leading experts in AMY anatomy and neurochemistry in humans and non-human primates. In pilot work, our team successfully demonstrated ability to delineate AMY nuclei at 7 Tesla (7T) and measure AMY Glu levels. Thus, we have assembled a highly unique and skilled team to accomplish critically needed research that is the first of its kind. It has potential to provide novel insights into the neurodevelopmental pathophysiology of BD, identifying specific AMY morphological and molecular targets for early detection, intervention and prevention. The study could have broad high impact, as it could establish new methodological approaches at 7T and benchmark values for studies in BD and in other psychiatric disorders.

NARRATIVE: Bipolar Disorder (BD) causes immeasurable suffering for the millions of individuals worldwide with the disorder, their families, and their communities, and is a leading risk factor for suicide; yet, its causes remain unknown and existing treatments are limited in effectiveness. Symptoms typically develop during adolescence and alterations in the development of the amygdala, a brain region central in emotions, are implicated in the early neurodevelopmental features of the disorder. In this R21, magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) study of the amygdala in adolescents with BD will be performed at ultra high magnetic field strength providing unprecedented ability to measure specific regions of the amygdala, as well as measures of the implicated neurotransmitter glutamate, likely to provide novel insights to aid elucidation of the neurodevelopmental pathophysiology of the disorder and early detection, intervention and prevention strategies.