Lithium (Li) is still a mainstay for the treatment of bipolar disorder (manic-depressive illness). Despite considerable research, Li's mechanism of action and regional distribution in brain are unknown. The symptoms of bipolar disorder suggest that certain brain regions are primarily involved in the illness. For example, abnormalities have been observed in brain regions known as the anterior limbic network. It is likely that Li's clinical effects in bipolar disorder arise from its effects in these brain regions and not from its presence in brain overall. Understanding the regional distribution of Li within the brain would clarify Li's mechanisms of therapeutic actions, neurotoxic effects, and the wide variations in patients'responsiveness to the drug. It would determine whether Li is achieving sufficient concentrations in critical brain regions. Magnetic resonance imaging (MRI) is a powerful clinical diagnostic tool. In standard clinical MRI, image contrast is provided primarily by differences in a variety of MRI signal parameters from hydrogen (1H) in tissue water. It is possible to generate MRI signals from elements other than 1H, such as 7Li, to provide a map of that element in the brain. For 7Li MRI, early attempts to map the spatial distribution of Li in the brain of a patient on Li therapy were unsuccessful. The low concentration of Li (~1 mM) in the brain during treatment, the lower sensitivity of 7Li relative to 1H, and the very long spin-lattice relaxation time (T1) made 7Li MRI too insensitive to provide usable information. Now these problems can be overcome by sensitivity increases from higher-magnetic-field scanners, improved electronics, and new MRI pulse sequences to reduce the effect of long T1. We will develop and implement in vivo 7Li MRI on a 4-T MRI research scanner in the Center for Imaging Research in the University of Cincinnati College of Medicine.
The specific aims of this proposal are: 1) to compare a standard gradient echo, low-tip-angle MRI sequence, a spin-echo, large-tip-angle MRI sequence, and a short-echo-time driven-equilibrium Fourier transform MRI sequence in test samples to determine the optimum sequence for in vivo 7Li MRI measurements;and 2) using the optimum 7Li MRI approach from Specific Aim 1, measure the distribution of Li in the brains of 10 patients being treated with Li for bipolar disorder and at steady state as a test of the validity of the method.

Public Health Relevance

Lithium is an important treatment for bipolar disorder, a devastating mental illness that occurs in about 3% of the population. Understanding how lithium distributes itself in the brain during treatment could lead to better, more effective treatment. In this project, an MRI method will be developed to map the regional distribution of lithium in the brains of bipolar-disorder patients.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
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Freund, Michelle
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University of Cincinnati
Schools of Medicine
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