Magnetic resonance imaging of lithium in human brain

描述(申请人提供)：锂(Li)仍然是治疗双相情感障碍(躁郁症)的主要药物。尽管进行了大量研究，但李的作用机制和大脑中的区域分布尚不清楚。双相情感障碍的症状表明，某些大脑区域主要与疾病有关。例如，在被称为前缘网络的大脑区域观察到了异常。李在双相情感障碍中的临床效果很可能来自于它在这些脑区的影响，而不是它在整个大脑中的存在。了解LI在大脑中的区域分布将有助于阐明LI的治疗作用机制、神经毒性效应以及患者对药物反应的巨大差异。这将决定Li是否在关键的大脑区域实现了足够的浓度。磁共振成像(MRI)是一种强大的临床诊断工具。在标准的临床MRI中，图像对比度主要是由组织水中氢(1H)的各种MRI信号参数的差异提供的。有可能从1H以外的元素(如7Li)中产生MRI信号，以提供大脑中该元素的图谱。对于7Li MRI，早期试图绘制LI治疗患者大脑中LI的空间分布图，但没有成功。治疗期间脑内Li浓度低(~1 mM)，7Li相对1H的敏感性较低，以及极长的自旋-晶格驰豫时间(T1)，使得7Li MRI对提供有用信息太不敏感。现在，这些问题可以通过更高磁场扫描仪的灵敏度提高、改进的电子学和新的MRI脉冲序列来克服，以减少长T1的影响。我们将在辛辛那提大学医学院影像研究中心的4-T MRI研究扫描仪上开发和实施活体7Li MRI。这项建议的具体目的是：1)在测试样本中比较标准梯度回波、低尖角MRI序列、自旋回波大尖角MRI序列和短回波时间驱动平衡傅立叶变换序列，以确定体内7Li MRI测量的最佳序列；以及2)使用特定目标1的最佳7Li MRI方法，测量10名接受LI治疗双相情感障碍的患者在稳态时LI在大脑中的分布，以测试该方法的有效性。与公共卫生相关：锂是双相情感障碍的重要治疗方法，这是一种毁灭性的精神疾病，发生在大约3%的人口中。了解锂在治疗过程中如何在大脑中分布可能会导致更好、更有效的治疗。在这个项目中，将开发一种核磁共振方法来绘制双相情感障碍患者大脑中锂的区域分布。

DESCRIPTION (provided by applicant): 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.