Estimating intracellular lithium in brain in vivo by localized ⁷Li magnetic resonance spectroscopy

Abstract

The therapeutic mechanism of action of lithium (Li) in bipolar disorder is unknown. While Li is presumed to work intracellularly in the brain, the fraction of intracellular Li in the brain in vivo is not known. It has not yet been possible to determine, directly and noninvasively, the intra-to extracellular distribution of Li in human brain in vivo. Lithium-7 ( 7 Li) MR is the only technique available for measuring noninvasively the concentration of Li in the brain in vivo. Here the individual components of biexponential 7 Li transverse (T 2 ) relaxation in rat brain in vivo are identified with intra-and extracellular Li, and used to estimate its compartmental distribution. Intracellular T 2 was 14.6 ؎ 6.9 ms, while extracellular T 2 was 160 ؎ 52 ms in nine rats. The fraction of intracellular brain Li ranged from 37% to 75% (mean: 63 ؎ 11%). Further, the biexponential T 2 results provided the basis for estimating Li compartmental distribution from monoexponential T 2 decays using a simple linear approximation. Lithium (Li) is an elemental cation used in the treatment of bipolar disorder. Despite its widespread use in clinical settings and extensive research into its mechanisms of action, there is still little agreement as to how Li exerts its clinical effects (1,2). Because Li is a simple ion, it must be viewed differently than other psychoactive drugs, which are usually organic compounds with clear receptor binding properties. Li competes with endogenous cations and thereby affects a wide range of biochemical processes, neurotransmitter synthesis and release, and cell membranes (3). Considerable attention has been focused on the effects of Li on phosphoinositide second-messenger metabolism (4 -6). But other possible mechanisms, including the effects on G-proteins (7), Na, K-adenosine triphosphatase (8), glycogen synthase kinase-3 (6,9), and gene expression (9 -11) are under investigation. Because most biochemical processes, including phosphoinositide second-messenger metabolism, occur within the cell, it is often presumed that Li exerts its clinically relevant effects in the intracellular space of neurons in the brain. However, because low intracellular Li concentrations have been found in some in vitro cellular systems, it has been suggested that the mechanism of action may be, at least in part, extracellular (12). The typical therapeutic serum concentration is 0.6 -1.2 mM. While the overall brain concentration is generally in the same range as the serum concentration (13-15), the fraction of intracellular Li in the brain in vivo is not known. Consequently, from a mechanistic point of view, the ratio of intracellular to extracellular Li in brain in vivo is an important parameter to measure because doing so may reveal how Li exerts its therapeutic effects.NMR has been widely used to measure cationic distribution in cellular preparations. Because most alkali-metal chemical shifts are relatively insensitive to the ionic environment, the intra-and extracellular resonances typically occur at the same chemical shift...

Investigation of lithium distribution in the rat brain ex vivo using lithium‐7 magnetic resonance spectroscopy and imaging at 17.2 T

“…Based on our observation of an insignificant wash‐out of Li from an ex vivo PFA‐fixated excised brain into its PFA bath, we can reasonably exclude this second hypothesis. With regard to our first hypothesis, the extracellular Li fraction was estimated to be 46% in the rat brain in vivo . Thus, the complete wash‐out of the extracellular Li could halve the brain‐to‐plasma ratios ex vivo .…”

“…Thus, the complete wash‐out of the extracellular Li could halve the brain‐to‐plasma ratios ex vivo . Interestingly, the application of the same approach as Komoroski et al to our ex vivo bi‐exponential T 2 relaxation decays (Figure A) would achieve an extracellular Li fraction of 26%. This extracellular (or rather free) Li may be interpreted as the remainder of the 46% reported in vivo , meaning that about 60% would have been washed out by our PFA infusion.…”

“…All fits were performed using Matlab (Mathworks, Natick, MA, USA) and a non‐weighted Levenberg–Marquardt algorithm, yielding average relaxation times. In addition to the fast and slow relaxation times corresponding to the pools of bound and free Li cations, their respective volume fractions were estimated …”

CHAPTER 15. Applications of Magnetic Resonance Spectroscopy to Psychiatric Disorders

“…An example of MR technique development pertinent to psychoactive drug action and translatable to humans is our work on the environment of lithium (Li) in rat brain using 7 Li MRS (see Section 15.2.4 below). 12,13 Studies that probe the etiology of psychiatric disorders often rely on post mortem tissue. Although the study of post mortem brain tissue has a long history in psychiatry, many challenges to its use remain.…”

“…46 Most published studies have focused on technique development or correlation of brain and serum Li levels in both humans and animals. 46,12,13 The major application so far has been the measurement of whole-brain Li. Very little work has dealt with correlation between brain Li levels and treatment measures.…”