3D 7Li magnetic resonance imaging of brain lithium distribution in bipolar disorder

Abstract

Lithium is a major treatment for bipolar disorder and the likelihood of a favourable response may be determined by its distribution in the brain. Lithium can be directly detected by magnetic resonance (MR), but previous 7Li MR spectroscopy studies have demonstrated that this is challenging compared to conventional 1H MR imaging due to the MR properties of the lithium nucleus and its low concentration in brain tissue, as dictated by therapeutic dose. We have tested and implemented a highly efficient balanced steady state free precession 7Li-MRI method to address these challenges and enable MRI of brain lithium in a short duration scan. We report a 3D 7Li-MRI acquisition with 25 mm isotropic resolution in an eight minute scan that demonstrates heterogeneity in lithium concentration within the brain in subjects with bipolar disorder. This represents the direct imaging of a pharmaceutical agent in its target organ and notably expands the repertoire of techniques available to investigate the effects of lithium in man.

Accumulation of Lithium in the Hippocampus of Patients With Bipolar Disorder: A Lithium-7 Magnetic Resonance Imaging Study at 7 Tesla

“…While [Li] P and [Li] B were strongly correlated, our results highlighted the heterogeneity of Li distribution in the brain as well as the interindividual variability of this distribution between Overall, a good correlation between both [Li] levels was observed across our cohort, as illustrated by the linear regression, with [Li] B being w40% of [Li] P (R = .74). The heterogeneity of Li distribution corroborates similar results obtained at lower spatial resolutions (24,28). It supports the hypothesis of an active transport of Li inside the brain, possibly through sodium and magnesium transporters (12,13).…”

“…Those global monoexponential T 1,mono and T 2,mono values were well within the range of previous reports (20,22,48). It is of interest to note here that the use of an SSFP sequence with an ultra-short TE minimizes the T 2 * weighting and reduces sensibly the T 2 weighting of the 7 Li image than a balanced SSFP sequence (28). Yet owing to our short TR, our quantification approach is vulnerable to local variations in T 1 .…”

“…Another favorable technical factor was the fact that our spatial resolution and our ultra-short echo-time SSFP Values are mean 6 SD, N = 21. Li MRI at 7T in Patients With Bipolar Disorder sequence limit the interference of Li contained in the cerebrospinal fluid compared with other in vivo 7 Li MRI studies (28). Still, this interference can be felt through the larger variabilities and lesser correlations observed for ROIs close to the ventricles (such as the midbrain or the brainstem).…”

“…Indeed, Lithium-7 ( 7 Li), the most abundant stable Li isotope, possesses a good NMR sensitivity (w29% of 1 H), and its detection using in vivo 7 Li NMR spectroscopy has been performed successfully in animal models as well as in humans (19)(20)(21). More recently, 7 Li NMR spectroscopic imaging (22)(23)(24)(25) and magnetic resonance imaging (MRI) (26)(27)(28) have been applied for the noninvasive determination of brain Li distribution in patients with BD. However, the spatial resolution and precision of those images remain limited by the low [Li] at therapeutic range (0.3-1.0 mmol/L in the plasma).…”

White matter microstructural properties in bipolar disorder and its relationship to the spatial distribution of lithium in the brain

“…Regionally specific effects of lithium would indicate either that brain regions are differentially sensitive to its effects or that the drug itself is heterogeneously distributed across the brain. Recent advances in multinuclear MRI ( 7 Li-MRI) have permitted the rapid determination of brain lithium distribution in vivo (Smith et al, 2018), demonstrating a heterogeneous distribution of lithium in bipolar disorder, in keeping with previous rodent imaging and human magnetic resonance spectroscopy studies (Lee et al, 2012;Zanni et al, 2017). It would therefore be reasonable to propose that the effects of lithium on white matter integrity relate to its regional concentration and the combination of 7 Li-MRI and dMRI affords the capability to explore this.…”