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

Jacques Stout (1) , Anne-Sophie Hanak (2, 3) , Lucie Chevillard (2, 3) , Boucif Djemaï (4, 1) , Patricia Risède (2, 3) , Eric Giacomini (1) , Joël Poupon (5) , David André Barrière (6, 1) , Frank Bellivier (3, 7) , Bruno Mégarbane (3, 8) , Fawzi Boumezbeur (1)

1 NEUROSPIN - Service NEUROSPIN
2 OPTeN (UMR_S 1144 / U1144) - Optimisation thérapeutique en Neuropsychopharmacologie
3 VariaPsy - U1144 - Variabilité de réponse aux Psychotropes
4 UNIRS - Unité d'imagerie par résonance magnétique à très haut champ et de spectroscopie
5 Laboratoire de Toxicologie Biologique, Hôpital Lariboisière
6 Pharmacologie fondamentale et clinique de la douleur
7 Département de Psychiatrie et de Médecine Addictologique
8 Service de réanimation médicale et toxicologique [AP-HP Hôpital Lariboisière]

Lithium is the first-line mood stabilizer for the treatment of patients with bipolar disorder. However, its mechanisms of action and transport across the blood–brain barrier remain poorly understood. The contribution of lithium-7 magnetic resonance imaging ($^7$Li MRI) to investigate brain lithium distribution remains limited because of the modest sensitivity of the lithium nucleus and the expected low brain concentrations in humans and animal models. Therefore, we decided to image lithium distribution in the rat brain ex vivo using a turbo-spin-echo imaging sequence at 17.2 T. The estimation of lithium concentrations was performed using a phantom replacement approach accounting for $B_1$ inhomogeneities and differential $T_1$ and $T_2$ weighting. Our MRI-derived lithium concentrations were validated by comparison with inductively coupled plasma-mass spectrometry (ICP-MS) measurements ([Li]$_{MRI}$ = 1.18[Li]$_{MS}$, $R$ = 0.95). Overall, a sensitivity of 0.03 mmol/L was achieved for a spatial resolution of 16 μL. Lithium distribution was uneven throughout the brain (normalized lithium content ranged from 0.4 to 1.4) and was mostly symmetrical, with consistently lower concentrations in the metencephalon (cerebellum and brainstem) and higher concentrations in the cortex. Interestingly, low lithium concentrations were also observed close to the lateral ventricles. The average brain-to-plasma lithium ratio was 0.34 ± 0.04, ranging from 0.29 to 0.39. Brain lithium concentrations were reasonably correlated with plasma lithium concentrations, with Pearson correlation factors ranging from 0.63 to 0.90.

Domaines: Toxicologie

Jacques Stout, Anne-Sophie Hanak, Lucie Chevillard, Boucif Djemaï, Patricia Risède, et al.. Investigation of lithium distribution in the rat brain ex vivo using lithium-7 magnetic resonance spectroscopy and imaging at 17.2 T. NMR in Biomedicine, 2017, 30 (11), pp.e3770. ⟨10.1002/nbm.3770⟩. ⟨hal-03822913⟩