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

Stout, Jacques; Hanak, Anne-Sophie; Chevillard, L; Djemaï, Boucif; Risède, Patricia; Giacomini, Eric; Poupon, Joël; Barrière, David André; Bellivier, Frank; Mégarbane, Bruno; Boumezbeur, Fawzi

doi:10.1002/nbm.3770

Cited by 12 publications

(13 citation statements)

References 36 publications

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“…Rodent MRSI studies have also reported regional variation in 7 Li signal intensity across the brain in vivo,36, 37 but to achieve adequate resolution, scan duration is often several hours such that pharmacokinetic factors must be considered when interpreting signal intensity 38–40. A recent ultra-high field strength, ex vivo 7 Li-MRI study of the rat brain also reported signal heterogeneity as well an overall correlation between signal intensity and mass spectroscopy derived lithium concentrations across brain regions 41. We observed heterogeneity in lithium distribution in all subjects, but visually different distributions between subjects.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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“…To estimate [Li] from the intensity of our 7 Li images, we adopted a modified phantom replacement approach that we validated in a previous ex vivo 7 Li MRI study of rats pretreated with Li (29). The same 7 Li MRI protocol was used to acquire at room temperature an image from a 7-L cylindrical phantom of Li chloride (50 mmol/L, pH = 7.0).…”

Section: Lithium Concentration Quantificationmentioning

confidence: 99%

“…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). Even so, those 7 Li-NMR studies have made important observations about Li compartmentation and its cerebral distribution (21,23,25,27,29). Yet so far, those studies have failed to identify regions of the brain where Li would accumulate significantly.…”

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confidence: 99%

“…In addition, we aimed at quantifying the total brain [Li]. For this purpose, we chose to use an ultra-short echo-time steady-state free-precession (SSFP) sequence combined with a twisted projection imaging k-space sampling scheme (30) with a reasonably short repetition time (TR) as was proposed by Boada et al (31) and a quantification pipeline that we validated in a previous ex vivo preclinical study on rats pretreated with Li (29).…”

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confidence: 99%

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

Stout

Hozer

Coste

et al. 2020

Biological Psychiatry

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BACKGROUND: Lithium (Li) is a first-line treatment for bipolar disorder (BD). To study its cerebral distribution and association with plasma concentrations, we used 7 Li magnetic resonance imaging at 7T in euthymic patients with BD treated with Li carbonate for at least 2 years. METHODS: Three-dimensional 7 Li magnetic resonance imaging scans (N = 21) were acquired with an ultra-short echo-time sequence using a non-Cartesian k-space sampling scheme. Lithium concentrations ([Li]) were estimated using a phantom replacement approach accounting for differential T 1 and T 2 relaxation effects. In addition to the determination of mean regional [Li] from 7 broad anatomical areas, voxel-and parcellation-based group analyses were conducted for the first time for 7 Li magnetic resonance imaging. RESULTS: Using unprecedented spatial sensitivity and specificity, we were able to confirm the heterogeneity of the brain Li distribution and its interindividual variability, as well as the strong correlation between plasma and average brain [Li] ([Li] B z 0.40 3 [Li] P , R = .74). Remarkably, our statistical analysis led to the identification of a well-defined and significant cluster corresponding closely to the left hippocampus for which high Li content was displayed consistently across our cohort. CONCLUSIONS: This observation could be of interest considering 1) the major role of the hippocampus in emotion processing and regulation, 2) the consistent atrophy of the hippocampus in untreated patients with BD, and 3) the normalization effect of Li on gray matter volumes. This study paves the way for the elucidation of the relationship between Li cerebral distribution and its therapeutic response, notably in newly diagnosed patients with BD.

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“…1994) used 6 Li(n. ) 3 H nuclear reaction in the presence of a dielectric a particle track detector to image lithium in adult rat brain, but the resolution was poor. Lithium-7 nuclear magnetic resonance ( 7 Li-NMR, 23. Stout et al, 2017) and 3D 7 Li magnetic resonance (62.…”

Section: Entry and Distribution Of Lithium In Developing Brainmentioning

confidence: 99%

Lithium Administered to Pregnant, Lactating and Neonatal Rats: Entry into Developing Brain.

Saunders¹,

Chiou²,

Kysenius³

et al. 2020

Preprint

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BackgroundLittle is known about the extent of drugs administered to pregnant and lactating women entering the developing brain. Lithium is one of the most commonly prescribed drugs for bipolar disorder. Here we studied transfer of lithium given to dams, into blood, brain and cerebrospinal fluid (CSF) in embryonic, postnatal and adult rats.MethodsLithium chloride in a clinically relevant dose (3.2mg/Kg body weight) was injected intraperitoneally into pregnant (E15-18) and lactating dams (birth-P16) or directly into postnatal pups (P0-P16). Acute treatment involved a single injection; chronic treatment involved twice daily injections for the duration of the experiment. Following terminal anaesthesia blood plasma, CSF and brains were collected. Lithium levels and brain distribution were measured using Laser Ablation Inductively Coupled Plasma Mass Spectrometry (LA-ICP-MS).Results Lithium was detected in blood, CSF and brain of all fetal and postnatal pups following lithium treatment of dams. Its concentration in pups’ blood was consistently below that in maternal blood (30-35%) indicating significant protection by the placenta and breast tissue. Levels of lithium in plasma fluctuated in different treatment groups but its concentration in CSF was stable at all ages, in agreement with known stable levels of endogenous ions in CSF. Only a small non-significant increase of lithium transfer into CSF occurred following application of Na+/K+ ATPase inhibitor (Digoxin) in vivo, indicating that Na+/K+ ATPase is at most only a minor mechanism for lithium transfer across choroid plexus cells into CSF early in development. Presumably lithium transfer across choroid plexus epithelial cell is occurring predominantly via other ion channels. ConclusionsInformation obtained on the distribution of lithium in developing brain provides a basis for studying possible deleterious effects on brain development and behaviour in offspring of mothers undergoing lithium therapy.

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

Cited by 12 publications

References 36 publications

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

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

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

Lithium Administered to Pregnant, Lactating and Neonatal Rats: Entry into Developing Brain.

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