Synopsis

Lithium is a major treatment for bipolar disorder (BD) 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 this is challenging compared to proton MRI due to lithium’s low therapeutic concentration in brain (<1mM). To overcome this challenge, we implemented a highly efficient balanced steady state free precession (b-SSFP) 7Li-MRI method. We report a 3D 7Li-MRI acquisition with 25mm isotropic resolution, acquired in 8 minutes using a 3T clinical scanner, demonstrating heterogeneity in lithium concentration within the brain in subjects with BD (n=14).

Purpose:

This study aimed to determine a b-SSFP protocol for ⁷Li-MRI and assess whether gains in image SNR could be achieved compared to conventional spoiled gradient echo (SPGR) imaging, thereby permitting assessment of brain lithium distribution in a clinically relevant scan time.

Materials and Methods:

All subjects in this study were adults taking lithium long-term for BD, with serum levels confirmed in the therapeutic range. MR data were acquired on a Philips 3T Achieva scanner (Philips Medical Systems, Best, The Netherlands) equipped with a quadrature, double tuned ¹H/⁷Li radiofrequency birdcage head coil (RAPID Biomedical, Rimpar, Germany).

A ⁷Li 3D b-SSFP gradient echo acquisition was acquired in 10 subjects (20 × 19 × 7 acquisition matrix and 24.0 × 25.3 × 25.0 voxel size, 480 × 480 × 175 mm field of view, with TR = 9.4 ms, TE = 4.5 ms, flip angle = 60 degrees, receiver bandwidth = 219 Hz/pixel, 500 averages per dynamic. Data were reconstructed into a 32 × 32 × 7 matrix (voxel size of 15 × 15 × 25 mm). Total acquisition time was eight minutes.

The scan protocol was also applied to phantoms containing lithium to evaluate image uniformity and the relationship between lithium concentration and ⁷Li signal intensity in b-SSFP images. Six 0.8 L aqueous phantoms were constructed, each containing a different concentration of LiCl (0.5, 0.75, 1.0, 1.5, 2.0 and 4.0 mmol/L) and NaCl at a concentration of 108 mmol/L.

In a further four subjects, ⁷Li 3D SPGR images (ie, standard gradient echo imaging) were also acquired together with ⁷Li b-SSFP data to compare the image SNR between the techniques. The ⁷Li SPGR imaging sequence was acquired with the same acquisition protocol as the ⁷Li b-SSFP acquisition but TR = 6.7 ms and TE = 2 ms, flip angle was the Ernst angle at 4.6 degrees and averages = 700 to maximise SNR. Each acquisition was eight minutes long and to increase image SNR, three scan dynamics were acquired in each subject (total acquisition 24 minutes) and the data averaged in complex form. Comparably, three ⁷Li b-SSFP dynamics were acquired in each subject (total acquisition 24 minutes), also averaged in complex form.

A 3D T₁-weighted image of brain anatomy was acquired for each subject with a ¹H gradient echo sequence (TR = 8.2 ms, TE = 4.6 ms, acquisition matrix = 180 × 200 × 146 mm reconstructed into a matrix size of 240 × 240 × 146 mm, isotropic 1 mm resolution, FOV = 216 × 240 × 175, one average).

All reconstructed lithium images were interpolated bilinearly to match the resolution parameters of the ¹H MRI using in-house software written in Matlab^® (The Mathworks^® Inc., Natick, MA, USA).

⁷Li images were analysed using ImageJ software¹ and Matlab. To determine the relationship between ⁷Li-MRI signal intensity and lithium concentration, a region of interest (ROI) was placed in the central image slice of each phantom. To evaluate the spatial distribution of ⁷Li-MRI signal intensity, a volume ROI was placed in each phantom image and the coefficient of variation (COV) measured.

For the comparison of signal intensity between the ⁷Li b-SSFP and SPGR sequences, mean ⁷Li-MRI signal amplitude was determined from an intracranial volume ROI drawn on ¹H structural scan images in native space. This ROI was also used to determine the COV in ⁷Li b-SSFP signal intensity.

Results:

In the uniform phantoms, a linear relationship between lithium concentration and ⁷Li b-SSFP image intensity was observed, with slice profiles through each phantom showing homogeneous signal intensity (Figure 1). In brain, lithium distribution was heterogeneous in all subjects. Figure 2 shows the entire 3D ⁷Li b-SSFP dataset from one subject; Figure 3 shows 3D ⁷Li b-SSFP data from a single slice in 8 subjects. The spoiled GE failed to produce interpretable images in three of four subjects due to insufficient signal-to-noise although the technique demonstrated heterogeneous distribution similar to the 3D ⁷Li b-SSFP image in one subject (Figure 4).

Discussion:

Our data demonstrates that ⁷Li b-SSFP MRI can rapidly image lithium distribution in the human brain in vivo, providing evidence of that tissue distribution is heterogeneous in BD. The use of an imaging-based acquisition rather than a spectroscopic imaging approach, coupled with the time- and signal- efficient SSFP methods, affords considerable advantages compared to previous reports.^2,3,4

Conclusions:

Lithium can be imaged in its target organ, the human brain, in a clinically applicable scan time of eight minutes. Our ⁷Li b-SSFP MRI notably expands the available methods to investigate the effects of lithium on the brain.

Acknowledgements

References

References:

1. Schneider, C.A.R., W. S. & Eliceiri, K. W (2012) 'NIH Image to ImageJ: 25 years of image analysis', Nature methods, 9(7), 671-675.

2. Lee, J.-H., Adler, C., Norris, M., Chu, W.-J., Fugate, E.M., Strakowski, S.M. and Komoroski, R.A. (2012) '4-T 7Li 3D MR spectroscopy imaging in the brains of bipolar disorder subjects', Magnetic Resonance in Medicine, 68(2), 363-368.

3. Girard, F., Suhara, T., Sassa, T., Okubo, Y., Obata, T., Ikehira, H., Sudo, Y., Koga, M., Yoshioka, H. and Yoshida, K. (2001) 'Li-7 2D CSI of human brain on a clinical scanner', Magnetic Resonance Materials in Physics Biology and Medicine, 13(1), 1-7.

4. Soares, J.C., Boada, F., Spencer, S., Mallinger, A.G., Dippold, C.S., Wells, K.F., Frank, E., Keshavan, M.S., Gershon, S. and Kupfer, D.J. (2001) 'Brain lithium concentrations in bipolar disorder patients: Preliminary Li-7 magnetic resonance studies at 3 T', Biological Psychiatry, 49(5), 437-443.