INTRODUCTION

Major depressive disorder (MDD) afflicts up to 20% of the total population in their lifetime,¹ and non-invasive imaging is expected to offer objective biomarkers. In MDD, one of the important structures is the anterior cingulate cortex (ACC), where changes from healthy controls (HC) have been reported.² ACC is a key area of antidepressant action.³ In a review of proton MRS studies of MDD, statistically significant differences in ACC have been reported for myo-inositol (Ins), glutamate (Glu) and creatine/phosphocreatine (tCr), but these differences were inconsistent between studies.^4,5 One of the reasons might be the different MRS sequences used.
Recently, the semi-adiabatic short-TE spin-echo full-intensity acquired localized (sSPECIAL) sequence has become available that enables low-concentration neurochemicals including γ-aminobutyric acid (GABA) with high SNR.⁶ The stimulated echo acquisition mode (STEAM) sequence also enables a short-TE acquisition. Therefore, these sequences were used to investigate presence or absence of neurochemical differences in MMD in this study.

METHODS

Eight patients with MDD (4 females, mean 53.8 y.o.) and 13 HC (9 females, mean 49.2 y.o.) were enrolled with written informed consent under an IRB-approved protocol. Scans were conducted on an investigational whole-body scanner (MAGNETOM 7T, Siemens Healthcare, Erlangen, Germany) using a single-transmit volume coil and a 32-channel receiver head coil (Nova Medical, MA, USA).
For proton MRS, a measurement voxel 20×30×20 mm³ (in RL, AP and SI directions) was placed in the ACC using a 3D whole-brain T₁-weighted MP2RAGE image (TR/TE 6000/2.9ms, TI1/TI2 800/2700ms, FA1/FA2 4°/5°, 0.7mm isotropic resolution) for guidance. FASTMAP and manual shimming were conducted. For MRS scans, a sSPECIAL sequence (inhouse research sequence: TR/TE 6500/16ms, spectral bandwidth 5kHz, 48 averages) and a STEAM (Siemens investigational prototype: TR/TE/TM 4000/5/45ms, spectral bandwidth 6 kHz, 48 averages) were used. Water unsuppressed spectra were also acquired for eddy-current correction and quantitation.
Spectral analysis was carried out using LCModel (version 6.3-1L) on Windows 10. Neurochemicals that attained %SD ≤ 20 in more than 80% of subjects were included for further analysis. Segmentation was conducted for GM, WM and CSF to correct water-referenced concentration estimates. Differences and correlations of concentration between the MRS sequences, as well as between patients and healthy controls were statistically compared. In addition, correlation analysis between taurine (Tau) and tCr was conducted. A p-value < 0.05 was considered statistically significant.

RESULTS

No significant difference was observed in mean age between MDD and HC (p = 0.53). The %SD ≤ 20 were attained in more than 80% of subjects for both sequences in 8 neurochemicals (Table 1): glutamine (Gln), Glu, glutathione (GSH), Ins, N-acetyl-aspartate (NAA), Tau, total choline (tCho) and tCr (See Figure 1 for representative results). The absolute concentrations were significantly different in all 8 neurochemicals between the two sequences, and differences remained in more than half after normalization by tCr. However, correlation coefficients of absolute concentrations between the two sequences ranged from 0.714 to 0.976 and were found to be highly correlated.
Between MDD and HC, no statistically significant difference was observed when tCr normalized concentrations were compared, but a difference in absolute concentration was found for Tau using SPECIAL (p = 0.02) and STEAM (p = 0.06, marginal). All other neurochemicals also decreased in MDD, but the differences were not statistically significant (Figure 2). Of the other neurochemicals, Cr had the second lowest p-values (< 0.2). The relation between Cr and Tau was statistically significant for both SPECIAL and STEAM (both, p < 0.01; Figure 3).

DISCUSSION

In this study, Tau was decreased in MDD for both sequences with slightly different statistically significant levels at 7T. Smith et al. investigated late-life depression (LLD) using a STEAM sequence at 7T and found no significant difference in GABA, Glu, GSH, NAA, N-acetyl-aspartyl-glutamate and mI between pre-therapeutic LDD and HC nor before and during Citalopram treatment at ACC.⁷ They used concentration normalized by tCr, and no result was presented as for Tau.
In a depression-like rat model, Tau was found to be decreased in an ex vivo MRS study at 11.7T.⁸ Tau serves various important functions, such as osmotic regulation of neuronal activity,⁹ membrane stabilization and tissue maintenance.¹⁰ It also protects neural cells from excitotoxicity induced by excitatory amino acids¹¹ and has anti-depressant effect on rats in chronic mild stress-induced depressive state.¹² MRS measurement of Tau is difficult at a lower magnetic field, but its reduction observed by both sequences will promote further investigations.
Significant reduction in tCr has been reported in childhood MDD that is considered attributable to decreased energy utilization.¹³ A non-significant reduction of tCr was also observed in this study, and concentration normalization by tCr may obscure reduction of other neurochemicals. In fact, there were significant linear correlations between Tau and tCr in measurements of both sequences, and the significant differences in Tau concentration between MDD and HC were lost. Caution needs to be taken when normalizing concentrations using tCr.

CONCLUSION

Almost the same number of cases were measured with %SD ≤ 20 in both MRS sequences. They found concentration differences in the same neurochemical, Tau. Consistent use of either of the two sequences will facilitate clinical use of MRS at 7T to elucidate pathological changes in neurochemicals.

Acknowledgements

This work was supported grants from AMED (21dm0307102h0003), JSPS KAKENHI (21H03806) and Siemens Healthcare KK, Japan. Authors are grateful to Dr. Hideto Kuribayashi and Mr. Yuta Urushibata for their support.

References

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