7 T MRS Investigation of the Glutamatergic System in Depression
Clark Lemke1,2, Charles Masaki1, Uzay Emir2, Beata Godlewska1, and Phil Cowen1

1Department of Psychiatry, University of Oxford, Oxford, United Kingdom, 2FMRIB, University of Oxford, Oxford, United Kingdom

Synopsis

The glutamatergic system is believed to play a significant role in depression pathology. While many magnetic resonance spectroscopy (MRS) studies of depression have targeted the glutamatergic system, they have all been performed at magnetic field strengths of 4 T or lower – limiting their ability to differentiate between glutamate and glutamine. This study presents the first investigation of the glutamatergic system in depressed subjects at 7 T. Voxels were placed in the occipital cortex, anterior cingulate cortex, and putamen and metabolites were quantified using LCModel. Results indicate a significant decrease in glutamate in the occipital cortex and a significant increase of glutamine in the putamen.

Target Audience

Scientists and clinicians who are interested in the neurochemistry of depression and associated mood disorders.

Introduction

Over the past two decades, magnetic resonance spectroscopy (MRS) has been used to study the role of glutamate neurotransmission in the pathophysiology of depression. Unfortunately, due to inconsistent methodology and patient heterogeneity, results have been variable (1). Regardless, glutamatergic abnormalities in anterior cingulate cortex (ACC) (3) are believed to be associated with depression pathogenesis. Additionally, basal ganglia abnormalities have been shown to be involved in depression pathophysiology (4). One limitation of previous MRS studies on depression is that they have used field strengths of 3 T or below and therefore cannot spectrally differentiate between glutamate and glutamine. Therefore, to further probe the glutamatergic interactions associated with depression, we have acquired spectra at 7 T in the OCC, the ACC and the putamen (PUT).

Methods

Subjects: Unmedicated depressed patients (n=40, 18 males, 22 females, average age = 32 ± 11) were studied after obtaining written informed consent. All patients were assessed for depression using the DSM-IV criteria for major depressive disorder with a Structured Clinical Interview (SCID-I). Healthy controls (n=28, 16 males, 12 females, average age = 33 ± 12) had no history of depression or other DSM-IV diagnoses. Magnetic Resonance Protocol: All subjects were scanned using a 7T whole body MR system (Siemens, Erlangen) with a Nova Medical 32-channel receive array head-coil. To aid in selecting the VOIs, structural 3D T1-weighted images were acquired with an MP-RAGE sequence (5) (FOV=192×192 mm2; TR=2.2 s; TE=2.82 ms; slice thickness = 1 mm; slices = 96; non- selective inversion; scan time 3 mins) for all subjects. Spectra were measured using semi-LASER (6), (TE=36 ms, TR = 7 s, nt = 64) with VAPOR water suppression and outer volume suppression (7). Signal was acquired from three separate volumes of interest (VOIs) – one in the OCC, one in the ACC and one in the PUT. Post-processing and Statistical Analysis: Metabolites were quantified with LCModel (8) using the unsuppressed water signal as reference. Only those measured reliably (Cramér-Rao lower bounds (CRLB) < 50%, cross correlation coefficients r > -0.5) were reported. Metabolite differences between groups and VOIs were assessed using a repeated measures ANOVA and post-hoc t-tests.

Results

Spectra with good SNR and spectral resolution were consistently obtained from all regions as illustrated in Figure 1. Average water linewidths were 13.5 ± 2.0 Hz for OCC, 15.3 Hz ± 2.6 Hz for ACC, 18.2 ± 2.5 Hz for PUT. Statistical testing identified lower Glu concentrations in the OCC (p-value < 0.05) of depressed subjects but no significant difference for Gln. No statistical difference for either metabolite was found in the ACC (p-value > 0.1). Significantly higher Gln (p-value < 0.05) but no difference in Glu was found in the PUT. Figure 2 illustrates metabolite concentration in healthy and depressed patients.

Discussion and Conclusion

This study provides one of the first examinations of the neurochemistry of depression at 7 T. We identified a significant decrease in Glu in occipital cortex but in contrast to other studies no change in ACC. A novel discovery is that that Gln concentrations increase in PUT in depressed subjects. This result requires further investigation and correlation with depressive symptomatology putatively linked to basal-ganglia, for example, retardation and anhedonia. Previous 3 T studies have generally found lowered levels of Glx (Gln and Glu) in ACC (1). As we determined no significant differences in the ACC but changes in OCC and putamen, our data suggest additional studies may be required in order to clarify the role of glutamate and glutamine in depression.

Acknowledgements

No acknowledgement found.

References

1. Yuksel, C, et al. (2010). Biol Psych. 68. 785-794. 2. Sanacora, G, et al. (1999). Arch Gen Psych. 56. 1043-1049. 3. Auer, DP, et al. (2000). Biol Psych. 47. 305-313. 4. Husain, MM, et al. (1991). Psych. 40. 95-99. 5. Brant-Zawadzki, M., et al. (1992). Radiology. 182: 769-775. 6. Öz, G. et al. (2011). MRM. 65, 901–910. 3. 7. Tkác, I. et al. (1999). MRM. 41, 649–656. 8. Provencher, SW. (2001). NMR Biomed. 14, 260–264.

Figures

Average in-vivo 1H semi-LASER spectra (TR = 7s; TE = 36 ms; Averages = 64) from the occipital cortex (OCC), anterior cingulate cortex (ACC) and putamen (PUT). The shaded region corresponds to the standard deviation.

Gln and Glu concentrations for healthy and depression subjects in the occipital cortex (OCC), anterior cingulate cortex (ACC) and putamen (PUT). Significant differences were determined for Glu in OCC and Gln in PUT.



Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)
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