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. 2016 Apr;41(3):E37-45.
doi: 10.1503/jpn.150223.

Elevated prefrontal cortex GABA in patients with major depressive disorder after TMS treatment measured with proton magnetic resonance spectroscopy

Marc J Dubin  1 , Xiangling Mao  1 , Samprit Banerjee  1 , Zachary Goodman  1 , Kyle A B Lapidus  1 , Guoxin Kang  1 , Conor Liston  1 , Dikoma C Shungu  1
Affiliations

Elevated prefrontal cortex GABA in patients with major depressive disorder after TMS treatment measured with proton magnetic resonance spectroscopy

Marc J Dubin et al. J Psychiatry Neurosci. 2016 Apr.

Abstract

Background: GABAergic and glutamatergic neurotransmitter systems are central to the pathophysiology of depression and are potential targets of repetitive transcranial magnetic stimulation (rTMS). We assessed the effect of 10-Hz rTMS over the left dorsolateral prefrontal cortex (DLPFC) of patients with major depressive disorder on the levels of medial prefrontal cortex (MPFC) γ-aminobutyric acid (GABA) and the combined resonance of glutamate and glutamine (Glx) as assessed in vivo with proton magnetic resonance spectroscopy ((1)H MRS).

Methods: Currently depressed individuals between the ages of 23 and 68 years participated in a 5-week naturalistic, open-label treatment study of rTMS, with (1)H MRS measurements of MPFC GABA and Glx levels at baseline and following 5 weeks of the rTMS intervention. We applied rTMS pulses over the left DLPFC at 10 Hz and 80%-120% of motor threshold for 25 daily sessions, with each session consisting of 3000 pulses. We assessed therapeutic response using the 24-item Hamilton Rating Scale for Depression (HAMD24). The GABA and Glx levels are expressed as ratios of peak areas relative to the area of the synchronously acquired and similarly fitted unsuppressed voxel water signal (W).

Results: Twenty-three currently depressed individuals (7 men) participated in the study. GABA/W in the MPFC increased 13.8% (p = 0.013) in all depressed individuals. There were no significant effects of rTMS on Glx/W. GABA/W and Glx/W were highly correlated in severely depressed patients at baseline but not after TMS.

Limitations: The primary study limitations are the open-label design and the inclusion of participants currently taking stable regimens of antidepressant medications.

Conclusion: These results implicate GABAergic and glutamatergic systems in the mechanism of action of rTMS for major depression, warranting further investigation in larger samples.

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Figures

Fig. 1
Fig. 1
(A, B) Magnetic resonance images showing medial prefrontal cortex (MPFC) voxel size and location. (C) J-editing spectra obtained using volume-selective point-resolved spectroscopy (PRESS) with the editing radiofrequency pulse (a) on and (b) off. (c) The difference of the spectra in (a) and (b), showing (c) the edited γ-aminobutyric acid (GABA) and combined resonance of glutamate and glutamine (Glx) peaks, with (d) best-fit model spectrum of (c), and (e) the residuals of the difference between the edited (c) and best-fit (d) spectra. The data were acquired in 13 min from a 2.5 × 2.5 × 3.0 cm3 voxel using an echo time (TE) of 68 ms and a repetition time (TR) of 1500 ms, and 256 interleaved excitations (512 total) with editing pulse on or off.
Fig. 2
Fig. 2
γ-Aminobutyric acid/unsuppressed voxel water signal (GABA/W) levels in the medial prefrontal cortex (MPFC) in depressed patients before and after a 25-session treatment with transcranial magnetic stimulation (TMS) over the left dorsolateral prefrontal cortex (DLPFC). Each graph shows GABA levels for the sample both at baseline (pre-) and post-TMS. (A) Full sample of 23 participants. Average GABA/W increases by 13.8% (p = 0.013). (B) Subgroup of TMS responders. GABA/W increases by 17.4% post-TMS compared with baseline (p = 0.07). In the subgroup of TMS nonresponders there was an 11.9% change in GABA/W post-TMS compared with baseline (p = 0.10). Glx = combined resonance of glutamate and glutamine; NS = nonsignificant.
Fig. 3
Fig. 3
γ-Aminobutyric acid/unsuppressed voxel water signal (GABA/W) in the medial prefrontal cortex (MPFC) plotted by depression severity (first and second rows) and baseline and post–transcranial magnetic stimulation (TMS; first and second columns). (A) GABA/W and combined resonance of glutamate and glutamine (Glx)/W are tightly correlated in severely depressed patients at baseline (r = 0.90, p < 0.001) and (B) uncorrelated in moderately depressed patients (r = 0.06, p = 0.86). (C) In patients who were severely depressed before treatment, this correlation was reduced post-TMS (r = 0.35, p = 0.29). (D) GABA/W and Glx/W remained uncorrelated in moderately depressed patients post-TMS (r = 0.10, p = 0.77). MDD = major depressive disorder.
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