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. 2019 Nov 1;44(6):386-394.
doi: 10.1503/jpn.180230.

Dorsolateral prefrontal γ-aminobutyric acid in patients with treatment-resistant depression after transcranial magnetic stimulation measured with magnetic resonance spectroscopy

Jennifer G. Levitt  1 , Guldamla Kalender  1 , Joseph O’Neill  1 , Joel P. Diaz  1 , Ian A. Cook  1 , Nathaniel Ginder  1 , David Krantz  1 , Michael J. Minzenberg  1 , Nikita Vince-Cruz  1 , Lydia D. Nguyen  1 , Jeffry R. Alger  1 , Andrew F. Leuchter  1
Affiliations

Dorsolateral prefrontal γ-aminobutyric acid in patients with treatment-resistant depression after transcranial magnetic stimulation measured with magnetic resonance spectroscopy

Jennifer G. Levitt et al. J Psychiatry Neurosci. .

Abstract

Background: The therapeutic mechanism of repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant depression (TRD) may involve modulation of γ-aminobutyric acid (GABA) levels. We used proton magnetic resonance spectroscopy (MRS) to assess changes in GABA levels at the site of rTMS in the left dorsolateral prefrontal cortex (DLPFC).

Methods: In 26 adults with TRD, we used Mescher–Garwood point-resolved spectroscopy (MEGA-PRESS) spectral-editing MRS to measure GABA in the left DLPFC before and after standard clinical treatment with rTMS. All participants but 1 were medicated, including 12 patients on GABA agonist agents.

Results: Mean GABA in the DLPFC increased 10.0% (p = 0.017) post-rTMS in the overall sample. As well, GABA increased significantly in rTMS responders (n = 12; 23.6%, p = 0.015) but not in nonresponders (n = 14; 4.1%, p = not significant). Changes in GABA were not significantly affected by GABAergic agonists, but clinical response was less frequent (p = 0.005) and weaker (p = 0.035) in the 12 participants who were receiving GABA agonists concomitant with rTMS treatment.

Limitations: This study had an open-label design in a population receiving naturalistic treatment.

Conclusion: Treatment using rTMS was associated with increases in GABA levels at the stimulation site in the left DLPFC, and the degree of GABA change was related to clinical improvement. Participants receiving concomitant treatment with a GABA agonist were less likely to respond to rTMS. These findings were consistent with earlier studies showing the effects of rTMS on GABA levels and support a GABAergic model of depression.

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Conflict of interest statement

I. Cook reports a grant from NeoSync and earns equity interest from Los Angeles TMS Institute Inc., Neuro-Sigma Inc., HeartCloud Inc., and BrainCloud Corporation, outside the submitted work. A. Leuchter reports grants from the National Institutes from Health, Neuronetics, NeuroSigma Inc., the US Department of Defense, and the CHDI Foundation. He is a consultant and stockholder of NeoSync Inc., a consultant with Ionis Pharmaceuticals and EIMindA, and earns equity from Brain Biomarker Analytics LCC. No other competing interests declared.

Figures

Fig. 1
Fig. 1
Meshcher–Garwood point resolved spectroscopy (MEGA-PRESS) voxel position and representative spectra. Left: series of sagittal T1-weighted MRI sections of the brain of a representative patient with treatment-resistant depression, showing the position of the 1H magnetic resonance spectroscopy (MRS) MEGA-PRESS (repetition time 2000 ms, echo time 68 ms) acquisition volume (voxel; pale areas, yellow arrow) in the left middle frontal cortex (dorsolateral prefrontal cortex). Upper right: averaged MEGA-PRESS spectra acquired on alternate scans with (invert, red) and without (control, green) the frequency-selective inversion pulse that avoids excitation of the γ-aminobutyric acid (GABA) C3 peak at 1.9 ppm. Lower right: edited spectrum (difference) generated by subtracting the invert from the control MEGA-PRESS spectrum. This editing operation yields a spectrum in which the GABA resonance at 3.0 ppm (obscured in conventional PRESS MRS by the much larger overlying creatine + phosphocreatine peak) can be quantified, because it appears in relative isolation from other metabolite signals.
Fig. 2
Fig. 2
γ-Aminobutyric acid (GABA) levels in the left dorsolateral prefrontal cortex. Left: pre- and post–repetitive transcranial magnetic stimulation (rTMS) cerebrospinal fluid (CSF)–corrected levels of GABA in the left dorsolateral prefrontal cortex of the full sample of patients with treatment-resistant depression (TRD) (n = 26). Each participant is indicated by a pre/post pair of dots connected by a dashed black line. Blue dots are for patients who took GABAergic agonist medication concurrent with the rTMS regimen; green dots are for patients who did not take GABA medication; black horizontal bars denote group means. For the overall sample, GABA increased by a mean of 10.0% after rTMS (F1,20 = 6.8, p = 0.017, repeated-measures analysis of variance). Right: the same analysis for rTMS responders only (n = 12). For this subsample, GABA increased a by mean of 23.6% after rTMS (t11 = −2.9, p = 0.01, post hoc protected t test). For the rTMS nonresponders (n = 14), 10 of whom were taking GABA agonists, GABA increased by a mean of only 4.1% after rTMS (p = NS). Responder status based on ≥ 30% reduction in 30-item Inventory of Depressive Symptomsscore after rTMS treatment. IU = institutional units; NS = not significant.
Fig. 3
Fig. 3
Glutamate + glutamine (Glx) versus γ-aminobutyric acid (GABA) levels in left dorsolateral prefrontal cortex before and after repetitive transcranial magnetic stimulation (rTMS). Left: pre-rTMS cerebrospinal fluid (CSF)–corrected levels of Glx versus GABA in the left dorsolateral prefrontal cortex of the full sample of patients with treatment-resistant depression (TRD) (n = 26). Each participant is indicated by a dot. The dashed line represents the least squares fit of the data. Glx increased with increasing GABA (r = +0.56, p = 0.003, Pearson). Right: the same analysis for post-rTMS. Though less strongly, Glx still increased significantly with increasing GABA (r = +0.45, p = 0.02). IU = institutional units.
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