Transcranial magnetic stimulation potentiates glutamatergic neurotransmission in depressed adolescents

Abstract

Abnormalities in glutamate neurotransmission may have a role in the pathophysiology of adolescent depression. The present pilot study examined changes in cortical glutamine/glutamate ratios in depressed adolescents receiving high-frequency repetitive transcranial magnetic stimulation. Ten adolescents with treatment-refractory major depressive disorder received up to 30 sessions of 10-Hz repetitive transcranial magnetic stimulation at 120% motor threshold with 3000 pulses per session applied to the left dorsolateral prefrontal cortex. Baseline, posttreatment, and 6-month follow-up proton magnetic resonance spectroscopy scans of the anterior cingulate cortex and left dorsolateral prefrontal cortex were collected at 3T with 8-cm(3) voxels. Glutamate metabolites were quantified with 2 distinct proton magnetic resonance spectroscopy sequences in each brain region. After repetitive transcranial magnetic stimulation and at 6 months of follow-up, glutamine/glutamate ratios increased in the anterior cingulate cortex and left dorsolateral prefrontal cortex with both measurements. The increase in the glutamine/glutamate ratio reached statistical significance with the TE-optimized PRESS sequence in the anterior cingulate cortex. Glutamine/glutamate ratios increased in conjunction with depressive symptom improvement. This reached statistical significance with the TE-optimized PRESS sequence in the left dorsolateral prefrontal cortex. High-frequency repetitive transcranial magnetic stimulation applied to the left dorsolateral prefrontal cortex may modulate glutamate neurochemistry in depressed adolescents.

Keywords: Adolescent depression; Glutamate; Glutamine; Proton magnetic resonance spectroscopy; Repetitive transcranial magnetic stimulation.

Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Figures

Figure 1

Locations of the two sampled MRS voxels. A) The anterior cingulate cortex (ACC) voxel is placed in the midline to sample pregenual anterior cingulate cortex (Brodmann’s areas 24a, 24b, and 32). B) The left dorsolateral prefrontal cortex voxel (L-DLPFC) voxel is placed to sample dorsolateral prefrontal cortex and subjacent white matter (Brodmann’s areas 9 and 46).

Figure 2

Representative TE-optimized PRESS spectrum obtained from the L-DLPFC. A) Fitted LCModel spectrum (red) overlaid on the source spectrum (black). B) Individual fit of the Glu metabolite. C) Individual fit of the Gln metabolite. Note that the area under the curve is significantly less than for Glu due to the relatively low concentration of Gln. D) Residual spectrum after subtracting the fitted spectrum from the original spectrum.

Figure 3

Change in the Gln/Glu ratio over time. A) Ratio assessed using the 2D J-averaged PRESS (2DJ) technique for measuring Glu. B) Ratio assessed using the TE-optimized PRESS technique (P80) for measuring Glu. Note the visually similar trend towards increasing Gln/Glu following treatment and at the 6-month follow-up time point regardless of the MRS method used to measure glutamate. The scale is different due to the different quantification units provided by LCModel.