Modulation of Dorsolateral Prefrontal Cortex Glutamate/Glutamine Levels Following Repetitive Transcranial Magnetic Stimulation in Young Adults With Autism

Abstract

Altered excitatory and inhibitory neurotransmission has been implicated in autism spectrum disorder (ASD). Interventions using repetitive transcranial magnetic stimulation (rTMS) to enhance or inhibit cortical excitability are under study for various targets, though the mechanistic effects of rTMS have yet to be examined in ASD. Here, we examined whether an excitatory rTMS treatment course modulates glutamatergic (Glx) or γ-aminobutyric acid (GABA) metabolite levels in emerging adults with ASD. Twenty-eight participants with ASD and executive function impairment [23.3 ± 4.69 years; seven-female] underwent two magnetic resonance spectroscopy (MRS) scans of the left dorsolateral prefrontal cortex (DLPFC). MRS scans were acquired before and after participants with ASD were randomized to receive a 20-session course of active or sham rTMS to the DLPFC. Baseline MRS data was available for 19 typically developing controls [23.8 ± 4.47 years; six-female]. Metabolite levels for Glx and GABA+ were compared between ASD and control groups, at baseline, and metabolite level change, pre-to-post-rTMS treatment, was compared in ASD participants that underwent active vs. sham rTMS. Absolute change in Glx was greater in the active vs. sham-rTMS group [F (1, 19) = 6.54, p = 0.02], though the absolute change in GABA+ did not differ between groups. We also examined how baseline metabolite levels related to pre/post-rTMS metabolite level change, in the active vs. sham groups. rTMS group moderated the relation between baseline Glx and pre-to-post-rTMS Glx change, such that baseline Glx predicted Glx change in the active-rTMS group only [b = 1.52, SE = 0.32, t (18) = 4.74, p < 0.001]; Glx levels increased when baseline levels were lower, and decreased when baseline levels were higher. Our results indicate that an interventional course of excitatory rTMS to the DLPFC may modulate local Glx levels in emerging adults with ASD, and align with prior reports of glutamatergic alterations following rTMS. Interventional studies that track glutamatergic markers may provide mechanistic insights into the therapeutic potential of rTMS in ASD. Clinical Trial Registration: Clinicaltrials.gov (ID: NCT02311751), https://ichgcp.net/clinical-trials-registry/NCT02311751?term=ameis&rank=1; NCT02311751.

Keywords: GABA; Glx; MEGA-PRESS; autism spectrum disorder; dorsolateral prefrontal cortex; magnetic resonance spectography; repetitive transcranial magnetic simulation.

Conflict of interest statement

ZJD received research support and in-kind equipment support for an investigator-initiated study from Brainsway Ltd. He has also received in-kind equipment support from Magventure for investigator-initiated research. DMB received research support and in-kind equipment support for an investigator-initiated study from Brainsway Ltd., and he is the site principal investigator for three sponsor-initiated studies for Brainsway Ltd. He receives in-kind equipment support from Magventure for investigator-initiated research. He received medication supplies for an investigator-initiated trial from Indivior. He has participated in an advisory board for Janssen. PEC has received research grant support from Pfizer Inc.; equipment support from Neuronetics Inc.; and received supplies and genotyping services from Assurex Health Inc., for investigator-initiated studies. He is the primary investigator for a multicenter study funded by Neuronetics Inc., and a site primary investigator for a study funded by NeoSync Inc. He has served as a paid consultant for Procter & Gamble Company and Myriad Neuroscience. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Moxon-Emre, Daskalakis, Blumberger, Croarkin, Lyon, Forde, Tani, Truong, Lai, Desarkar, Sailasuta, Szatmari and Ameis.

Figures

FIGURE 1

1H-MRS voxel position, tissue segmentation, and representative spectra from a single participant. (A) 20 mm × 40 mm × 30 mm voxel, placed in the left dorsolateral prefrontal cortex (DLPFC). (B) Segmentation of T1-weighted MRI, used to correct water-scaled metabolite concentrations for voxel tissue composition. Gray matter (blue), white matter (yellow), and CSF (red). (C) Sample output from the MEGA-PRESS sequence, with representative fits of GABA+ and Glx peaks shown in the edited spectrum.

FIGURE 2

Pre- and post-rTMS GABA+, Glx, and GABA+/Glx ratio, in the left dorsolateral prefrontal cortex (DLPFC). (A–C) Levels of pre- and post-rTMS metabolites (GABA+, Glx) and the GABA+/Glx ratio, in the full ASD sample with MRS data; active rTMS (pre: n = 16; post: n = 12), sham rTMS (pre: n = 12; post: n = 12). Black lines denote the group medians. (D–F) Each participant is indicated by a pre-/post-rTMS pair of points, connected by a line. Unconnected points are from participants with MRS scans at a single time point. Active rTMS (pre: n = 16; post: n = 12), sham rTMS (pre: n = 12; post: n = 12). (G–I) The absolute value of the change in metabolites from pre- to post-rTMS in the ASD sample with matched pre- and post-rTMS scans only; active rTMS (n = 12), sham rTMS (n = 10). Black lines denote the group medians. *The absolute value change in Glx level was greater in the active compared to the sham rTMS group [F(1,19) = 6.54, p = 0.02].

FIGURE 3

Active rTMS modulates Glx levels. (A) Associations between Glx levels at baseline, and change in Glx from pre- to post-rTMS in the left dorsolateral prefrontal cortex (DLPFC), in the active and sham rTMS groups; active rTMS (n = 12), sham rTMS (n = 10). Baseline Glx was associated with Glx change in the active rTMS group only: b = 1.49, SE = 0.31, t(18) = 4.77, p < 0.001. (B) To visually demonstrate that Glx level increased in participants with lower baseline Glx levels, and that Glx level decreased in participants with higher baseline Glx levels, in the active rTMS group only, participants were stratified according to the median split of the baseline Glx level (median Glx level for entire ASD sample = 0.12) and their pre-/post-rTMS pair of points were plotted.