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://clinicaltrials.gov/ct2/show/NCT02311751?term=ameis&rank=1; NCT02311751.

Effects of non-invasive neurostimulation on autism spectrum disorder: A systematic review

“…With respect to TMS trials, three trials stimulated posterior superior temporal sulcus (pSTS) with one unilaterally ( 27 ) and two bilaterally ( 29 , 30 ). Two trials chose to intervene over bilateral DLPFC ( 26 , 28 ), and one focused on bilateral dorsomedial prefrontal cortex (dmPFC) ( 21 ) ( Table 3 ). Similarly, TMS at 50 Hz with 600 pulses in total, namely intermittent theta burst stimulation (iTBS), was given to the participants in those trials focused on pSTS ( 29 , 30 ).…”

“…Given these two tasks, nonetheless, are not specific to the pSTS activities, they also adopted the repetitive behavior scale-revised (RBS-R) as the exploratory outcome ( 30 ). Interestingly, both Liu et al and Moxon-Emre et al showed interest in the objective outcome, thereby fMRI and GlX and GABA level was applied for outcome assessment ( 27 , 28 ). A different set of scales including BRIEF-MCI and the Cambridge Neuropsychological Test Automated Battery (CANTAB) task were adopted by Ameis et al ( 26 ).…”

NAA/Glu Ratio Associated with Suicidal Ideation in Pilot Sample of Autistic Youth and Young Adults

“…Reliable biomarkers of SI in ASD youth and young adults may help identify at-risk individuals, with plausible utility for treatment planning (i.e., predicting potential for treatment response) and tracking neurobiological responses to interventions. We recently found that bilateral rTMS to DLPFC modulates Glx levels in the left DLPFC (MRS data were not collected from the right DLPFC) and that baseline Glx predicted change in Glx from pre- to post-rTMS in the same ASD sample included here [ 15 ]. There is evidence that excitatory rTMS alters the glutamatergic system [ 16 , 17 , 18 ] and may normalize NAA levels in treatment-resistant depression [ 19 ].…”

“…Participants: Twenty-eight ASD youth and young adults (mean (SD) = 23.3 (4.69) years, range 16–33 years, 21 male/7 female assigned at birth) underwent 1 H-MRS scans during a baseline assessment of our recently completed repetitive transcranial magnetic stimulation (rTMS) clinical trial (Clinicaltrials.gov; ID: NCT02311751) [ 15 , 20 , 21 ]. The present sample is identical to the baseline ASD sample from Moxon–Emre et al (2021), wherein we detail specifics pertaining to final sample selection, including quality control (QC) of 1 H-MRS data used here.…”

Repetitive transcranial magnetic stimulation for insomnia in patients with autism spectrum disorder: Study protocol for a randomized, double-blind, and sham-controlled clinical trial

“…For glutamate and GABAergic circuits that are abnormal in ASD, one study found that rTMS (1 Hz) treatment for 2 weeks effectively alleviated the acquired autistic-like symptoms in a rat model by regulating synaptic GABA transmission ( 65 ). Furthermore, in adults with ASD, one study found that rTMS to the DLPFC may modulate local glutamate levels ( 66 ).…”