Supplementary Material for: The Glutamatergic Effects of Clinical Repetitive Transcranial Magnetic Stimulation in Depressed Populations: A Preliminary Meta-Analysis of Proton Magnetic Resonance Spectroscopy Studies

Background:
Repetitive transcranial magnetic stimulation (rTMS) alleviates symptoms of major depressive disorder, but its neurobiological mechanisms remain to be fully understood. Growing evidence from proton magnetic resonance spectroscopy (1HMRS) studies suggests that rTMS alters excitatory and inhibitory neurometabolites. This preliminary meta-analysis aims to quantify current trends in the literature and identify future directions for the field.
Methods:
Ten eligible studies that quantified Glutamate (Glu), Glutamate+Glutamine (Glx), or GABA before and after an rTMS intervention in depressed samples were sourced from PubMed, MEDLINE, PsychInfo, Google Scholar, and primary literature following PRISMA guidelines. Data were pooled using a random effects model, Cohen’s d effect sizes were calculated, and moderators, such as neurometabolite and 1HMRS sequence, were assessed. It was hypothesized that rTMS would increase cortical neurometabolites.
Results:
Within-subjects data from 224 cases encompassing 31 neurometabolite effects (k) were analyzed. Active rTMS in clinical responders (n=128; k=22) nominally increased glutamatergic neurometabolites (d=0.15 [95% CI:-0.01, 0.30], p=0.06). No change was found in clinical non-responders (p=0.8) or sham rTMS participants (p=0.4). A significant increase was identified in Glx (p=0.01), but not Glu (p=0.6). Importantly, effect size across conditions was associated with the number of rTMS pulses patients received (p=0.05), suggesting dose dependence.
Conclusions and Relevance:
Clinical rTMS is associated with a nominal, dose-dependent increase in glutamatergic neurometabolites, suggesting rTMS may induce glutamate-dependent neuroplasticity and upregulate neurometabolism. More, larger-scale studies adhering to established acquisition and reporting standards are needed to further elucidate the neurometabolic mechanisms of rTMS.