Repetitive Transcranial Magnetic Stimulation-Associated Changes in Neocortical Metabolites in Major Depression: A Systematic Review

Abstract

Introduction: Repetitive Transcranial magnetic stimulation (rTMS) is an FDA approved treatment for major depressive disorder (MDD). However, neural mechanisms contributing to rTMS effects on depressive symptoms, cognition, and behavior are unclear. Proton magnetic resonance spectroscopy (MRS), a noninvasive neuroimaging technique measuring concentrations of biochemical compounds within the brain in vivo, may provide mechanistic insights.

Methods: This systematic review summarized published MRS findings from rTMS treatment trials to address potential neurometabolic mechanisms of its antidepressant action. Using PubMed, Google Scholar, Web of Science, and JSTOR, we identified twelve empirical studies that evaluated changes in MRS metabolites in a within-subjects, pre- vs. post-rTMS treatment design in patients with MDD.

Results: rTMS protocols ranged from four days to eight weeks duration, were applied at high frequency to the left dorsolateral prefrontal cortex (DLPFC) in most studies, and were conducted in patients aged 13-to-70. Most studies utilized MRS point resolved spectroscopy acquisitions at 3 Tesla in the bilateral anterior cingulate cortex and DLPFC. Symptom improvements were correlated with rTMS-related increases in the concentration of glutamatergic compounds (glutamate, Glu, and glutamine, Gln), GABA, and N-acetylated compounds (NAA), with some results trend-level.

Conclusions: This is the first in-depth systematic review of metabolic effects of rTMS in individuals with MDD. The extant literature suggests rTMS stimulation does not produce changes in neurometabolites independent of clinical response; increases in frontal lobe glutamatergic compounds, N-acetylated compounds and GABA following high frequency left DLPFC rTMS therapy were generally associated with clinical improvement. Glu, Gln, GABA, and NAA may mediate rTMS treatment effects on MDD symptomatology through intracellular mechanisms.

Keywords: GABA; Glutamate; Glutamine; Glx; Intracellular mechanisms; Magnetic resonance spectroscopy; Major depressive disorder; NAA; Neuroimaging; Repetitive transcranial magnetic stimulation; Treatment resistant depression.

Fig. 1

PRISMA Flowchart of Included Studies.

Fig. 2

Hypothesized rTMS Intracellular Effects on the Glu/GABA-Gln Pathway. A schematic representation of hypothesized rTMS intracellular effects on the Glu/GABA-Gln cycle, overlaid on neural-astrocyte Glu/GABA-Gln pathway of Bak et al. (2006). Fig. 2A: In the Glu-Gln pathway, green arrows represent rTMS-induced increases in glucose, phosphate-activated glutaminase (PAG), and glutamine synthetase (GS), leading to tricarboxylic acid (TCA) cycle upregulation and increased intracellular glutamate (Glu) and glutamine (Gln) production. Fig. 2B: In the GABA-Gln pathway, green arrows represent rTMS-induced increases in glucose, phosphate-activated glutaminase (PAG), glutamine synthetase (GS), and glutamate decarboxylase (GAD) leading to tricarboxylic acid (TCA) cycle upregulation and increased intracellular GABA and glutamine (Gln) production. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)