Does rTMS modulate phenotype of microglia in patients with treatment-resistant depression? A transcriptome analysis using iMG cells

• The first iMG study using the microarray analysis in patients with TRD by rTMS. • In rTMS responders, the RNA expression of 21 genes were significantly increased. • rTMS treatment may alter iMG genes including immunity in patients with TRD. Background The neuroinflammatory hypothesis has been proposed as the pathophysiology of depression, and microglia are suggested to have crucial roles by modulating neuroinflammatory responses in patients with depression. We have originally developed human blood induced microglia-like (iMG) cells, which are surrogate cells to predict activities of human brain microglia for reverse-translational research. Repetitive transcranial magnetic stimulation (rTMS) is an effective therapeutic method for improving depressive symptoms in patients with treatment-resistant depression (TRD); however, its details remain unknown. The aim of this study was to predict how rTMS alters the phenotype of microglia using iMG cells of patients with TRD. Methods Five patients with TRD were enrolled in a frequency (10 Hz) rTMS study. Microarray analysis of the iMG cells of patients with TRD at baseline and the end of the 6-week rTMS treatment was performed in the five domains of immunity, inflammation, phagocytosis, metabolic syndrome, and lipids. Results Three of the five were rTMS responders and two were non-responders for depressive symptoms. Microarray analysis of responders showed that rTMS treatment significantly increased the RNA expression of 21 genes, including genes related to neuroinflammation, acting in a direction to promote neuroinflammation, and significantly decreased four genes. Limitations The main limitations were the small sample size and the lack of control conditions using the sham rTMS procedure. Conclusion This study suggests that rTMS treatment may alter iMG genes, including immune-related genes, in patients with TRD. Future studies should confirm these findings using a larger patient sample size and a sham rTMS procedure.