Abstract
Definitive data are lacking on the mechanism of action and biomarkers of repetitive transcranial magnetic stimulation (rTMS) for the treatment of depression. Low-intensity rTMS (LI-rTMS) has demonstrated utility in preclinical models of rTMS treatments but the effects of LI-rTMS in murine models of depression are unknown. We examined the behavioral and neurobiologic changes in olfactory bulbectomy (OB) mice with medium-intensity rTMS (MI-rTMS) treatment and fluoxetine hydrochloride. We then compared 10-Hz rTMS sessions for 3 min at intensities (measured at the cortical surface) of 4 mT (LI-rTMS), 50 mT (medium-intensity rTMS [MI-rTMS]), or 1 T (high-intensity rTMS [HI-rTMS]) 5 days per week over 4 weeks in an OB model of agitated depression. Behavioral effects were assessed with forced swim test; neurobiologic effects were assessed with brain levels of 5-hydroxytryptamine, brain-derived neurotrophic factor (BDNF), and neurogenesis. Peripheral metabolomic changes induced by OB and rTMS were monitored through enzyme-linked immunosorbent assay and ultrapressure liquid chromatography-driven targeted metabolomics evaluated with ingenuity pathway analysis (IPA). MI-rTMS and HI-rTMS attenuated psychomotor agitation but only MI-rTMS increased BDNF and neurogenesis levels. HI-rTMS normalized the plasma concentration of α-amino-n-butyric acid and 3-methylhistidine. IPA revealed significant changes in glutamine processing and glutamate signaling in the OB model and following MI-rTMS and HI-rTMS treatment. The present findings suggest that MI-rTMS and HI-rTMS induce differential neurobiologic changes in a mouse model of agitated depression. Further, α-amino-n-butyric acid and 3-methylhistidine may have utility as biomarkers to objectively monitor the response to rTMS treatment of depression.
Highlights
Definitive data are lacking on the mechanism of action and biomarkers of repetitive transcranial magnetic stimulation for the treatment of depression
We investigated brain markers of plasticity, brain serotonin, and plasma metabolites in an attempt to better understand how the cellular and molecular effects of repetitive transcranial magnetic stimulation (rTMS) intensity relate to behavioral outcomes
Follow-up tests for simple effects of time within each group showed a significant decrease in immobility time in the forced swim test (FST) from pre-surgery to post-surgery in all groups (P-values < 0.05) except for sham/sham (P = 0.42), confirming that olfactory bulbectomy (OB)-induced hyperactivity consistent with a phenotype of agitated depression (Fig. 2b)
Summary
Definitive data are lacking on the mechanism of action and biomarkers of repetitive transcranial magnetic stimulation (rTMS) for the treatment of depression. We examined the behavioral and neurobiologic changes in olfactory bulbectomy (OB) mice with medium-intensity rTMS (MI-rTMS) treatment and fluoxetine hydrochloride. 1234567890():,; 1234567890():,; Introduction elucidating mechanisms of action and contributes to Repetitive transcranial magnetic stimulation (rTMS) has diverse clinical outcomes Notwithstanding their limitabeen used clinically since 2008 for treatment-resistant tions, animal and preclinical models are key tools in major depressive disorder. Low-intensity rTMS may modulate cortical excitability in the frontal cortex of humans, thereby addressing clinical psychiatric symptoms. These author contributed : Alesha Heath, Daniel R. The present study examined a mouse olfactory bulbectomy (OB) model to investigate differential effects of rTMS stimulation intensities on depression-related behaviors and neurobiologic characteristics. We investigated brain markers of plasticity (i.e., brain-derived neurotrophic factor [BDNF] and hippocampal neurogenesis), brain serotonin, and plasma metabolites in an attempt to better understand how the cellular and molecular effects of rTMS intensity relate to behavioral outcomes
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