Abstract
Background: Major depressive disorder (MDD) is a public health problem worldwide. There is increasing interest in using non-invasive therapies such as repetitive transcranial magnetic stimulation (rTMS) to treat MDD. However, the changes induced by rTMS on neural circuits remain poorly characterized. The present study aims to test whether the brain regions previously targeted by deep brain stimulation (DBS) in the treatment of MDD respond to rTMS, and whether functional connectivity (FC) measures can predict clinical response.Methods: rTMS (20 sessions) was administered to five MDD patients at the left-dorsolateral prefrontal cortex (L-DLPFC) over 4 weeks. Magnetoencephalography (MEG) recordings and Montgomery-Asberg depression rating scale (MADRS) assessments were acquired before, during and after treatment. Our primary measures, obtained with MEG source imaging, were changes in power spectral density (PSD) and changes in FC as measured using coherence.Results: Of the five patients, four met the clinical response criterion (40% or greater decrease in MADRS) after 4 weeks of treatment. An increase in gamma power at the L-DLPFC was correlated with improvement in symptoms. We also found that increases in delta band connectivity between L-DLPFC/amygdala and L-DLPFC/pregenual anterior cingulate cortex (pACC), and decreases in gamma band connectivity between L-DLPFC/subgenual anterior cingulate cortex (sACC), were correlated with improvements in depressive symptoms.Conclusions: Our results suggest that non-invasive intervention techniques, such as rTMS, modulate the ongoing activity of depressive circuits targeted for DBS, and that MEG can capture these changes. Gamma oscillations may originate from GABA-mediated inhibition, which increases synchronization of large neuronal populations, possibly leading to increased long-range FC. We postulate that responses to rTMS could provide valuable insights into early evaluation of patient candidates for DBS surgery.
Highlights
Major depressive disorder (MDD) is characterized by depressed mood, anhedonia, irritability, poor concentration, feelings of hopelessness, thoughts of self-harm, inappropriate guilt, and abnormal appetite and sleep patterns
The brain-derived neurotrophic factor (BDNF) hypothesis (Nestler and Carlezon, 2006; Krishnan and Nestler, 2008; Pittenger and Duman, 2008) implies that an increase in BDNF at the ventral tegmental area (VT area) and nucleus accumbens (NAc) may increase neurovegetative symptoms associated with depression
The results indicate that better clinical efficacy was obtained when L-Dorsolateral prefrontal cortex (DLPFC) coordinates were negatively correlated with subgenual ACC (sACC), which accounted for 70% of the variance in clinical efficacy
Summary
Major depressive disorder (MDD) is characterized by depressed mood, anhedonia, irritability, poor concentration, feelings of hopelessness, thoughts of self-harm, inappropriate guilt, and abnormal appetite and sleep patterns. Previous studies have proposed that MDD is a circuit-based disorder in which several regions of the brain (prefrontal cortex, amygdala, striatum, pallidum and medial thalamus) are functionally aberrant (Drevets et al, 1992). Activity in the limbic regions, the amygdala and anterior cingulate cortex (ACC; Brodmann’s area 25), is associated with depressive symptoms. The brain-derived neurotrophic factor (BDNF) hypothesis (Nestler and Carlezon, 2006; Krishnan and Nestler, 2008; Pittenger and Duman, 2008) implies that an increase in BDNF at the VT area and nucleus accumbens (NAc) may increase neurovegetative symptoms associated with depression. The present study aims to test whether the brain regions previously targeted by deep brain stimulation (DBS) in the treatment of MDD respond to rTMS, and whether functional connectivity (FC) measures can predict clinical response
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