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a b s t r a c tBackground: Intermittent theta-burst stimulation (iTBS), a novel repetitive transcranial magnetic stimulation (rTMS) technique, appears to have antidepressant effects when applied over left dorsolateral prefrontal cortex (DLPFC). However, its underlying neurobiological mechanisms are unclear. Proton magnetic resonance spectroscopy ( 1 H-MRS) provides in vivo measurements of cerebral metabolites altered in major depressive disorder (MDD) like N-acetyl-aspartate (NAA) and choline-containing compounds (Cho). We used MRS to analyse effects of iTBS on the associations between the shifts in the NAA and Cho levels during therapy and MDD improvement. Methods: In-patients with unipolar MDD (N ¼ 57), in addition to treatment as usual, were randomized to receive 20 iTBS or sham stimulations applied over left DLPFC over four weeks. Single-voxel 1 H-MRS of the anterior cingulate cortex (ACC) was performed at baseline and follow-up. Increments of concentrations, as well as MDD improvement, were defined as endpoints. We tested a moderated mediation model of effects using the PROCESS macro (an observed variable ordinary least squares and logistic regression path analysis modeling tool) for SPSS. Results: Improvement of depressive symptoms was significantly associated with decrease of Cho/NAA ratio, mediated by NAA. iTBS had a significant moderating effect enhancing the relationship between NAA change and depression improvement. Conclusions: Our findings suggest a potential neurochemical pathway and mechanisms of antidepressant action of iTBS, which may moderate the improvement of metabolic markers of neuronal viability. iTBS might increase neuroplasticity, thus facilitating normalization of neuronal circuit function.

The amygdala plays a crucial role in the pathogenesis of major depressive disorder (MDD). While robust findings support a negative impact of illness duration on hippocampal volume in MDD, morphometric studies of the amygdala have yielded inhomogeneous results. Considering the methodical problems of automatic segmentation methods, a standardized segmentation protocol with proven inter- and intra-rater reliability was employed using high-resolution magnetic resonance imaging. To identify the effect of MDD on amygdala morphometry, 23 unipolar depressed patients who responded to antidepressant medication and 30 age-matched healthy controls (HC) were enrolled. First, gray matter volumes (GMV) of the bilateral amygdala were delineated manually in 3D by three blinded experts using the MultiTracer. The whole brain GMV was determined by using voxel-based morphometry. Second, the differences of the whole brain and the bilateral amygdala GMV values between MDD and HC were calculated with t-statistics. The GMV of the whole brain and the amygdala did not differ between HC and MDD patients. Third, MDD characteristics were correlated with amygdala GMV. Within the normal range, the left amygdala GMV was larger in patients with later onset and smaller in cases of prolonged depression. In line with prior reports of depressed patients responding to antidepressant treatment, amygdala GMV was negatively related to illness duration, suggesting volume loss with disease progression. It remains unclear as to whether the association between illness duration and GMV reduced left amygdala volume indicates a neurotoxic effect of prolonged MDD or is rather a negative predictor of chronic depression.

HighlightsWe here present a structural neuroimaging study reporting on a large multi-site patient sample with unipolar depression that underwent ECT.Patients showed grey matter increases in the medial temporal lobe.Connectivity modeling revealed that this altered brain region was involved in networks related to affect processing and memory.This provides a potential explanation, how these structural changes during ECT are involved in both main and side effects of the treatment.