Treatment Associated Changes of Functional Connectivity of Midbrain/Brainstem Nuclei in Major Depressive Disorder

Abstract

Previous functional magnetic resonance imaging (fMRI) studies demonstrated an abnormally coordinated network functioning in Major Depression Disorder (MDD) during rest. The main monoamine-producing nuclei within midbrain/brainstem are functionally integrated within these specific networks. Therefore, we aimed to investigate the resting-state functional connectivity (RSFC) of these nuclei in 45 MDD patients and differences between patients receiving two different classes of antidepressant drugs. Patients showed reduced RSFC from the ventral tegmental area (VTA) to dorsal anterior cingulate cortex (dACC) and stronger RSFC to the left amygdala and dorsolateral prefrontal cortex (DLPFC). Patients treated with antidepressants influencing noradrenergic and serotonergic neurotransmission showed different RSFC from locus coeruleus to DLPFC compared to patients treated with antidepressants influencing serotonergic neurotransmission only. In the opposite contrast patients showed stronger RSFC from dorsal raphe to posterior brain regions. Enhanced VTA-RSFC to amygdala as a central region of the salience network may indicate an over-attribution of the affective salience to internally-oriented processes. Significant correlation between decreased VTA-dACC functional connectivity and the BDI-II somatic symptoms indicates an association with diminished volition and behavioral activation in MDD. The observed differences in the FC of the midbrain/brainstem nuclei between two classes of antidepressants suggest differential neural effects of SSRIs and SNRIs.

Figure 1

Whole-brain resting-state functional connectivity maps with seed region in the ventral tegmental area (VTA). In the upper part of the figure, the comparison between healthy controls vs. depressed patients demonstrated that patients had weaker functional connectivity from VTA to dACC, mediodorsal thalamus and bilateral cerebellum. The average BOLD time course of the voxels within the VTA was extracted for the FC analysis from the unsmoothed midbrain/brainstem functional data, which were normalized using the SUIT toolbox and DARTEL approach. In the lower left part of the figure, functional connectivity from VTA to dACC is shown split according to the class antidepressant treatment. The error bars in the graphs of the RSFC from VTA to dACC represent standard deviation. In the lower right part of the figure, a significant correlation between the functional connectivity from the VTA to dACC and BDI-II somatic symptoms in patients with MDD is depicted. The somatic factor as computed according to Vanheule, et al. is composed of BDI-II items such as fatigue, appetite disturbance, loss of sexual interest and concentration difficulties. Abbr.: dACC, dorsal anterior cingulate cortex; PCC, posterior cingulate cortex; THAL, thalamus; CEREB, cerebellum; SSRI, selective serotonin reuptake inhibitors; SNRI, serotonin and noradrenalin reuptake inhibitors; NaSSA, noradrenergic and specific serotonergic antidepressants.

Figure 2

Whole-brain resting-state functional connectivity maps with seed region in the ventral tegmental area (VTA). The comparison between depressed patients vs. healthy controls demonstrated that patients had stronger functional connectivity from VTA to the left amygdala (yellow color) and absent “anti-correlation” from VTA to the sensorimotor and temporal cortices, posterior insula and the right DLPFC (blue color). The error bars in the graphs of the RSFC from VTA to the amygdala as well as to the motor cortex represent standard deviations. Abbr.: aHC, anterior hippocampus; Amy, amygdala; pI, posterior insula; DLPFC, dorsolateral prefrontal cortex; SMCx, sensorimotor cortex, TCx, temporal cortex.

Figure 3

Differences between the classes of antidepressant medication in the whole-brain resting-state functional connectivity maps with seed region in the dorsal raphe nucleus (DRN). Depressed patients with an SSRI demonstrated stronger FC from DRN to the posterior brain regions in contrast to patients taking an SNRI/NaSSA (blue color). In the opposite contrast, patients with an SNRI/NaSSA showed stronger FC to the right DLPF and VLPFC (yellow color). Abbr.: SSRI, selective serotonin re-uptake inhibitor; SNRI, serotonin and noradrenalin reuptake inhibitor; NaSSA, noradrenergic and specific serotonergic antidepressant; DLPFC, dorsolateral prefrontal cortex; VLPFC, ventrolateral prefrontal cortex; OCx, occipital cortex; Cereb., cerebellum.

Figure 4

Differences between the classes of antidepressant medication in the whole-brain resting-state functional connectivity maps with seed region in the locus coeruleus (LC). Depressed patients with an SNRI or NaSSA antidepressant demonstrated stronger FC from LC to the DLPFC, VMPFC and cerebellum in contrast to patients taking an SSRI. Abbr.: SSRI, selective serotonin re-uptake inhibitor; SNRI, serotonin and noradrenalin reuptake inhibitor; NaSSA, noradrenergic and specific serotonergic antidepressant; DLPFC, dorsolateral prefrontal cortex; VMPFC, ventromedial prefrontal cortex.