Single dose of mirtazapine modulates whole-brain functional connectivity during emotional narrative processing

Abstract

The link between neurotransmitter-level effects of antidepressants and their clinical effect remain poorly understood. A single dose of mirtazapine decreases limbic responses to fearful faces in healthy subjects, but it is unknown whether this effect applies to complex emotional situations and dynamic connectivity between brain regions. Thirty healthy volunteers listened to spoken emotional narratives during functional magnetic resonance imaging (fMRI). In an open-label design, 15 subjects received 15mg of mirtazapine two hours prior to fMRI while 15 subjects served as a control group. We assessed the effects of mirtazapine on regional neural responses and dynamic functional connectivity associated with valence and arousal. Mirtazapine attenuated responses to unpleasant events in the right fronto-insular cortex, while modulating responses to arousing events in the core limbic regions and the cortical midline structures (CMS). Mirtazapine decreased responses to unpleasant and arousing events in sensorimotor areas and the anterior CMS implicated in self-referential processing and formation of subjective feelings. Mirtazapine increased functional connectivity associated with positive valence in the CMS and limbic regions. Mirtazapine triggers large-scale changes in regional responses and functional connectivity during naturalistic, emotional stimuli. These span limbic, sensorimotor, and midline brain structures, and may be relevant to the clinical effectiveness of mirtazapine.

Movies and narratives as naturalistic stimuli in neuroimaging

“…In an early EEG study, anxiolytic effects of smoking occurred in conjunction with right-hemisphere activity in smokers, suggesting that acetylcholine plays a role in emotion regulation given that nicotine stimulates the acetylcholine system ( Gilbert et al, 1989 ). In an fMRI study, a single dose of the antidepressant mirtazapine increased subjects’ functional connectivity associated with positive emotional valence in cortical midline and limbic structures while they listened to a narrative, suggesting that the histamine and serotonin systems are involved in emotion regulation ( Komulainen et al, 2017 ). Also, prenatal cocaine exposure has been observed to modulate responses to food cues in the ventral striatum, ACC, and MPFC, with this effect correlated with self-reported food cravings ( Yip et al, 2014 ).…”

7T ultra-high-field neuroimaging for mental health: an emerging tool for precision psychiatry?

“…A second scan could be performed after the first (test) dose of the drug or right at the beginning of other therapeutic interventions to predict the potential success of the therapy from the start. Indeed, alterations in brain connectivity have been detected using a 3 T fMRI as early as two hours after a single dose of antidepressant [ 73 ]. Therefore, an early trend towards an alignment of parameters that were noticeably deviant in the initial session could be indicative for a probable therapeutic success.…”

Molecular imaging of the human emotion circuit

“…Serotonin receptor (and norepinephrine) antagonist mirtazapine attenuates responses to unpleasant events in sensorimotor areas and anterior while modulating responses to arousing events in cortical midline structures. These effects are paralleled with increased functional connectivity between cortical midline and limbic areas during pleasant events (Komulainen et al, 2017), suggesting large-scale modulation of affective processing by serotonergic drugs.…”