تسهیل تنظیم احساسات با یک دوز واحد از مصرف همزمان داروی escitalopram: یک مطالعه تصادفی FMRI

Abstract Acute antidepressant administration modulates neural activity consistent with decreases in negative emotion processing bias. However, studies are yet to examine whether treatment facilitates neural activity during reappraisal, an adaptive emotion regulation strategy associated with behavioral treatment response. Here we examine the impact of acute administration on reappraisal of negative stimuli using pharmaco-fMRI. Thirty-six healthy female participants completed two sessions of fMRI scanning, separated by a one-week washout period. A single dose of the selective serotonin reuptake inhibitor, escitalopram (20 mg) was administered to participants using a double-blind, randomized, placebo-controlled crossover design. When participants were administered escitalopram (relative to a placebo) and asked to reappraise negative emotional stimuli, left amygdala activation was decreased and right inferior frontal gyrus (R IFG) activation was increased. Also observed was a greater negative left amygdala-R IFG functional connectivity when participants were administered escitalopram relative to placebo, and this change in connectivity was associated with reductions in subjective ratings of valence and arousal of negative stimuli. Further analysis revealed connectivity modulation across multiple frontal regions. Results suggest that the acute effect of a commonly prescribed antidepressant may include facilitating the regulation of negative emotional stimuli, providing new important leads for models of antidepressant action.

Introduction Major depressive disorder and generalized anxiety disorder are associated with high prevalence along with great personal and societal burden (World Health Organization, 2008). Current perspectives suggest that these disabilities are underpinned by cognitive dysfunction which in turn relates to negative emotion processing biases and dysregulation of emotion, particularly in the context of negative emotion (Beck et al., 1979, Beck, 2008 and Gotlib and Joormann, 2010). These dysfunctions can be countered to some extent by employing adaptive emotion regulation strategies, and behavioral studies indicate that reappraisal of negative stimuli results in diminishing affective disorder symptoms (Aldao et al., 2010, Berking and Wupperman, 2012, Cisler and Olatunji, 2012 and McRae et al., 2014). Furthermore, behavioral evidence suggests that effective antidepressant treatment facilitates reappraisal (Ehring et al., 2010, Gotlib and Joormann, 2010, Berking and Wupperman, 2012 and McRae et al., 2014). However, the neural mechanism underpinning the antidepressant-related facilitatory effects of reappraisal is yet to be examined. Emotion regulation refers to a diverse set of processes that modulate the manner in which emotions are experienced and expressed (Gross, 1998 and Gross, 2008). Reappraisal is an emotion regulation strategy that involves reframing a situation or stimulus (Gross, 1998 and Gross and Thompson, 2007), thereby impacting two interacting, functionally connected neural systems involved in emotion generation and its control (Aron et al., 2004, Ochsner and Gross, 2005, Banks et al., 2007 and Goldin et al., 2008). Processes governing the latter have been associated with increased activity within the prefrontal cortex (Aron et al., 2004, Goldin et al., 2008, Ochsner et al., 2012 and Buhle et al., 2014), which subsequently decrease limbic activity such as that of the amygdala, associated with emotion generation (Ochsner and Gross, 2005 and Banks et al., 2007). These regions are thought to decrease emotional reactivity in an iterative manner, with limbic emotional reactivity continually modified by frontal processes automatically and volitionally (Ochsner and Gross, 2008 and Ochsner et al., 2012). Frontal processes are engaged in the appraisal of stimuli and reappraisal; however, the key difference is that reappraisal may be employed to decrease emotional reactivity to negative stimuli (Gross, 1998 and Goldin et al., 2008). Key prefrontal cortex regions involved in reappraisal include the right inferior frontal gyrus (R IFG), as well as the dorsomedial, dorsolateral, and ventrolateral regions (Aron et al., 2004, Goldin et al., 2008, Ochsner et al., 2012 and Buhle et al., 2014). In order to understand the mechanisms through which antidepressants facilitate reappraisal, it may be beneficial to investigate how the functional connectivity between the amygdala and frontal regions change when an individual reappraises negative emotional stimuli, and how antidepressants modulate this connectivity. Single doses of antidepressants have been shown to modulate IFG and amygdala activity in healthy participants, enhancing positive emotion processing biases while attenuating negative emotion processing biases (Kemp et al., 2004a, Outhred et al., 2013 and Outhred et al., 2014b). In order to further understand these changes, more specific neurocognitive processes must be dissected. The facilitation of reappraisal may be one mechanism through which modulation of emotion processing bias with single dose administration can occur. To date, studies remain to determine whether a single dose of an antidepressant is able to sufficiently facilitate reappraisal of negative emotional stimuli resulting in a decrease in neural and behavioral emotional reactivity. Based on our previous findings (Kemp et al., 2004a, Outhred et al., 2013 and Outhred et al., 2014b) that single doses of antidepressants modulate L amygdala and R IFG activity, along with findings that reappraisal results in heightened negative connectivity between the amygdala and frontal regions (Ochsner and Gross, 2005 and Banks et al., 2007), as well as behavioral findings by others indicating that antidepressants facilitate reappraisal (Ehring et al., 2010, Gotlib and Joormann, 2010, Berking and Wupperman, 2012 and McRae et al., 2014), we formed the following predictions. We predicted that the functional connectivity between the L amygdala and R IFG activity would be modulated by escitalopram during reappraisal of negative emotional stimuli, such that decreased L amygdala activity would be associated with increased R IFG activity (i.e., heightened negative connectivity between these regions under escitalopram). In addition to examining this a priori hypothesis, we explored functional connectivity changes over broader regions in the frontal cortex in order to examine potential modulation with other regulatory regions. Finally, we predicted that L amygdala-R IFG functional connectivity changes would be reflected in behavioral responses.

. Results 3.1. fMRI results: second-level model The ROI analysis on the effect of treatment on emotion regulation revealed significant activation of the R IFG and L amygdala, p<0.05 (uncorrected, k=20). See Table 1 for peak activation statistics. The paired t-test revealed that, relative to placebo, escitalopram increased R IFG activation and decreased L amygdala activation during reappraisal of negative stimuli (relative to the ‘watch’ condition). Table 1. Peak L amygdala and R IFG activation of the effect of treatment on emotion regulation (Reappraise Negative>Watch Negative). Peak voxel (MNI) Group contrast Region k Peak t value p x y z Escitalopram>Placebo R IFG 40 2.18 .018 44 10 20 2.05 .024 48 12 22 Placebo>Escitalopram L amygdala 30 2.94 .003 −20 −4 −20 L amygdala=left amygdala; R IFG=right inferior frontal gyrus; k=cluster extent; t=paired t statistic with degrees of freedom [35]; n.s.=no significant voxels. Table options 3.2. fMRI results: functional connectivity model (gPPI) Fig 1 illustrates the R IFG and L amygdala connectivity under escitalopram, demonstrating heightened negative connectivity relative to placebo. The one-sample t-tests showed significant negative coupling between the L amygdala and the R IFG target for both the escitalopram session (β=−0.828, t[35]=4.134, p<0.001) and the placebo session (β=−0.397, t[35]=1.760, p=0.044), indicating that decreases in L amygdala were associated with increases in R IFG under reappraisal under each treatment condition. Importantly, the functional coupling beta contrast estimates of the escitalopram session during reappraisal were significantly more negative than that of the placebo session, t[35]=2.410, p=0.011. Therefore, escitalopram heightened the negative functional connectivity between the L amygdala and R IFG during the reappraisal condition, relative to placebo. Functional connectivity (gPPI) modulation by escitalopram between the left ... Fig. 1. Functional connectivity (gPPI) modulation by escitalopram between the left amygdala seed (L AMY) and the right inferior frontal gyrus (R IFG) target during reappraisal. Panel A. The left amygdala volume of interest: a 6 mm sphere at [−20, −4, −20]) that was employed as a seed in the gPPI analysis. Panel B: the R IFG cluster activation (k=1605) that was significantly functionally connected with the L AMY seed. Panel C: the functional coupling contrast estimates for each treatment condition, showing heightened negative functional connectivity between the L AMY seed and the R IFG target with reappraisal under escitalopram relative to watch. Error bars represent standard error of the mean. Figure options In addition to the R IFG analysis, the wider ROI analysis showed L amygdala functional connectivity modulation with escitalopram administration across a number of regions (see Table 2). These regions included the dorsolateral, dorsomedial, ventromedial, and ventrolateral prefrontal cortex. Table 2. Peak L amygdala and frontal functional connectivity of the effect of treatment on emotion regulation. Peak voxel (MNI) Region (AAL label) PFC division k Peak t value p x y z R IFG; Frontal_Inf_Oper_R DLPFC 119 10.425 <0.0001 50 −2 24 4.226 0.0001 44 2 22 3.503 0.0006 60 4 16 Frontal_Sup_R DLPFC 101 5.150 <0.0001 16 0 74 4.261 0.0001 18 8 72 3.971 0.0002 22 −8 76 Supp_Motor_Area_L 95 4.326 0.0001 6 −4 56 4.052 0.0001 4 −8 56 3.854 0.0002 8 −8 50 3.727 0.0003 6 −10 62 Frontal_Mid_R DMPFC 93 4.512 <0.0001 42 −4 64 3.846 0.0002 54 −8 52 3.513 0.0006 50 −2 52 Frontal_Mid_R VMPFC 45 4.026 0.0001 32 54 22 R IFG; Frontal_Inf_Tri_R VLPFC 27 3.918 0.0002 54 30 0 Paracentral_Lobule_L 24 4.473 <0.0001 −12 −10 80 3.836 0.0003 −16 −10 78 3.513 0.0006 −6 −8 78 k=cluster extent; t=paired t statistic with degrees of freedom [35]. Table options 3.3. fMRI results: functional connectivity modulation and negative image ratings Results from the simple regression demonstrated that changes in negative valence ratings are significantly associated (at αBonferroni=0.025) with changes in functional connectivity between the L amygdala and R IFG during reappraisal with escitalopram administration (relative to placebo), R2=0.144, R2 adjusted=0.118, F(1, 34)=5.697, p=0.023. More specifically, heightened negative functional connectivity between the L amygdala and R IFG during reappraisal under escitalopram was associated with greater decreases in subjective ratings of negative valence. Similarly, change in arousal ratings with escitalopram (relative to placebo) were significantly (at αBonferroni=0.025) associated with change in functional connectivity during reappraisal with escitalopram (relative to placebo), R2=0.154, R2 adjusted=0.130, F(1, 34)=6.211, p=0.018. Therefore, the heightened negative functional connectivity between the L amygdala and R IFG during reappraisal under escitalopram was associated with greater decreases in subjective ratings of arousal. Taken together, these regression results support the interpretation that heightened negative connectivity with escitalopram is associated with facilitation of reappraisal processes that decrease emotional reactivity to negative stimuli.