یک مطالعه fMRI از کنترل توجه در زمینه انحراف کننده عاطفی در بزرگسالان مبتلا به اختلال دوقطبی خلق طبیعی

Abstract Inability to modulate attention away from emotional stimuli may be a key component of dysregulated emotion in bipolar disorder (BD). Previous studies of BD indicate abnormalities in neural circuitry underlying attentional control, yet few studies examined attentional control in the context of emotional distracters. We compared activity and connectivity in neural circuitry supporting attentional control and emotion processing among 22 individuals with BD type 1, currently remitted and euthymic, and 19 healthy controls. Participants performed an emotional n-back paradigm, comprising high and low attentional demand conditions, each with either emotional (happy, fearful), neutral or no face flanker distracters. During the high attentional control demand conditions without emotional distracters, BD individuals showed reduced activity relative to controls in dorsolateral prefrontal cortex, dorsal anterior cingulate cortex (dACC), and inferior parietal cortex. During the high attentional control demand conditions with fearful-face distracters, BD individuals showed greater activity than controls in these regions and amygdala and striatum. Relative to controls, BD individuals also showed abnormal patterns of effective connectivity between dACC and amygdala during high attentional control demand with emotional face distracters. Inter-episode bipolar disorder is characterized by abnormal recruitment of attentional control neural circuitry, especially in the context of emotionally distracting information.

Introduction Bipolar disorder (BD), one of the 10 most debilitating illnesses worldwide (World Health Organization, 2004), is characterized by a central deficit in the ability to regulate emotion (Goodwin and Jamison, 2007). Importantly, this deficit may persist even during remission (Phillips et al., 2003); thus, examining the neural basis of emotion dysregulation in BD may advance understanding of key pathophysiologic processes of the illness. The ability to flexibly redirect attention (i.e., attentional control) away from emotionally distracting stimuli represents an important component of emotion regulation that may be deficient in BD (Phillips et al., 2008a). Attentional control entails 1. selective attention toward goal-relevant stimuli, and 2. redirection of attention away from distracting, goal-irrelevant stimuli (Phillips et al., 2008a). Attentional control is fundamental to a range of cognitive tasks, including working memory (Gazzaley, 2010), sustained attention (Braver et al., 2003), and attentional set shifting (Nagahama et al., 2001). Maintaining attention to pertinent information is particularly challenging in the presence of distracting emotional stimuli, which compete for cognitive resources (Luo et al., 2007). Distributed prefrontal and parietal–cortical, anterior cingulate-cortical, and striatal-thalamo circuitry mediates attentional control (Alexander and Crutcher, 1990 and Bush and Shin, 2006). Furthermore, maintaining attention in the presence of emotional distracters is dependent on this circuitry (Bishop et al., 2004, Dolcos and McCarthy, 2006, Erk et al., 2007 and Goldstein et al., 2007) and intact functional coupling between prefrontal and anterior cingulate cortices and amygdala (Etkin et al., 2006 and Urry et al., 2006). Attentional control deficits have been documented among BD individuals using tests of sustained attention (Clark et al., 2002, Clark et al., 2005 and Maalouf et al., 2010) and working memory (Martínez-Arán et al., 2005 and Thompson et al., 2007). Neuroimaging studies employing working memory paradigms reported reduced (Lagopoulos et al., 2007, Monks et al., 2004 and Townsend et al., 2010), but also increased (Adler et al., 2004), activity in prefrontal attentional control circuitry in BD individuals relative to controls. Studies using the Stroop color-word selective attention task reported reduced activity in BD individuals vs. controls in ventral prefrontal regions (Blumberg et al., 2003, Kronhaus et al., 2006 and Strakowski et al., 2005) and anterior cingulate cortex (ACC) (Gruber et al., 2004), although greater activity in dorsolateral prefrontal cortex (dlPFC) (Gruber et al., 2004). Although some inconsistencies remain, these findings suggest that attentional control deficits among BD individuals may reflect diminished recruitment of underlying attentional control neural circuitry. Paradigms with intersecting cognitive and emotional demands may be particularly relevant to BD, given the aforementioned attentional control deficiencies and consistent findings of abnormally increased activity in subcortical regions supporting emotion processing among BD individuals (Altshuler et al., 2005, Almeida et al., 2010, Hassel et al., 2008, Hassel et al., 2009 and Lawrence et al., 2004). The few studies in this area have provided conflicting results, with some studies indicating that BD individuals show abnormally elevated activity in attentional control prefrontal cortical ( Deckersbach et al., 2008, Elliott et al., 2004 and Wessa et al., 2007) and in emotion processing subcortical ( Wessa et al., 2007) circuitry during cognitive task performance with emotional distraction, while others have found abnormally reduced activity in attentional control circuitry relative to healthy controls ( Malhi et al., 2005, Strakowski et al., 2005 and Lagopoulos and Malhi, 2007). Several factors likely contributed to these discrepancies, including the use of different paradigms, unequal between-group task performance ( Malhi et al., 2005), and recruitment of BD individuals in different mood states. Furthermore, while all of the tasks used in these studies required attentional control, they addressed slightly different domains of executive functioning, from response inhibition (e.g., affective Go/No-Go; Elliott et al., 2004 and Wessa et al., 2007), set shifting (e.g., emotional Stroop; Lagopoulos and Malhi, 2007 and Malhi et al., 2005), to working memory ( Deckersbach et al., 2008), each engaging partially distinct patterns of cortical activation. Another factor is the use of different types of emotionally distracting stimuli, from emotional words ( Elliott et al., 2004 and Wessa et al., 2007), to pictures ( Strakowski et al., 2011), to induced negative mood ( Deckersbach et al., 2008). Also noteworthy is that some studies employed only negative emotionally distracting information ( Deckersbach et al., 2008), while other used negative emotional and neutral distracters ( Lagopoulos and Malhi, 2007 and Strakowski et al., 2011), or negative and positive emotional distracters ( Elliott et al., 2004, Malhi et al., 2005 and Wessa et al., 2007). Further research is clearly required to elucidate possible neural system abnormalities among BD individuals during cognitive tasks requiring redirection of attention away from emotional distracters. Given that attentional control is mediated by distributed neural circuitry, connectivity analyses are a natural extension of this literature. Functional connectivity (FC) measures correlations over time between activity in different neural regions, while effective connectivity (EC) measures the impact of activity in one region over another (Roebroeck et al., 2005). Thus far, studies employing these techniques in BD have used emotion processing paradigms, and reported decreased amygdala-vlPFC FC (Foland et al., 2008), decreased amygdala-ACC FC (Wang et al., 2009), increased parahippocampal-subgenual cingulate cortical EC (Almeida et al., 2009a), and reduced vmPFC-amygdala EC in BD individuals vs. controls (Almeida et al., 2009b). One study also described decreased resting state amygdala-VPFC FC among BD individuals relative to controls (Chepenik et al., 2010). In the current study, we employed the Emotional Face N-Back (EFNBACK) task, a paradigm requiring direction of attention away from emotional (fearful and happy) and neutral-face distracters to perform an n-back working memory task ( Ladouceur et al., 2009). The paradigm also includes a no-distracter, attentional control condition. We previously showed slower task performance on the attentional demand condition with fearful-face distracters in high trait anxiety individuals at risk of mood disorders ( Ladouceur et al., 2009), and significantly greater dlPFC activity to this condition in remitted individuals with a history of major depressive disorder ( Kerestes et al., 2012). We used a region of interest (ROI) approach to examine differences in activity and EC between BD individuals and controls within: 1. attentional control neural circuitry: prefrontal and parietal cortices, ACC and striatum during attentional control; and 2. this neutral circuitry and the amygdala, a key emotion processing region, during attentional control in the context of emotional distracters. The EFNBACK has two important features, the combination of which distinguishes it from previous paradigms examining attentional control in the context of emotional distracters in BD. First, the distracters in this task are distinct from the stimuli comprising the attentional control component (unlike, for example, affective Go/No-Go tasks). Second, the paradigm includes neutral, positive, and negative emotional distracters, enabling us to comprehensively examine neural circuitry supporting attentional control vs. attentional control in the context of different types of emotional and neutral distracting stimuli. Furthermore, we examined neural circuitry when task performance was equivalent across groups, to avoid the potential confound of poor task performance upon neural activity of some studies in BD ( Adler et al., 2004, Gruber et al., 2004, Malhi et al., 2005, Strakowski et al., 2005 and Thermenos et al., 2010). We examined remitted, euthymic BD individuals to identify functional neural abnormalities that were mood state independent. We formulated the following hypotheses based on the collection of previous attentional control studies in BD, as well as the neural model of emotion regulation deficits in BD previously described by our group (Phillips et al., 2008a). This model highlights the role of abnormal dorsolateral, ventrolateral and dorsomedial (including dACC) prefrontal cortices activity during voluntary regulation of attention away from emotional distracters among BD individuals. In light of previous studies of attentional control neural circuitry in BD (Blumberg et al., 2003, Kronhaus et al., 2006, Lagopoulos et al., 2007, Monks et al., 2004 and Strakowski et al., 2004), we hypothesized that BD individuals would show reduced activity in attentional control neural circuitry vs. controls, particularly in dlPFC and dACC, during the no-distracter, attentional control condition. We hypothesized that during attentional control in the context of emotional distracters, BD individuals would show abnormally elevated activity in this circuitry and amygdala vs. controls, given that the only previous study of euthymic BD individuals using a paradigm employing both positive and negative emotional distracters documented greater activity in BD vs. healthy individuals ( Wessa et al., 2007). Exploratory analyses compared EC between neural regions in attentional control circuitry and the amygdala during attentional control in the context of emotional distracters in BD individuals vs. controls.

Results 3.1. Task performance MANOVA revealed significant main effects of attentional load, F(2,38) = 20.28, P < 0.001, and emotional distracter condition, F(6,34) = 4.43, P = .0.002. The effect of diagnostic group was non-significant, and there were no significant diagnostic group * attentional load or group * emotional distracter condition interactions, or a significant group * attentional load * emotional distracter interaction. Overall accuracy on the task was good; both groups had mean accuracies over 90% even on the more difficult 2-back conditions (Supplementary Table 2). Accuracy was lower, F(1,39) = 17.07, P < 0.001, partial η2 = 0.30 (2-back mean = 34.04 vs. 0-back mean = 35.48), and reaction times were slower, F(1,39) = 39.41, P < 0.001, partial η2 = 0.50 (2-back mean = 766.76 ms vs. 0-back mean = 578.15 ms), in the high vs. low attentional load condition. Reaction times were also slower, F(3,96) = 6.26, P < 0.001, partial η2 = 0.15 (mean for emotional-face distracter conditions = 685.99 vs. no-distracter condition = 631.86 ms), but accuracy was equivalent, in the emotional face distracter vs. no-face condition. Post hoc tests indicated that reaction time in all participants was significantly slower during neutral-face (P = 0.001, mean = 690.13 ms), fearful-face (P = 0.004, mean = 689.41 ms) and happy-face (P = 0.001, mean = 678.42 ms) distracters than the no-distracter condition. Accuracy did not differ significantly among the emotion face distracter conditions. 3.2. Neuroimaging findings 3.2.1. Attentional control For the 2-back no-distracter vs. 0-back no-distracter contrast, BD individuals showed significantly reduced activity vs. controls in right dlPFC, right dACC, bilateral inferior parietal cortex, and right putamen (P < 0.05, corrected; Fig. 2; Table 2). Significantly reduced activity in BD individuals relative to controls during the ... Fig. 2. Significantly reduced activity in BD individuals relative to controls during the high vs. low attentional control condition without face distracters in (a) right dorsolateral prefrontal cortex (175 voxels, [peak voxel = 56, 18, 27], and (b) right putamen (125 voxels, [peak voxel = 23, − 13, 12]. Graphs represent activity in each region during the 2-back high attentional demand no-distracters condition relative to the 0-back low attentional demand no-distracters condition. Individual bars represent mean group BOLD signal change, and error bars represent standard deviations. Between group differences were significant using corrected regional thresholds (clusterwise) at P < 0.05. Abbreviations: BD = individuals with bipolar disorder, HC = healthy control individuals, R = Right, L = Left, dlPFC = dorsolateral prefrontal cortex. Figure options Table 2. Between group differences during high vs. low attentional control conditions without emotional face distracters. Region of interest analyses, with a voxelwise threshold of P < 0.05, corrected for multiple comparisons using AlphaSim Monte Carlo simulations. Each line in the table represents the voxel of peak activity difference within the specified region. None of the regions of interest showed greater activity in BD individuals than HC in the attentional control condition. Talairach coordinates Region BA k x y z t P value Attentional control: 2-back no-distracter vs. 0-back no-distracter BD individuals < Controls Right dorsolateral prefrontal cortex 9 175 56 18 27 3.49 0.001 Right anterior cingulate cortex 31 55 8 − 7 46 2.93 0.002 Right inferior parietal cortex 40 354 53 − 38 46 3.85 < 0.001 Left inferior parietal cortex 40 306 − 46 − 47 41 3.30 0.001 Right putamen 125 23 − 13 12 3.49 0.001 Abbreviations: BA = Brodmann area; k = cluster size in voxels. Table options 3.2.2. Attentional control with emotional distracters For the 2-back fearful-face vs. neutral-face distracter contrast, BD individuals showed significantly greater activity relative to controls in left dlPFC, bilateral inferior parietal cortex, right amygdala, and right putamen (P < 0.05, corrected; Fig. 3; Table 3). Significantly greater activity in BD individuals relative to controls during the ... Fig. 3. Significantly greater activity in BD individuals relative to controls during the 2-back high attentional demand condition with fearful-face vs. neutral-face distracters in (a) left dorsolateral prefrontal cortex (74 voxels, [peak voxel = − 45, 18, 36], and (b) right amygdala (11 voxels, [peak voxel = 29, − 7, − 15]. Graphs represent activity in each region during the 2-back high attentional demand with fearful-face distracters relative to the neutral-face distracter condition. Individual bars represent mean group BOLD signal change, and error bars represent standard deviations. Between group differences were significant using corrected regional thresholds (clusterwise) at P < 0.05. Abbreviations: BD = individuals with bipolar disorder, HC = healthy control individuals, R = Right, L = Left, dlPFC = dorsolateral prefrontal cortex. Figure options Table 3. Between group differences during attentional control in the context of emotional distracters. Region of interest analyses, with a voxelwise threshold of P < 0.05, corrected for multiple comparisons using AlphaSim Monte Carlo simulations. Each line in the table represents the voxel of peak activity difference within the specified region. No regions exceeded AlphaSim thresholds for the happy vs. neutral-face or neutral vs. no-distracter contrasts. Talairach coordinates Region BA k x y z t P value Attentional control with emotional distracters: 2-back fearful-face vs. 2-back neutral-face BD individuals > Controls Left dorsolateral prefrontal cortex 9 74 − 45 18 36 2.92 0.003 Left inferior parietal cortex 40 132 − 50 − 59 43 2.70 0.003 Right inferior parietal cortex 40 95 47 − 44 53 2.59 0.007 Right amygdala 11 29 − 7 − 15 2.78 0.003 Right putamen 305 23 8 11 3.70 < 0.001 Abbreviations: BA = Brodmann area; k = cluster size in voxels. Table options There were no significant between-group findings for the 2-back happy-face vs. neutral-face distracter, or neutral-face vs. no-distracter contrasts. 3.2.3. EC To the 2-back fearful-face distracter condition, controls showed significantly greater preceding EC from rostral/dACC to amygdala than BD individuals (t(39) = − 3.40, P = 0.002; Fig. 4). Group differences in effective connectivity during attentional control in the ... Fig. 4. Group differences in effective connectivity during attentional control in the context of emotional distracters. Using Granger Causality Mapping (GCM), BD individuals exhibited (a) significantly reduced preceding “top–down” effective connectivity from rostral/dorsal anterior cingulate cortex (ACC; peak voxel = − 1, 25, 27; 48 voxels) to the amygdala vs. controls during the 2-back fearful-face distracter condition; and (b) significantly greater preceding “top–down” effective connectivity from rostral/dorsal ACC to the amygdala (peak voxel = 5, 40, 12; 55 voxels) vs. controls during the 2-back happy-face distracter condition (shown as the red clusters). The Granger map was corrected (FDR(q) < 0.01) at the whole brain level. Figure options To the 2-back happy-face distracter condition, BD individuals showed significantly greater preceding EC from rostral/dACC to amygdala than controls (t(39) = 2.83, P = 0.007; Fig. 4). There were no significant between-group differences in amygdala EC to the 2-back neutral-face or no-distracter conditions. 3.2.4. Task performance, clinical variables, and neural activity and EC For BD individuals, activity in left parietal cortex to the 2-back fearful-face vs. neutral-face condition was negatively associated with age of illness onset (r = −0.614, P = 0.002). No other relationships between clinical, demographic, medication or reaction time variables and activity or EC in any of the clusters showing between-group differences in activity survived Bonferroni correction (see Supplementary Analyses for the small number of exploratory findings at P < 0.05 not meeting Bonferroni thresholds).