Exp Res (2016) 234:2653–2665 DOI 10.1007/s00221-016-4669-6

RESEARCH ARTICLE

Emotion moderates the association between HTR2A (rs6313) genotype and antisaccade latency

Mark Mills1 · Olivia Wieda1 · Scott F. Stoltenberg1 · Michael D. Dodd1

Received: 10 November 2015 / Accepted: 29 April 2016 / Published online: 9 May 2016 © Springer-Verlag Berlin Heidelberg 2016

Abstract The serotonin system is heavily involved in influence. This effect was reduced in C/C versus T/_ indi- cognitive and emotional control processes. Previous work viduals, suggesting a weaker capacity to downregulate has typically investigated this system’s role in control pro- emotional processing of task-irrelevant stimuli. cesses separately for cognitive and emotional domains, yet it has become clear the two are linked. The present study, Keywords Serotonin · Antisaccade · Emotion · Inhibitory therefore, examined whether variation in a serotonin recep- control tor (HTR2A, rs6313) moderated effects of emotion on inhibitory control. An emotional antisaccade task was used in which participants looked toward (prosaccade) or away Introduction (antisaccade) from a target presented to the left or right of a happy, angry, or neutral face. Overall, antisaccade latencies There is an increased interest in the interplay between were slower for rs6313 C allele homozygotes than T allele emotion and cognition function (Pessoa 2009; Vuilleum- carriers, with no effect of genotype on prosaccade latencies. ier 2005), along with growing recognition that individual Thus, C allele homozygotes showed relatively weak inhibi- differences in these relations may be relevant to funda- tory control but intact reflexive control. Importantly, the mental differences in behavior (Kanske 2012) and risk of emotional stimulus was either present during target presen- psychopathology. In particular, there is growing evidence tation (overlap trials) or absent (gap trials). The gap effect that individual differences in behavioral inhibitory control (slowed latency in overlap versus gap trials) in antisaccade (Crosbie et al. 2013) and in sensitivity to emotional stimuli trials was larger with angry versus neutral faces in C allele (Anokhin et al. 2010) are at least partially heritable and, homozygotes. This impairing effect of negative valence on therefore, represent promising candidate inhibitory control was larger in C allele homozygotes than for genetic investigation. Recently, molecular genetic stud- T allele carriers, suggesting that angry faces disrupted/ ies have linked polymorphisms in structural for sero- competed with the control processes needed to gener- tonin receptors to individual variation in cognitive (Passetti ate an antisaccade to a greater degree in these individuals. et al. 2003) and emotional (Fisher et al. 2009, 2011) control The genotype difference in the negative valence effect on processes. Although cognition and emotion exert strong antisaccade latency was attenuated when trial N-1 was an influence on each other, research investigating the relation- antisaccade, indicating top-down regulation of emotional ship between serotonin receptors and cognitive functioning on the one hand, and between serotonin receptors and emo- tion processing on the other, has developed largely in paral- lel with little crossover, leaving the role of serotonin recep- tors on the cognition–emotion interface unclear. The goal * Mark Mills of the present study, therefore, was to examine whether [email protected] genetic variation in a polymorphic region of a candidate 1 Department of Psychology, University of Nebraska-Lincoln, serotonin receptor plays a role in the impact of emotional 238 Burnett Hall, Lincoln, NE 68588, USA stimuli on inhibitory control.

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The 5-hydroxytryptamine (5-HT or serotonin) sys- 2011). Taken together, this work suggests that polymor- tem has long been implicated in a wide array of cogni- phisms in its structural gene may play a role in individual tive, behavioral, and emotional control processes. A role differences in the interplay between emotion and inhibitory for 5-HT in cognitive functioning, in particular inhibitory control. control, is suggested by findings of impulse control failure Among polymorphisms in the structural gene for the following reductions in 5-HT transmission. For example, 5-HT2A receptor (HTR2A, 13q14.2), one that has received 5-HT levels are reduced in patients with mania (Thakore considerable attention for its role in both cognitive and et al. 1996), alcohol-mediated aggression (Coccaro 1989), emotional control processes is a single nucleotide poly- and suicidal patients with depression (Linnoila and Virk- morphism (SNP) at codon 102 (rs6313; either thymine, T, kunen 1992). Such findings are consistent with the notion or cytosine, C). It is a synonymous substitution that does that 5-HT mediates behavioral inhibition (Soubrié 1986). not alter amino acid sequence but is associated with dif-

Studies investigating the molecular mechanisms of such ferential mRNA and 5-HT2A receptor protein expression impairments have implicated variation in 5-HT receptors (Polesskaya and Sokolov 2002), and is in complete link- as key, especially the 2A receptor—a G protein-coupled age disequilibrium with a promoter polymorphism (; receptor expressed at high levels in the neocortex (includ- Smith et al. 2013). Therefore, rs6313 represents a candidate ing primary motor, supplementary motor, premotor, pari- gene polymorphism of interest. The C allele of rs6313 is etal, and occipital cortices) and prefrontal cortex, and at associated with low gene expression. Homozygosity for the intermediate levels in the hippocampus, nucleus accum- C allele (i.e., C/C genotype) is associated with character- bens, and the hypothalamus (Dwivedi and Pandey 1998; istic features of several psychiatric disorders, in particular, see Aznar and Klein 2013, for a review). The 5-HT2A impaired cognitive function (e.g., Becker et al. 2004; Üҫok receptor has received considerable attention for its impli- et al. 2007; Vyas et al. 2012). For example, previous work cations in executive functioning and risk of disorder (e.g., has found that individuals with the C/C genotype make Gong et al. 2011; Lane et al. 2008; Wingen et al. 2007). more errors than those with the T/_ genotypes (i.e., T/C or

This work suggests that 5-HT, through the 5-HT2A receptor, T/T genotypes) on a test of behavioral control (Bjork et al. is involved in regulating aspects of cognitive functioning, 2002). Although this work supports the presence of func- including inhibitory control (Passetti et al. 2003). tional genetic variants in the 5-HT2A receptor in patient There is also evidence that 5-HT plays a role in emo- populations, the role that functional genetic variants in tional control processes (Cools et al. 2008). A role for the 5-HT2A receptor play in cognition and risk of disorder 5-HT in the processing of emotional stimuli is evident by within the normal population is unclear. Here, we exam- the fact that selective serotonin reuptake inhibitors have a ine whether rs6313 genotype plays a role in behavioral positive effect in treating major depression and anxiety dis- response inhibition (the ability to suppress actions that are orders (Blier and de Montigny 1999), whereas acute tryp- no longer behaviorally relevant or contextually appropri- tophan depletion increases negative emotion (Van der Veen ate), as measured via oculomotor response within a modi- et al. 2007). Furthermore, reductions in 5-HT neurotrans- fied antisaccade task. To our knowledge, this is the first mission have been associated with enhanced processing of investigation of antisaccade performance with the rs6313 negative emotional content (Murphy et al. 2002). Neuro- polymorphism. physiological studies have shown that the 5-HT system also The antisaccade task (Hallett 1978) is a widely used modulates the responsiveness of the amygdala and con- measure of oculomotor response inhibition and a key tool nected medial frontal regions to threat-related content. For for health professionals in testing for frontal lobe dysfunc- example, reductions in 5-HT neurotransmission have been tion. In this task, a peripheral onset stimulus is presented associated with enhanced amygdala activation in response to one side of a central fixation stimulus (usually some- to threat-related stimuli (von dem Hagen et al. 2011). Thus, thing innocuous like a “ ” sign) and participants are cued + dysfunction in the 5-HT system is associated with impaired either to look toward (prosaccade) or away (antisaccade) emotion processing. Here, too, the 5-HT2A receptor appears from it. It is generally assumed that prosaccades are elic- key. Bilateral amygdala damage, for example, has been ited exogenously (reflexively or effortlessly) in response to associated with a decrease in 5-HT2A receptors signaling a the peripheral onset, whereas antisaccades are generated loss of the capacity to feel fear or stress (Hurlemann et al. endogenously (volitionally or effortful) by actively inhibit- 2009). Importantly, recent work has shown that the level of ing the prosaccade and executing a saccade to the mirror postsynaptic excitatory 5-HT2A receptor binding and den- location. Correct performance on antisaccade trials, there- sity in the medial prefrontal cortex is inversely correlated fore, is thought to require at least two intact subprocesses: with threat-related amygdala activity (Fisher et al. 2009, inhibition of a reflexive prosaccade and generation of an

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Overlap Condition Gap Condition

Target (until response) Target (until response)

Gap (500 ms) Emotion Stimulus (500 ms)

Emotion Stimulus (500 ms) Task Cue (500 ms)

Task Cue (500 ms)

Fig. 1 Example trial sequence for overlap (left) and gap (right) tri- In overlap trials, the onset target was presented, while the emotional als. Every trial started with 500-ms task cue (the color which indi- stimulus was still present. In gap trials, the emotional stimulus was cated whether a prosaccade or an antisaccade was required), followed removed and a blank screen was presented for 500 ms before target immediately by an emotional stimulus that was presented for 500 ms. presentation effortful antisaccade. As these processes take time to unfold a result, performance may be impaired on tasks that do not on antisaccade trials and are not required on prosaccade require the processing of emotional stimuli. For individuals trials (given that prosaccades are elicited exogenously), with trait-level impairments in inhibitory control, such as antisaccade latencies tend to be considerably longer than C allele homozygotes, this implies there may be even more prosaccade latencies. Furthermore, as a failure to inhibit or resources available to spill over to emotion processing and cancel the reflexive prosaccade on an antisaccade trial will so even greater emotional interference might be expected result in an erroneous saccade toward the peripheral onset, relative to those with a T allele. Thus, an inhibitory defi- there tend to be more antisaccade errors (i.e., erroneous cit may also be reflected in a failure to resist disruption prosaccade on antisaccade trials) than prosaccade errors or interference from the task-irrelevant emotion stimulus, (i.e., erroneous antisaccade on prosaccade trials). A general which would be evident by slower antisaccades when the inhibitory deficit, therefore, would be evident by difficulty central fixation stimulus was emotional in nature (happy or performing antisaccades (i.e., slow and/or error prone anti- angry face) compared with neutral. saccades). Accordingly, if the C/C genotype is associated In the standard antisaccade task, removing the central with a general inhibitory deficit, then these individuals fixation point before presentation of the peripheral onset should exhibit slower and/or more error prone antisaccades stimulus (gap trials) tends to shorten saccadic latencies compared with T allele carriers (i.e., T/T or T/C). relative to leaving it on during onset presentation (overlap To investigate the impact of a distracting (i.e., task- trials), a phenomenon referred to as the gap effect (Saslow irrelevant) emotional stimulus on oculomotor control pro- 1967). The gap effect is thought to reflect the tendency to cesses, the antisaccade task was modified to include either keep the eyes on a currently fixated stimulus, which com- a happy, angry, or neutral facial expression as the central petes with the signal to generate a saccade in the overlap fixation stimulus (as opposed to a “ ” sign). Distraction condition. If the centrally fixated stimulus is no longer + challenges our ability to maintain focus on goal-relevant present at the time of onset presentation, then there is no information, and emotional stimuli are particularly potent competition and the saccade can be generated more quickly distractors that can capture attention and reallocate pro- (Fischer and Weber 1993). Accordingly, emotional inter- cessing resources (Hansen and Hansen 1988), which can ference may be especially evident by the presence of a in turn impair performance on measures of cognitive func- gap effect (shorter latencies on gap versus overlap trials) tion. Previous work, for example, has shown reduced per- on antisaccade trials. Support for this idea comes from a formance on measures of response inhibition following previous study in which a larger gap effect was observed presentation of task-irrelevant emotional stimuli (Dennis for task-irrelevant fearful versus neutral faces (West et al. et al. 2008; Kalanthroff et al. 2013; Padmala et al. 2011; 2011). On overlap trials, the task-irrelevant stimulus is pre- Pessoa et al. 2012; Sagaspe et al. 2011; Verbruggen and sented concurrently with the target and therefore may need De Houwer 2007), presumably because emotional stimuli to be inhibited before an antisaccade can be executed (see capture attention automatically, interrupting or competing Fig. 1). In contrast, on gap trials, the task-irrelevant stim- with ongoing activities and leaving fewer resources avail- ulus is removed prior to target presentation and therefore able for effortful control (Kanske 2012; Pessoa 2009). As does not need to be inhibited. Thus, if the C/C genotype is

1 3 2656 Exp Brain Res (2016) 234:2653–2665 associated with a general inhibitory deficit, then those with than .5°. Viewing was binocular, but only the dominant eye that genotype should show a larger antisaccade gap effect was recorded. than those carrying a T allele, regardless of the content of the task-irrelevant stimulus. However, to the extent that Procedure task-irrelevant emotional stimuli are particularly disruptive to ongoing processing, then the genotype difference in the Participants completed two blocks of 72 trials. Blocks were antisaccade gap effect should be selectively larger for emo- identical with the exception of a gap manipulation. In one tional versus neutral stimuli. condition, a central emotional stimulus remained present during target presentation (overlap condition), whereas in the other condition it was removed prior to target presenta- Methods tion (gap condition). An example trial sequence for overlap and gap trials is shown in Fig. 1. A trial began with presen- Participants tation of a 500-ms task cue at fixation (green or red circle), which indicated whether the current trial required a prosac- Healthy undergraduates from the University of cade or an antisaccade. An emotional face (angry, happy, or Nebraska-Lincoln participated in exchange for course neutral) then replaced the cue for 500 ms, followed by a credit (N 116; 64 % female; 86 % white; mean peripheral onset target appearing 5° or 10° either to the left = age 20.23 years). All participants had normal or cor- or right fixation.1 Participants were instructed to look = rected-to-normal vision, were naïve to the purpose of the toward the target (prosaccade) or away from the target study, and were informed of their rights of participation (antisaccade) depending on the task cue (green toward; = according to the University of Nebraska-Lincoln Institu- red away). = tional Review Board. Data analysis Genotyping The extent to which saccade (prosaccade or antisaccade), Participants donated buccal cells, from which DNA was gap (gap or overlap), emotion (angry, happy, or neutral), extracted using the PureGene kit, (Qiagen, Venlo, Neth- and genotype (C/C or T/_) predicted task performance erlands). The rs6313 SNP of the HTR2A was genotyped was examined—separately for saccade latencies and using a StepOnePlus Real-Time PCR system, TaqMan errors—in a sample of 16,704 saccades, which were SNP Genotyping Assay (C___3042197_1_; Life Tech- nested within 144 trials and within 116 subjects and nologies, Carlsbad, CA) per manufacturer’s instructions. where trials and subjects were crossed (given that each Allele frequencies were consistent with the HapMap CEU subject responded to each trial). A saccade was defined population (C .61, T .39), and genotype frequencies as an eye movement with an amplitude > 3°. The latency = = (C/C 39 %, C/T 44 %, T/T 17 %) were in Hardy– of the first correct saccade was defined as the interval = = = Weinberg equilibrium (χ2 .71, p > .05). between target presentation and the initiation of a sac- = cade. An error was defined when the first saccade was Apparatus directed toward the target (in antisaccade trials) or away from the target (in prosaccade trials). Anticipations Stimuli were displayed on a Pentium IV PC with VGA (latencies < 100 ms) and late saccades (laten- monitor (85 Hz) in a dimly lit, sound-attenuated testing cies > 800 ms) were discarded (5.4 %), as were error tri- room. Participants were seated approximately 44 cm from als in latency models (15.6 %). After all exclusions, the monitor. Eye movements were recorded using an SR 13,107 saccades remained for analysis of saccade laten- Research Ltd. EyeLink II system (Mississauga, Ontario, cies and 15,801 saccades remained for analysis of sac- Canada), which has high spatial resolution and a sampling cade errors. Data were analyzed via general (latency) and rate of 500 Hz. Thresholds for detecting the onset of sac- generalized (errors) linear mixed models with subjects cadic movements were accelerations of 8000°/s2, veloci- and trials specified as crossed random effects (Baayen ties of 30°/s, and distances of .5° of visual angle. Move- ment offset was detected when velocity fell below 30°/s and remained at that level for 10 consecutive samples. Each participant underwent a nine-point calibration pro- 1 cedure followed by a nine-point calibration accuracy test. Emotional face stimuli were selected from the NimStim set of facial expressions (Tottenham et al. 2009). Model IDs were the fol- Calibration was repeated if any point was in error by more lowing: happy (01F_HA_O), angry (01F_AN_O), neutral (01F_ than 1° or if the average error for all points was greater NE_C).

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Fig. 2 Mean probability of .40 Angry Happy Neutral .40 Angry Happy Neutral an error, p(error), in each gap (overlap, gap), emotion (angry, .30 .30 happy, neutral), and genotype (C/C, T/_) condition, plotted .20 .20 (error) separately for antisaccades (left p (error) .10 p .10 panel) and prosaccades (right panel). Error bars represent 1 .00 .00 standard error ± C/C T/_ C/C T/_ C/C T/_ C/C T/_ Overlap Gap Overlap Gap

Fig. 3 Mean saccade latency in 425 Angry Happy Neutral 425 Angry Happy Neutral each gap (overlap, gap), emo-

400 400 tion (angry, happy, neutral), and 375 375 genotype (C/C, T/_) condition, plotted separately for antisac- 350 350 cades (left panel) and prosac- 325 325 Latency (ms) cades (right panel). Error bars 300 Latency (ms) 300 represent 1 standard error 275 275 ± C/CT/_ C/CT/_ C/CT/_ C/CT/_

Overlap Gap OverlapGap et al. 2008; Hoffman 2014) and by-subject random slopes As expected, there was a significant main effect of saccade, for within-unit manipulations (Barr et al. 2013).2 F(1, 110) 124.96, p < .001, such that the probability of = an error was greater in antisaccade (M .20, SE .013) = = versus prosaccade (M .07, SE .006) trials. There was = = Results also a trend toward a greater probability of error in overlap (M .13, SE .009) versus gap (M .11, SE .008) trials, = = = = Errors F(1, 104) 3.46, p .067. No other effects were significant. = = Figure 2 shows the mean probability of an error in each Latency gap, genotype, and emotion condition, plotted separately for antisaccades (left panel) and prosaccades (right panel). Figure 3 shows mean saccade latency in each gap, geno- type, and emotion condition, separately for antisac- cades (left panel) and prosaccades (right panel). As 2 Latency models were estimated within SAS PROC MIXED using expected, there was a significant main effect of saccade, restricted maximum likelihood estimation and Satterthwaite denomi- F(1, 109) 191.06, p < .001, such that saccade latency nator degrees of freedom. The latency model included random inter- = was longer on antisaccade (M 386, SE 4.7) versus cepts for mean differences between subjects, 2ΔLL(1) 798.0, = = p < .001, and between trials, 2ΔLL(1) 30.1,− p < .001,= as well prosaccade trials (M 308, SE 4.6). There was also a − = = = as random slopes for mean differences across subjects in the effects significant main effect of gap, F(1, 111) 4.95, p .03, saccade, 2ΔLL(2) 577.7, p < .001, gap, 2ΔLL(3) 130.2, = = − = − = such that saccade latency was shorter on gap (M 343, p < .001, and their interaction, 2ΔLL(5) 126.3, p < .001. Given = − = SE 4.0) versus overlap trials (M 351, SE 4.1). The that accuracy is a dichotomous outcome (correct or incorrect sac- = = = cade), for analysis of errors, a generalized linear function modeling gap effect (overlap minus gap) was significant in prosac- the logit of the probability of an errant saccade was selected. Param- cade trials (M 16, SE 3.9, t 4.16, p < .001) and was eter estimates, therefore, are on a logit scale, which is unbounded = = = significantly larger than the gap effect in antisaccade trials and symmetric around zero. A logit of zero means that a saccade was (M .49, SE 4.1), evident by a significant saccade by equally likely to be incorrect as correct—i.e., a logit of zero is equiv- = = alent to a probability p of .50, where p exp(logit)/(1 exp(logit)). gap interaction, F(1, 107) 7.75, p < .01. The gap effect = + = To facilitate interpretation, we transformed the mean logit of an error in antisaccade trials was not significant (t .28, p .78). in each condition back onto the probability scale for plotting pur- = = Regarding effects of genotype, there were two main poses (Fig. 2) using the equation above. Error models were estimated within SAS PROC GLIMMIX using pseudo-maximum likelihood findings. The first was a significant saccade by genotype estimation and Satterthwaite denominator degrees of freedom. The interaction, F(1, 107) 5.37, p .02, indicating that the = = model included random intercepts for mean differences between sub- genotype effect differed between pro- and antisaccades jects, 2ΔLL(1) 2133.9, p < .001, and trials, 2ΔLL(1) 84.7, (Fig. 4). Whereas antisaccade latencies were significantly p < .001,− as well as= random slopes for mean differences− between= sub- longer in those with C/C versus T/_ genotypes (t 2.86, jects in the effects saccade, 2ΔLL(2) 824.1, p < .001, and gap, = − 2ΔLL(3) 135.4, p < .001.− = p < .01), prosaccade latencies did not differ between − = 1 3 2658 Exp Brain Res (2016) 234:2653–2665

425 prosaccades. The gap by emotion by genotype interaction 400 C/C T/_ was significant for antisaccades, F(2, 172) 6.01, p < .01, = 375 but not prosaccades, F < 1. As can be seen in Fig. 6, the gen- 350 otype difference in the gap effect for angry faces was larger 325 for antisaccades than for prosaccades (M 45, SE 16.9, Latency (ms) = − = 300 t 2.69, p < .01). The genotype difference in the gap 275 = − Antisaccade Prosaccade effect for happy faces was also larger for antisaccades than for prosaccades, though the difference was not significant (M 20, SE 16.2, t 1.26, p .21). In contrast, the Fig. 4 Mean saccade latency in antisaccade and prosaccade trials for = − = = − = each genotype (C/C and T/_). Mean values are displayed above each genotype difference in the gap effect for neutral faces did not bar. Error bars represent 1 standard error differ at all between antisaccades and prosaccades (M .97, ± = SE 15.0, t .06, p .95). = = = To summarize, relative to those with a T allele, C allele 40 C/C T/_ homozygotes exhibited intact reflexive control (no effect 20 of genotype on prosaccade latencies) but deficient inhibi- tory control. This inhibitory deficit in C allele homozygotes

fect (ms) 0 was evident by a) longer antisaccade latencies relative to T -20 allele carriers, reflecting generally greater difficulty inhibit- Gap Ef ing a reflexive prosaccade response and executing an effort- -40 Angry Happy Neutral ful antisaccade, and b) a larger gap effect in antisaccade tri- als with an angry distractor relative to T allele carriers (i.e., Fig. 5 Mean gap effect (latency in overlap trials minus latency in gap antisaccade performance was slowed for those with the C/C trials) for each emotion (angry, happy, neutral) and genotype (C/C, T/_). Error bars represent 1 standard error genotype when the angry face remained on the screen to a ± greater extent than for those carrying a T allele), suggesting that the general inhibitory deficit was exacerbated in the genotypes (t .09, p .92). This pattern supports the presence of threat-related content. = − = hypothesized inhibitory deficit in C allele homozygotes. A number of studies have shown that the disruptive Moreover, as prosaccade latencies did not differ between effect of emotional stimuli can be attenuated by top-down genotypes, this indicates that C allele homozygotes have an processes (Cohen et al. 2011; Kalanthroff et al. 2013; Pes- intact reflexive saccade system. soa et al. 2012; Sagaspe et al. 2011; Verbruggen and De The second was a significant gap by emotion by geno- Houwer 2007; see also, Cohen and Henik 2012), leading type interaction, F(2, 140) 4.89, p .01. As can be seen in to the suggestion that activation of the executive network = = Fig. 5, the gap effect for angry faces was significantly larger attenuates the emotional system. The idea in these studies in those with C/C versus T/_ genotypes (M 17.1, SE 8.7, is that strong trace representations of emotional stimuli dis- = = t 2.03, p .048), suggesting that the inhibitory deficit in rupt/compete with top-down attention mechanisms devoted = = C allele homozygotes was exacerbated in the presence of to goal-directed behavior. Thus, the present genotype dif- threat. The gap effect did not differ significantly between ference in the effect of emotion on the gap effect in antisac- genotypes for happy (M 2.1, SE 8.54, t .24, p .81) cade trials may not be driven solely by threat processing = = = = or neutral faces (M 11.0, SE 9.3, t 1.19, p .24). (such as enhanced capture by threat and/or reduced ability = − = = − = This pattern was qualified by a significant saccade by gap to disengage from threat in C/C versus T/_ genotypes) but by emotion by genotype interaction, F(2, 210) 3.02, also by reciprocal interactions between activation of top- = p .048, indicating that genotype differences in the effect of down inhibitory control and emotion processing. In par- = emotion on the gap effect differed between antisaccades and ticular, it is possible that executive influence on emotional

Fig. 6 Mean gap effect (latency 40 C/C T/_ 40 C/C T/_ in overlap trials minus latency in gap trials) for each emotion 20 20 (angry, happy, neutral) and gen- otype (C/C, T/_) in prosaccade 0 0 (left panel) and antisaccade fect (ms) fect (ms) (right panel) trials. Error bars -20 -20 represent 1 standard error Gap Ef Gap Ef ± -40 -40 Angry HappyNeutral AngryHappyNeutral

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435 Angry Neutral 40 N-1 Ant N-1 Pro

420 405 20 390 375 0 Latency (ms) 360 -20 345 N-1 Ant N-1 ProN-1 AntN-1 Pro Angry - Neutral (ms) -40 C/CT/_ C/C T/_

Fig. 7 The left panel shows mean antisaccade latency in trial N as (left panel). The right panel shows the mean negativity effect (angry a function of trial N-1 saccade (N-1 antisaccade, N-1 prosaccade) minus neutral) by genotype for trial N-1 anti- and prosaccades. Error for each genotype (C/C, T/_) in angry and neutral distractor trials bars represent 1 standard error ±

435 Happy Neutral

40 N-1 Ant N-1 Pro 420 405 20 390 375 0 Latency (ms) 360 -20 345 N-1 Ant N-1 Pro N-1 Ant N-1 Pro Happy - Neutral (ms) -40 C/C T/_ C/CT/_

Fig. 8 The left panel shows mean antisaccade latency in trial N as (left panel). The right panel shows the mean positivity effect (happy a function of trial N-1 saccade (N-1 antisaccade, N-1 prosaccade) minus neutral) by genotype for trial N-1 anti- and prosaccades. Error for each genotype (C/C, T/_) in happy and neutral distractor trials bars represent 1 standard error ± processing exists that results from a top-down regulatory distractors (left panel); also shown is the negativity effect mechanism which reduces emotional influence when the (angry minus neutral) by genotype for trial N-1 anti- and task requires conflict resolution processes. We examine this prosaccades (right panel). Figure 8 shows the same, but possibility next. for happy and neutral distractors. Conflict adaptation is reflected by a reduced (i.e., less positive) effect of emotion Sequential analysis in trial N when trial N-1 was an antisaccade (conflict) trial. In those with the C/C genotype, the negative valence effect The sequential analysis uses only part of the data—trials (angry minus neutral) on antisaccade latencies appears to that fit to a particular sequence (antisaccade trials in the be reduced (less positive) when trial N-1 was an antisac- overlap condition). If inhibitory control attenuates activa- cade versus prosaccade, suggesting that activation of the tion in amygdala, then we would expect to find enhanced executive network attenuated the emotional system. In inhibitory control on trials that follow antisaccade trials, those with T/_ genotypes, the negative valence effect on reflecting the fact that sequential activation of top-down antisaccade latencies also appears to be reduced (less posi- inhibitory control mechanisms attenuates amygdala activ- tive) when trial N-1 was an antisaccade versus prosaccade. ity, resulting is less competition and, consequently, faster Note that for those with the C/C genotype, antisaccades antisaccades. Accordingly, this account predicts that emo- still appear slower than prosaccades. Also, trial N antisac- tional influence in a given trial (trial N) should be modu- cades still appear slower for angry versus neutral faces— lated by activation of the conflict resolution process in the effect is simply attenuated when trial N-1 was also an the previous trial (trial N-1). Specifically, the difference antisaccade. This means that the sequential effect did not between trials with angry and neutral faces in trial N should improve executive performance but rather only attenuated be decreased after an antisaccade in trial N-1 compared the deleterious effect of emotional processing on executive with a prosaccade in trial N-1. performance. Figure 7 shows mean antisaccade latency in trial N as a There was a significant main effect of trial N-1 sac- function of trial N-1 saccade (N-1 antisaccade, N-1 prosac- cade, F(1, 90) 5.22, p .03, such that antisac- = = cade) for each genotype in trials with angry or neutral cade latency on trial N was faster when trial N-1 was

1 3 2660 Exp Brain Res (2016) 234:2653–2665 a prosaccade (M 379, SE 5.8) than an antisaccade Discussion = = (M 390, SE 5.9). There was also a significant main = = effect of genotype, F(1, 101) 10.25, p .01, such The present study investigated whether emotional influence = = that antisaccade latency on trial N was slower in C/C on inhibitory control is modulated by the rs6313 polymor- (M 402, SE 8.6) versus T/_ (M 367, SE 6.5) phism of the 5-HT receptor gene. Inhibitory control was = = = = 2A individuals. The emotion by genotype interaction was measured with the antisaccade task. Participants were cued also significant, F(2, 75) 3.7, p .03. For the C/C to make a saccade either toward (prosaccade) or away from = = genotype, the effect of emotion was marginally signifi- (antisaccade) a peripheral onset stimulus. As expected in cant, F(2, 73) 2.95, p .052. The mean latency of this task, antisaccade latencies were longer than prosaccade = = trial N antisaccades was significantly slower for angry latencies, reflecting the time needed to inhibit or cancel the (M 410, SE 8.4) than neutral (M 397, SE 9.3) reflexive prosaccade response triggered by the peripheral = = = = distractors, t(170) 1.99, p .05. The mean latency onset and to execute an effortful (anti)saccade in the oppos- = = of trial N antisaccades was also slower for angry than ing direction (i.e., inhibitory control). Importantly, we happy (M 398, SE 8.7) distractors, t(173) 1.87, found that rs6313 genotype modulated this effect (Fig. 3), = = = − p .069, though not significant. The mean latency of consistent with the hypothesis that this polymorphism is = trial N antisaccades did not differ significantly between linked to individual differences in inhibitory control. Spe- neutral and happy distractors, t(165) .15, p .88. For T cifically, antisaccade latencies were significantly longer in = = allele carriers, the effect of emotion was significant, F(2, C allele homozygotes than in T allele carriers. This find- 76) 2.18, p .04. There was a trend toward faster trial ing is congruent with previous findings obtained using = = N antisaccades with angry (M 362, SE 7.1) versus other executive tasks (e.g., Becker et al. 2004; Bjork et al. = = neutral (M 373, SE 7.8) distractors, t(71) 1.64, 2002; Üҫok et al. 2007; Vyas et al. 2012) and suggests that = = = − p .09. The mean latency of trial N antisaccades was inhibition of a prosaccade response was impaired or more = nonsignificantly faster for angry than happy (M 366, effortful in C allele homozygotes relative to T allele car- = SE 7.3) distractors, t(68) .40, p .69. There was riers. At the same time, prosaccade latencies were not sig- = = = a trend toward faster trial N antisaccades with happy nificantly affected by rs6313 genotype (Fig. 2). Lack of versus neutral distractors, t(67) 1.71, p .08. The emotion and genotype effects on prosaccades indicate that = − = difference between angry and neutral distractors was the genotype difference in antisaccade latency was not due significantly different between those with the C/C geno- to individual differences in overall speed of response but type (M 12, SE 9.3) and those with T/_ genotypes rather to individual differences in inhibitory control. This = = (M 11.1, SE 7.5), t(74) 2.43, p .02. The dif- finding reinforces the idea that these two factors (genotype = − = = = ference between happy and neutral distractors did not and emotion) impact inhibitory control given that such con- differ significantly between those with the C/C geno- trol is not required to make a prosaccade. Thus, whereas type (M 1.3, SE 9.2) and those with T/_ genotypes those with the C/C genotype have relatively weaker effort- = = (M 8.2, SE 7.4), t(81) .64, p .52. The dif- ful behavioral control than those with a T allele, reflexive = − = = = ference between angry and happy distractors was nearly control appears spared. To our knowledge, this is the first significantly different between those with the C/C geno- investigation of antisaccade performance with the rs6313 type (M 11.7, SE 9.4) and those with T/_ geno- polymorphism. = − = types (M 2.9, SE 7.4), t(80) 1.95, p .051. Emotional influence on inhibitory control was examined = = = = In sum, sequential analysis indicated that recruitment by presenting a task-irrelevant emotional stimulus (happy, of executive processes attenuated emotional influence angry, or neutral facial expression) at central fixation and such that emotional influence in a given trial was dimin- varying whether the peripheral onset was presented, while ished following a conflict (antisaccade) response in the the emotional stimulus was present (overlap trials) or just previous trial. Moreover, this conflict adaptation effect was after the emotional stimulus had been removed (gap tri- smaller in the C/C versus T/_ individuals, suggesting that als). Saccade execution on overlap trials, therefore, stood to top-down regulation of emotional processing was more benefit from suppression of emotional distractors, at least difficult for C allele homozygotes. In any case, this top- to the degree that saccade execution is effortful (i.e., anti- down regulation mechanism did not eliminate the impact saccade trials). This was not the case, however, on gap tri- of angry faces, suggesting that two separable control sys- als, given that the emotional stimulus is removed prior to tems may regulate responses in the present emotional anti- target presentation and therefore does not need to be inhib- saccade task, one reactive (threat) and one self-regulative ited. Thus, the difference between overlap and gap trials (effortful control). measures the additional time needed to execute a saccade

1 3 Exp Brain Res (2016) 234:2653–2665 2661 due to emotional interference. We found that latencies in emotional stimuli impair inhibitory control (Pessoa 2009). antisaccade trials with angry distractors were prolonged on In this view, low-intensity emotional stimuli improve inhib- overlap versus gap trials to a greater extent for individuals itory control by recruiting but not completely consuming with the C/C genotype relative to individuals with T/_ gen- processing resources (or at least not consuming them to the otypes (Fig. 6). This finding is consistent with the notion same degree as high-intensity emotional stimuli), leaving that threat-related stimuli capture attention and receive available more resources than would be for neutral stim- prioritized processing, which draws attention away from uli. These leftovers are then available for other processes, executive resources needed for inhibitory control, thereby such as inhibitory control. As a result, effortful control is resulting in impaired inhibitory control. Thus, the genotype strengthened, leading to faster antisaccades in trials with difference in the gap effect in antisaccade trials with angry low-intensity emotional stimuli (overlap trials with happy distractors reinforces the presence of an inhibitory deficit distractors) than without (gap trials). If inhibitory control in the C allele homozygotes and suggests further that this is deficient to begin with, however, which appears to be deficit was exacerbated in the presence of threat-related the case with C allele homozygotes, then greater resource content. availability may not make much difference. Thus, C allele Relative to neutral faces, greater interference was homozygotes did not show a gap effect in trials with happy observed for angry versus happy distractors, which cor- distractors, whereas T allele carriers showed a reversed gap roborates previous studies showing that positive stimuli effect. On the flipside, if an individual is sensitive to threat, elicit less attention than negative stimuli do, thereby pro- which also appears to be the case with C allele homozy- ducing less interference (Baumeister et al. 2001). A moti- gotes, then even mild threat might consume resources vational aspect might also account for this finding. The needed for inhibitory control. Thus, C allele homozygotes prioritization of the processing of negative stimuli may showed a gap effect in trials with angry distractors, whereas be driven by the protection of the self, as negative stimuli T allele carriers did not. quickly signal the potential for danger in the environment In addition, we found that activation of executive pro- and prepare the organism to face such danger by inter- cesses in trial N-1 attenuated emotional influence in trial N rupting or slowing ongoing behavior and mental processes such that emotional influence in trial N was diminished fol- (Öhman and Mineka 2001). Thus, on overlap trials, angry lowing a conflict (antisaccade) response in trial N-1 (Figs. 7 faces may have “froze” the reflexive prosaccade response and 8). A number of studies have shown that the disruptive which, in turn, speeded antisaccade responses. In contrast, effect of emotional stimuli can be attenuated by top-down on gap trials, the angry face was not present to “freeze” processes (Cohen et al. 2011; Kalanthroff et al. 2013; Pes- the prosaccade response and, consequently, antisaccade soa et al. 2012; Sagaspe et al. 2011; Verbruggen and De responses were not speeded and thus were slower relative Houwer 2007), leading to the suggestion that activation of to overlap trials. Likewise, it has been suggested that the the executive network attenuates the emotional system. In presence of positive stimuli serves as signals to safety and support, neuroimaging studies have found decreased acti- opportunity and thus facilitates or energizes ongoing motor vation in brain regions considered to process emotional behavior (Depue and Lenzenweger 2001; Gray 1987; Mills stimuli. Specifically, executive processes, namely selective et al. 2014). Thus, motor inhibition may have been facili- attention, have been shown to attenuate activation in brain tated when acting within the context of a negative stimulus regions associated with emotional processing, namely the (overlap trials), whereas motor execution may have been amygdala (Blair et al. 2007; Etkin et al. 2006; Hart et al. facilitated when acting within the context of a positive 2010; Hariri et al. 2000; Liberzon et al. 2000; Mitchell stimulus (overlap trials). et al. 2008; Vuilleumier 2005). During conflict the amyg- Interestingly, although it might be anticipated with a dala is modulated by the prefrontal cortex (Ongur and 500-ms temporal asynchrony separating offset of fixa- Price 2000), anterior cingulate cortex (Bishop et al. 2004), tion stimulus and onset of peripheral onset that a gap orbitofrontal cortex (Blair et al. 2007), and frontoparietal effect might not be observed, the gap effect in antisac- regions (Mitchell et al. 2008). These findings suggest that cade trials for T allele carriers was in the opposite direc- attentional processes can modulate the activation of brain tion of what would be expected (Fig. 6). Specifically, anti- regions that are involved in emotional processing via top- saccades were faster on overlap than gap trials; however, down regulatory brain circuits. If inhibitory control simi- this was found only with emotional distractors. When the larly attenuates activation in amygdala, then we would fixation stimulus was a neutral face, T allele carriers did expect to find enhanced inhibitory control on trials that fol- not show a gap effect. This could be indicative of emo- low the requirement to make an antisaccade, reflecting the tional stimuli improving inhibitory control for these indi- fact that sequential activation of top-down inhibitory con- viduals. It has been suggested that low-intensity emotional trol mechanisms attenuates amygdala activity, resulting is stimuli improve inhibitory control, whereas high-intensity less competition and, consequently, faster antisaccades.

1 3 2662 Exp Brain Res (2016) 234:2653–2665

Accordingly, this account predicts that emotional influ- pathways in mediating these effects is not fully under- ence in a given trial (trial N) should be modulated by acti- stood (Holmes 2008). A strongly reactive amygdala might vation of the conflict resolution process in the previous provide the signal of threat/distress that could easily allow trial (trial N-1). Specifically, the difference between trials speeded responses to events that stimulate overlapping with angry and neutral faces in trial N should be decreased neural activation. In the case of overlap trials, this may after an antisaccade in trial N-1 compared with a prosac- result in rapid engagement of attentional resources to the cade in trial N-1. The present sequential analysis supported angry face. The engagement of attention on the angry face this prediction. In particular, the recruitment of executive should in turn leave fewer resources available to execute processes attenuated emotional influence such that emo- an effortful (anti)saccade and result in slowed saccade tional influence in a given trial was diminished follow- latencies relative to trials where angry face is removed ing a conflict (antisaccade) response in the previous trial. (gap trials). Moreover, this conflict adaptation effect was reduced in the Attentional resource theories emphasize the importance C/C versus T/_ genotype, suggesting that top-down regula- of available resources for solving a cognitive conflict. In tion of emotional processing was more difficult in C allele contrast, attentional breadth theories emphasize the impact homozygotes. Thus, consistent with previous work (Cohen of negative information on attentional allocation. These et al. 2011), we found that executive influence on emotional theories claim that negative stimuli narrow attention and processing resulting from top-down regulation reduced hence reduce interference of distracting or irrelevant infor- emotional influence when saccade execution required con- mation (Derryberry and Tucker 1994; van Steenbergen flict resolution processes. Importantly, however, this top- et al. 2011). In the present study, then, negative stimuli down regulation mechanism did not eliminate the impact of may narrow attentional focus and, therefore, make periph- angry faces, which implies that two separable control sys- eral targets more difficult to detect since they would fall tems may regulate responses in the present emotional anti- outside the focus of attention. In contrast, positive stimuli saccade task, one reactive (threat) and one self-regulative may broaden attentional focus and, therefore, make periph- (effortful control). eral targets easier to detect since they would fall within the Previous work implicates a corticolimbic circuit com- focus of attention. posed of structural and functional connections between In sum, the present results demonstrate that relative to the amygdala and regions of the medial prefrontal cor- T allele carriers, C allele homozygotes exhibited deficient tex, including the anterior cingulate cortex, in generating inhibitory control, evident by longer antisaccade laten- and regulating behavioral and physiological responses to cies (reflecting a general inhibitory control deficit) and by threat-related stimuli (Hariri et al. 2006; Pezawas et al. a larger antisaccade gap effect in the presence of threat- 2005; Phelps et al. 2004; Quirk et al. 2003). Regions of related content (reflecting a specific inhibitory control defi- the medial prefrontal cortex are involved in the integration cit driven by threat). This leads to the notion that a specific and subsequent regulation of stimulus-driven amygdala 5-HT2A receptor signaling pathway is involved in mediat- response, partly via glutamatergic projections to popula- ing these effects. In addition, we observed a genotype dif- tions of GABAergic neurons within the amygdala (Likh- ference in the effect of emotion on conflict adaptation, sug- tik et al. 2005; Quirk et al. 2003). Importantly, 5-HT2A gesting that a separate 5-HT2A receptor signaling pathway receptors are instrumental in determining 5-HT modula- is involved in top-down regulation of emotional processing. tion of this corticolimbic circuit (Fisher et al. 2011). The Thus, the genotype difference in the effect of emotion on anatomical localization of this receptor within prefrontal the gap effect in antisaccade trials was not driven solely by cortex positions it to mediate effectively the effects of threat processing (such as enhanced capture by threat and/ 5-HT signaling on corticolimbic circuit dynamics. Vari- or reduced ability to disengage from threat in C/C versus ability in the structure and function of this corticolimbic T/_ genotypes) but also by reciprocal interactions between circuitry have been associated with individual differences activation of top-down inhibitory control and emotion pro- in personality measures, reflecting sensitivity to environ- cessing. Accordingly, two separable control systems, one mental threat and related risk of psychopathology (Buck- reactive (threat) and one self-regulative (effortful control), holtz et al. 2008; Etkin et al. 2004; Pezawas et al. 2005; are implicated in performance in the present emotional Shin et al. 2005). Neuroimaging studies in humans have antisaccade task. mapped individual differences in amygdala reactivity to The present results should be considered in light of two biologically salient environmental stimuli (e.g., facial limitations. First, effects of emotion were investigated with expressions of threat) onto variability in 5-HT signal- only three different facial expressions. Faces displaying ing within this corticolimbic circuitry (Bigos et al. 2008; other emotions as well as other types of emotional stimuli Fisher et al. 2009; Hariri et al. 2002; Pezawas et al. 2005). should be investigated in future research. Second, the pre- However, the role of specific 5-HT receptor signaling sent design did not contain a no-face condition, meaning

1 3 Exp Brain Res (2016) 234:2653–2665 2663 our baseline comparison for emotional faces was a neu- Baumeister RF, Bratslavsky E, Finkenauer C, Vohs KD (2001) Bad is tral face. As it is well established that attention is biased stronger than good. Rev Gen Psychol 5:323–370 Becker KG, Barnes KC, Bright TJ, Wang SA (2004) The genetic toward faces per se regardless of their emotional content, it association database. Nat Genet 36:431–432 is unclear whether the present results reflect a pure effect of Bigos KL, Pollock BG, Aizenstein HJ, Fisher PM, Bies RR, Hariri emotional content or an interaction of emotional and bio- AR (2008) Acute 5-HT reuptake blockade potentiates human logical significance. amygdala reactivity. Neuropsychopharmacology 33:3221–3225 Bishop S, Duncan J, Lawrence A (2004) Prefrontal cortical function In conclusion, the present study demonstrated that and anxiety: controlling attention to threat-related stimuli. Nat rs6313 genotype is associated with individual differences Neurosci 7:184–188 in inhibitory control more generally, as well as with indi- Bjork JM, Moeller FG, Dougherty DM, Swann AC, Machado MA, vidual differences in the effect of emotion on inhibitory Hanis CL (2002) Serotonin 2a receptor T102C polymorphism and impaired impulse control. Am J Med Genet B 114:336–339 control. These findings are consistent with evidence that Blair KS, Smith BW, Mitchell DGV, Morton J, Vythilingam M, Pes- variation in this gene may play a role in risk of schizo- soa L, Blair RJ (2007) Modulation of emotion by cognition and phrenia, a disorder for which antisaccade performance and cognition by emotion. NeuroImage 35:430–440 emotion regulation are considered to be endophenotypes Blier P, de Montigny D (1999) Serotonin and drug-induced therapeu- tic responses in major depression, obsessive–compulsive and (Greenwood et al. 2011). In contrast to the relatively con- panic disorders. Neuropsychopharmacology 21:91S–98S sistent findings in the literature, the extent Buckholtz JW, Callicott JH, Kolachana B, Hariri AR, Goldberg TE, and nature of antisaccade deficits in other psychiatric popu- Genderson M et al (2008) Genetic variation in MAOA modulates lations is less clear. Most disorders associated with 5-HT ventromedial prefrontal circuitry mediating individual differ- 2A ences in human personality. Mol Psychiatry 13:313–324 receptor functioning are complex genetic disorders, yet Coccaro EF (1989) Central serotonin and impulsive aggression. Br J known genetic variants account for only a small portion Psychiatry 8:52–62 of the estimated disease risk, leaving substantial “missing Cohen N, Henik A (2012) Do irrelevant emotional stimuli impair or heritability” (Manolio et al. 2009). A greater understand- improve executive control? Front Integr Neurosci 6:461–464. doi:10.3389/fnint.2012.00033 ing of genetic variants with functional consequences in key Cohen N, Henik A, Mor N (2011) Can emotion modulate attention? risk genes marks a crucial step forward in characterizing Evidence for reciprocal links in the attentional network test. Exp this missing heritability. Finally, as the results of the cur- Psychol 58:171–179 rent study and others implicate variation at rs6313 on the Cools R, Roberts AC, Robbins TW (2008) Serotoninergic regulation of emotional and behavioural control processes. Trends Cogn Sci impact of emotion on inhibitory control, and to some extent 12:31–40 on the impact of top-down regulation of emotional process- Crosbie J, Arnold P, Paterson A, Swanson J, Dupuis A, Li X et al ing, future work using neuroimaging may help to further (2013) Response inhibition and ADHD traits: correlates and characterize the biological circuits involved. Though provi- heritability in a community sample. J Abnorm Child Psychol 41:497–507 sional, the present findings suggest that at least two poten- Dennis TA, Chen C-C, McCandliss BD (2008) Threat-related atten- tially separate pathways may be involved, one reflexive and tional biases: an analysis of three attention systems. Depress one effortful. Anxiety 25:1–10 Depue RA, Lenzenweger MF (2001) A neurobehavioral dimensional Acknowledgments This research was supported by a University of model. In: Livesley WJ (ed) Handbook of personality disorders: Nebraska-Lincoln Substance Abuse and Violence Initiative (SAVI) theory, research, and treatment. Guilford Press, New York, pp seed grant to S.S. and M.D. We thank Grace Sullivan for her help- 136–176 ful comments throughout the development of the manuscript. Corre- Derryberry D, Tucker DM (1994) Motivating the focus of attention. spondence may be sent to Mark Mills, the University of Nebraska- In: Niedenthal PM, Kitayama S (eds) The heart’s eye: emotional Lincoln, 238 Burnett Hall, Lincoln, NE, USA 68588 (mark.mills2@ influences in perception and attention. Academic Press, San huskers.unl.edu). Diego, pp 167–196 Dwivedi Y, Pandey GN (1998) Quantitation of 5-HT2A receptor mRNA in human postmortem brain using competitive RT-PCR. NeuroReport 9:3761–3765 References Etkin A, Klemenhagen KC, Dudman JT, Rogan MT, Hen R, Kandel ER, Hirsch J (2004) Individual differences in trait anxiety predict Anokhin AP, Golosheykin S, Heath AC (2010) Heritability of indi- the response of the basolateral amygdala to unconsciously pro- vidual differences in cortical processing of facial affect. Behav cessed fearful faces. Neuron 44:1043–1055 Genet 40:178–185 Etkin A, Egner T, Peraza DM, Kandel ER, Hirsch J (2006) Resolving Aznar S, Klein AB (2013) Regulating prefrontal cortex activation: an emotional conflict: a role for the rostral anterior cingulate cortex emerging role for the 5-HT2A serotonin receptor in the modula- in modulating activity in the amygdala. Neuron 51:871–882 tion of emotional-based actions? Mol Neurobiol 48:841–853 Fischer B, Weber H (1993) Express saccades and visual attention. Baayen RH, Davidson DJ, Bates DM (2008) Mixed-effects modeling Behav Brain Sci 16:553–567 with crossed random effects for subjects and items. J Mem Lang Fisher PM, Meltzer CC, Price JC, Coleman RL, Ziolko SK, Moses- 59:390–412 Kolko EL, Berga SL, Hariri AR (2009) Medial prefrontal cor- Barr DJ, Levy R, Scheepers C, Tily HJ (2013) Random effects struc- tex 5-HT2A density is correlated with amygdala reactivity, ture for confirmatory hypothesis testing: keep it maximal. J Mem response habituation, and functional coupling. Cereb Cortex Lang 68:255–278 19:2499–2507

1 3 2664 Exp Brain Res (2016) 234:2653–2665

Fisher PM, Price JC, Meltzer CC, Moses-Kolko EL, Becker C, Berga distracters: an antagonistic relationship between the amygdala and SL, Hariri AR (2011) Medial prefrontal cortex serotonin 1A and frontoparietal cortices. NeuroImage 40:859–868 2A receptor binding interacts to predict threat-related amygdala Murphy FC, Smith KA, Cowen PJ, Robbins TW, Sahakian BJ (2002) reactivity. Biol Mood Anxiety Disord 1:11 The effects of tryptophan depletion on cognitive and affec- Gong P, Li J, Wang J, Lei X, Chen D, Zhang K et al (2011) Varia- tive processing in healthy volunteers. Psychopharmacology tions in 5-HT2A influence spatial cognitive abilities and working 163:42–53 memory. Can J Neurol Sci 38:303–308 Öhman A, Mineka S (2001) Fears, phobias, and preparedness: toward Gray J (1987) The neuropsychology of emotion and personality. In: an evolved module of fear and fear learning. Psychol Rev Stahl SM, Iversen SD, Goodman EC (eds) Cognitive neurochem- 108:483–522 istry. Oxford University Press, Oxford, pp 171–190 Ongur D, Price JL (2000) The organization of networks within the Greenwood TA, Lazzeroni LC, Murray SS, Cadenhead KS, Calkins orbital and medial prefrontal cortex of rats, monkeys and ME, Dobie DJ et al (2011) Analysis of 94 candidate genes and humans. Cereb Cortex 10:206–219 12 endophenotypes for schizophrenia from the Consortium on Padmala S, Bauer A, Pessoa L (2011) Negative emotion impairs con- the of Schizophrenia. Am J Psychiatry 168:930–946 flict-driven executive control. Front Psychol 2:192 Hallett PE (1978) Primary and secondary saccades to goals defined by Passetti F, Dalley J, Robbins T (2003) Double dissociation of seroton- instructions. Vis Res 18:1279–1296 ergic and dopaminergic mechanisms on attentional performance Hansen CH, Hansen RD (1988) Finding the face in the crowd: an using a rodent five-choice reaction time task. Psychopharmacol- anger superiority effect. J Pers Soc Psychol 54:917–924 ogy 165:136–145 Hariri A, Bookheimer S, Mazziotta J (2000) Modulating emotional Pessoa L (2009) How do emotion and motivation direct executive responses: effects of a neocortical network on the limbic system. control? Trends Cogn Sci 13:160–166 NeuroReport 11:43–48 Pessoa L, Padmala S, Kenzer A, Bauer A (2012) Interactions between Hariri AR, Mattay VS, Tessitore A, Kolachana B, Fera F, Goldman D, cognition and emotion during response inhibition. Emotion Egan MF, Weinberger DR (2002) Serotonin transporter genetic 12:192–197 variation and the response of the human amygdala. Science Pezawas L, Meyer-Lindenberg A, Drabant EM, Verchinski BA, 297:400–403 Munoz KE, Kolachana BS et al (2005) 5-HTTLPR polymor- Hariri A, Drabant EM, Weinberger DR (2006) Imaging genetics: per- phism impacts human cingulate-amygdala interactions: a spectives from studies of genetically driven variation in seroto- genetic susceptibility mechanism for depression. Nat Neurosci nin function and corticolimbic affective processing. Biol Psy- 8:828–834 chiatry 59:888–897 Phelps EA, Delgado MR, Nearing KI, LeDoux JE (2004) Extinction Hart SJ, Green SR, Casp M, Belger A (2010) Emotional prim- learning in humans: role of the amygdala and vmPFC. Neuron ing effects during Stroop task performance. NeuroImage 43:897–905 49:2662–2670 Polesskaya OO, Sokolov BP (2002) Differential expression of the Hoffman L (2014) Longitudinal analysis: modeling within-person “C” and “T” alleles of the 5-HT2A receptor gene in the temporal fluctuation and change. Routledge Academic, New York cortex of normal individuals and schizophrenics. J Neurosci Res Holmes A (2008) Genetic variation in cortico-amygdala serotonin 67:812–822 function and risk for stress-related disease. Neurosci Biobehav Quirk GJ, Likhtik E, Pelletier JG, Pare D (2003) Stimulation of Rev 32:1293–1314 medial prefrontal cortex decreases the responsiveness of central Hurlemann R, Schlaepfer TE, Matusch A, Reich H, Shah NJ, Zilles amygdala output neurons. J Neurosci 23:8800–8807 K, Maier W, Bauer A (2009) Reduced 5-HT2A receptor signal- Sagaspe P, Schwartz S, Vuilleumier P (2011) Fear and stop: a role for ing following selective bilateral amygdala damage. Soc Cogn the amygdala in motor inhibition by emotional signals. Neuro- Affect Neurosci 4:79–84 Image 55:1825–1835 Kalanthroff E, Cohen N, Henik A (2013) Stop feeling: inhibition of Saslow MG (1967) Effects of components of displacement-step emotional interference following stop-signal trials. Front Hum upon latency for saccadic eye movements. J Opt Soc Am A Neurosci 7:341–347. doi:10.3389/fnhum.2013.00078 57:1024–1029 Kanske P (2012) On the influence of emotion on conflict processing. Shin LM, Wright CI, Cannistraro PA, Wedig MM, McMullin K, Mar- Front Integr Neurosci 6:457–460. doi:10.3389/fnint.2012.00042 tis B et al (2005) A functional magnetic resonance imaging study Lane H-Y, Liu Y-C, Huang C-L, Hsieh C-L, Chang Y-L, Chang L, of amygdala and medial prefrontal cortex responses to overtly Chang Y-C, Chang W-H (2008) Prefrontal executive function and presented fearful faces in posttraumatic stress disorder. Arch Gen D1, D3, 5-HT2A and 5-HT6 receptor gene variations in healthy Psychiatry 62:273–281 adults. J Psychiatry Neurosci 33:47–53 Smith RM, Papp AC, Webb A, Ruble CL, Munsie LM, Nisenbaum Liberzon I, Taylor S, Fig L, Decker L, Koeppe R, Minoshima S LK et al (2013) Multiple regulatory variants modulate expres- (2000) Limbic activation and psychophysiologic responses to sion of 5-Hydroxytryptamine 2A receptors in human cortex. Biol aversive visual stimuli: interaction with cognitive task. Neu- Psychiatry 73:546–554 ropsychopharmacology 23:508–516 Soubrié P (1986) Reconciling the role of central serotonin neurons in Likhtik E, Pelletier JG, Paz R, Pare D (2005) Prefrontal control of the human and animal behavior. Behav Brain Sci 9:319–335 amygdala. J Neurosci 23:7429–7437 Thakore JH, O’Keane V, Dinan TG (1996) d-Fenfluramine-induced Linnoila VM, Virkkunen M (1992) Aggression, suicidality, and sero- prolactin responses in mania: evidence for serotonergic subsen- tonin. J Clin Psychiatry 53:46–51 sitivity. Am J Psychiatry 153:1460–1463 Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter Tottenham N et al (2009) The NimStim set of facial expressions: DJ et al (2009) Finding the missing heritability of complex dis- judgments from untrained research participants. Psychiatry Res eases. Nat Rev 461:747–753 168:242–249 Mills M, Smith KB, Hibbing JR, Dodd MD (2014) The politics of the Üҫok A, Alpsan H, Ҫakir S, Saruhan-Direskeneli G (2007) Associa- face-in-the-crowd. J Exp Psychol Gen 143:1199–1213 tion of a serotonin receptor 2A gene polymorphism with cogni- Mitchell D, Luo Q, Mondillo K, Vythilingam M, Finger E, Blair R tive functions in patients with schizophrenia. Am J Med Genet B (2008) The interference of operant task performance by emotional 144:704–707

1 3 Exp Brain Res (2016) 234:2653–2665 2665

Van der Veen FM, Evers EAT, Deutz NEP, Schmitt JAJ (2007) Effects Vuilleumier P (2005) How beware: neural mechanisms of emo- of acute tryptophan depletion on mood and facial emotion per- tional attention. Trends Cogn Sci 9:585–594 ception related brain activation and performance in healthy Vyas NS, Lee Y, Ahn K, Ternouth A, Stahl DR, Al-Chalabi A, Pow- women with and without a family history or depression. Neu- ell JF, Puri BK (2012) Association of a serotonin receptor 2A ropsychopharmacology 32:216–224 gene polymorphism with visual sustained attention in early-onset van Steenbergen H, Band GPH, Hommel B (2011) Threat but schizophrenia patients and their non-psychotic siblings. Aging not arousal narrows attention: evidence from pupil dilation Dis 3:291–300 and saccade control. Front Psychol 2:239–243. doi:10.3389/ West GL, Al-Aidroos N, Susskind J, Pratt J (2011) Emotion and fpsyg.2011.00281 action: the effect of fear on saccadic performance. Exp Brain Res Verbruggen F, De Houwer J (2007) Do emotional stimuli interfere 209:153–158 with response inhibition? Evidence from the stop signal para- Wingen M, Kuypers KPC, Ramaekers JG (2007) The role of digm. Cogn Emot 21:391–403 5-HT1a and 5-HT2a receptors in attention and motor control: a von dem Hagen EAH, Passamonti L, Nutland S, Sambrook J, Calder mechanistic study in healthy volunteers. Psychopharmacology AJ (2011) The serotonin transporter gene polymorphism and the 190:391–400 effect of baseline on amygdala response to emotional faces. Neu- ropsychologia 49:674–680

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