Individuals who inherit the low expressing variant of the serotonin transporter-linked polymorphic region (5-HTTLPR) of the serotonin transporter gene (SLC6A4) and experience significant life stress appear to be at greater risk for depression than people who inherit two copies of the high expressing 5-HTTLPR allele (e.g., Caspi et al., 2003
; Kendler, Kuhn, Vittum, Prescott, & Riley, 2005
). These landmark studies have stimulated research aimed at understanding why
the low expressing 5-HTTLPR variant putatively increases sensitivity to life stress and, in turn, increases vulnerability to depression. One possibility is that the 5-HTTLPR polymorphism biases the processing of emotional information. Therefore, we sought to examine whether healthy adult carriers of the low expressing 5-HTTLPR allele display more pronounced attentional biases for emotional stimuli than individuals homozygous for the high expressing 5-HTTLPR allele.
The serotonin transporter (5-HTT) regulates the reuptake of serotonin to the presynaptic neuron for recycling or degradation after serotonin has been released. It thus plays a critical role in determining the duration and intensity of serotonin communication with post-synaptic receptors and targets, such as those in limbic regions involved in the regulation of emotional information (for a review, see Hariri & Holmes, 2006
). Importantly, the efficiency with which the 5-HTT returns serotonin to the presynaptic neuron appears to be influenced by the 5-HTTLPR polymorphism. A common deletion polymorphism in the promoter region of the 5-HTT gene results in 2 variants: a short (S) allele and a long (L) allele. The presence of one or two short alleles, rather than two copies of the long allele, is associated with reduced transcriptional efficiency that putatively results in significant decreases (approximately 50%) in serotonin reuptake (Heinz et al., 2000
; Lesch et al., 1996
). Short 5-HTTLPR allele carriers should thus have increased levels of extracellular serotonin and increased serotonin signaling compared to long allele homozygotes.
This difference in how serotonin is regulated appears to impact a cortical-limbic circuit that is critical for regulating emotional information. For instance, among healthy participants, Pezawas et al. (2005)
found that short 5-HTTLPR allele carriers had significant reduction in gray matter volume in the perigenual anterior cingulate (pACC) and the rostral anterior cingulated—regions of the prefrontal cortex previously implicated in affect regulation (Drevets, 2000
)—compared to long allele homozygotes. Further, using fMRI analyses to assess relative activation of the pACC and amygdala in response to negative stimuli (e.g., angry and scared facial expressions), short 5-HTTLPR allele carriers had less functional coupling between the pACC and the amygdala. The “uncoupling” of this emotion circuit may explain why short-allele carriers have greater amygdala responses to emotional stimuli (Bertolino et al., 2005
; Hariri et al., 2005
; Hariri et al., 2002
Other research has similarly found that reduced functional coupling between the prefrontal cortex and limbic system is associated with biased processing of emotional information at a neural level. Heinz et al. (2005)
reported that a region of the prefrontal cortex more dorsal and rostral to the pACC was over-activated in short 5-HTTLPR allele carriers than long 5-HTTLPR homozygotes when presented with emotional images. Activation of the ventromedial prefrontal cortex region was positively correlated with amygdala activation, suggesting a compensatory effort to regulate exaggerated amygdala responses of the short allele carriers. This heightened amygdala response in short 5-HTTLPR allele carriers likely applies to a variety of emotional stimuli, as the amygdala also responds to positive stimuli (Cunningham, Van Bavel, & Johnsen, 2008
), as well as novel, salient, and ambiguous stimuli (Whalen, 2007
Difficulty regulating emotional information at a neural level may have important implications for the cognitive processing of emotional information. The ability to allocate attention to emotional cues in the environment is a crucial element of adaptive self-regulation (Posner & Rothbart, 2000
). Although it is adaptive for salient stimuli to capture attention, successful behavioral regulation requires some flexibility and control over attention. This may include strategic filtering of certain stimuli, timely disengagement from stimuli, and being appropriately vigilant for meaningful emotional cues. In line with this conclusion, Hasler et al. (2004)
argued that biased processing of emotional stimuli is a highly plausible and important putative intermediate phenotype for MDD. Further, they specifically identified the 5-HTTLPR as a highly promising candidate gene that may be associated with biased processing of emotional information (see , pg. 1766).
Trial sequence for valid and invalid trials. Fixation cross and probe are not to scale.
Despite this promising neuroimaging research, few studies have examined associations between the 5-HTTLPR polymorphism and behavioral assessments of biased processing of emotional information. Roiser et al. (2005)
reported that among Ecstasy users, a drug that causes long term reductions in synaptic 5-HT release, short 5-HTTLPR allele carriers showed abnormal emotional processing (e.g., more likely to make errors of commission) than long 5-HTTLPR allele homozygotes on an affective Go/No-Go test. Similarly, Hayden et al. (2008)
reported that children who were homozygous for the short 5-HTTLPR allele showed greater self-referent encoding of negative stimuli than the other 5-HTTLPR allele groups. Consistent with these analyses, work by Fallgatter and colleagues using event-related potentials indicates that short 5-HTTLPR allele carriers experience greater brain electrical activity during evaluation of an erroneous behavioral response than age and gender-matched controls homozygous for the long 5-HTTLPR allele (Fallgatter et al., 2004
The current study builds upon this research and provides an additional test of whether the 5-HTTLPR polymorphism is associated with biased processing of emotional stimuli. In our previous work, using a standard dot-probe task, Beevers et al. (2007)
reported that short 5-HTTLPR allele carriers displayed biased attention for anxious-relevant words when paired with neutral words compared to long 5-HTTLPR allele homozygotes. Although those findings were intriguing, that study had a number of limitations. Participants were a heterogeneous mix of psychiatric inpatients experiecing a variety of emotional states and pharmacological treatments, which may have influenced the serotonin system and emotion processing. Further, there are concerns that the dot-probe task, especially when used with longer stimulus durations, may not directly assess attention engagement but might instead assess difficulty with the disengagement of attention. As a result, researchers have suggested using tasks that separately measure attention engagement and disengagement (e.g., Koster, De Raedt, Goeleven, Franck, & Crombez, 2005
; Posner & Petersen, 1990
We therefore used a spatial cueing task that allowed us to assess general attentional bias, attentional engagement, and difficulty with attentional disengagement from emotional stimuli (Koster et al., 2005
). For this version of the task, a cue is presented to the left or right side of visual field. Cues are faces expressing an emotion (e.g., happiness, sadness) or no emotion (e.g., neutral). After the offset of the cue, a target appears either in the same location of the cue (e.g., valid cue trial) or in the opposite side of visual field (e.g., invalid cue trial). The dependent measure is latency to identify the location of the cue. Typically, reaction times are shorter for valid cue trials than invalid cue trials, although this pattern can reverse when cues are presented for longer durations (i.e., inhibition of return effect). The difference in mean reaction time for invalid and valid trials is referred to as the cue validity effect. A positive cue validity effect is interpreted as maintained attention to the cue.
With the emotional modification of the spatial cuing task it is possible to determine whether the cue validity effect is influenced by cue valence (e.g., happy, sad, neutral facial expressions). Three different but related outcomes can be examined: (a) general measure of biased attention, (b) attentional engagment, and (c) difficulty with attentional disengagment. Each of these outcomes compares reaction time to identify targets following emotional cues relative to neutral cues. For instance, if the cue validity effect was stronger for emotional cues than neutral cues, we would observe a positive biased attention score for emotional stimuli. This would indicate attention was maintained by emotional cues to a greater extent than neutral cues (Mogg, Holmes, Garner, & Bradley, 2008
). Similarly, faster latencies following emotional valid cues than neutral valid cues suggests that emotional stimuli facilitated attentional engagement, whereas longer latencies following invalid emotional cues compared to invalid neutral cues suggests difficulty disengaging attention from emotional cues. Together, these outcomes provide a general assessment of maintained attention and the specific attentional processes related to maintained attention (Koster et al., 2005
Using the spatial cueing task, we conducted two studies designed to address the limitations of our previous study and provide a more precise test of the hypothesis that the 5-HTTLPR polymophism is associated with attentional biases for emotional stimuli. Specifically, in Study 1, we recruited a sample of healthy adults who did not meet criteria for a current psychiatric disorder or a past history of a mood disorder and who were not currently taking any psychiatric medications. These individuals were genotyped for the 5-HTTLPR polymorphism and then completed a spatial cueing task that used sad, happy, and neutral facial expressions as cues. For Study 2, we recruited a large sample of unmedicated, non-depressed undergraduate students. We administered the same spatial cueing task as in Study 1 but also included fear facial expressions as cues.
We expected to observe an interaction between cue validity, stimuli valence, and 5-HTTLPR allele group when predicting response time latencies on the spatial cueing task. We hypothesized that carriers of the low expressing 5-HTTLPR allele would display biased attention for emotional stimuli in general; however, given the lack of specificity with which we measured biased attention in our previous work, it was unclear whether we should expect enhanced attentional engagement or increased difficulty with attentional disengagement among the low expressing 5-HTTLPR allele carriers. Therefore, we did not make specific hypotheses regarding each component of biased attention.