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Biased attention for emotional stimuli has been associated with vulnerability to psychopathology. This study examines the neural substrates of biased attention. Twenty-three adult women completed high-resolution structural imaging followed by a standard behavioral measure of biased attention (i.e. spatial cueing task). Participants were also genotyped for the serotonin transporter-linked promoter region (5-HTTLPR) gene. Results indicated that lateral prefrontal cortex (lPFC) morphology was inversely associated with maintained attention for positive and negative stimuli, but only among short 5-HTTLPR allele carriers. No such associations were observed for the medial prefrontal cortex (mPFC) or the amygdala. Results from this study suggest that brain regions involved in cognitive control of emotion are also associated with attentional biases for emotion stimuli among short 5-HTTLPR allele carriers.
Prominent cognitive theories of depression (Beck 1976; Teasdale 1988) posit that biased processing of emotion stimuli is an important marker of depression vulnerability. Similarly, other theorists have asserted that the ability to allocate attention to emotion 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 flexibility and control over attention. This includes strategic filtering, timely disengagement and being appropriately vigilant for meaningful emotion cues.
To understand factors that contribute to biased processing of emotion stimuli, we sought to identify neural substrates involved in processing of emotion stimuli. Our analyses will focus two cortical regions, lateral and medial prefrontal cortices, and one subcortical region, the amygdala (Johnstone et al. 2007). The lateral prefrontal region includes primarily ventral lateral regions (Brodmann areas 45, 46 and 47) and the rostral middle frontal, pars triangularis and pars orbitalis regions (Brodmann areas 10, 11, 25 and 32). The medial prefrontal region includes the medial orbital frontal and rostral anterior cingulate regions. We identify these cortical and white matter (WM) regions in Fig. 1.
Figure 1. Prefrontal regions examined in the current study. Panel a is a coronal slice with all 10 cortical and associated WM regions of the PFC displayed. The left side of panel b is a medial sagittal slice (showing the medial orbital frontal and the rostral anterior cingulate) and the right side of panel b is a lateral sagittal slice (showing rostral middle frontal, pars triangularis and pars orbitalis).
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The lateral prefrontal cortex (lPFC) has previously been implicated in cognitive regulation of emotional information (Ochsner & Gross 2005; Ochsner et al. 2002). It is involved in cognitive control in general, especially when competing responses have to be inhibited or new information is selected (e.g. Aron & Poldrack 2005; Nee et al. 2007). The ventral lateral prefrontal cortex (vlPFC), in particular, is thought to modulate emotion responses through an attentional biasing mechanism that acts on subcortical regions, such as the amygdala (Wager et al. 2008).
The medial prefrontal cortex (mPFC) also has an important role in the regulation of emotion information, particularly for the assessment of emotion experience and how it relates to the self (Beer & Ochsner 2006; Craik et al. 1999; Kelley et al. 2002). For instance, mPFC is recruited when comparing the desirability of self with others (e.g. Ochsner et al. 2005) or when a negative emotional experience is anticipated (e.g. Ploghaus et al. 1999). It is also involved in evaluating emotion stimuli, particularly when evaluating one's own emotion (Lee & Siegle 2009).
The amygdala is a subcortical region that has repeatedly been implicated in detecting, attending to and encoding into memory emotional information (Phelps & LeDoux 2005; Whalen & Phelps 2009). The amygdala produces rapid physiological and behavioral arousal in response to salient, emotion stimuli (Adolphs 2008). In addition to influencing the activity of hypothalamic and brainstem autonomic centers, the amygdala also initiates activity in the ventromedial and orbitofrontal cortices (Whalen & Davis 2001). A recent meta-analysis documented that the amygdala is consistently activated during emotion processing tasks (Kober et al. 2008).
A recent study (Wager et al. 2008) showed that the vlPFC acts upon the amygdala to moderate emotional experience during cognitive reappraisal of emotion information (i.e. self-reported failure to effectively reappraise emotion stimuli). As expected, several medial prefrontal cortical regions, including the medial frontal pole, vlPFC and rostral mPFC, also contributed to the experience of negative emotion. Thus, coordinated activity among the lPFC, mPFC and the amygdala was critically involved in the cognitive regulation and experience of emotion stimuli.
Based on this review, we hypothesized that lPFC may be an important neural substrate that underlies biased attention for emotional stimuli. To examine this possibility, we examined whether cortical and WM morphology in the lPFC is associated with individual differences in biased attention for negative and positive stimuli. To test for specificity, we also examined whether mPFC and amygdala volume, regions that are hypothesized to be involved in the experience rather than control of emotion stimuli, were not associated with biased attention for emotion stimuli.
Participants in the current study were also genotyped for the serotonin transporter-linked polymorphic region (5-HTTLPR) gene because this polymorphism has been associated with morphology of the vlPFC (Canli et al. 2005), as well as less functional coupling between regions of the prefrontal cortex (PFC) and the amygdala (Pezawas et al. 2005). 5-HTTLPR genotype predicts differential activation in limbic (including the amygdala), striatal and cortical brain regions in response to negative, positive and neutral word stimuli (Canli et al. 2005). Given these findings, and evidence that brain morphology and function are associated (Brodtmann et al. 2009), we reasoned that lPFC morphology may be particularly relevant to the processing of emotion stimuli for carriers of the low expressing 5-HTTLPR allele.
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This overarching goal of the current study was to identify morphological underpinnings of biased attention for emotion cues. We expected individual differences in lateral prefrontal regions (i.e. areas involved in cognitive control of emotion) to be associated with biased attention for emotion stimuli. Medial prefrontal and amygdala volumes, regions involved in the experience (but not control) of emotion, were not expected to be associated with biased attention for emotion cues. Furthermore, we hypothesized that the 5-HTTLPR polymorphism may moderate these associations, given that the 5-HTTLPR polymorphism modulates a cortical–limbic circuit implicated in the regulation of emotion (Pezawas et al. 2005).
Using high-resolution structural brain imaging, morphology of the lPFC was strongly associated with biased attention for emotion stimuli among short 5-HTTLPR allele carriers. Although there were no 5-HTTLPR allele group differences for lateral prefrontal volume, the morphology of this region was strongly associated with biased attention for positive and negative stimuli among short 5-HTTLPR allele carriers—smaller volumes were associated with greater biased attention. Attentional biases were not significantly associated with morphology of the medial prefrontal region and the amygdala, suggesting the effects were specific to the lateral prefrontal region. Importantly, these effects were observed among a sample of healthy, non-depressed, non-medicated women. Therefore, the results from the current study are not a symptomatic outcome of altered mood state.
The 5-HTTLPR polymorphism may moderate the association between lateral PFC morphology and biased attention for emotion stimuli because the 5-HTTLPR polymorphism impacts a cortical–limbic circuit that is critical for regulating emotional information. For instance, among healthy participants, Pezawas et al. (2005) used fMRI to assess relative activation of the perigenual anterior cingulate cortex (pACC) and amygdala in response to negative stimuli (e.g. angry and scared facial expressions) and found that short 5-HTTLPR allele carriers had less functional coupling between the pACC and the amygdala. The ‘ncoupling’ of this emotion circuit may explain why short-allele carriers have greater amygdala responses to emotional stimuli (Bertolino et al. 2005; Hariri et al. 2002, 2005). Given heightened neural reactivity, lateral prefrontal morphology may be particularly important for successful regulation of emotion stimuli among carriers of the low expressing 5-HTTLPR alleles.
Brain region volumes included both WM and GM. White matter volume reflects the density of WM (i.e. axonal myelin and fiber tracts) and is critical to the transmission of electrical signals that guide the performance of higher order cognitive functions (Bartzokis 2004). As a result, decreased WM volume in lateral prefrontal regions may reflect lower functional connectivity between cortical regions that are critical to cognitive control of emotional responses to stimuli. This may be particularly important for regulating emotion among short 5-HTTLPR allele carriers, because of enhanced reactivity (and therefore greater regulatory demand) to emotional stimuli.
So what factors might contribute to individual differences in development of the PFC? There are many possibilities, including genetics, nutrition, toxins, bacteria, viruses, hormones, among others (Giedd 2004). One intriguing possibility is engagement (or lack thereof) of the lPFC during important developmental periods (i.e. when arborization and pruning occur) may have influenced WM and GM development in those regions. There are a number of reasons why some individuals may engage this region less often (e.g. differential exposure to environmental stress, coping styles, genetic propensity, etc.), but regardless of etiology, this differential development may have better equipped some individuals for cognitive regulation of emotion. Given that the PFC continues to develop until early adulthood (Barnea-Goraly et al. 2005), many opportunities likely exist for interactions with environmental stressors to impact the morphology of this region, particularly for short 5-HTTLPR allele carriers who have heightened sensitivity to environmental stress (Gotlib et al. 2008).
It was notable that morphological associations with biased attention were, for the most part, consistent for positive and negative emotion cues. That is, neural substrates underlying attentional biases were similar even though the correlation between biased attention for positive and negative stimuli was moderate (r = 0.44). This suggests that the lateral prefrontal region plays a critical role for regulating emotional information in general (Ochsner & Gross 2005). Most prior research has studied regulation of negative stimuli, so this possibility remains largely untested. Additional research examining regulation of positive and negative stimuli is needed to further refine current models of emotion regulation (cf. Britton et al. 2006).
While these findings document relations between genetic, neural and cognitive risk factors for depression, future work must continue to identify factors mediating these relationships. Specifically, it remains unclear how 5-HTTLPR variation influences the expression of specific neurological differences that may, in turn, produce cognitive and behavioral risk factors for depression. Individuals with a history of major depression (and suicide) have significantly reduced serotonin transporter receptor density in prefrontal cortical regions (including dramatic reductions in vlPFC); however, these differences appear to be unrelated to 5-HTTLPR variation (Arango et al. 1995; Mann et al. 2000). Future efforts must focus on identifying plausible mediating factors for observed relations between genes, brain structure and attentional bias.
Future work should consider testing associations between lateral prefrontal morphology and biased attention following dysphoric mood manipulations. Cognitive biases are more likely to be showed following dysphoric mood provocations (Scher et al. 2005) and increased mood-linked negative thinking predicts onset of major depressive disorder (Segal et al. 2006). Given that short 5-HTTLPR allele carriers appear to be more susceptible to self-referent negative thinking following a dysphoric mood induction (Beevers et al. 2009), lateral prefrontal morphology may be an important predictor of biased processing of emotional stimuli following dysphoric mood inductions. Furthermore, individual differences in lateral prefrontal morphology may explain why carriers of the low expressing 5-HTTLPR have difficulty in regulating emotional states in the context of life stress (Caspi et al. 2003).
Several limitations of this study should be noted. First, this study only included female participants. Women are twice as likely to experience major depressive disorder than men (Kessler et al. 2003), so they are an appropriate group to recruit for a depression vulnerability study. However, additional work is needed to determine whether our findings are applicable to men. Second, as with any genetic association study, population stratification is a potential concern (Hutchison et al. 2004). Population stratification occurs when cases and controls differ with respect to their ethnic background or another variable that may have led to a pattern of non-random mating. In our study, this confound is unlikely as 5-HTTLPR allele frequencies did not differ across race or ethnicity. Third variable explanations, such as the 5-HTTLPR promoter polymorphism is in linkage disequilibrium with another functional genetic marker, should also be considered as explanations for the observed effects. Finally, future research with larger samples should examine the newly identified single nucleotide polymorphism that occurs at the sixth nucleotide (adenine to guanine; A to G) in the first of two extra 20–23 bp repeats in the L allele (Hu et al. 2005).
Nevertheless, we believe that this study makes an important and interesting contribution to identify neural substrates that contribute to biased processing of emotion cues. Individuals with lower GM and WM volumes in lateral prefrontal regions who inherit the short variant of the 5-HTTLPR gene display significant attentional biases for positive and negative stimuli. This focus on emotional aspects of the environment, in turn, may increase sensitivity to life stress and place these individuals at greater risk for depression. Additional work is now needed that examines complex etiological models of depression that link these various mechanisms of risk. Studying mechanisms of risk across levels of analyses (genetic, neural, cognitive and environmental) will facilitate development of comprehensive models of depression vulnerability and further our understanding of this debilitating disorder.