Volition diminishes genetically mediated amygdala hyperreactivity
Introduction
Recent advances in imaging genetics have provided promising new insights into the complex interplay of genes, neural processing and behavior (Esslinger et al., 2009, Green et al., 2008, Meyer-Lindenberg and Weinberger, 2006). For example, the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) is critically involved in emotional processing, stimulating imaging genetic studies of this neuromodulatory system (Hahn and Blakely, 2007). One well-described determinant of this system is the serotonin transporter (5-HTT), which regulates 5-HT reuptake from the synaptic cleft (Hariri and Holmes, 2006). On the molecular level, genetic regulation of 5-HTT mRNA and protein expression is influenced by a common polymorphism found in the 5-HTT linked promoter region (5-HTTLPR) of the serotonin transporter gene SLC6A4. In the presence of at least one short (s) allele, the level of 5-HTT mRNA and 5-HT reuptake in human lymphoblastoid cells is approximately two-fold lower compared with cells that are homozygous for the long (l) allele.
Genetic variation within the serotonin transporter gene also influences psychological measures of negative emotionality: in comparison to l/l-homozygotes, the s-carriers show higher neuroticism, harm avoidance, anxiety and depression (Ansorge et al., 2004, Hoefgen et al., 2005, Lesch et al., 1996). In addition, it was assumed that depression mainly developed in those risk allele carriers who had suffered stressful life events (Caspi et al., 2003). The latter findings however could not be substantiated by two recent meta-analyses (Munafo et al., 2008, Risch et al., 2009).
In contrast to the effects on behavior, the influence of the serotonin transporter genotype on neurophysiological parameters is more consistent (Munafo et al., 2008). A number of recent studies showed that the amygdala, a key region for emotional processing which is densely innervated by serotonergic neurons (Hariri et al., 2006, Hensler, 2006), is more reactive in s-carriers during the passive perception of negative emotions compared to l-homozygotes (Bertolino et al., 2005, Hariri et al., 2002, Hariri et al., 2005, Heinz et al., 2005, Pezawas et al., 2005, Rhodes et al., 2007, Smolka et al., 2007). During passive perception, the 5-HTTLPR genotype was also related to alterations in the functional connectivity between the amygdala and the prefrontal cortex (Heinz et al., 2005, Pezawas et al., 2005); additional structural differences were found in the amygdala, the dorsolateral (dlPFC) and ventrolateral (vlPFC) prefrontal cortex, the dorsomedial prefrontal cortex (dmPFC) and the anterior cingulate cortex (Canli et al., 2005, Heinz et al., 2005, Pezawas et al., 2005). The observed genotype-dependent dysregulations regarding the structure, function and connectivity within the amygdala-prefrontal emotion network are thought to contribute to the increased negative emotionality observed in s-allele carriers (Canli and Lesch, 2007, Hariri and Holmes, 2006).
These findings clearly underscore the relevance of genetic variation within the serotonergic system with respect to the central processing of emotions, despite heterogeneous results regarding the influence of the 5-HTTLPR genotype on direct measures of 5-HTT central availability. While some studies found that 5-HTT central availability and mRNA levels in midbrain regions are influenced by the serotonin transporter genotype (Little et al., 1998, Reimold et al., 2007, van Dyck et al., 2004), others failed to find an association (Parsey et al., 2006, Shioe et al., 2003). For example, a PET investigation with the radiotracer [11C]McN 5652 found no effect of 5-HTTLPR genotypes on serotonin transporter binding potential in the amygdala (Parsey et al., 2006). This led the authors to conclude that 5-HTTLPR related neural effects cannot be explained by altered serotonin transporter binding but may be due to differences in methylation patterns or changes in maximum velocity in the 5-HTT enzymatic reaction. Since the association between the 5-HTTLPR and central measures of emotional reactivity has however been reliably replicated, it also seems reasonable to assume that a relative loss in serotonin transporter function related to the short variant might have a detrimental effect especially during the development of the neural circuits involved in emotional regulation (Hariri and Holmes, 2006, Parsey et al., 2006). Consistent with this notion, in rodents a disruption in 5-HT functioning during early development entails alterations in neural structure and function, such as for example lasting emotional abnormalities (Esaki et al., 2005, Gaspar et al., 2003).
However, all previous investigations of 5-HTTLPR-dependent effects on the neural processing of emotions have been restricted to passive perception. In turn, the willful employment of cognitive strategies is known to be effective in changing subjective and physiological responses to emotional stimuli. Amygdala activation is effectively reduced during e.g. labeling (Hariri et al., 2003), cognitive reappraisal (Goldin et al., 2008, Ochsner et al., 2002, Ochsner et al., 2004) and detachment (Beauregard et al., 2001, Levesque et al., 2004) through top–down influences from the dlPFC and vlPFC, the orbitofrontal cortex (OFC) and the parietal cortex. Thus, the question arises if willful emotion regulation is able to alter genetically determined differences in amygdala reactivity. This question is not only relevant within cognitive and clinical neuroscience but also touches questions related to the power of conscious will. Recent years have witnessed a number of studies trying to answer questions related to the power of conscious will not by armchair philosophy but by conducting empirical studies of the will using neuroscientific means (Bechara, 2005, Haggard, 2008, Soon et al., 2008, Walter, 2001, Wegner, 2004).
To investigate the effect that willful cognitive acts have on genetically predisposed emotional processing, we conducted a functional magnetic resonance imaging (fMRI) study investigating the passive perception and explicit regulation of negative and neutral emotional material in female 5-HTTLPR short and long individuals. Since on the one hand the s-allele of the serotonin transporter genotype has been associated with amygdala hyperreactivity (Hariri et al., 2002, Hariri et al., 2005), and on the other hand, amygdala BOLD signal is effectively attenuated through cognitive emotion regulation (Beauregard et al., 2001, Goldin et al., 2008, Levesque et al., 2004, Ochsner et al., 2002, Ochsner et al., 2004), this region was designated our a priori region of interest.
Our primary goal was to evaluate whether a willful effort, i.e. the deliberate use of a cognitive emotion regulation strategy, can reduce the genetically mediated amygdala hyperreactivity to aversive emotional material. We used negative stimuli that evoked either fear or disgust in order to evaluate whether s-allele carriers show increased neural activation to the perception of aversive versus neutral stimuli (Calder et al., 2001, Hariri et al., 2002). Since fear stimuli are more relevant in the context of anxiety and depression, we hypothesized that amygdala hyperreactivity in the short genotype group is primarily related to the perception of fear and less to the perception of disgust (Hariri et al., 2005, Lau et al., 2009, Schienle et al., 2005). Regarding the effects of emotion regulation on 5-HTTLPR-mediated amygdala hyperreactivity, two alternative assumptions arise: as prior work suggests that the dysfunctions within the amygdala-prefrontal emotion network are caused by developmental changes, the bias towards negativity might be unspecific with respect to the presence or absence of willful efforts. In this case, the s-group should show increased amygdala reactivity during passive perception and less or even no amygdala attenuation during cognitive emotion regulation compared with l/l-homozygotes. On the other hand, cognitive emotion regulation might counteract the genetically determined amygdala hyperreactivity, in which case we should find equal or even larger amygdala signal reductions during the regulation of negative affect in s-carriers. To address these questions, we compared the neural responses of the two genotype groups in both the presence and absence of regulation.
Section snippets
Participants
Forty-four right-handed female university students of central European descent with no history of neurological/psychiatric illness or substance abuse participated in the study. Only female subjects were studied to ensure comparability with previous studies on cognitive emotion regulation which were also restricted to females (Drabant et al., 2009, Eippert et al., 2009, Goldin et al., 2008, Ochsner et al., 2002, Ochsner et al., 2004, Schaefer et al., 2002, Walter et al., 2009) and to avoid
Personality scores
The 5-HTTLPR genotype groups did not differ regarding harm avoidance or neuroticism scores (HA: t[35] = − 1.55, p = 0.13; N: t[35] = − 1.66, p = 0.11). The habitual use of suppression was also unaffected by 5-HTTLPR genotype (ERQ-S: t[35] = 0.63, p = 0.53). However, the habitual use of reappraisal was more frequent in l/l-homozygotes compared with 5-HTTLPR s-allele carriers (t[35] = − 2.42, p = 0.02).
Manipulation check
Both fear and disgust stimuli were perceived as significantly more unpleasant in comparison with the neutral
Discussion
Here, we show that heightened amygdala reactivity attributable to the 5-HTTLPR short variant can be successfully attenuated by the willful, cognitive regulation of emotions (Fig. 1), that this effect is present for fear but not observed for disgust, and that it is mediated in s-carriers by altered functional coupling between the amygdala and the medial and ventrolateral prefrontal cortices (Fig. 2).
Both fear and disgust induced reliable activation in the amygdala amongst other regions in
Conflict of interest
The authors report no potential conflicts of interest.
Acknowledgments
This study was supported by the Volkswagen Foundation (grants II/80777, II/80774) and the German Federal Ministry of Education and Research (BMBF; grant 01GS08159) in the context of the National Genome Research Network (NGFN plus). We thank Christine Schmäl for her help in proofreading the manuscript.
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