Serotonin Transporter Genotype and Action Monitoring Dysfunction: A Possible Substrate Underlying Increased Vulnerability to Depression

Department of Psychology, Harvard University, Cambridge, MA 02138, USA.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Impact Factor: 7.05). 04/2010; 35(5):1186-97. DOI: 10.1038/npp.2009.223
Source: PubMed


A variable number of tandem repeats (short (S) vs long (L)) in the promoter region of the serotonin transporter gene (5-HTTLPR) and a functional variant of a single-nucleotide polymorphism (rs25531) in 5-HTTLPR have been recently associated with increased risk for major depressive disorder (MDD). In particular, relative to L/L or L(A) homozygotes (hereafter referred to as L' participants), S carriers or L(g)-allele carriers (S' participants) have been found to have a higher probability of developing depression after stressful life events, although inconsistencies abound. Previous research indicates that patients with MDD are characterized by executive dysfunction and abnormal activation within the anterior cingulate cortex (ACC), particularly in situations requiring adaptive behavioral adjustments following errors and response conflict (action monitoring). The goal of this study was to test whether psychiatrically healthy S' participants would show abnormalities similar to those of MDD subjects. To this end, 19 S' and 14 L' participants performed a modified Flanker task known to induce errors, response conflict, and activations in various ACC subdivisions during functional magnetic resonance imaging. As hypothesized, relative to L' participants, S' participants showed (1) impaired post-error and post-conflict behavioral adjustments; (2) larger error-related rostral ACC activation; and (3) lower conflict-related dorsal ACC activation. As similar behavioral and neural dysfunctions have been recently described in MDD patient samples, the current results raise the possibility that impaired action monitoring and associated ACC dysregulation may represent risk factors increased vulnerability to depression.

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    • "Participants then completed five blocks of 70 trials (46 congruent, 24 incongruent), for a total of 350 trials (230 congruent, 120 incongruent). To ensure adequate difficulty, a response deadline corresponding to the 85th percentile of the RT distribution on incongruent trials in the preceding block was established; for the first block, the practice RT distribution was used (Holmes et al. 2010). Stimulus presentation was followed by a fixation cross (1400 ms). "
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    • "The evidence suggests that this marker is also associated with vulnerability to depression. For example, an increased activation of the rostral ACC in response to errors is seen both in depressed patients (Holmes and Pizzagalli, 2008) and in nondepressed volunteers who carry the short allele of the 5HTTPR gene that is thought to confer vulnerability to depression (Holmes et al., 2010). High rostral ACC activity is also associated with depressed mood in healthy (nondepressed) children (Boes et al., 2008), and with pessimism (Sharot et al., 2007) and negative emotionality (Santesso et al., 2012) in nondepressed adults. "
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    • "Previous studies suggest that already in healthy individuals showing dysphoric compared to non-dysphoric affective states the experience of self-agency and self-serving attributions are reduced (Aarts et al., 2006). Moreover, for depression the possibility has been raised that impaired action monitoring may represent an important depressive endophenotype (Olvet and Hajcak, 2008; Holmes et al., 2010), as reflected for example in impaired post-error behavioral adaptation (Holmes and Pizzagalli, 2008). The role of these monitoring abnormalities for the attenuated self-serving biases in action awareness in these patients, however, remains unclear. "
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