B1118 - Dopamine Function Cognitive Flexibility and Emotion Regulation - 09/02/2011
Existing research has shown the relevance of the dopamine pathway in the development and maintenance of cognitive traits. Efforts to tease out the functional role of specific elements of this pathway, however, have struggled to yield reliable assertions as to the causal relationship between dopamine function, cognitive flexibility and emotion regulation The use of genetically-influenced variation in this system to examine functional/behavioural inter-individual differences has the potential to delivery causal statements about the role of dopamine in behaviour.
Here we propose to use a genotype reliably associated with functional variation in prefrontal cortex dopamine neurotransmission (Lachman et al., 1996) to examine the causal role of the dopamine pathway in cognitive flexibility and emotion regulation. Evidence suggests that the COMT Val158Met polymorphism influences prefrontal function (in particular maintenance aspects of working memory and cognitive flexibility) and emotion regulation. This polymorphism has been reported to be a risk factor for anxiety-related psychopathology, although the mechanism of this association remains unclear. One possibility is that this genotype influences cognitive flexibility, in particular with respect to emotional material, which in turn influences risk of anxiety-related psychopathology.
COMT Met/Met status has been linked to increased incidence of emotional disorder, including anxiety (Enoch et al., 2003), panic (Woo et al., 2004), depression (Ohara et alk. 1998), bipolar disorder (Mynett-Johnson et al., 1998; Papolas et al., 1998) and obsessive compulsive disorder (Karayiorgou et al., 1999), although there have also been failures to replicate these associations (e.g., Ohara et al., 1998; Domschke 1998). Met/Met homozygotes show less top-down regulation when having to ignore emotional distracters, while Val/Val homozygotes show a general enhancement in the processing of aversive stimuli, such as rapid disengagement of cortical circuits (e.g., Heinz & Smolka 2006; Xu et al., 2006; Tunbridge et al., 2006). Passive viewing of emotional images cause increase in prefrontal cortex (PFC) and limbic activation in Met/Met homozygotes as compared to Val/Val (Smolka et al., 2006).
COMT Met/Met homozygotes appear to show advantages on working memory tasks that especially tap "maintenance" aspects of working memory. For example, they show enhanced performance on the N-back working memory task (Egan et al., 2001; Goldberg et al.2003), the Wechsler Memory Scale (Bilder et al., 2002), the dots-mixed tasks which requires the online maintenance of two rule sets (Diamond et al., 2004) and they are able to acquire an initial rule as part of a cognitive task more quickly (Nolan et al., 2004). However, these benefits in the maintenance aspects of working memory come at the expense of cognitive flexibility, and it is argued that this is where Val/Val homozygotes tend to excel. For example, Val/Val homozygotes perform better at reversal learning and regulation of response competition (e.g., Fossella et al., 2002; Nolan et al., 2004). Furthermore, although Met/Met homozygotes can acquire an initial rule more quickly, Val/Val homozygotes can switch to a subsequent rule more easily (Nolan et al., 2004). In other words they are more able to inhibit a prepotent response.
To explain these findings it has been suggested that Met/Met homozygotes have increased tonic dopamine (DA) neurotransmission in the PFC and decreased phasic neurotransmission (and vice versa for Val/Val homozygotes). Having higher tonic DA neurotransmission in the PFC improves performance on a number of working memory tasks (particularly those that require a maintenance aspect). However, having stronger phasic neurotransmission (as with Val/Val homozygotes) means an enhanced performance on tasks requiring cognitive flexibility. It is argued that the differing effects on emotional information processing may be due to the inflexibility of the cortical networks in Met/Met homozygotes. For example, Drabant et al., (2006) argue that Met/Met homozygotes are "more easily locked into an affective processing set, reverberating emotional information through this re-entrant loop." They argue that this leads to biases in information processing that could remain dormant but lead to increased vulnerability to affective disorders.
Furthermore, the relationship between DA levels in the PFC and performance can be thought of as following an inverted-U relationship. Met/Met homozygotes are thought to be at the peak of the inverted-U, which conveys benefits on certain aspects of working memory tasks. However, any further increase in dopamine will push them onto the downwords slope, reducing performance. Val/Val homozygotes however, are thought to be on the upwards slope of the inverted-U, so that increases in dopamine should cause improved performance on working memory tasks. Research investigating amphetamine-induced shifts in dopamine levels supports this theory (Mattay et al., 2003). In addition, when under stress Met/Met homozygotes show deficits in working memory performance on tasks that they usually excel on as compared to Val/Val homozygotes (Bishop et al., 2008).
In a sample selected for a balanced representation of genotypes at COMT(rs4680)*, we therefore wish to test the following prediction:
Cognitive retraining, designed to modify cognitive response to emotional cues, should be more effective in individuals with lower PFC dopamine levels.
Translated to a "natural experiment", where genetic variation acts as a proxy measure for dopamine neurotransmission, we hypothesise that participants with Val/Val homozygotes will be more receptive to cognitive retraining in this model when compared to Val/Met heterozygotes or Met/Met homozygotes.
We will measure cognitive flexibility in response to emotional cues, using an emotional working memory modification task. This is a variant of the widely-used N-back working memory task, designed to experimentally induce temporary changes in the cognitive processing of emotional material.
This behavioural challenge to the dopamine system is expected to amplify effects of genotype on task performance. We propose to freely recruit 150 mothers from the ALSPAC study (i.e., not pre-selected on the basis of any specific characteristic), on whom demographic and COMT genotype data already exist, in a recall design. Participants would be invited through the ALSPAC study team, and if interested in the study invited to attend a single testing session in the School of Experimental Psychology. COMT genotype frequencies are approximately evenly distributed in samples of European ancestry, which will maximise statistical power.
Testing would consist of completion of a retraining task (described below), followed by three assessment tasks to assess the transfer of any effects of retraining to other measures. We will use existing genotype data to test for associations between COMT genotype and performance on the retraining task, adjusted for age, socioeconomic status, and educational status / IQ.