Manuel Garcia-Garcia

The role of the dopamine transporter DAT1 genotype on the neural correlates of cognitive flexibility

Cognitive flexibility, the ability to adapt goal‐oriented behaviour in response to changing environmental demands, varies widely amongst individuals, yet its underlying neural mechanisms are not fully understood. Neuropharmacological and human clinical studies have suggested a critical role for striatal dopaminergic function mediated by the dopamine transporter (DAT). The present study aimed at revealing the role of the DAT in the individual brain response stereotypy underlying cognitive flexibility. A task‐switching protocol was administered to a sample divided according to the presence or absence of the 9‐repeat (9R) allele of the DAT1 polymorphism, while registering behavioural and electrophysiological novelty‐P3 responses. The absence of the 9R (higher gene expression) is related to less striatal DA availability. Individuals lacking the 9R (9R−) showed specific response time (RT) increases for sensory change and task‐set reconfiguration, as well as brain modulations not observed in participants with the 9R allele (9R+), suggesting that task performance of the former group depended on immediate local context. In contrast, individuals displaying high striatal DA showed larger RT costs than 9R− individuals to any sensory change, with no further increase for task‐set reconfiguration, and a larger early positive brain response irrespective of the task condition, probably reflecting larger inhibition of any previous interference as well as stronger activation of the current task set. However, the polymorphic groups did not differ in their mean RTs in trials requiring task‐set reconfiguration. This distinct stereotypy of cerebral responses reveals different patterns of cognitive control according to the DAT1 gene polymorphism.

Electrophysiological and behavioral evidence of gender differences in the modulation of distraction by the emotional context.

Gender differences in brain activity while processing emotional stimuli have been demonstrated by neuroimaging and electrophysiological studies. However, the possible differential effects of emotion on attentional mechanisms between women and men are less understood. The present study aims to elucidate any gender differences in the modulation of unexpected auditory stimulus processing using an emotional context elicited by aversive images. Fourteen men and fourteen women performed a well-established auditory-visual distraction paradigm in which distraction was elicited by novel stimuli within a neutral or negative emotional context induced by images from the IAPS. Response time increased after unexpected novel sounds as a behavioral effect of distraction, and this increase was larger for women, but not for men, within the negative emotional context. Novelty-P3 was also modulated by the emotional context for women but not for men. These results reveal stronger novelty processing in women than in men during a threatening situation.

Emotional context enhances auditory novelty processing: behavioural and electrophysiological evidence

Viewing emotionally negative pictures has been proposed to attenuate brain responses towards sudden auditory events, as more attentional resources are allocated to the affective visual stimuli. However, peripheral reflexes have been shown intensified. These observations have raised the question of whether an emotional context actually facilitates or attenuates processing in the auditory novelty system. Using scalp event‐related potentials we measured brain responses induced by novel sounds when participants responded to visual stimuli displaying either threatening or neutral sceneries. We then tested the modulatory effect of the emotional task conditions on auditory responses. Novel sounds yielded a stronger behavioural disruption on subjects’ visual task performance when responding to negative pictures compared with when responding to the neutral ones. Accordingly, very early novelty‐P3 responses to novel sounds were enhanced in negative context. These results provide strong evidence that the emotional context enhances the activation of neural networks in the auditory novelty system, gating acoustic novelty processing under potentially threatening conditions.

Dopamine transporter regulates the enhancement of novelty processing by a negative emotional context

The dopaminergic (DA) system has been recently related the emotional modulation of cognitive processes. Moreover, patients with midbrain DA depletion, such as Parkinsons Disease (PD), have shown diminished reactivity during unpleasant events. Here, we examined the role of DA in the enhancement of novelty processing during negative emotion. Forty healthy volunteers were genotyped for the dopamine transporter (DAT) gene SLC6A3 or DAT1 and performed an auditory-visual distraction paradigm in negative and neutral emotional context conditions. 9R- individuals, associated to a lesser striatal DA display, failed to show increased distraction during negative emotion, but experienced an enhancement of the early phase of the novelty-P3 brain response, associated to the evaluation of novel events, in the negative relative to the neutral context. However, 9R+ individuals (associated to larger striatal DA display) showed larger distraction during negative emotion and larger amplitudes of the novelty-P3, irrespective of the condition. These results suggest a blunted reactivity to novelty during negative emotion in 9R- individuals due to a lesser DA display and stronger activation of the representation of novel events in the 9R+ group, due to a larger DA availability, thus reaching a ceiling effect in the neutral context condition with no further enhancement during negative emotion. The present results might help to understand the functional implications of dopamine in some neuropsychiatric disorders.

Tuning the brain for novelty detection under emotional threat: the role of increasing gamma phase-synchronization

Effective orienting of attention towards novel events is crucial for survival, particularly if they occur in a dangerous situation. This is why stimuli with emotional value are more efficient in capturing attention than neutral stimuli, and why the processing of unexpected novel stimuli is enhanced under a negative emotional context. Here we measured the phase-synchronization (PS) of gamma-band responses (GBR) from human EEG scalp-recordings during performance of a visual discrimination task in which task-irrelevant standard and novel sounds were presented in either a neutral or a negative emotional context, in order to elucidate the brain mechanisms by which emotion tunes the processing of novel events. Visual task performance was distracted by novel sounds, and this distraction was enhanced by the negative emotional context. Similarly, gamma PS was enhanced after novel as compared to standard sounds and it was also larger to auditory stimuli in the negative than in the neutral emotional context, reflecting the synchronization of neural networks for increasing of attentional processing. Remarkably, the larger PS increase of GBR after novel sounds in the negative as compared to the neutral emotional context over midline and right frontal regions reveals that a negative emotional context tunes novelty processing by means of the PS of brain activity in the gamma frequency band around 40 Hz in specific neural networks.

The role of DAT1 gene on the rapid detection of task novelty

In an environment with a myriad of different stimuli, the fast detection of novel and behaviorally relevant signals becomes crucial for an adaptive behavior. The detection of task-novelty has been related to striatum-prefrontal cortex (PFC) pathways involving dopaminergic (DA) neurotransmission. Here we thus tested the hypothesis that DA regulates the detection of task novelty through the modulation of the auditory N1 potential, an auditory potential peaking at 100 ms and previously shown to be modulated by the detection of sensory novelty. Thirty-five healthy volunteers were divided in two groups according to the presence or absence of the 9-repetition allele (9R) of the SLC6A3/DAT1 gene for the dopamine transporter. Participants performed a cued task-switching paradigm that dissociated the effects of exogenous sensory novelty from those of endogenous task novelty. Individuals with the 9R allele showed an amplitude enhancement of the auditory N1 elicited to sensory changes requiring a task-set reconfiguration as compared to sensory changes with no task novelty. In contrast, individuals without the 9R allele did not have their N1 waveform modulated by task novelty. The present results suggest that individuals homozygous for the 10-repeat allele fail to detect the behavioral relevance of new stimuli at early stages.

COMT and DRD2/ANKK-1 gene-gene interaction account for resetting of gamma neural oscillations to auditory stimulus-driven attention

Attention capture by potentially relevant environmental stimuli is critical for human survival, yet it varies considerably among individuals. A large series of studies has suggested that attention capture may depend on the cognitive balance between maintenance and manipulation of mental representations and the flexible switch between goal-directed representations and potentially relevant stimuli outside the focus of attention; a balance that seems modulated by a prefrontostriatal dopamine pathway. Here, we examined inter-individual differences in the cognitive control of attention through studying the effects of two single nucleotide polymorphisms regulating dopamine at the prefrontal cortex and the striatum (i.e., COMTMet108/158Val and ANKK1/DRD2TaqIA) on stimulus-driven attention capture. Healthy adult participants (N = 40) were assigned to different groups according to the combination of the polymorphisms COMTMet108/158Val and ANKK1/DRD2TaqIA, and were instructed to perform on a well-established distraction protocol. Performance in individuals with a balance between prefrontal dopamine display and striatal receptor density was slowed down by the occurrence of unexpected distracting events, while those with a rather unbalanced dopamine activity were able maintain task performance with no time delay, yet at the expense of a slightly lower accuracy. This advantage, associated to their distinct genetic profiles, was paralleled by an electrophysiological mechanism of phase-resetting of gamma neural oscillation to the novel, distracting events. Taken together, the current results suggest that the epistatic interaction between COMTVal108/158Met and ANKK1/DRD2 TaqIa genetic polymorphisms lies at the basis of stimulus-driven attention capture.