Nicotinergic Modulation of Attention-Related Neural Activity Differentiates Polymorphisms of DRD2 and CHRNA4 Receptor Genes.

Cognitive and neuronal effects of nicotine show high interindividual variability. Recent findings indicate that genetic variations that affect the cholinergic and dopaminergic neurotransmitter system impact performance in cognitive tasks and effects of nicotine. The current pharmacogenetic functional magnetic resonance imaging (fMRI) study aimed to investigate epistasis effects of CHRNA4/DRD2 variations on behavioural and neural correlates of visuospatial attention after nicotine challenge using a data driven partial least squares discriminant analysis (PLS-DA) approach. Fifty young healthy non-smokers were genotyped for CHRNA4 (rs1044396) and DRD2 (rs6277). They received either 7 mg transdermal nicotine or a matched placebo in a double blind within subject design prior to performing a cued target detection task with valid and invalid trials. On behavioural level, the strongest benefits of nicotine in invalid trials were observed in participants carrying both, the DRD2 T- and CHRNA4 C+ variant. Neurally, we were able to demonstrate that different DRD2/CHRNA4 groups can be decoded from the pattern of brain activity in invalid trials under nicotine. Neural substrates of interindividual variability were found in a network of attention-related brain regions comprising the pulvinar, the striatum, the middle and superior frontal gyri, the insula, the left precuneus, and the right middle temporal gyrus. Our findings suggest that polymorphisms in the CHRNA4 and DRD2 genes are a relevant source of individual variability in pharmacological studies with nicotine.

Modulation of nicotine effects on selective attention by DRD2 and CHRNA4 gene polymorphisms.

RATIONALE: Pharmacological and genetic modulation of cholinergic nicotinic neurotransmission influence visuospatial attention in humans. Prior studies show that nicotine as well as a single nucleotide polymorphism (SNP) in the gene coding for the alpha 4 subunit of the nicotinic acetylcholine receptor (CHRNA4) modulate visuospatial attention and distractor interference. The CHRNA4 gene synergistically interacts with a polymorphism in the dopaminergic receptor type d2 (DRD2) gene and impacts brain structure and cognition. OBJECTIVE: We aimed to investigate whether CHRNA4 and DRD2 genotypes alter the effects of nicotine on distractor interference. METHODS: Fifty-eight young healthy non-smokers were genotyped for CHRNA4 (rs1044396) and DRD2 (rs6277). They received either 7 mg transdermal nicotine or a matched placebo in a double-blind, within-subject design 1 h prior to performing a visual search task with distractors. RESULTS: In isolation, DRD2 but not CHRNA4 genotype modulated the effects of nicotine on distractor interference with DRD2 CC carriers showing the strongest reduction of distractor interference after nicotine administration. A further analysis provided additional evidence that this effect was driven by those subjects, who carried at least one C allele in the CHRNA4 gene. CONCLUSION: The effects of nicotine on distractor interference are modulated synergistically by cholinergic and dopaminergic genetic variations. Hence, both genes may contribute to the often reported individual variability in cognitive and neural effects of nicotine.

Nicotine reduces distraction under low perceptual load.

RATIONALE: Several studies provide evidence that nicotine alleviates the detrimental effects of distracting sensory stimuli. It is been suggested that nicotine may either act as a stimulus filter that prevents irrelevant stimuli entering awareness or by enhancing the attentional focus to relevant stimuli via a boost in processing capacity. OBJECTIVES: To differentiate between these two accounts, we administered nicotine to healthy non-smokers and investigated distractor interference in a visual search task with low and high perceptual load to tax processing capacity. METHODS: Thirty healthy non-smokers received either 7 mg transdermal nicotine or a matched placebo in a double blind within subject design 1 h prior to performing the visual search task with different fixation distractors. RESULTS: Nicotine reduced interference of incongruent distractors, but only under low-load conditions, where distractor effects were large. No effects of nicotine were observed under high-load conditions. Highly distractible subjects showed the largest effects of nicotine. CONCLUSIONS: The findings suggest that nicotine acts primarily as a stimulus filter that prevents irrelevant stimuli from entering awareness in situations of high distractor interference.

Long-term effects of attentional performance on functional brain network topology.

Individuals differ in their cognitive resilience. Less resilient people demonstrate a greater tendency to vigilance decrements within sustained attention tasks. We hypothesized that a period of sustained attention is followed by prolonged changes in the organization of "resting state" brain networks and that individual differences in cognitive resilience are related to differences in post-task network reorganization. We compared the topological and spatial properties of brain networks as derived from functional MRI data (N = 20) recorded for 6 mins before and 12 mins after the performance of an attentional task. Furthermore we analysed changes in brain topology during task performance and during the switches between rest and task conditions. The cognitive resilience of each individual was quantified as the rate of increase in response latencies over the 32-minute time course of the attentional paradigm. On average, functional networks measured immediately post-task demonstrated significant and prolonged changes in network organization compared to pre-task networks with higher connectivity strength, more clustering, less efficiency, and shorter distance connections. Individual differences in cognitive resilience were significantly correlated with differences in the degree of recovery of some network parameters. Changes in network measures were still present in less resilient individuals in the second half of the post-task period (i.e. 6-12 mins after task completion), while resilient individuals already demonstrated significant reductions of functional connectivity and clustering towards pre-task levels. During task performance brain topology became more integrated with less clustering and higher global efficiency, but linearly decreased with ongoing time-on-task. We conclude that sustained attentional task performance has prolonged, "hang-over" effects on the organization of post-task resting-state brain networks; and that more cognitively resilient individuals demonstrate faster rates of network recovery following a period of attentional effort.

Variability of fMRI-response patterns at different spatial observation scales.

Functional organization units of the cerebral cortex exist over a wide range of spatial scales, from local circuits to entire cortical areas. In the last decades, scale-space representations of neuroimaging data suited to probe the multi-scale nature of cortical functional organization have been introduced and methodologically elaborated. For this purpose, responses are statistically detected over a range of spatial scales using a family of Gaussian filters, with small filters being related to fine and large filters-to coarse spatial scales. The goal of the present study was to investigate the degree of variability of fMRI-response patterns over a broad range of observation scales. To this aim, the same fMRI data set obtained from 18 subjects during a visuomotor task was analyzed with a range of filters from 4- to 16-mm full width at half-maximum (FWHM). We found substantial observation-scale-related variability. For example, using filter widths of 6- to 8-mm FWHM, in the group-level results, significant responses in the right secondary visual but not in the primary visual cortex were detected. However, when larger filters were used, the responses in the right primary visual cortex reached significance. Often, responses in probabilistically defined areas were significant when both small and large filters, but not intermediate filter widths were applied. This suggests that brain responses can be organized in local clusters of multiple distinct activation foci. Our findings illustrate the potential of multi-scale fMRI analysis to reveal novel features in the spatial organization of human brain responses.

Impact of brain networks involved in vigilance on processing irrelevant visual motion.

The ability to sustain attention over prolonged periods of time is called vigilance. Vigilance is a fundamental component of attention which impacts on performance in many situations. We here investigate whether similar neural mechanisms are responsible for vigilant attention over long and short durations of time and whether neural activity in brain regions sensitive to vigilant attention is related to processing irrelevant information. Brain activity was measured by means of functional magnetic resonance imaging (fMRI) in a 32 min visual vigilance task with varying inter-target intervals and irrelevant peripheral motion stimuli. Changes in neural activity were analysed as a function of time on task to capture long-term aspects of vigilance and as a function of time between target stimuli to capture short-term aspects of vigilance. Several brain regions including the inferior frontal, posterior parietal, superior and middle temporal cortices and the anterior insular showed decreases in neural activity as a function of time on task. In contrast, increasing inter-target intervals resulted in increased neural activity in a widespread network of regions involving lateral and medial frontal areas, temporal areas, cuneus and precuneus, inferior occipital cortex (right), posterior insular cortices, the thalamus, nucleus accumbens and basal forebrain. A partial least square analysis revealed that neural activity in this latter network covaried with neural activity related to processing irrelevant motion stimuli. Our results provide neural evidence that two separate mechanisms are responsible for sustaining attention over long and short durations. We show that only brain areas involved in sustaining attention over short durations of time are related to processing irrelevant stimuli and suggest that these areas can be segregated into two functionally different networks, one possibly involved in motivation, the other in arousal.