Effects of Nicotine on Task Switching and Distraction in Non-smokers. An fMRI Study.

Nicotine improves sustained attention and reduces distractor interference, promoting cognitive stability. While stable performance may be beneficial in some situations, others require flexible updating of task demands. Frontoparietal networks, basal ganglia and thalamus contribute to an optimal balance of stable and flexible performance. We aimed to test how the cholinergic agonist nicotine modulates this balance and used an ongoing visual task including switch and distractor trials to gauge cognitive flexibility and stability respectively. Young healthy non-smokers (n = 39) received either a 7 mg transdermal nicotine or placebo patch in a double-blind, within-subject design one hour prior to performing the task in a 3 T MR scanner. Nicotine enhanced response times in all task conditions but did not significantly impact distractor or switch costs. Neurally, there was no significant nicotine induced modulation of distractor- or switch-related activity on group level. However, a brain-behaviour correlation analysis revealed that the nicotine-induced alterations of distractor costs correlated positively with distractor-related neural activity in the right intraparietal sulcus and the right pulvinar nucleus of the thalamus. We suggest that a nicotinic contribution to balancing stability and flexibility is weak in young healthy non-smokers. The brain-behaviour correlations imply that if nicotine reduces distractor interference, the modulation is found in thalamic-parietal networks.

Increased dopamine availability magnifies nicotine effects on cognitive control: A pilot study.

INTRODUCTION AND OBJECTIVES: The ability to adapt to new task demands flexibly and to stabilise performance in the presence of distractors is termed cognitive control and is mediated by dopaminergic and cholinergic neurotransmission. We aimed to test the hypothesis that the effect of the cholinergic agonist nicotine on cognitive control depends on baseline dopamine levels. METHODS: Thirty-eight healthy non-smokers (16 males; Mage=24.05 years) performed a cognitive control task including distractor and switch trials twice. Subjects were split into two parallel groups. One group received 2 g of L-tyrosine two hours prior to testing to manipulate dopamine availability experimentally, while the other group received placebo on both days. One hour later, both groups received in a within-subject design: on one day, a 7 mg nicotine patch; on the other day, a matched placebo. Response time costs for distractor and switch trials served as measures of cognitive stability and flexibility. RESULTS: Nicotinic modulation reduced response time costs in switch trials and increased costs in distractor trials (nicotine×condition, p=0.027) with a trend-wise interaction between nicotine, L-tyrosine and trial type (nicotine×L-tyrosine×condition, p=0.068), which was due to stronger nicotine effects under L-tyrosine. CONCLUSIONS: Our data provide preliminary evidence that nicotine has opponent effects on cognitive stability and flexibility. Subjects who received the dopamine precursor L-tyrosine were more prone to nicotine effects on behaviours, which are improvements in cognitive flexibility at the cost of decreased cognitive stability.

Healthy Subjects With Extreme Patterns of Performance Differ in Functional Network Topology and Benefits From Nicotine.

Do subjects with atypical patterns in attentional and executive behaviour show different brain network topology and react differently towards nicotine administration? The efficacy of pro-cognitive drugs like nicotine considerably varies between subjects and previous theoretical and empirical evidence suggest stronger behavioural nicotine effects in subjects with low performance. One problem is, however, how to best define low performance, especially if several cognitive functions are assessed for subject characterisation. We here present a method that used a multivariate, robust outlier detection algorithm to identify subjects with suspicious patterns of performance in attentional and executive functioning. In contrast to univariate approaches, this method is sensitive towards extreme positions within the multidimensional space that do not have to be extreme values in the individual behavioural distributions. The method was applied to a dataset of healthy, non-smoking subjects (n = 34) who were behaviorally characterised by an attention and executive function test on which N = 12 volunteers were classified as outliers. All subjects then underwent a resting-state functional magnetic resonance imaging (fMRI) scan to characterise brain network topology and an experimental behavioural paradigm under placebo and nicotine (7 mg patch) that gauged aspects of attention and executive function. Our results indicate that subjects with an atypical multivariate pattern in attention and executive functioning showed significant differences in nodal brain network integration in visual association and pre-motor brain regions during resting state. These differences in brain network topology significantly predicted larger individual nicotine effects on attentional processing. In summary, the current approach successfully identified a subgroup of healthy volunteers with low behavioural performance who differ in brain network topology and attentional benefit from 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.

Expression of the IGF-1, IGFBP-3 and IGF-1 receptors in dental pulp stem cells and impacted third molars.

IGF-1 regulates the metabolism of hard dental tissue through binding to the IGF-1 receptor on target cells. Furthermore, IGF-binding-protein-3 promotes the accessibility of IGF-1. The aim of this study was to investigate the expression of IGF-1, IGFBP-3 and IGF-1R in STRO-1-positive dental pulp stem cells (DPSCs) and fully impacted wisdom teeth in relation to tooth development. Third molars were surgically removed from 60 patients and classified into two groups: teeth showing ongoing development (group 1) and teeth that had completed root shaping (group 2). The transcript and protein levels of IGF-1, IGFBP-3 and IGF-1R were investigated using RT-PCR and immunohistochemistry. The expression of the same proteins was also analyzed in DPSCs. The teeth from group 1 showed significantly stronger expression of IGF-1 and IGF-1R. The major sources of all of the proteins investigated immunohistochemically in sections of wisdom teeth were odontoblasts, cementoblasts and cell colonies in the pulpal mesenchyme. These colonies were identified as stem cells in view of their positivity for STRO-1, and the cells were subsequently sorted by flow cytometry. These DPSCs demonstrated high levels of pluripotency markers and IGF-1 and IGF-1R. We conclude that members of the IGF-1 family are involved in the late stage of tooth development and the process of pulpal differentiation.