Brain-behaviour correlations in the insula and inferior frontal cortex.

<p>Correlation of subjects’ failure rates with the difference scores obtained from activation to both feedback values (ROI value negative feedback – ROI value positive feedback). Results of the correlation analyses are depicted for the left insula and inferior frontal cortex IFC. FB = feedback.</p

Time course of stimulus presentation in the word-learning task.

<p>Each trial started with an encoding phase consisting of 5 successively presented name-object pairs. Simultaneous with each object presentation a pseudoword, serving as object name, was presented via headphones. Subjects were instructed to memorize the name of each object. Recognition performance was tested after a jittered delay period and involved the presentation of one of the objects with one of the pseudowords. Participants had to indicate whether the pseudoword matched the object presented and responded on two buttons of a response pad (right index for correct and middle finger for incorrect). Feedback was provided immediately. In the informative group, feedback depended on performance, indicating either success or failure (positive or negative smiley). In the non-informative group, feedback was not dependent on performance. A neutral smiley appeared after each trial, giving no indication on success or failure.</p

Effects of L-dopa during Auditory Instrumental Learning in Humans

<div><p>The dopaminergic neurotransmitter system is critically involved in promoting plasticity in auditory cortex. We combined functional magnetic resonance imaging (fMRI) and a pharmacological manipulation to investigate dopaminergic modulation of neural activity in auditory cortex during instrumental learning. Volunteers either received 100 mg L-dopa (Madopar) or placebo in an appetitive, differential instrumental conditioning paradigm, which involved learning that a specific category of frequency modulated tones predicts a monetary reward when fast responses were made in a subsequent reaction time task. The other category of frequency modulated tones was not related to a reward. Our behavioral data provides evidence that dopaminergic stimulation differentially impacts on the speed of instrumental responding in rewarded and unrewarded trials. L-dopa increased neural BOLD activity in left auditory cortex to tones in rewarded and unrewarded trials. This increase was related to plasma L-dopa levels and learning rate. Our data thus provides evidence for dopaminergic modulation of neural activity in auditory cortex, which occurs for both auditory stimuli related to a later reward and those not related to a reward.</p> </div

Results of the full factorial ANOVA with effects of drug treatment (A) and reward anticipation (B).

<p>Results of the full factorial ANOVA with effects of drug treatment (A) and reward anticipation (B).</p

Averaged beta values as a function of group and condition in regions of interest to illustrate the results shown in <b>Figure 3</b>.

<p>Note that neural activity in the left auditory cortex was significantly enhanced in the L-dopa group compared to the placebo group without any significant differences between CS+ and CS− trials. Differences in CS+ and CS− trials were evident in dopaminergic brain regions (B and C). The plots further illustrates higher neural responses in the midbrain under L-dopa. Black bars show rewarded (CS+) trials, gray bars unrewarded (CS−) trials. Statistically significant differences are marked by asterisks (two factorial ANOVA corrected for multiple comparisons).</p

Results of the linear regression analysis using the slope of the individual learning curves: (A) L-dopa group, (B) placebo group and (C) differences between placebo and L-dopa.

<p>Results of the linear regression analysis using the slope of the individual learning curves: (A) L-dopa group, (B) placebo group and (C) differences between placebo and L-dopa.</p

Behavioral data.

<p>(A) Learning curves: Cumulative sum of correct answers to reward expectations as function of trial number for each individual subject. Bold lines (blue and red) indicate the mean of each group (L-dopa and placebo, respectively). Bold black lines indicate 100% and 50% (chance) correct answers. (B) Speed of instrumental responding: Reaction times in the number comparison task in rewarded (CS+, solid lines) and unrewarded (CS−, dashed lines) as function of trial number for each group.</p

Neural activity for main effect of group (A) and condition (B).

<p>Neural activity for (A) main effect of group, which yields stronger activation in the auditory cortex (AC), inferior frontal gyrus (Broca’s area) and anterior cingulate cortex (ACC)/left medial frontal gyrus for the L-dopa treated group compared to the placebo group. (B) Main effect of condition which shows stronger activation for rewarded (CS+) compared to non-rewarded tones (CS−), in several dopaminergic brain areas, such as nucleus accumbens (NAC) and midbrain regions (SN/VTA), as well as insula.</p

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

<div><p>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.</p></div

Identified brain regions contributing to genotype classification.

<p>¹ Center of gravity coordinate of the clusters.</p><p>² Only clusters that exceeded the voxel extent threshold of k≥40 are reported.</p><p>³ Clusters showing increased (+) or decreased (-) BOLD levels under nicotine (p≤0.05) for each genotype group (CHRNA4 / DRD2) during invalid trials. Post-hoc tests of mean cluster BETA values; tendencies (p≤0.1) are indicated by rectangle brackets.</p><p>Identified brain regions contributing to genotype classification.</p