Christine Stelzel

Trait anxiety modulates the neural efficiency of inhibitory control

An impairment of attentional control in the face of threat-related distracters is well established for high-anxious individuals. Beyond that, it has been hypothesized that high trait anxiety more generally impairs the neural efficiency of cognitive processes requiring attentional control—even in the absence of threat-related stimuli. Here, we use fMRI to show that trait anxiety indeed modulates brain activation and functional connectivities between task-relevant brain regions in an affectively neutral Stroop task. In high-anxious individuals, dorsolateral pFC showed stronger task-related activation and reduced coupling with posterior lateral frontal regions, dorsal ACC, and a word-sensitive area in the left fusiform gyrus. These results support the assumption that a general (i.e., not threat-specific) impairment of attentional control leads to reduced neural processing efficiency in anxious individuals. The increased dorsolateral pFC activation is interpreted as an attempt to compensate for suboptimal connectivity within the cortical network subserving task performance.

Effects of dopamine-related gene–gene interactions on working memory component processes

Dopamine modulates complex cognitive functions like working memory and cognitive control. It is widely accepted that an optimal level of prefrontal dopamine supports working memory performance. In the present study we used a molecular genetic approach to test whether the optimal activity of the dopamine system for different component processes of working memory is additionally related to the availability of dopamine D2 receptors. We sought evidence for this assumption by investigating the interaction effect (epistasis) of variations in two dopaminergic candidate genes: the catechol‐O‐methyltransferase (COMT) Val158Met polymorphism, which has been shown to influence prefrontal dopamine concentration, and the DRD2/ANKK1‐Taq‐Ia polymorphism, which has been related to the density of D2 receptors. Our results show that COMT effects on working memory performance are modulated by the DRD2/ANKK1‐TAQ‐Ia polymorphism and the specific working memory component process under investigation. Val− participants – supposedly characterized by increased prefrontal dopamine concentrations – outperformed Val+ participants in the manipulation of working memory contents, but only when D2 receptor density could be considered to be high. No such effect was present for passive maintenance of working memory contents or for maintenance in the face of distracting information. This beneficial effect of a balance between prefrontal dopamine availability and D2 receptor density reveals the importance of considering epistasis effects and different working memory subprocesses in genetic association studies.

Epistasis of the DRD2/ANKK1 Taq Ia and the BDNF Val66Met Polymorphism Impacts Novelty Seeking and Harm Avoidance

Mounting evidence from animal studies show that the mesolimbic dopaminergic pathways are modulated by the brain-derived neurotrophic factor (BDNF). This study investigates in N=768 healthy Caucasian participants the influence of two prominent functional single-nucleotide polymorphisms (SNPs) on the BDNF gene (BDNF Val66Met SNP) and the ankyrin repeat and kinase domain containing 1 (ANKK1) gene (DRD2 Taq Ia/ANKK1 SNP) on the personality traits of Novelty Seeking and Harm Avoidance, which are mediated, in part, through dopaminergic mesolimbic circuitry. Carriers of the 66Met+/A1+ variant scored lowest on Novelty Seeking and highest on Harm Avoidance, compared to all other genotype groups. These participants are characterized by a relatively low D2 receptor density in the striatum and an impaired activity-dependent secretion of BDNF. This is one of the first genetic association studies to show a modulatory role for BDNF genetic variation on genetically mediated differences in the mesolimbic dopaminergic system in the context of human personality.

Trait anxiety and the neural efficiency of manipulation in working memory

The present study investigates the effects of trait anxiety on the neural efficiency of working memory component functions (manipulation vs. maintenance) in the absence of threat-related stimuli. For the manipulation of affectively neutral verbal information held in working memory, high- and low-anxious individuals (N = 46) did not differ in their behavioral performance, yet trait anxiety was positively related to the neural effort expended on task processing, as measured by BOLD signal changes in fMRI. Higher levels of anxiety were associated with stronger activation in two regions implicated in the goal-directed control of attention—that is, right dorsolateral prefrontal cortex (DLPFC) and left inferior frontal sulcus—and with stronger deactivation in a region assigned to the brain’s default-mode network—that is, rostral–ventral anterior cingulate cortex. Furthermore, anxiety was associated with a stronger functional coupling of right DLPFC with ventrolateral prefrontal cortex. We interpret our findings as reflecting reduced processing efficiency in high-anxious individuals and point out the need to consider measures of functional integration in addition to measures of regional activation strength when investigating individual differences in neural efficiency. With respect to the functions of working memory, we conclude that anxiety specifically impairs the processing efficiency of (control-demanding) manipulation processes (as opposed to mere maintenance). Notably, this study contributes to an accumulating body of evidence showing that anxiety also affects cognitive processing in the absence of threat-related stimuli.

The BDNF Val66Met polymorphism and smoking

Although the brain derived neurotrophic factor (BDNF) has been mainly investigated in the context of depression and anxiety disorders, several studies also suggest an association between BDNF and smoking. BDNF represents a protein which crucially influences several processes in the cell ranging from growth to apoptosis. A functional variant of the BDNF gene - the BDNF Val66Met polymorphism - is one of the main targets in BDNF research because of its influence on BDNF secretion. Recently an association between the 66Met allele and smoking has been reported in a sample of 320 Caucasians. The aim of the present study was to replicate this association in a sample nearly twice as large consisting of N=614 German Caucasian participants. A link between smoking and the BDNF Val66Met polymorphism could not be found in our data.

Functional connectivity separates switching operations in the posterior lateral frontal cortex

Task representations consist of different aspects such as the representations of the relevant stimuli, the abstract rules to be applied, and the actions to be performed. To be flexible in our daily lives, we frequently need to switch between some or all aspects of a task. In the present study, we examined whether switching between abstract task rules and switching between response hands is associated with overlapping regions in the posterior lateral frontal cortex and whether switching between these two aspects of a task representation is neurally implemented by distinct functional brain networks. Subjects performed a cue-based task-switching paradigm where the location of the task cue additionally specified the response hand to be used. Overlapping activity for switching between abstract rules versus response hands was present in the inferior frontal junction area of the posterolateral frontal cortex. This region, however, showed very distinct patterns of functional connectivity depending on the content of the switch: Increased functional connectivity with anterior prefrontal, superior frontal, and hippocampal regions was present for abstract rule switching, whereas response hand switching led to increased coupling with motor regions surrounding the central sulcus. These results reveal that a rather general involvement of the posterior lateral frontal cortex in different switching contexts can be further characterized by highly specific functional interactions with other task-relevant regions, depending on the content of the switch.