Carsten Giessing

The modulatory effects of nicotine on parietal cortex activity in a cued target detection task depend on cue reliability

This functional magnetic resonance imaging study investigates the effects of nicotine in a cued target detection task when changing cue reliability. Fifteen non-smoking volunteers were studied under placebo and nicotine (Nicorette polacrilex gum 1 and 2 mg). Validly and invalidly cued trials were arranged in blocks with high, middle and low cue reliability. Two effects of nicotine were investigated: its influence on i) parietal cortex activity underlying the processing of invalid vs. valid trials (i.e. validity effect) and ii) neural activity in the context of low, middle and high informative value of the cue (i.e. cue reliability effect). Nicotine did not affect behavioral performance. However, nicotine reduced the difference in the blood oxygenation level dependent (BOLD) signal between invalid and valid trials in the right intraparietal sulcus. The reduction of parietal activity in invalid trials was smaller in the low cue reliability condition. The same posterior parietal region exhibited a nicotinic modulation of BOLD activity in valid trials which was dependent on cue reliability: Nicotine specifically enhanced the neural activity during valid trials in the context of low cue reliability, i.e. when subjects are already in a state of low certainty. We speculate that the right intraparietal sulcus might be part of two networks working in parallel: one responsible for reorienting attention and the other for the cholinergic modulation of cue reliability. By reducing the use of the cue, nicotine modulates parietal activity related to reorienting attention in conditions with higher cue certainty. On the other hand, nicotine increases parietal activity in states of low certainty. This enhanced activation might influence brain regions, such as the posterior cingulate, directly involved in the processing of cue reliability.

Human Brain Functional Network Changes Associated with Enhanced and Impaired Attentional Task Performance

How is the cognitive performance of the human brain related to its topological and spatial organization as a complex network embedded in anatomical space? To address this question, we used nicotine replacement and duration of attentionally demanding task performance (time-on-task), as experimental factors expected, respectively, to enhance and impair cognitive function. We measured resting-state fMRI data, performance and brain activation on a go/no-go task demanding sustained attention, and subjective fatigue in n = 18 healthy, briefly abstinent, cigarette smokers scanned repeatedly in a placebo-controlled, crossover design. We tested the main effects of drug (placebo vs Nicorette gum) and time-on-task on behavioral performance and brain functional network metrics measured in binary graphs of 477 regional nodes (efficiency, measure of integrative topology; clustering, a measure of segregated topology; and the Euclidean physical distance between connected nodes, a proxy marker of wiring cost). Nicotine enhanced attentional task performance behaviorally and increased efficiency, decreased clustering, and increased connection distance of brain networks. Greater behavioral benefits of nicotine were correlated with stronger drug effects on integrative and distributed network configuration and with greater frequency of cigarette smoking. Greater time-on-task had opposite effects: it impaired attentional accuracy, decreased efficiency, increased clustering, and decreased connection distance of networks. These results are consistent with hypothetical predictions that superior cognitive performance should be supported by more efficient, integrated (high capacity) brain network topology at greater connection distance (high cost). They also demonstrate that brain network analysis can provide novel and theoretically principled pharmacodynamic biomarkers of pro-cognitive drug effects in humans.

fMRI Data Predict Individual Differences of Behavioral Effects of Nicotine: A Partial Least Square Analysis

Reorienting of visuospatial attention can be investigated by comparing reaction times to validly and invalidly cued targets (validity effect). The cholinergic agonist nicotine reduces the validity effect and neural activity in the posterior parietal cortex. Behavioral effects of nicotine in nonsmokers are weak and it has been suggested that differences in baseline behavior before nicotine exposure may influence the effect of nicotine. This study investigates whether individual differences in reorienting-related neural activity under placebo may be used to predict individual nicotine effects. Individual nicotine effects are defined as the behavioral effects under nicotine that cannot be predicted by the behavioral data under placebo. Fifteen nonsmoking subjects were given either placebo or nicotine gum (2 mg) prior to performing a cued target detection task inside a magnetic resonance imaging scanner. The results of a partial least square analysis suggest that neural data under placebo can be used to predict individual behavioral effects of nicotine. Neural activity in the left posterior cingulate cortex, the right superior parietal cortex, the right dorsal medial prefrontal cortex, and the left ventral medial prefrontal cortex significantly contributes to that prediction. We conclude that nicotine effects on reorienting attention depend on individual differences in reorienting-related neural activity under placebo and suggest that functional magnetic resonance imaging data can contribute to the prediction of individual drug effects.

Functional Interactions during the Retrieval of Conceptual Action Knowledge: An fMRI Study

Impaired retrieval of conceptual knowledge for actions has been associated with lesions of left premotor, left parietal, and left middle temporal areas [Tranel, D., Kemmerer, D., Adolphs, R., Damasio, H., & Damasio, A. R. Neural correlates of conceptual knowledge for actions. Cognitive Neuropsychology, 409432, 2003]. Here we aimed at characterizing the differential contribution of these areas to the retrieval of conceptual knowledge about actions. During functional magnetic resonance imaging (fMRI), different categories of pictograms (whole-body actions, manipulable and nonmanipulable objects) were presented to healthy subjects. fMRI data were analyzed using SPM2. A conjunction analysis of the neural activations elicited by all pictograms revealed ( p < .05, corrected) a bilateral inferior occipito-temporal neural network with strong activations in the right and left fusiform gyri. Action pictograms contrasted to object pictograms showed differential activation of area MT, the inferior and superior parietal cortex, and the premotor cortex bilaterally. An analysis of psychophysiological interactions identified contribution-dependent changes in the neural responses when pictograms triggered the retrieval of conceptual action knowledge: Processing of action pictograms specifically enhanced the neural interaction between the right and left fusiform gyri, the right and left middle temporal cortices (MT), and the left superior and inferior parietal cortex. These results complement and extend previous neuropsychological and neuroimaging studies by showing that knowledge about action concepts results from an increased coupling between areas concerned with semantic processing (fusiform gyrus), movement perception (MT), and temporospatial movement control (left parietal cortex).

Visuospatial attention: how to measure effects of infrequent, unattended events in a blocked stimulus design

This fMRI study investigates the differences between a blocked and event-related analysis in a cued target detection task, the so-called Posner paradigm, using a hybrid design. Validly and invalidly cued trials were presented intermingled in different blocks containing 50%, 75%, or 100% valid trials. Four analyses were conducted: (i) an event-related analysis comparing invalid and valid trials, (ii) a blocked analysis comparing blocks with 50% valid and invalid trials to blocks with 100% valid trials, (iii) a blocked analysis detecting differences between block models when modeled as epochs or chains of events, and (iv) a blocked analysis that modeled blocks as chains of events to scale regressors equally to the event-related analysis. Irrespective of the type of analysis (blocked or event related), significant activation of the right intraparietal sulcus was observed. A larger cluster size was evident in the blocked analysis, which can be attributed to higher efficiency. In addition to this common right parietal activation, the event-related analysis revealed activations in right superior parietal cortex and left intraparietal sulcus. In contrast, the blocked analysis yielded additional activity in the right occipitoparietal junction. No influences of the block model (epoch versus chain of events) were found in regions activated in the blocked or event-related analysis, respectively. In summary, using a hybrid design and both event-related and blocked analysis techniques, we show both sustained and transient neural processes underlying reorienting of visuospatial attention.

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.

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.

The efficiency of functional brain networks does not differ between smokers and non-smokers

Acute nicotine consumption in smokers impacts on functional brain network topology indicating an increase in the efficiency of information transfer and attentional task performance. The effects of chronic nicotine consumption on functional brain network topology are unknown. We here investigated the effects of chronic smoking-behaviour on functional brain network topology. Minimally-deprived smokers (N=18) and non-smokers (N=17) were measured within an fMRI scanner during a resting state condition. Graph-theoretical metrics of functional network integration (global efficiency and clustering) that have been shown to be affected by acute nicotine administration were compared between both groups. Our results revealed that smoking status did not significantly change functional network integration. Additional tests for non-inferiority confirmed the similarity of regional or nodal network properties. Brain regions such as the left insular and middle frontal gyrus, in which acute nicotine consumption affected network topology, did not reveal any decrease in functional network efficiency following chronic nicotine consumption. Within the limitation of the investigated sample size, our data suggest that the integration of functional brain networks is not altered in minimally-deprived smokers. Our findings are of relevance for clinical studies showing changes in network topology between psychiatric patients with high prevalence of smoking and healthy control subjects.

Pro-cognitive drug effects modulate functional brain network organization

Previous studies document that cholinergic and noradrenergic drugs improve attention, memory and cognitive control in healthy subjects and patients with neuropsychiatric disorders. In humans neural mechanisms of cholinergic and noradrenergic modulation have mainly been analyzed by investigating drug-induced changes of task-related neural activity measured with functional magnetic resonance imaging (fMRI). Endogenous neural activity has often been neglected. Further, although drugs affect the coupling between neurons, only a few human studies have explicitly addressed how drugs modulate the functional connectome, i.e., the functional neural interactions within the brain. These studies have mainly focused on synchronization or correlation of brain activations. Recently, there are some drug studies using graph theory and other new mathematical approaches to model the brain as a complex network of interconnected processing nodes. Using such measures it is possible to detect not only focal, but also subtle, widely distributed drug effects on functional network topology. Most important, graph theoretical measures also quantify whether drug-induced changes in topology or network organization facilitate or hinder information processing. Several studies could show that functional brain integration is highly correlated with behavioral performance suggesting that cholinergic and noradrenergic drugs which improve measures of cognitive performance should increase functional network integration. The purpose of this paper is to show that graph theory provides a mathematical tool to develop theory-driven biomarkers of pro-cognitive drug effects, and also to discuss how these approaches can contribute to the understanding of the role of cholinergic and noradrenergic modulation in the human brain. Finally we discuss the “global workspace” theory as a theoretical framework of pro-cognitive drug effects and argue that pro-cognitive effects of cholinergic and noradrenergic drugs might be related to higher network integration.

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.