Human brain functional network changes associated with enhanced and impaired attentional task performance

Abstract

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.

Figure 1.

Experimental task and nicotine effects on behavior. A, Paradigm. Subjects were assessed in two fMRI sessions, once after placebo and once after nicotine in a double-blind crossover design. Each fMRI session consisted of four resting-state and two task periods. B, Task. During task periods, subjects performed a continuous performance test; during rest periods, subjects kept their eyes open and looked at a centrally presented stimulus (%%%). C, Behavioral effects of nicotine. Left, Nicotine significantly reduced reaction times to go trials (error bars indicate mean ± SEM); right, scatter plot of the effect of nicotine on errors in no-go trials [no-go errors (nicotine) − no-go errors (placebo); y-axis] versus no-go errors at baseline, after placebo (x-axis). Participants who performed the task least well at baseline demonstrated the greatest performance-enhancing effects of nicotine (gray areas within the regression plot represent the 95% confidence interval for the fitted regression line).

Figure 2.

Effects of nicotine and time-on-task on brain network topology. A, Nicotine effects on global efficiency. Nicotine increased global efficiency mostly in sparse networks with low connection density. The plot shows the effect of nicotine (global efficiency nicotine − global efficiency placebo) as a function of connection density averaged over the four resting-state periods. B, Nicotine effects on clustering as a function of connection density. Nicotine decreased clustering especially at sparse densities. C, Global efficiency and clustering are plotted for placebo and nicotine (averaged over the 4 resting-state periods and the entire range of connection densities). D, E, Time-on-task effects on global efficiency (D) and clustering (E) are plotted for each resting-state period over the range of connection densities: greater time-on-task is associated with decreased efficiency and increased clustering of networks in later resting-state periods compared with the first period of resting-state data. F, Global efficiency linearly decreased and mean clustering linearly increased over time on average over all connection densities.

Figure 3.

Nicotine and time-on-task effects changed nodal topology of brain regions. A, No-go task activations. Brain regions in which BOLD activation signal significantly increased during no-go trials compared with go trials within the placebo condition (averaged over both task periods). Significance threshold: red, familywise error corrected p < 0.05; yellow, uncorrected p < 0.001. B, C, For each brain node, we tested whether nicotine and time-on-task significantly increased or decreased nodal efficiency or clustering in resting-state networks. B, Nicotine increased nodal efficiency (red voxels) and decreased clustering (yellow voxels). C, Time-on-task decreased nodal efficiency (red voxels) and increased clustering (yellow voxels; significance threshold, p < 0.002, two-sided). Brain nodes in which changes in network topology overlap with significant changes in task activation (threshold, p < 0.001, uncorrected) are marked by ovals.

Figure 4.

Global changes in network topology were correlated with behavioral effects. A–C, Effects on network topology were correlated with effects on behavior. A, The effect of nicotine on global efficiency correlated with the effects of nicotine on no-go errors: subjects with larger increases of global efficiency after nicotine showed greater nicotine-induced decrease of no-go errors. B, The effect of nicotine on clustering. Subjects with larger decreases of mean clustering after nicotine showed greater nicotine-induced decreases of no-go errors. C, The linear increase in mean clustering over resting-state periods correlated with an increase in no-go errors in both task blocks. To estimate time-related changes, we regressed clustering for each subject on time-on-task; gray areas within the regression plots represent the 95% confidence intervals for the fitted regression lines.

Figure 5.

Effects of nicotine and time-on-task on connection distance. A, Mean connection distance (in millimeters) for each resting-state network averaged over the range of connection densities (1.7–50%) in placebo and nicotine treatment groups. B, Effects of time on the histogram of connection distances; gray bars show distances with a significant decrease or increase in number of connected edges (permutation test, p < 0.05). C, Effects of nicotine on the histogram of network connection distances. D, E, Nicotine-induced changes in connection distance correlated significantly with its effects on global efficiency (r₍₁₆₎ = 0.77, p = 0.0002) and clustering (r₍₁₆₎ = −0.65, p = 0.004). F, Nicotine-induced changes in connection distance correlated significantly with its effects on behavioral errors (r₍₁₆₎ = −0.70, p = 0.001).

Figure 6.

Frequency of cigarette smoking was correlated with effects of nicotine replacement on behavioral performance and network topology. A, Effects of nicotine on no-go errors (no-go errors nicotine − no-go errors placebo) were significantly correlated with the number of cigarettes smoked per day. Higher-frequency smokers had greater reductions of no-go errors after nicotine replacement. B, Effects of nicotine on clustering (clustering nicotine − clustering placebo): higher-frequency smokers had greater nicotine-related reductions of network clustering.