Activity and Connectivity Differences Underlying Inhibitory Control Across the Adult Life Span

Abstract

Inhibitory control requires precise regulation of activity and connectivity within multiple brain networks. Previous studies have typically evaluated age-related changes in regional activity or changes in interregional interactions. Instead, we test the hypothesis that activity and connectivity make distinct, complementary contributions to performance across the life span and the maintenance of successful inhibitory control systems. A representative sample of healthy human adults in a large, population-based life span cohort performed an integrated Stop-Signal (SS)/No-Go task during functional magnetic resonance imaging (n = 119; age range, 18-88 years). Individual differences in inhibitory control were measured in terms of the SS reaction time (SSRT), using the blocked integration method. Linear models and independent components analysis revealed that individual differences in SSRT correlated with both activity and connectivity in a distributed inhibition network, comprising prefrontal, premotor, and motor regions. Importantly, this pattern was moderated by age, such that the association between inhibitory control and connectivity, but not activity, differed with age. Multivariate statistics and out-of-sample validation tests of multifactorial functional organization identified differential roles of activity and connectivity in determining an individual's SSRT across the life span. We propose that age-related differences in adaptive cognitive control are best characterized by the joint consideration of multifocal activity and connectivity within distributed brain networks. These insights may facilitate the development of new strategies to support cognitive ability in old age.SIGNIFICANCE STATEMENT The preservation of cognitive and motor control is crucial for maintaining well being across the life span. We show that such control is determined by both activity and connectivity within distributed brain networks. In a large, population-based cohort, we used a novel whole-brain multivariate approach to estimate the functional components of inhibitory control, in terms of their activity and connectivity. Both activity and connectivity in the inhibition network changed with age. But only the association between performance and connectivity, not activity, differed with age. The results suggest that adaptive control is best characterized by the joint consideration of multifocal activity and connectivity. These insights may facilitate the development of new strategies to maintain cognitive ability across the life span in health and disease.

Keywords: aging; functional magnetic resonance imaging (fMRI); individual differences; inhibitory control; network connectivity; regional activity.

Figure 1.

Schematic representation of the task, imaging processing, analysis pipeline and hypotheses in the current study. SSD, Period of variable length to titrate participants' performance at 50% successful response cancellation of all Stop trials (20% of all trials; i.e., the number of successful inhibition trials, unsuccessful inhibition trials, and No-Go trials was similar; ∼10% of all trials, see text); Ti, time course of ith component; β, β coefficients; C1, HRF-convolved time course for condition 1; X, regressors for covariates of no interest including head motion, WM, and CSF.

Figure 2.

Latency (left) and accuracy (right) measures for Go, No-Go, and Stop-Signal trials of each subject, where each subject's performance is denoted with a circle in the scatter plots and red solid lines denote linear trends across the lifespan with corresponding effect sizes; denoted lines are 95% confidence bounds for the fitted coefficients.

Figure 3.

Top left, Group-level component responsivity (difference in condition-specific component activity across contrast) for the contrast SuccStop > UnsuccStop, where each component is shown in a unique color scheme. Lighter color within a given color scheme reflects a higher loading value for a given voxel (i.e., a stronger association between the time course of the voxel and the time course of the component). Top center, Direction of reactivity of the reactive components—higher (hot colors) and lower (cold colors) reactivity for SuccStop > UnsuccStop, where the reactivity of the component is weighted by the loading value of the voxel on the component (see Materials and Methods). Top right, Group effects using traditional univariate GLM analysis in SPM. Regional brain activation for SuccStop > UnsuccStop, warm color scheme; and for UnsuccStop > SuccStop, cold color scheme. Thresholded at a significance level of p < 0.001, uncorrected. There was a high spatial overlap in gray matter activations between the group ICA and GLM methods (r = 0.59, p < 0.001). The differences between the two approaches originated mainly in white matter, vascular, and CSF territories, indicating that group ICA may be less sensitive to individual and age-related differences of physiological signals of non-neuronal origin than traditional univariate GLM analysis. Bottom, Event-related time courses for four types of trials.

Figure 4.

Chord diagrams representing group and age effects of spontaneous connectivity (left) and context-specific connectivity (SuccStop > UnsuccStop; right) for responsive components. Component responsivity (difference in context-dependent component activity across contrasts) for the contrast SuccStop > UnsuccStop is shown in the inner band (higher and lower responsivity are shown in hot and cold colors, respectively), with components having significant group (main) effects (top) and age effects (bottom) denoted with a black outline (p < 0.01, FDR corrected). For labels of components (inner band) and their network correspondence (outer band), see text. l, Left; r, right.

Figure 5.

Significant models of brain measures predicting individual variability in response inhibition (SSRT). Specifically, the significant models include responsivity only (A in Model 1, larger activity in CO and SM nodes during UnsuccStop vs SuccStop was associated with faster SSRT), context-specific connectivity (cPPI in Model 3, larger connectivity modulations between SuccStop and UnsuccStop were associates with faster SSRT), and their joint contribution (Model 4). While context-specific connectivity predicted individual, age-related, and age-moderated variances in SSRT, activity was a significant predictor of the first two only. Below each circular plot, a scatter plot of corresponding bivariate correlation for three equally sized age groups is shown. The relationship between SSRT and connectivity is higher for older (formally confirmed by moderation analysis, see Age × cPPI in Model 3), suggesting that good performance in older adults relies more strongly on a good connectivity profile between functional components. The model with functional connectivity (Model 2) is not shown as it was not significant. l, Left; r, right.

Figure 6.

Top, Event-related time courses for six components during SuccStop (green lines) and UnsuccStop (red lines) across two SSRT groups of individuals (continuous line, fast SSRT; dotted line, slow SSRT). Bottom left, Additional set of analyses demonstrating the activity exclusively in bilateral MOG, as observed during SuccStop > UnsuccStop (Figs. 3, 4). Left, Unilateral activity in medial occipital areas increases in response to arrow orientation to the contralateral side, indicating that the involvement of MOG might be implicated in stimulus response. Right, No activation differences in MOG due to perceptual processing in stimulus differences (e.g., red vs black arrow, UnsuccStop > Go or Go > UnsuccStop). Center, Bilateral activations during correctly performed trials vs error/baseline trials, independent of stimulus lateralization (i.e., SuccStop Left > UnsuccStop Left). Right bottom, Additional set of analyses demonstrating the behavioral relevance of regional activity during SuccStop > Go in terms of predicting individual variability in response inhibition, SSRT (identical to Model 1 in Fig. 5). The correlation between regional activity of the 19 ICs responsive to SuccStop > Go contrast and SSRT was significant (r = −0.270, p = 0.005), of which only 4 ICs contributed significantly. Namely, higher activation in right MiFG and left MOG during SuccStop vs Go trials was associated with faster SSRTs. In addition, lower activation in left PoCG and Pre-CG during SuccStop vs Go was associated with faster SSRTs. Moderation analysis revealed that the association between regional activity and performance remained (r = 0.117, p < 0.001) beyond the effects of aging (r = 0.144, p < 0.001), which did not vary across the life span (i.e., insignificant moderation effect, p = 0.24). Furthermore, the test results using context-dependent connectivity among all 19 ICs to predict SSRTs in multiple linear regression (equivalent to Model 3 in Fig. 5) was insignificant, indicating that the contrast SuccStop vs Go trials might be a less sensitive brain-wide connectivity modulation with behavioral relevance to inhibition control.