Linda Geerligs

A Brain-Wide Study of Age-Related Changes in Functional Connectivity

Aging affects functional connectivity between brain areas, however, a complete picture of how aging affects integration of information within and between functional networks is missing. We used complex network measures, derived from a brain-wide graph, to provide a comprehensive overview of age-related changes in functional connectivity. Functional connectivity in young and older participants was assessed during resting-state fMRI. The results show that aging has a large impact, not only on connectivity within functional networks but also on connectivity between the different functional networks in the brain. Brain networks in the elderly showed decreased modularity (less distinct functional networks) and decreased local efficiency. Connectivity decreased with age within networks supporting higher level cognitive functions, that is, within the default mode, cingulo-opercular and fronto-parietal control networks. Conversely, no changes in connectivity within the somatomotor and visual networks, networks implicated in primary information processing, were observed. Connectivity between these networks even increased with age. A brain-wide analysis approach of functional connectivity in the aging brain thus seems fundamental in understanding how age affects integration of information.

Reduced Specificity of Functional Connectivity in the Aging Brain During Task Performance

The importance of studying connectivity in the aging brain is increasingly recognized. Recent studies have shown that connectivity within the default mode network is reduced with age and have demonstrated a clear relation of these changes with cognitive functioning. However, research on age‐related changes in other functional networks is sparse and mainly focused on prespecified functional networks. Using functional magnetic resonance imaging, we investigated age‐related changes in functional connectivity during a visual oddball task in a range of functional networks. It was found that compared with young participants, elderly showed a decrease in connectivity between areas belonging to the same functional network. This was found in the default mode network and the somatomotor network. Moreover, in all identified networks, elderly showed increased connectivity between areas within these networks and areas belonging to different functional networks. Decreased connectivity within functional networks was related to poorer cognitive functioning in elderly. The results were interpreted as a decrease in the specificity of functional networks in older participants. Hum Brain Mapp 35:319–330, 2014.

State and Trait Components of Functional Connectivity: Individual Differences Vary with Mental State

Resting-state functional connectivity, as measured by functional magnetic resonance imaging (fMRI), is often treated as a trait, used, for example, to draw inferences about individual differences in cognitive function, or differences between healthy or diseased populations. However, functional connectivity can also depend on the individuals mental state. In the present study, we examined the relative contribution of state and trait components in shaping an individuals functional architecture. We used fMRI data from a large, population-based human sample (N = 587, age 18–88 years), as part of the Cambridge Centre for Aging and Neuroscience (Cam-CAN), which were collected in three mental states: resting, performing a sensorimotor task, and watching a movie. Whereas previous studies have shown commonalities across mental states in the average functional connectivity across individuals, we focused on the effects of states on the pattern of individual differences in functional connectivity. We found that state effects were as important as trait effects in shaping individual functional connectivity patterns, each explaining an approximately equal amount of variance. This was true when we looked at aging, as one specific dimension of individual differences, as well as when we looked at generic aspects of individual variation. These results show that individual differences in functional connectivity consist of state-dependent aspects, as well as more stable, trait-like characteristics. Studying individual differences in functional connectivity across a wider range of mental states will therefore provide a more complete picture of the mechanisms underlying factors such as cognitive ability, aging, and disease. SIGNIFICANCE STATEMENT The brains functional architecture is remarkably similar across different individuals and across different mental states, which is why many studies use functional connectivity as a trait measure. Despite these trait-like aspects, functional connectivity varies over time and with changes in cognitive state. We measured connectivity in three different states to quantify the size of the trait-like component of functional connectivity, compared with the state-dependent component. Our results show that studying individual differences within one state (such as resting) uncovers only part of the relevant individual differences in brain function, and that the study of functional connectivity under multiple mental states is essential to disentangle connectivity differences that are transient versus those that represent more stable, trait-like characteristics of an individual.

Brain mechanisms underlying the effects of aging on different aspects of selective attention.

The ability to suppress irrelevant information declines with age, while the ability to enhance relevant information remains largely intact. We examined mechanisms behind this dissociation in an fMRI study, using a selective attention task in which relevant and irrelevant information appeared simultaneously. Slowing of response times due to distraction by irrelevant targets was larger in older than younger participants. Increased distraction was related to larger increases in activity and connectivity in areas of the dorsal attention network, indicating a more pronounced (re-)orientation of attention. The decreases in accuracy in target compared to nontarget trials were smaller in older compared to younger participants. In older adults we found increased recruitment of areas in the fronto-parietal control network (FPCN) during target detection. Moreover, older adults showed increased connectivity between the FPCN, supporting cognitive control, and somatomotor areas implicated in response selection and execution. This connectivity increase was related to improved target detection, suggesting that older adults engage additional cognitive control, which might enable the observed intact performance in detecting and responding to target stimuli.

Connectomics and neuroticism: an altered functional network organization

The personality trait neuroticism is a potent risk marker for psychopathology. Although the neurobiological basis remains unclear, studies have suggested that alterations in connectivity may underlie it. Therefore, the aim of the current study was to shed more light on the functional network organization in neuroticism. To this end, we applied graph theory on resting-state functional magnetic resonance imaging (fMRI) data in 120 women selected based on their neuroticism score. Binary and weighted brain-wide graphs were constructed to examine changes in the functional network structure and functional connectivity strength. Furthermore, graphs were partitioned into modules to specifically investigate connectivity within and between functional subnetworks related to emotion processing and cognitive control. Subsequently, complex network measures (ie, efficiency and modularity) were calculated on the brain-wide graphs and modules, and correlated with neuroticism scores. Compared with low neurotic individuals, high neurotic individuals exhibited a whole-brain network structure resembling more that of a random network and had overall weaker functional connections. Furthermore, in these high neurotic individuals, functional subnetworks could be delineated less clearly and the majority of these subnetworks showed lower efficiency, while the affective subnetwork showed higher efficiency. In addition, the cingulo-operculum subnetwork demonstrated more ties with other functional subnetworks in association with neuroticism. In conclusion, the ‘neurotic brain’ has a less than optimal functional network organization and shows signs of functional disconnectivity. Moreover, in high compared with low neurotic individuals, emotion and salience subnetworks have a more prominent role in the information exchange, while sensory(-motor) and cognitive control subnetworks have a less prominent role.

Flexible Connectivity in the Aging Brain Revealed by Task Modulations

Recent studies have shown that aging has a large impact on connectivity within and between functional networks. An open question is whether elderly still have the flexibility to adapt functional network connectivity (FNC) to the demands of the task at hand. To study this, we collected fMRI data in younger and older participants during resting state, a selective attention (SA) task and an n‐back working memory task with varying levels of difficulty. Spatial independent component (IC) analysis was used to identify functional networks over all participants and all conditions. Dual regression was used to obtain participant and task specific time‐courses per IC. Subsequently, functional connectivity was computed between all ICs in each of the tasks. Based on these functional connectivity matrices, a scaled version of the eigenvector centrality (SEC) was used to measure the total influence of each IC in the complete graph of ICs. The results demonstrated that elderly remain able to adapt FNC to task demands. However, there was an age‐related shift in the impetus for FNC change. Older participants showed the maximal change in SEC patterns between resting state and the SA task. Young participants, showed the largest shift in SEC patterns between the less demanding SA task and the more demanding 2‐back task. Our results suggest that increased FNC changes from resting state to low demanding tasks in elderly reflect recruitment of additional resources, compared with young adults. The lack of change between the low and high demanding tasks suggests that elderly reach a resource ceiling. Hum Brain Mapp 35:3788–3804, 2014.

The Relationship between P3 Amplitude and Working Memory Performance Differs in Young and Older Adults

While some elderly show deteriorations in cognitive performance, others achieve performance levels comparable to young adults. To examine whether age-related changes in brain activity varied with working memory performance efficiency, we recorded electroencephalography (EEG) from young and older healthy adults during performance on an n-back task with two loads (0- and 1-back) and two versions (identity and integrated). Young adults showed a typical P3 amplitude pattern with a parietal-maximum. Compared to young adults, the P3 amplitude of older adults was characterized by frontal hyperactivity coupled with posterior hypoactivity. Moreover, P3 amplitude in young and older adults varied with working memory performance efficiency. Among young adults, more efficient performance correlated with a larger P3 amplitude at parietal sites. In contrast, a higher P3 amplitude at midline electrode sites in older adults correlated with less efficient performance. Particularly, the enhanced frontal midline EEG activity in older adults during working memory performance seems to reflect inefficient use of neural resources due to frontal lobe dysfunction.

Compensation through increased functional connectivity: Neural correlates of inhibition in old and young

With increasing age, people experience more difficulties with suppressing irrelevant information, which may have a major impact on cognitive functioning. The extent of decline of inhibitory functions with age is highly variable between individuals. In this study, we used ERPs and phase locking analyses to investigate neural correlates of this variability in inhibition between individuals. Older and younger participants performed a selective attention task in which relevant and irrelevant information was presented simultaneously. The participants were split into high and low performers based on their level of inhibition inefficiency, that is, the slowing of RTs induced by information that participants were instructed to ignore. P1 peak amplitudes were larger in low performers than in high performers, indicating that low performers were less able to suppress the processing of irrelevant stimuli. Phase locking analyses were used as a measure of functional connectivity. Efficient inhibition in both age groups was related to the increased functional connectivity in the alpha band between frontal and occipito-parietal ROIs in the prestimulus interval. In addition, increased power in the alpha band in occipito-parietal ROIs was related to better inhibition both before and after stimulus onset. Phase locking in the upper beta band before and during stimulus presentation between frontal and occipito-parietal ROIs was related to a better performance in older participants only, suggesting that this is an active compensation mechanism employed to maintain adequate performance. In addition, increased top–down modulation and increased power in the alpha band appears to be a general mechanism facilitating inhibition in both age groups.

Functional connectivity and structural covariance between regions of interest can be measured more accurately using multivariate distance correlation

Studies of brain-wide functional connectivity or structural covariance typically use measures like the Pearson correlation coefficient, applied to data that have been averaged across voxels within regions of interest (ROIs). However, averaging across voxels may result in biased connectivity estimates when there is inhomogeneity within those ROIs, e.g., sub-regions that exhibit different patterns of functional connectivity or structural covariance. Here, we propose a new measure based on “distance correlation”; a test of multivariate dependence of high dimensional vectors, which allows for both linear and non-linear dependencies. We used simulations to show how distance correlation out-performs Pearson correlation in the face of inhomogeneous ROIs. To evaluate this new measure on real data, we use resting-state fMRI scans and T1 structural scans from 2 sessions on each of 214 participants from the Cambridge Centre for Ageing & Neuroscience (Cam-CAN) project. Pearson correlation and distance correlation showed similar average connectivity patterns, for both functional connectivity and structural covariance. Nevertheless, distance correlation was shown to be 1) more reliable across sessions, 2) more similar across participants, and 3) more robust to different sets of ROIs. Moreover, we found that the similarity between functional connectivity and structural covariance estimates was higher for distance correlation compared to Pearson correlation. We also explored the relative effects of different preprocessing options and motion artefacts on functional connectivity. Because distance correlation is easy to implement and fast to compute, it is a promising alternative to Pearson correlations for investigating ROI-based brain-wide connectivity patterns, for functional as well as structural data.

Acute Stress Modulates Feedback Processing in Men and Women: Differential Effects on the Feedback-Related Negativity and Theta and Beta Power

Sex-specific prevalence rates in mental and physical disorders may be partly explained by sex differences in physiological stress responses. Neural networks that might be involved are those underlying feedback processing. Aim of the present EEG study was to investigate whether acute stress alters feedback processing, and whether stress effects differ between men and women. Male and female participants performed a gambling task, in a control and a stress condition. Stress was induced by exposing participants to a noise stressor. Brain activity was analyzed using both event-related potential and time-frequency analyses, measuring the feedback-related negativity (FRN) and feedback-related changes in theta and beta oscillatory power, respectively. While the FRN and feedback-related theta power were similarly affected by stress induction in both sexes, feedback-related beta power depended on the combination of stress induction condition and sex. FRN amplitude and theta power increases were smaller in the stress relative to the control condition in both sexes, demonstrating that acute noise stress impairs performance monitoring irrespective of sex. However, in the stress but not in the control condition, early lower beta-band power increases were larger for men than women, indicating that stress effects on feedback processing are partly sex-dependent. Our findings suggest that sex-specific effects on feedback processing may comprise a factor underlying sex-specific stress responses.