Total Sleep Deprivation Increases Brain Age Prediction Reversibly in Multisite Samples of Young Healthy Adults.

Sleep loss pervasively affects the human brain at multiple levels. Age-related changes in several sleep characteristics indicate that reduced sleep quality is a frequent characteristic of aging. Conversely, sleep disruption may accelerate the aging process, yet it is not known what will happen to the age status of the brain if we can manipulate sleep conditions. To tackle this question, we used an approach of brain age to investigate whether sleep loss would cause age-related changes in the brain. We included MRI data of 134 healthy volunteers (mean chronological age of 25.3 between the age of 19 and 39 years, 42 females/92 males) from five datasets with different sleep conditions. Across three datasets with the condition of total sleep deprivation (>24 h of prolonged wakefulness), we consistently observed that total sleep deprivation increased brain age by 1-2 years regarding the group mean difference with the baseline. Interestingly, after one night of recovery sleep, brain age was not different from baseline. We also demonstrated the associations between the change in brain age after total sleep deprivation and the sleep variables measured during the recovery night. By contrast, brain age was not significantly changed by either acute (3 h time-in-bed for one night) or chronic partial sleep restriction (5 h time-in-bed for five continuous nights). Together, the convergent findings indicate that acute total sleep loss changes brain morphology in an aging-like direction in young participants and that these changes are reversible by recovery sleep.SIGNIFICANCE STATEMENT Sleep is fundamental for humans to maintain normal physical and psychological functions. Experimental sleep deprivation is a variable-controlling approach to engaging the brain among different sleep conditions for investigating the responses of the brain to sleep loss. Here, we quantified the response of the brain to sleep deprivation by using the change of brain age predictable with brain morphologic features. In three independent datasets, we consistently found increased brain age after total sleep deprivation, which was associated with the change in sleep variables. Moreover, no significant change in brain age was found after partial sleep deprivation in another two datasets. Our study provides new evidence to explain the brainwide effect of sleep loss in an aging-like direction.

BrainAGE: Revisited and reframed machine learning workflow.

Since the introduction of the BrainAGE method, novel machine learning methods for brain age prediction have continued to emerge. The idea of estimating the chronological age from magnetic resonance images proved to be an interesting field of research due to the relative simplicity of its interpretation and its potential use as a biomarker of brain health. We revised our previous BrainAGE approach, originally utilising relevance vector regression (RVR), and substituted it with Gaussian process regression (GPR), which enables more stable processing of larger datasets, such as the UK Biobank (UKB). In addition, we extended the global BrainAGE approach to regional BrainAGE, providing spatially specific scores for five brain lobes per hemisphere. We tested the performance of the new algorithms under several different conditions and investigated their validity on the ADNI and schizophrenia samples, as well as on a synthetic dataset of neocortical thinning. The results show an improved performance of the reframed global model on the UKB sample with a mean absolute error (MAE) of less than 2 years and a significant difference in BrainAGE between healthy participants and patients with Alzheimer's disease and schizophrenia. Moreover, the workings of the algorithm show meaningful effects for a simulated neocortical atrophy dataset. The regional BrainAGE model performed well on two clinical samples, showing disease-specific patterns for different levels of impairment. The results demonstrate that the new improved algorithms provide reliable and valid brain age estimations.

Sex classification from functional brain connectivity: Generalization to multiple datasets.

Machine learning (ML) approaches are increasingly being applied to neuroimaging data. Studies in neuroscience typically have to rely on a limited set of training data which may impair the generalizability of ML models. However, it is still unclear which kind of training sample is best suited to optimize generalization performance. In the present study, we systematically investigated the generalization performance of sex classification models trained on the parcelwise connectivity profile of either single samples or compound samples of two different sizes. Generalization performance was quantified in terms of mean across-sample classification accuracy and spatial consistency of accurately classifying parcels. Our results indicate that the generalization performance of parcelwise classifiers (pwCs) trained on single dataset samples is dependent on the specific test samples. Certain datasets seem to "match" in the sense that classifiers trained on a sample from one dataset achieved a high accuracy when tested on the respected other one and vice versa. The pwCs trained on the compound samples demonstrated overall highest generalization performance for all test samples, including one derived from a dataset not included in building the training samples. Thus, our results indicate that both a large sample size and a heterogeneous data composition of a training sample have a central role in achieving generalizable results.

Mapping the interplay of atrial fibrillation, brain structure, and cognitive dysfunction.

INTRODUCTION: Atrial fibrillation (AF) is associated with an elevated risk of cognitive impairment and dementia. Understanding the cognitive sequelae and brain structural changes associated with AF is vital for addressing ensuing health care needs. METHODS AND RESULTS: We examined 1335 stroke-free individuals with AF and 2683 matched controls using neuropsychological assessments and multimodal neuroimaging. The analysis revealed that individuals with AF exhibited deficits in executive function, processing speed, and reasoning, accompanied by reduced cortical thickness, elevated extracellular free-water content, and widespread white matter abnormalities, indicative of small vessel pathology. Notably, brain structural differences statistically mediated the relationship between AF and cognitive performance. DISCUSSION: Integrating a comprehensive analysis approach with extensive clinical and magnetic resonance imaging data, our study highlights small vessel pathology as a possible unifying link among AF, cognitive decline, and abnormal brain structure. These insights can inform diagnostic approaches and motivate the ongoing implementation of effective therapeutic strategies. Highlights We investigated neuropsychological and multimodal neuroimaging data of 1335 individuals with atrial fibrillation (AF) and 2683 matched controls. Our analysis revealed AF-associated deficits in cognitive domains of attention, executive function, processing speed, and reasoning. Cognitive deficits in the AF group were accompanied by structural brain alterations including reduced cortical thickness and gray matter volume, alongside increased extracellular free-water content as well as widespread differences of white matter integrity. Structural brain changes statistically mediated the link between AF and cognitive performance, emphasizing the potential of structural imaging markers as a diagnostic tool in AF-related cognitive decline.

A systematic comparison of VBM pipelines and their application to age prediction.

Voxel-based morphometry (VBM) analysis is commonly used for localized quantification of gray matter volume (GMV). Several alternatives exist to implement a VBM pipeline. However, how these alternatives compare and their utility in applications, such as the estimation of aging effects, remain largely unclear. This leaves researchers wondering which VBM pipeline they should use for their project. In this study, we took a user-centric perspective and systematically compared five VBM pipelines, together with registration to either a general or a study-specific template, utilizing three large datasets (n>500 each). Considering the known effect of aging on GMV, we first compared the pipelines in their ability of individual-level age prediction and found markedly varied results. To examine whether these results arise from systematic differences between the pipelines, we classified them based on their GMVs, resulting in near-perfect accuracy. To gain deeper insights, we examined the impact of different VBM steps using the region-wise similarity between pipelines. The results revealed marked differences, largely driven by segmentation and registration steps. We observed large variability in subject-identification accuracies, highlighting the interpipeline differences in individual-level quantification of GMV. As a biologically meaningful criterion we correlated regional GMV with age. The results were in line with the age-prediction analysis, and two pipelines, CAT and the combination of fMRIPrep for tissue characterization with FSL for registration, reflected age information better.

Brain-age prediction: A systematic comparison of machine learning workflows.

The difference between age predicted using anatomical brain scans and chronological age, i.e., the brain-age delta, provides a proxy for atypical aging. Various data representations and machine learning (ML) algorithms have been used for brain-age estimation. However, how these choices compare on performance criteria important for real-world applications, such as; (1) within-dataset accuracy, (2) cross-dataset generalization, (3) test-retest reliability, and (4) longitudinal consistency, remains uncharacterized. We evaluated 128 workflows consisting of 16 feature representations derived from gray matter (GM) images and eight ML algorithms with diverse inductive biases. Using four large neuroimaging databases covering the adult lifespan (total N = 2953, 18-88 years), we followed a systematic model selection procedure by sequentially applying stringent criteria. The 128 workflows showed a within-dataset mean absolute error (MAE) between 4.73-8.38 years, from which 32 broadly sampled workflows showed a cross-dataset MAE between 5.23-8.98 years. The test-retest reliability and longitudinal consistency of the top 10 workflows were comparable. The choice of feature representation and the ML algorithm both affected the performance. Specifically, voxel-wise feature spaces (smoothed and resampled), with and without principal components analysis, with non-linear and kernel-based ML algorithms performed well. Strikingly, the correlation of brain-age delta with behavioral measures disagreed between within-dataset and cross-dataset predictions. Application of the best-performing workflow on the ADNI sample showed a significantly higher brain-age delta in Alzheimer's and mild cognitive impairment patients compared to healthy controls. However, in the presence of age bias, the delta estimates in the patients varied depending on the sample used for bias correction. Taken together, brain-age shows promise, but further evaluation and improvements are needed for its real-world application.

Impact of sample size and regression of tissue-specific signals on effective connectivity within the core default mode network.

Interactions within brain networks are inherently directional, which are inaccessible to classical functional connectivity estimates from resting-state functional magnetic resonance imaging (fMRI) but can be detected using spectral dynamic causal modeling (DCM). The sample size and unavoidable presence of nuisance signals during fMRI measurement are the two important factors influencing the stability of group estimates of connectivity parameters. However, most recent studies exploring effective connectivity (EC) have been conducted with small sample sizes and minimally pre-processed datasets. We explore the impact of these two factors by analyzing clean resting-state fMRI data from 330 unrelated subjects from the Human Connectome Project database. We demonstrate that both the stability of the model selection procedures and the inference of connectivity parameters are highly dependent on the sample size. The minimum sample size required for stable DCM is approximately 50, which may explain the variability of the DCM results reported so far. We reveal a stable pattern of EC within the core default mode network computed for large sample sizes and demonstrate that the use of subject-specific thresholded whole-brain masks for tissue-specific signals regression enhances the detection of weak connections.

Lack of structural brain alterations associated with insomnia: findings from the ENIGMA-Sleep Working Group.

Existing neuroimaging studies have reported divergent structural alterations in insomnia disorder (ID). In the present study, we performed a large-scale coordinated meta-analysis by pooling structural brain measures from 1085 subjects (mean [SD] age 50.5 [13.9] years, 50.2% female, 17.4% with insomnia) across three international Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA)-Sleep cohorts. Two sites recruited patients with ID/controls: Freiburg (University of Freiburg Medical Center, Freiburg, Germany) 42/43 and KUMS (Kermanshah University of Medical Sciences, Kermanshah, Iran) 42/49, while the Study of Health in Pomerania (SHIP-Trend, University Medicine Greifswald, Greifswald, Germany) recruited population-based individuals with/without insomnia symptoms 75/662. The influence of insomnia on magnetic resonance imaging-based brain morphometry using an insomnia brain score was then assessed. Within each cohort, we used an ordinary least-squares linear regression to investigate the link between the individual regional cortical and subcortical volumes and the presence of insomnia symptoms. Then, we performed a fixed-effects meta-analysis across cohorts based on the first-level results. For the insomnia brain score, weighted logistic ridge regression was performed on one sample (Freiburg), which separated patients with ID from controls to train a model based on the segmentation measurements. Afterward, the insomnia brain scores were validated using the other two samples. The model was used to predict the log-odds of the subjects with insomnia given individual insomnia-related brain atrophy. After adjusting for multiple comparisons, we did not detect any significant associations between insomnia symptoms and cortical or subcortical volumes, nor could we identify a global insomnia-related brain atrophy pattern. Thus, we observed inconsistent brain morphology differences between individuals with and without insomnia across three independent cohorts. Further large-scale cross-sectional/longitudinal studies using both structural and functional neuroimaging are warranted to decipher the neurobiology of insomnia.

Hippocampal metabolic subregions and networks: Behavioral, molecular, and pathological aging profiles.

INTRODUCTION: Hippocampal local and network dysfunction is the hallmark of Alzheimer's disease (AD). METHODS: We characterized the spatial patterns of hippocampus differentiation based on brain co-metabolism in healthy elderly participants and demonstrated their relevance to study local metabolic changes and associated dysfunction in pathological aging. RESULTS: The hippocampus can be differentiated into anterior/posterior and dorsal cornu ammonis (CA)/ventral (subiculum) subregions. While anterior/posterior CA show co-metabolism with different regions of the subcortical limbic networks, the anterior/posterior subiculum are parts of cortical networks supporting object-centered memory and higher cognitive demands, respectively. Both networks show relationships with the spatial patterns of gene expression pertaining to cell energy metabolism and AD's process. Finally, while local metabolism is generally lower in posterior regions, the anterior-posterior imbalance is maximal in late mild cognitive impairment with the anterior subiculum being relatively preserved. DISCUSSION: Future studies should consider bidimensional hippocampal differentiation and in particular the posterior subicular region to better understand pathological aging.

Cross-cohort replicability and generalizability of connectivity-based psychometric prediction patterns.

An increasing number of studies have investigated the relationships between inter-individual variability in brain regions' connectivity and behavioral phenotypes, making use of large population neuroimaging datasets. However, the replicability of brain-behavior associations identified by these approaches remains an open question. In this study, we examined the cross-dataset replicability of brain-behavior association patterns for fluid cognition and openness predictions using a previously developed region-wise approach, as well as using a standard whole-brain approach. Overall, we found moderate similarity in patterns for fluid cognition predictions across cohorts, especially in the Human Connectome Project Young Adult, Human Connectome Project Aging, and Enhanced Nathan Kline Institute Rockland Sample cohorts, but low similarity in patterns for openness predictions. In addition, we assessed the generalizability of prediction models in cross-dataset predictions, by training the model in one dataset and testing in another. Making use of the region-wise prediction approach, we showed that first, a moderate extent of generalizability could be achieved with fluid cognition prediction, and that, second, a set of common brain regions related to fluid cognition across cohorts could be identified. Nevertheless, the moderate replicability and generalizability could only be achieved in specific contexts. Thus, we argue that replicability and generalizability in connectivity-based prediction remain limited and deserve greater attention in future studies.

Evaluation of thresholding methods for activation likelihood estimation meta-analysis via large-scale simulations.

In recent neuroimaging studies, threshold-free cluster enhancement (TFCE) gained popularity as a sophisticated thresholding method for statistical inference. It was shown to feature higher sensitivity than the frequently used approach of controlling the cluster-level family-wise error (cFWE) and it does not require setting a cluster-forming threshold at voxel level. Here, we examined the applicability of TFCE to a widely used method for coordinate-based neuroimaging meta-analysis, Activation Likelihood Estimation (ALE), by means of large-scale simulations. We created over 200,000 artificial meta-analysis datasets by independently varying the total number of experiments included and the amount of spatial convergence across experiments. Next, we applied ALE to all datasets and compared the performance of TFCE to both voxel-level and cluster-level FWE correction approaches. All three multiple-comparison correction methods yielded valid results, with only about 5% of the significant clusters being based on spurious convergence, which corresponds to the nominal level the methods were controlling for. On average, TFCE's sensitivity was comparable to that of cFWE correction, but it was slightly worse for a subset of parameter combinations, even after TFCE parameter optimization. cFWE yielded the largest significant clusters, closely followed by TFCE, while voxel-level FWE correction yielded substantially smaller clusters, showcasing its high spatial specificity. Given that TFCE does not outperform the standard cFWE correction but is computationally much more expensive, we conclude that employing TFCE for ALE cannot be recommended to the general user.

A Connectivity-Based Psychometric Prediction Framework for Brain-Behavior Relationship Studies.

The recent availability of population-based studies with neuroimaging and behavioral measurements opens promising perspectives to investigate the relationships between interindividual variability in brain regions' connectivity and behavioral phenotypes. However, the multivariate nature of connectivity-based prediction model severely limits the insight into brain-behavior patterns for neuroscience. To address this issue, we propose a connectivity-based psychometric prediction framework based on individual regions' connectivity profiles. We first illustrate two main applications: 1) single brain region's predictive power for a range of psychometric variables and 2) single psychometric variable's predictive power variation across brain region. We compare the patterns of brain-behavior provided by these approaches to the brain-behavior relationships from activation approaches. Then, capitalizing on the increased transparency of our approach, we demonstrate how the influence of various data processing and analyses can directly influence the patterns of brain-behavior relationships, as well as the unique insight into brain-behavior relationships offered by this approach.

The Aging Brain and Executive Functions Revisited: Implications from Meta-analytic and Functional-Connectivity Evidence.

Healthy aging is associated with changes in cognitive performance, including executive functions (EFs) and their associated brain activation patterns. However, it has remained unclear which EF-related brain regions are affected consistently, because the results of pertinent neuroimaging studies and earlier meta-analyses vary considerably. We, therefore, conducted new rigorous meta-analyses of published age differences in EF-related brain activity. Out of a larger set of regions associated with EFs, only left inferior frontal junction and left anterior cuneus/precuneus were found to show consistent age differences. To further characterize these two age-sensitive regions, we performed seed-based resting-state functional connectivity (RS-FC) analyses using fMRI data from a large adult sample with a wide age range. We also assessed associations of the two regions' whole-brain RS-FC patterns with age and EF performance. Although our results largely point toward a domain-general role of left inferior frontal junction in EFs, the pattern of individual study contributions to the meta-analytic results suggests process-specific modulations by age. Our analyses further indicate that the left anterior cuneus/precuneus is recruited differently by older (compared with younger) adults during EF tasks, potentially reflecting inefficiencies in switching the attentional focus. Overall, our findings question earlier meta-analytic results and suggest a larger heterogeneity of age-related differences in brain activity associated with EFs. Hence, they encourage future research that pays greater attention to replicability, investigates age-related differences in deactivation, and focuses on more narrowly defined EF subprocesses, combining multiple behavioral assessments with multimodal imaging.

Inter-subject and inter-parcellation variability of resting-state whole-brain dynamical modeling.

Modern approaches to investigate complex brain dynamics suggest to represent the brain as a functional network of brain regions defined by a brain atlas, while edges represent the structural or functional connectivity among them. This approach is also utilized for mathematical modeling of the resting-state brain dynamics, where the applied brain parcellation plays an essential role in deriving the model network and governing the modeling results. There is however no consensus and empirical evidence on how a given brain atlas affects the model outcome, and the choice of parcellation is still rather arbitrary. Accordingly, we explore the impact of brain parcellation on inter-subject and inter-parcellation variability of model fitting to empirical data. Our objective is to provide a comprehensive empirical evidence of potential influences of parcellation choice on resting-state whole-brain dynamical modeling. We show that brain atlases strongly influence the quality of model validation and propose several variables calculated from empirical data to account for the observed variability. A few classes of such data variables can be distinguished depending on their inter-subject and inter-parcellation explanatory power.

Functional parcellation of human and macaque striatum reveals human-specific connectivity in the dorsal caudate.

A wide homology between human and macaque striatum is often assumed as in both the striatum is involved in cognition, emotion and executive functions. However, differences in functional and structural organization between human and macaque striatum may reveal evolutionary divergence and shed light on human vulnerability to neuropsychiatric diseases. For instance, dopaminergic dysfunction of the human striatum is considered to be a pathophysiological underpinning of different disorders, such as Parkinson's disease (PD) and schizophrenia (SCZ). Previous investigations have found a wide similarity in structural connectivity of the striatum between human and macaque, leaving the cross-species comparison of its functional organization unknown. In this study, resting-state functional connectivity (RSFC) derived striatal parcels were compared based on their homologous cortico-striatal connectivity. The goal here was to identify striatal parcels whose connectivity is human-specific compared to macaque parcels. Functional parcellation revealed that the human striatum was split into dorsal, dorsomedial, and rostral caudate and ventral, central, and caudal putamen, while the macaque striatum was divided into dorsal, and rostral caudate and rostral, and caudal putamen. Cross-species comparison indicated dissimilar cortico-striatal RSFC of the topographically similar dorsal caudate. We probed clinical relevance of the striatal clusters by examining differences in their cortico-striatal RSFC and gray matter (GM) volume between patients (with PD and SCZ) and healthy controls. We found abnormal RSFC not only between dorsal caudate, but also between rostral caudate, ventral, central and caudal putamen and widespread cortical regions for both PD and SCZ patients. Also, we observed significant structural atrophy in rostral caudate, ventral and central putamen for both PD and SCZ while atrophy in the dorsal caudate was specific to PD. Taken together, our cross-species comparative results revealed shared and human-specific RSFC of different striatal clusters reinforcing the complex organization and function of the striatum. In addition, we provided a testable hypothesis that abnormalities in a region with human-specific connectivity, i.e., dorsal caudate, might be associated with neuropsychiatric disorders.

Hippocampus co-atrophy pattern in dementia deviates from covariance patterns across the lifespan.

The hippocampus is a plastic region and highly susceptible to ageing and dementia. Previous studies explicitly imposed a priori models of hippocampus when investigating ageing and dementia-specific atrophy but led to inconsistent results. Consequently, the basic question of whether macrostructural changes follow a cytoarchitectonic or functional organization across the adult lifespan and in age-related neurodegenerative disease remained open. The aim of this cross-sectional study was to identify the spatial pattern of hippocampus differentiation based on structural covariance with a data-driven approach across structural MRI data of large cohorts (n = 2594). We examined the pattern of structural covariance of hippocampus voxels in young, middle-aged, elderly, mild cognitive impairment and dementia disease samples by applying a clustering algorithm revealing differentiation in structural covariance within the hippocampus. In all the healthy and in the mild cognitive impaired participants, the hippocampus was robustly divided into anterior, lateral and medial subregions reminiscent of cytoarchitectonic division. In contrast, in dementia patients, the pattern of subdivision was closer to known functional differentiation into an anterior, body and tail subregions. These results not only contribute to a better understanding of co-plasticity and co-atrophy in the hippocampus across the lifespan and in dementia, but also provide robust data-driven spatial representations (i.e. maps) for structural studies.

Within- and across-network alterations of the sensorimotor network in Parkinson's disease.

PURPOSE: Parkinson's disease (PD) is primarily defined by motor symptoms and is associated with alterations of sensorimotor areas. Evidence for network changes of the sensorimotor network (SMN) in PD is inconsistent and a systematic evaluation of SMN in PD yet missing. We investigate functional connectivity changes of the SMN in PD, both, within the network, and to other large-scale connectivity networks. METHODS: Resting-state fMRI was assessed in 38 PD patients under long-term dopaminergic treatment and 43 matched healthy controls (HC). Independent component analysis (ICA) into 20 components was conducted and the SMN was identified within the resulting networks. Functional connectivity within the SMN was analyzed using a dual regression approach. Connectivity between the SMN and the other networks from group ICA was investigated with FSLNets. We investigated for functional connectivity changes between patients and controls as well as between medication states (OFF vs. ON) in PD and for correlations with clinical parameters. RESULTS: There was decreased functional connectivity within the SMN in left inferior parietal and primary somatosensory cortex in PD OFF. Across networks, connectivity between SMN and two motor networks as well as two visual networks was diminished in PD OFF. All connectivity decreases partially normalized in PD ON. CONCLUSION: PD is accompanied by functional connectivity losses of the SMN, both, within the network and in interaction to other networks. The connectivity changes in short- and long-range connections are probably related to impaired sensory integration for motor function in PD. SMN decoupling can be partially compensated by dopaminergic therapy.

Sex Classification by Resting State Brain Connectivity.

A large amount of brain imaging research has focused on group studies delineating differences between males and females with respect to both cognitive performance as well as structural and functional brain organization. To supplement existing findings, the present study employed a machine learning approach to assess how accurately participants' sex can be classified based on spatially specific resting state (RS) brain connectivity, using 2 samples from the Human Connectome Project (n1 = 434, n2 = 310) and 1 fully independent sample from the 1000BRAINS study (n = 941). The classifier, which was trained on 1 sample and tested on the other 2, was able to reliably classify sex, both within sample and across independent samples, differing both with respect to imaging parameters and sample characteristics. Brain regions displaying highest sex classification accuracies were mainly located along the cingulate cortex, medial and lateral frontal cortex, temporoparietal regions, insula, and precuneus. These areas were stable across samples and match well with previously described sex differences in functional brain organization. While our data show a clear link between sex and regionally specific brain connectivity, they do not support a clear-cut dimorphism in functional brain organization that is driven by sex alone.

Influence of Processing Pipeline on Cortical Thickness Measurement.

In recent years, replicability of neuroscientific findings, specifically those concerning correlates of morphological properties of gray matter (GM), have been subject of major scrutiny. Use of different processing pipelines and differences in their estimates of the macroscale GM may play an important role in this context. To address this issue, here, we investigated the cortical thickness estimates of three widely used pipelines. Based on analyses in two independent large-scale cohorts, we report high levels of within-pipeline reliability of the absolute cortical thickness-estimates and comparable spatial patterns of cortical thickness-estimates across all pipelines. Within each individual, absolute regional thickness differed between pipelines, indicating that in-vivo thickness measurements are only a proxy of actual thickness of the cortex, which shall only be compared within the same software package and thickness estimation technique. However, at group level, cortical thickness-estimates correlated strongly between pipelines, in most brain regions. The smallest between-pipeline correlations were observed in para-limbic areas and insula. These regions also demonstrated the highest interindividual variability and the lowest reliability of cortical thickness-estimates within each pipeline, suggesting that structural variations within these regions should be interpreted with caution.

Functional network reorganization in older adults: Graph-theoretical analyses of age, cognition and sex.

Healthy aging has been associated with a decrease in functional network specialization. Importantly, variability of alterations of functional connectivity is especially high across older adults. Whole-brain functional network reorganization, though, and its impact on cognitive performance within particularly the older generation is still a matter of debate. We assessed resting state functional connectivity (RSFC) in 772 older adults (55-85 years, 421 males) using a graph-theoretical approach. Results show overall age-related increases of between- and decreases of within-network RSFC. With similar phenomena observed in young to middle-aged adults, i.e. that RSFC reorganizes towards more pronounced functional network integration, the current results amend such evidence for the old age. The results furthermore indicate that RSFC reorganization in older adults particularly pertain to early sensory networks (e.g. visual and sensorimotor network). Importantly, RSFC differences of these early sensory networks were found to be a relevant mediator in terms of the age-related cognitive performance differences. Further, we found systematic sex-related network differences with females showing patterns of more segregation (i.e. default mode and ventral attention network) and males showing a higher integrated network system (particularly for the sensorimotor network). These findings underpin the notion of sex-related connectivity differences, possibly facilitating sex-related behavioral functioning.