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Functional connectomics is one of the most rapidly expanding areas of neuroimaging research. Yet, concerns remain regarding the use of resting-state fMRI (R-fMRI) to characterize inter-individual variation in the functional connectome. In particular, recent findings that “micro” head movements can introduce artifactual inter-individual and group-related differences in R-fMRI metrics have raised concerns. Here, we first build on prior demonstrations of regional variation in the magnitude of framewise displacements associated with a given head movement, by providing a comprehensive voxel-based examination of the impact of motion on the BOLD signal (i.e., motion–BOLD relationships). Positive motion–BOLD relationships were detected in primary and supplementary motor areas, particularly in low motion datasets. Negative motion–BOLD relationships were most prominent in prefrontal regions, and expanded throughout the brain in high motion datasets (e.g., children). Scrubbing of volumes with FD>0.2 effectively removed negative but not positive correlations; these findings suggest that positive relationships may reflect neural origins of motion while negative relationships are likely to originate from motion artifact. We also examined the ability of motion correction strategies to eliminate artifactual differences related to motion among individuals and between groups for a broad array of voxel-wise R-fMRI metrics. Residual relationships between motion and the examined R-fMRI metrics remained for all correction approaches, underscoring the need to covary motion effects at the group-level. Notably, global signal regression reduced relationships between motion and inter-individual differences in correlation-based R-fMRI metrics; Z-standardization (mean-centering and variance normalization) of subject-level maps for R-fMRI metrics prior to group-level analyses demonstrated similar advantages. Finally, our test–retest (TRT) analyses revealed significant motion effects on TRT reliability for R-fMRI metrics. Generally, motion compromised reliability of R-fMRI metrics, with the exception of those based on frequency characteristics — particularly, amplitude of low frequency fluctuations (ALFF). The implications of our findings for decision-making regarding the assessment and correction of motion are discussed, as are insights into potential differences among volume-based metrics of motion. •Positive but not negative motion-BOLD relationships appear to be neural in origin.•Motion should always be accounted for in group-level analyses.•Global signal regression and Z-standardization mitigate motion effects.•Motion compromises test-retest reliability, and correction strategies improve.

•We related age-related cortical thickness differences with indices of brain network architecture in a surface-based spatial correlation analysis of a large population-based sample.•Age effects on cortical thickness were strongest in sensorimotor areas.•Regional age-related differences were strongly correlated within the structurally defined node neighborhood.•The overall pattern of thickness differences was found to be anchored in the functional network hierarchy as encoded by macroscale functional connectivity gradients.•Taken together, we demonstrate a link between functional and structural brain network topology and age effects on cortical morphology. Age-related cortical atrophy, approximated by cortical thickness measurements from magnetic resonance imaging, follows a characteristic pattern over the lifespan. Although its determinants remain unknown, mounting evidence demonstrates correspondence between the connectivity profiles of structural and functional brain networks and cortical atrophy in health and neurological disease. Here, we performed a cross-sectional multimodal neuroimaging analysis of 2633 individuals from a large population-based cohort to characterize the association between age-related differences in cortical thickness and functional as well as structural brain network topology. We identified a widespread pattern of age-related cortical thickness differences including “hotspots” of pronounced age effects in sensorimotor areas. Regional age-related differences were strongly correlated within the structurally defined node neighborhood. The overall pattern of thickness differences was found to be anchored in the functional network hierarchy as encoded by macroscale functional connectivity gradients. Lastly, the identified difference pattern covaried significantly with cognitive and motor performance. Our findings indicate that connectivity profiles of functional and structural brain networks act as organizing principles behind age-related cortical thinning as an imaging surrogate of cortical atrophy.

As researchers increase their efforts to characterize variations in the functional connectome across studies and individuals, concerns about the many sources of nuisance variation present and their impact on resting state fMRI (R-fMRI) measures continue to grow. Although substantial within-site variation can exist, efforts to aggregate data across multiple sites such as the 1000 Functional Connectomes Project (FCP) and International Neuroimaging Data-sharing Initiative (INDI) datasets amplify these concerns. The present work draws upon standardization approaches commonly used in the microarray gene expression literature, and to a lesser extent recent imaging studies, and compares them with respect to their impact on relationships between common R-fMRI measures and nuisance variables (e.g., imaging site, motion), as well as phenotypic variables of interest (age, sex). Standardization approaches differed with regard to whether they were applied post-hoc vs. during pre-processing, and at the individual vs. group level; additionally they varied in whether they addressed additive effects vs. additive+multiplicative effects, and were parametric vs. non-parametric. While all standardization approaches were effective at reducing undesirable relationships with nuisance variables, post-hoc approaches were generally more effective than global signal regression (GSR). Across approaches, correction for additive effects (global mean) appeared to be more important than for multiplicative effects (global SD) for all R-fMRI measures, with the exception of amplitude of low frequency fluctuations (ALFF). Group-level post-hoc standardizations for mean-centering and variance-standardization were found to be advantageous in their ability to avoid the introduction of artifactual relationships with standardization parameters; though results between individual and group-level post-hoc approaches were highly similar overall. While post-hoc standardization procedures drastically increased test–retest (TRT) reliability for ALFF, modest reductions were observed for other measures after post-hoc standardizations—a phenomena likely attributable to the separation of voxel-wise from global differences among subjects (global mean and SD demonstrated moderate TRT reliability for these measures). Finally, the present work calls into question previous observations of increased anatomical specificity for GSR over mean centering, and draws attention to the near equivalence of global and gray matter signal regression. •Global mean and SD for R-fMRI measures showed strong site, motion and age effects.•Post-hoc standardizations were more effective in reducing nuisance effects than GSR.•Correction for additive effects is more important than for multiplicative effects.•Group-level standardizations are advantageous to individual-level standardizations.

Graph theoretical explorations of functional interactions within the human connectome, are rapidly advancing our understanding of brain architecture. In particular, global and regional topological parameters are increasingly being employed to quantify and characterize inter-individual differences in human brain function. Head motion remains a significant concern in the accurate determination of resting-state fMRI based assessments of the connectome, including those based on graph theoretical analysis (e.g., motion can increase local efficiency, while decreasing global efficiency and small-worldness). This study provides a comprehensive examination of motion correction strategies on the relationship between motion and commonly used topological parameters. At the individual-level, we evaluated different models of head motion regression and scrubbing, as well as the potential benefits of using partial correlation (estimated via graphical lasso) instead of full correlation. At the group-level, we investigated the utility of regression of motion and mean intrinsic functional connectivity before topological parameters calculation and/or after. Consistent with prior findings, none of the explicit motion-correction approaches at individual-level were able to remove motion relationships for topological parameters. Global signal regression (GSR) emerged as an effective means of mitigating relationships between motion and topological parameters; though at the risk of altering the connectivity structure and topological hub distributions when higher density graphs are employed (e.g., >6%). Group-level analysis correction for motion was once again found to be a crucial step. Finally, similar to recent work, we found a constellation of findings suggestive of the possibility that some of the motion-relationships detected may reflect neural or trait signatures of motion, rather than simply motion-induced artifact.

INTRODUCTION Functional connectomics studies leverage the power of interregional brain relationships using graph theory of glycolytic metabolism to establish neural connections and their roles in cognition and disease and to monitor therapeutic responses. METHODS Using a retrospective clinical population (N = 431) from ADNI, we evaluated disease changes using metabolic covariance analysis. In addition, we developed a novel region set enrichment analysis (RSEA) to detect brain functional changes based on metabolic variations. Results were aligned with transcriptomic signatures and clinical cognitive assessments (CCAs). RESULTS Our findings highlight sexual dimorphic changes across the disease spectrum, which suggest brain network reorganization occurs as compensatory mechanisms due to pathological disruptions. RSEA indicated functional changes in motor, memory, language, and cognitive functions related to disease progression, and these changes were supported by transcriptomic signatures. DISCUSSION Together, metabolic covariance analysis, regional connectomics, and RSEA allow for AD progression tracking and functional alteration identification based on metabolic readouts, consistent with CCA. Highlights Our findings support the idea that the brain undergoes a network reorganization as a compensatory mechanism during AD progression. An analytical method to assess functional variations via metabolic readouts was developed. Metabolic connectomics analysis tracks the sexually dimorphic changes in AD progression. Brain network efficiency drops at two critical timepoints, as revealed by path length analysis. Changes in network connectivity changes are supported by transcriptomic signatures and CCAs.

In statistical theory, reliability serves as an upper limit of validity and is measurable in practice while validity is more difficult to measure directly (e.g., specific trait and disease) thus often approximated by predictive validity (Kraemer, 2014). [...]high reliability is a required standard for both research and clinical use. Related to human arousal, as demonstrated in Wang et al., test-retest reliability of human functional connectomics can be significantly improved by removing the impact of sleep using measures of heart rate variability derived from simultaneous electrocardiogram recording. Common algorithms have been recently given a state of art review in terms of their test-retest reliability (Zuo and Xing, 2014), indicating that network metrics derived from graph theory applied to rfMRI signal are less reliable (Zuo et al., 2012) than usually required while both local functional homogeneity measure (Zuo et al., 2013) and global network measure with dual regression of independent component analysis (drICA) (Zuo et al., 2010a) almost reach the clinical standard of reliability. Funding This work was supported in part by the National Basic Research (973) Program (2015CB351702), the Natural Science Foundation of China (81471740, 81220108014), Beijing Municipal Science and Tech Commission (Z161100002616023, Z171100000117012), the China - Netherlands CAS-NWO Programme (153111KYSB20160020), the Major Project of National Social Science Foundation of China (14ZDB161), the National R&D Infrastructure and Facility Development Program of China, Fundamental Science Data Sharing Platform (DKA2017-12-02-21), and Guangxi BaGui Scholarship (201621 to X-NZ).

The detection of mild cognitive impairment (MCI), the transitional stage between normal cognitive changes of aging and the cognitive decline caused by AD, is of paramount clinical importance, since MCI patients are at increased risk of progressing into AD. Electroencephalographic (EEG) alterations in the spectral content of brainwaves and connectivity at resting state have been associated with early-stage AD. Recently, cognitive event-related potentials (ERPs) have entered into the picture as an easy to perform screening test. Motivated by the recent findings about the role of cross-frequency coupling (CFC) in cognition, we introduce a relevant methodological approach for detecting MCI based on cognitive responses from a standard auditory oddball paradigm. By using the single trial signals recorded at Pz sensor and comparing the responses to target and non-target stimuli, we first demonstrate that increased CFC is associated with the cognitive task. Then, considering the dynamic character of CFC, we identify instances during which the coupling between particular pairs of brainwave frequencies carries sufficient information for discriminating between normal subjects and patients with MCI. In this way, we form a multiparametric signature of impaired cognition. The new composite biomarker was tested using data from a cohort that consists of 25 amnestic MCI patients and 15 age-matched controls. Standard machine-learning algorithms were employed so as to implement the binary classification task. Based on leave-one-out cross-validation, the measured classification rate was found reaching very high levels (95%). Our approach compares favorably with the traditional alternative of using the morphology of averaged ERP response to make the diagnosis and the usage of features from spectro-temporal analysis of single-trial responses. This further indicates that task-related CFC measurements can provide invaluable analytics in AD diagnosis and prognosis.

Recent neuroimaging studies have shown that functional connectomes are unique to individuals, i.e., two distinct fMRIs taken over different sessions of the same subject are more similar in terms of their connectomes than those from two different subjects. In this study, we present new results that identify specific parts of resting state and task-specific connectomes that are responsible for the unique signatures. We show that a very small part of the connectome can be used to derive features for discriminating between individuals. A network of these features is shown to achieve excellent training and test accuracy in matching imaging datasets. We show that these features are statistically significant, robust to perturbations, invariant across populations, and are localized to a small number of structural regions of the brain. Furthermore, we show that for task-specific connectomes, the regions identified by our method are consistent with their known functional characterization. We present a new matrix sampling technique to derive computationally efficient and accurate methods for identifying the discriminating sub-connectome and support all of our claims using state-of-the-art statistical tests and computational techniques.

[This corrects the article DOI: 10.3389/fnins.2019.00117.].

Previous studies suggest that the topological properties of structural and functional neural networks in glioma patients are altered beyond the tumor location. These alterations are due to the dynamic interactions with large-scale neural circuits. Understanding and describing these interactions may be an important step towards deciphering glioma disease evolution. In this study, we analyze structural and functional brain networks in terms of determining the correlation between network robustness and topological features regarding the default-mode network (DMN), comparing prognostically differing patient groups to healthy controls. We determine the driver nodes of these networks, which are receptive to outside signals, and the critical nodes as the most important elements for controllability since their removal will dramatically affect network controllability. Our results suggest that network controllability and robustness of the DMN is decreased in glioma patients. We found losses of driver and critical nodes in patients, especially in the prognostically less favorable IDH wildtype (IDHwt) patients, which might reflect lesion-induced network disintegration. On the other hand, topological shifts of driver and critical nodes, and even increases in the number of critical nodes, were observed mainly in IDH mutated (IDHmut) patients, which might relate to varying degrees of network plasticity accompanying the chronic disease course in some of the patients, depending on tumor growth dynamics. We hereby implement a novel approach for further exploring disease evolution in brain cancer under the aspects of neural network controllability and robustness in glioma patients.