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Large-scale dynamics of the brain are routinely modelled using systems of nonlinear dynamical equations that describe the evolution of population-level activity, with distinct neural populations often coupled according to an empirically measured structural connectivity matrix. This modelling approach has been used to generate insights into the neural underpinnings of spontaneous brain dynamics, as recorded with techniques such as resting state functional MRI (fMRI). In fMRI, researchers have many degrees of freedom in the way that they can process the data and recent evidence indicates that the choice of pre-processing steps can have a major effect on empirical estimates of functional connectivity. However, the potential influence of such variations on modelling results are seldom considered. Here we show, using three popular whole-brain dynamical models, that different choices during fMRI preprocessing can dramatically affect model fits and interpretations of findings. Critically, we show that the ability of these models to accurately capture patterns in fMRI dynamics is mostly driven by the degree to which they fit global signals rather than interesting sources of coordinated neural dynamics. We show that widespread deflections can arise from simple global synchronisation. We introduce a simple two-parameter model that captures these fluctuations and performs just as well as more complex, multi-parameter biophysical models. From our combined analyses of data and simulations, we describe benchmarks to evaluate model fit and validity. Although most models are not resilient to denoising, we show that relaxing the approximation of homogeneous neural populations by more explicitly modelling inter-regional effective connectivity can improve model accuracy at the expense of increased model complexity. Our results suggest that many complex biophysical models may be fitting relatively trivial properties of the data, and underscore a need for tighter integration between data quality assurance and model development.

Adverse life events can inflict substantial long-term damage, which, paradoxically, has been posited to stem from initially adaptative responses to the challenges encountered in one's environment. Thus, identification of the mechanisms linking resilience against recent stressors to longer-term psychological vulnerability is key to understanding optimal functioning across multiple timescales. To address this issue, our study tested the relevance of neuro-reproductive maturation and senescence, respectively, to both resilience and longer-term risk for pathologies characterised by accelerated brain aging, specifically, Alzheimer's Disease (AD). Graph theoretical and partial least squares analyses were conducted on multimodal imaging, reported biological aging and recent adverse experience data from the Lifespan Human Connectome Project (HCP). Availability of reproductive maturation/senescence measures restricted our investigation to adolescent (N = 178) and middle-aged (N = 146) females. Psychological resilience was linked to age-specific brain senescence patterns suggestive of precocious functional development of somatomotor and control-relevant networks (adolescence) and earlier aging of default mode and salience/ventral attention systems (middle adulthood). Biological aging showed complementary associations with the neural patterns relevant to resilience in adolescence (positive relationship) versus middle-age (negative relationship). Transcriptomic and expression quantitative trait locus data analyses linked the neural aging patterns correlated with psychological resilience in middle adulthood to gene expression patterns suggestive of increased AD risk. Our results imply a partially antagonistic relationship between resilience against proximal stressors and longer-term psychological adjustment in later life. They thus underscore the importance of fine-tuning extant views on successful coping by considering the multiple timescales across which age-specific processes may unfold.

The integration of modern neuroimaging methods with genetically informative designs and data can shed light on the molecular mechanisms underlying the structural and functional organization of the human connectome. Here, we review studies that have investigated the genetic basis of human brain network structure and function through three complementary frameworks: (1) the quantification of phenotypic heritability through classical twin designs; (2) the identification of specific DNA variants linked to phenotypic variation through association and related studies; and (3) the analysis of correlations between spatial variations in imaging phenotypes and gene expression profiles through the integration of neuroimaging and transcriptional atlas data. We consider the basic foundations, strengths, limitations, and discoveries associated with each approach. We present converging evidence to indicate that anatomical connectivity is under stronger genetic influence than functional connectivity and that genetic influences are not uniformly distributed throughout the brain, with phenotypic variation in certain regions and connections being under stronger genetic control than others. We also consider how the combination of imaging and genetics can be used to understand the ways in which genes may drive brain dysfunction in different clinical disorders.

Brain function relies on a precisely coordinated and dynamic balance between the functional integration and segregation of distinct networks. Characterizing the way in which brain regions reconfigure their interactions to give rise to distinct but hidden brain states remains an open challenge. In this paper, we propose a Bayesian method for characterizing community structure-based latent brain states and showcase a novel strategy based on posterior predictive discrepancy using the latent block model to detect transitions between community structures in blood oxygen level-dependent (BOLD) time series. The set of estimated parameters in the model includes a latent label vector that assigns network nodes to communities, and also block model parameters that reflect the weighted connectivity within and between communities. Besides extensive in-silico model evaluation, we also provide empirical validation (and replication) using the Human Connectome Project (HCP) dataset of 100 healthy adults. Our results obtained through an analysis of task-fMRI data during working memory performance show appropriate lags between external task demands and change-points between brain states, with distinctive community patterns distinguishing fixation, low-demand and high-demand task conditions.

The structure of the adult brain is the result of complex physical mechanisms acting in three-dimensional space through development. Consequently, the brain’s spatial embedding plays a key role in its organization, including the gradient-like patterning of gene expression that encodes the molecular underpinning of functional specialization. However, we do not yet understand how changes in brain shape and size that occur across development influence the brain’s transcriptional architecture. Here we investigate the spatial embedding of transcriptional patterns of over 1800 genes across seven time points through mouse-brain development using data from the Allen Developing Mouse Brain Atlas. We find that transcriptional similarity decreases exponentially with separation distance across all developmental time points, with a correlation length scale that follows a power-law scaling relationship with a linear dimension of brain size. This scaling suggests that the mouse brain achieves a characteristic balance between local molecular similarity (homogeneous gene expression within a specialized brain area) and longer-range diversity (between functionally specialized brain areas) throughout its development. Extrapolating this mouse developmental scaling relationship to the human cortex yields a prediction consistent with the value measured from microarray data. We introduce a simple model of brain growth as spatially autocorrelated gene-expression gradients that expand through development, which captures key features of the mouse developmental data. Complementing the well-known exponential distance rule for structural connectivity, our findings characterize an analogous exponential distance rule for transcriptional gradients that scales across mouse brain development, providing new understanding of spatial constraints on the brain’s molecular patterning.

Numerous studies have investigated grey matter (GM) volume changes in diverse patient groups. Reports of disorder-related GM reductions are common in such work, but many studies also report evidence for GM volume increases in patients. It is unclear whether these GM increases and decreases are independent or related in some way. Here, we address this question using a novel meta-analytic network mapping approach. We used a coordinate-based meta-analysis of 64 voxel-based morphometry studies of psychiatric disorders to calculate the probability of finding a GM increase or decrease in one region given an observed change in the opposite direction in another region. Estimating this co-occurrence probability for every pair of brain regions allowed us to build a network of concurrent GM changes of opposing polarity. Our analysis revealed that disorder-related GM increases and decreases are not independent; instead, a GM change in one area is often statistically related to a change of opposite polarity in other areas, highlighting distributed yet coordinated changes in GM volume as a function of brain pathology. Most regions showing GM changes linked to an opposite change in a distal area were located in salience, executive-control and default mode networks, as well as the thalamus and basal ganglia. Moreover, pairs of regions showing coupled changes of opposite polarity were more likely to belong to different canonical networks than to the same one. Our results suggest that regional GM alterations in psychiatric disorders are often accompanied by opposing changes in distal regions that belong to distinct functional networks.

Head motion is a major confounding factor in neuroimaging studies. While numerous studies have investigated how motion impacts estimates of functional connectivity, the effects of motion on structural connectivity measured using diffusion MRI have not received the same level of attention, despite the fact that, like functional MRI, diffusion MRI relies on elaborate preprocessing pipelines that require multiple choices at each step. Here, we report a comprehensive analysis of how these choices influence motion-related contamination of structural connectivity estimates. Using a healthy adult sample (N = 294), we evaluated 240 different preprocessing pipelines, devised using plausible combinations of different choices related to explicit head motion correction, tractography propagation algorithms, track seeding methods, track termination constraints, quantitative metrics derived for each connectome edge, and parcellations. We found that an approach to motion correction that includes outlier replacement and within-slice volume correction led to a dramatic reduction in cross-subject correlations between head motion and structural connectivity strength, and that motion contamination is more severe when quantifying connectivity strength using mean tract fractional anisotropy rather than streamline count. We also show that the choice of preprocessing strategy can significantly influence subsequent inferences about network organization, with the location of network hubs varying considerably depending on the specific preprocessing steps applied. Our findings indicate that the impact of motion on structural connectivity can be successfully mitigated using recent motion-correction algorithms that include outlier replacement and within-slice motion correction.

Resting-state connectivity measures the temporal coherence of the spontaneous neural activity of spatially distinct regions, and is commonly measured using BOLD-fMRI. The BOLD response follows neuronal activity, when changes in the relative concentration of oxygenated and deoxygenated haemoglobin cause fluctuations in the MRI T2* signal. Since the BOLD signal detects changes in relative concentrations of oxy/deoxy-haemoglobin, individual differences in haemoglobin levels may influence the BOLD signal-to-noise ratio in a manner independent of the degree of neural activity. In this study, we examined whether group differences in haemoglobin may confound measures of functional connectivity. We investigated whether relationships between measures of functional connectivity and cognitive performance could be influenced by individual variability in haemoglobin. Finally, we mapped the neuroanatomical distribution of the influence of haemoglobin on functional connectivity to determine where group differences in functional connectivity are manifest.In a cohort of 518 healthy elderly subjects (259 men), each sex group was median-split into two groups with high and low haemoglobin concentration. Significant differences were obtained in functional connectivity between the high and low haemoglobin groups for both men and women (Cohen's d 0.17 and 0.03 for men and women respectively). The haemoglobin connectome in males showed a widespread systematic increase in functional connectivity correlation values, whilst the female connectome showed predominantly parietal and subcortical increases and temporo-parietal decreases. Despite the haemoglobin groups having no differences in cognitive measures, significant differences in the linear relationships between cognitive performance and functional connectivity were obtained for all 5 cognitive tests in males, and 4 out of 5 tests in females.Our findings confirm that individual variability in haemoglobin levels that give rise to group differences are an important confounding variable in BOLD-fMRI-based studies of functional connectivity. Controlling for haemoglobin variability as a potentially confounding variable is crucial to ensure the reproducibility of human brain connectome studies, especially in studies that compare groups of individuals, compare sexes, or examine connectivity-cognition relationships.

One of the most controversial procedures in the analysis of resting-state functional magnetic resonance imaging (rsfMRI) data is global signal regression (GSR): the removal, via linear regression, of the mean signal averaged over the entire brain. On one hand, the global mean signal contains variance associated with respiratory, scanner-, and motion-related artifacts, and its removal via GSR improves various quality-control metrics, enhances the anatomical specificity of functional-connectivity patterns, and can increase the behavioral variance explained by such patterns. On the other hand, GSR alters the distribution of regional signal correlations in the brain, can induce artifactual anticorrelations, may remove real neural signal, and can distort case-control comparisons of functional-connectivity measures. Global signal fluctuations can be identified visually from a matrix of colour-coded signal intensities, called a carpet plot, in which rows represent voxels and columns represent time. Prior to GSR, large, periodic bands of coherent signal changes that affect most of the brain are often apparent; after GSR, these apparently global changes are greatly diminished. Here, using three independent datasets, we show that reordering carpet plots to emphasize cluster structure in the data reveals a greater diversity of spatially widespread signal deflections (WSDs) than previously thought. Their precise form varies across time and participants, and GSR is only effective in removing specific kinds of WSDs. We present an alternative, iterative correction method called Diffuse Cluster Estimation and Regression (DiCER), that identifies representative signals associated with large clusters of coherent voxels. DiCER is more effective than GSR at removing diverse WSDs as visualized in carpet plots, reduces correlations between functional connectivity and head-motion estimates, reduces inter-individual variability in global correlation structure, and results in comparable or improved identification of canonical functional-connectivity networks. Using task fMRI data across 47 contrasts from 7 tasks in the Human Connectome Project, we also present evidence that DiCER is more successful than GSR in preserving the spatial structure of expected task-related activation patterns. Our findings indicate that care must be exercised when examining WSDs (and their possible removal) in rsfMRI data, and that DiCER is a viable alternative to GSR for removing anatomically widespread and temporally coherent signals. All code for implementing DiCER and replicating our results is available at https://github.com/BMHLab/DiCER.