Age-Related Changes in Human Anatomical and Functional Brain Networks

Thesis (Ph.D.) - Indiana University, Psychological and Brain Sciences, 2015i) The first component characterizes age-related changes in specific connections. We find that functional connections within and between intrinsic connectivity networks (ICNs) follow distinct lifespan trajectories. We further characterize these changes in terms of each ICN’s “modularity” and find that most ICNs become less modular (i.e. less segregated) with age. In anatomical networks we find that hub regions are disproportionately affected by age and become less efficiently connected to the rest of the brain. Finally, we find that, with age stronger functional connections are supported by longer (multi-step) anatomical pathways for communication. ii) The second component is concerned with characterizing age-related changes in the boundaries of ICNs. To this end we used a multi-layer variant of modularity maximization to decompose networks into modules at different organizational scales, which we find exhibit scale-specific trends with age. At coarse scales, for example, we find that modules become more segregated whereas modules defined at finer scales become less segregated. We also find that module composition changes with age, and specific areas associated with memory change their module allegiance with age. iii) In the final component we use generative models to uncover wiring rules for the anatomical brain networks. Modeling network growth as a spatial penalty combined with homophily, we find that we can generate synthetic networks with many of the same properties as real-world brain networks. Fitting this model to individuals, we show that the parameter governing the severity of the spatial penalty weakens monotonically with age and that the overall ability to reproduce realistic connectomes for older individuals suffers. These results suggest that, with age, additional constraints may play an important role in shaping the topology of brain structural networks

High-amplitude co-fluctuations in cortical activity drive resting-state functional connectivity

Resting-state functional connectivity is used throughout neuroscience to study brain organization and to generate biomarkers of development, disease, and cognition. The processes that give rise to correlated activity are, however, poorly understood. Here, we decompose resting-state functional connectivity using a “temporal unwrapping” procedure to assess the contributions of moment-to-moment activity co-fluctuations to the overall connectivity pattern. This approach temporally resolves functional connectivity at a timescale of single frames, which enables us to make direct comparisons of co-fluctuations of network organization with fluctuations in the BOLD time series. We show that, surprisingly, only a small fraction of frames exhibiting the strongest co-fluctuation amplitude are required to explain a significant fraction of variance in the overall pattern of connection weights as well as the network’s modular structure. These frames coincide with frames of high BOLD activity amplitude, corresponding to activity patterns that are remarkably consistent across individuals and identify fluctuations in default mode and control network activity as the primary driver of resting-state functional connectivity. Finally, we demonstrate that co-fluctuation amplitude synchronizes across subjects during movie-watching and that high-amplitude frames carry detailed information about individual subjects (whereas low-amplitude frames carry little). Our approach reveals fine-scale temporal structure of resting-state functional connectivity, and discloses that frame-wise contributions vary across time. These observations illuminate the relation of brain activity to functional connectivity and open a number of new directions for future research

Specificity and robustness of long-distance connections in weighted, interareal connectomes

Brain areas’ functional repertoires are shaped by their incoming and outgoing structural connections. In empirically measured networks, most connections are short, reflecting spatial and energetic constraints. Nonetheless, a small number of connections span long distances, consistent with the notion that the functionality of these connections must outweigh their cost. While the precise function of long-distance connections is unknown, the leading hypothesis is that they act to reduce the topological distance between brain areas and increase the efficiency of interareal communication. However, this hypothesis implies a nonspecificity of long-distance connections that we contend is unlikely. Instead, we propose that long-distance connections serve to diversify brain areas’ inputs and outputs, thereby promoting complex dynamics. Through analysis of five weighted interareal network datasets, we show that long-distance connections play only minor roles in reducing average interareal topological distance. In contrast, areas’ long-distance and short-range neighbors exhibit marked differences in their connectivity profiles, suggesting that long-distance connections enhance dissimilarity between areal inputs and outputs. Next, we show that—in isolation—areas’ long-distance connectivity profiles exhibit nonrandom levels of similarity, suggesting that the communication pathways formed by long connections exhibit redundancies that may serve to promote robustness. Finally, we use a linearization of Wilson–Cowan dynamics to simulate the covariance structure of neural activity and show that in the absence of long-distance connections a common measure of functional diversity decreases. Collectively, our findings suggest that long-distance connections are necessary for supporting diverse and complex brain dynamics

Non-assortative community structure in resting and task-evoked functional brain networks

Brain networks exhibit community structure that reconfigures during cognitively demanding tasks. Extant work has emphasized a single class of communities: those that are assortative, or internally dense and externally sparse. Other classes that may play key functional roles in brain function have largely been ignored, leading to an impoverished view in the best case and a mischaracterization in the worst case. Here, we leverage weighted stochastic blockmodeling, a community detection method capable of detecting diverse classes of communities, to study the community structure of functional brain networks while subjects either rest or perform cognitively demanding tasks. We find evidence that the resting brain is largely assortative, although higher order association areas exhibit non-assortative organization, forming cores and peripheries. Surprisingly, this assortative structure breaks down during tasks and is supplanted by core, periphery, and disassortative communities. Using measures derived from the community structure, we show that it is possible to classify an individual’s task state with an accuracy that is well above average. Finally, we show that inter-individual differences in the composition of assortative and non-assortative communities is correlated with subject performance on in-scanner cognitive tasks. These findings offer a new perspective on the community organization of functional brain networks and its relation to cognition

Diversity of meso-scale architecture in human and non-human connectomes

Brain function is reflected in connectome community structure. The dominant view is that communities are assortative and segregated from one another, supporting specialized information processing. However, this view precludes the possibility of non-assortative communities whose complex inter-community interactions could engender a richer functional repertoire. We use weighted stochastic blockmodels to uncover the meso-scale architecture of Drosophila, mouse, rat, macaque, and human connectomes. We find that most communities are assortative, though others form core-periphery and disassortative structures, which better recapitulate observed patterns of functional connectivity and gene co-expression in human and mouse connectomes compared to standard community detection techniques. We define measures for quantifying the diversity of communities in which brain regions participate, showing that this measure is peaked in control and subcortical systems in humans, and that inter-individual differences are correlated with cognitive performance. Our report paints a more diverse portrait of connectome communities and demonstrates their cognitive relevance

Spatiotemporal ontogeny of brain wiring

The wiring of the brain provides the anatomical skeleton for cognition and behavior. Connections among brain regions have a diverse and characteristic strength. This strength heterogeneity is captured by the wiring cost and homophily principles. Moreover, brains have a characteristic global network topology, including modularity and short path lengths. However, the mechanisms underlying the inter-regional wiring principles and global network topology of brains are unknown. Here, we address this issue by modeling the ontogeny of brain connectomes. We demonstrate that spatially embedded and heterochronous neurogenetic gradients, without the need of axonal-guidance molecules or activity-dependent plasticity, can reconstruct the wiring principles and shape the global network topology observed in adult brain connectomes. Thus, two fundamental dimensions, that is, space and time, are key components of a plausible neurodevelopmental mechanism with a universal scope, encompassing vertebrate and invertebrate brains

Space-independent community and hub structure of functional brain networks

Coordinated brain activity reflects underlying cognitive processes and can be modeled as a network of inter-regional functional connections. The most costly connections in the network are long-distance correlations that, in the absence of underlying structural connections, are maintained by sustained energetic inputs. Here, we present a spatial modeling approach that amplifies contributions made by long-distance functional connections to whole-brain network architecture, while simultaneously suppressing contributions made by short-range connections. We use this method to characterize the long-distance architecture of functional networks and to identify aspects of community and hub structure that are driven by long-distance correlations and that, we argue, are of greater functional significance. We find that based only on patterns of long-distance connectivity, primary sensory cortices occupy increasingly central positions and appear more “hub-like”. Additionally, we show that the community structure of long-distance connections spans multiple topological levels and differs from the community structure detected in networks that include both short-range and long-distance connections. In summary, these findings highlight the complex relationship between the brain’s physical layout and its functional architecture. The results presented here inform future analyses of community structure and network hubs in health, across development, and in the case of neuropsychiatric disorders

Diversity of meso-scale architecture in human and non-human connectomes

Brain function is reflected in connectome community structure. The dominant view is that communities are assortative and segregated from one another, supporting specialized information processing. However, this view precludes the possibility of non-assortative communities whose complex inter-community interactions could engender a richer functional repertoire. We use weighted stochastic blockmodels to uncover the meso-scale architecture of Drosophila, mouse, rat, macaque, and human connectomes. We find that most communities are assortative, though others form core-periphery and disassortative structures, which better recapitulate observed patterns of functional connectivity and gene co-expression in human and mouse connectomes compared to standard community detection techniques. We define measures for quantifying the diversity of communities in which brain regions participate, showing that this measure is peaked in control and subcortical systems in humans, and that inter-individual differences are correlated with cognitive performance. Our report paints a more diverse portrait of connectome communities and demonstrates their cognitive relevance

Temporal fluctuations in the brain's modular architecture during movie-watching

Brain networks are flexible and reconfigure over time to support ongoing cognitive processes. However, tracking statistically meaningful reconfigurations across time has proven difficult. This has to do largely with issues related to sampling variability, making instantaneous estimation of network organization difficult, along with increased reliance on task-free (cognitively unconstrained) experimental paradigms, limiting the ability to interpret the origin of changes in network structure over time. Here, we address these challenges using time-varying network analysis in conjunction with a naturalistic viewing paradigm. Specifically, we developed a measure of inter-subject network similarity and used this measure as a coincidence filter to identify synchronous fluctuations in network organization across individuals. Applied to movie-watching data, we found that periods of high inter-subject similarity coincided with reductions in network modularity and increased connectivity between cognitive systems. In contrast, low inter-subject similarity was associated with increased system segregation and more rest-like architectures. We then used a data-driven approach to uncover clusters of functional connections that follow similar trajectories over time and are more strongly correlated during movie-watching than at rest. Finally, we show that synchronous fluctuations in network architecture over time can be linked to a subset of features in the movie. Our findings link dynamic fluctuations in network integration and segregation to patterns of inter-subject similarity, and suggest that moment-to-moment fluctuations in functional connectivity reflect shared cognitive processing across individuals

Edge-centric functional network representations of human cerebral cortex reveal overlapping system-level architecture

Network neuroscience has relied on a node-centric network model in which cells, populations, and regions are linked to one another via anatomical or functional connections. This model cannot account for interactions of edges with one another. Here, we develop an edge-centric network model, which generates the novel constructs of “edge time series” and “edge functional connectivity” (eFC). Using network analysis, we show that at rest eFC is consistent across datasets and reproducible within the same individual over multiple scan sessions. We demonstrate that clustering eFC yields communities of edges that naturally divide the brain into overlapping clusters, with regions in sensorimotor and attentional networks exhibiting the greatest levels of overlap. We go on to show that eFC is systematically and consistently modulated by variation in sensory input. In future work, the edge-centric approach could be used to map the connectional architecture of brain circuits and for the development of brain-based biomarkers of disease and development