Mechanisms of Zero-Lag Synchronization in Cortical Motifs

Zero-lag synchronization between distant cortical areas has been observed in a diversity of experimental data sets and between many different regions of the brain. Several computational mechanisms have been proposed to account for such isochronous synchronization in the presence of long conduction delays: Of these, the phenomenon of "dynamical relaying" - a mechanism that relies on a specific network motif - has proven to be the most robust with respect to parameter mismatch and system noise. Surprisingly, despite a contrary belief in the community, the common driving motif is an unreliable means of establishing zero-lag synchrony. Although dynamical relaying has been validated in empirical and computational studies, the deeper dynamical mechanisms and comparison to dynamics on other motifs is lacking. By systematically comparing synchronization on a variety of small motifs, we establish that the presence of a single reciprocally connected pair - a "resonance pair" - plays a crucial role in disambiguating those motifs that foster zero-lag synchrony in the presence of conduction delays (such as dynamical relaying) from those that do not (such as the common driving triad). Remarkably, minor structural changes to the common driving motif that incorporate a reciprocal pair recover robust zero-lag synchrony. The findings are observed in computational models of spiking neurons, populations of spiking neurons and neural mass models, and arise whether the oscillatory systems are periodic, chaotic, noise-free or driven by stochastic inputs. The influence of the resonance pair is also robust to parameter mismatch and asymmetrical time delays amongst the elements of the motif. We call this manner of facilitating zero-lag synchrony resonance-induced synchronization, outline the conditions for its occurrence, and propose that it may be a general mechanism to promote zero-lag synchrony in the brain.Comment: 41 pages, 12 figures, and 11 supplementary figure

The interplay of microscopic and mesoscopic structure in complex networks

Not all nodes in a network are created equal. Differences and similarities exist at both individual node and group levels. Disentangling single node from group properties is crucial for network modeling and structural inference. Based on unbiased generative probabilistic exponential random graph models and employing distributive message passing techniques, we present an efficient algorithm that allows one to separate the contributions of individual nodes and groups of nodes to the network structure. This leads to improved detection accuracy of latent class structure in real world data sets compared to models that focus on group structure alone. Furthermore, the inclusion of hitherto neglected group specific effects in models used to assess the statistical significance of small subgraph (motif) distributions in networks may be sufficient to explain most of the observed statistics. We show the predictive power of such generative models in forecasting putative gene-disease associations in the Online Mendelian Inheritance in Man (OMIM) database. The approach is suitable for both directed and undirected uni-partite as well as for bipartite networks

Exponential Random Graph Modeling for Complex Brain Networks

Exponential random graph models (ERGMs), also known as p* models, have been utilized extensively in the social science literature to study complex networks and how their global structure depends on underlying structural components. However, the literature on their use in biological networks (especially brain networks) has remained sparse. Descriptive models based on a specific feature of the graph (clustering coefficient, degree distribution, etc.) have dominated connectivity research in neuroscience. Corresponding generative models have been developed to reproduce one of these features. However, the complexity inherent in whole-brain network data necessitates the development and use of tools that allow the systematic exploration of several features simultaneously and how they interact to form the global network architecture. ERGMs provide a statistically principled approach to the assessment of how a set of interacting local brain network features gives rise to the global structure. We illustrate the utility of ERGMs for modeling, analyzing, and simulating complex whole-brain networks with network data from normal subjects. We also provide a foundation for the selection of important local features through the implementation and assessment of three selection approaches: a traditional p-value based backward selection approach, an information criterion approach (AIC), and a graphical goodness of fit (GOF) approach. The graphical GOF approach serves as the best method given the scientific interest in being able to capture and reproduce the structure of fitted brain networks

Enhanced reconstruction of weighted networks from strengths and degrees

Network topology plays a key role in many phenomena, from the spreading of diseases to that of financial crises. Whenever the whole structure of a network is unknown, one must resort to reconstruction methods that identify the least biased ensemble of networks consistent with the partial information available. A challenging case, frequently encountered due to privacy issues in the analysis of interbank flows and Big Data, is when there is only local (node-specific) aggregate information available. For binary networks, the relevant ensemble is one where the degree (number of links) of each node is constrained to its observed value. However, for weighted networks the problem is much more complicated. While the naive approach prescribes to constrain the strengths (total link weights) of all nodes, recent counter-intuitive results suggest that in weighted networks the degrees are often more informative than the strengths. This implies that the reconstruction of weighted networks would be significantly enhanced by the specification of both strengths and degrees, a computationally hard and bias-prone procedure. Here we solve this problem by introducing an analytical and unbiased maximum-entropy method that works in the shortest possible time and does not require the explicit generation of reconstructed samples. We consider several real-world examples and show that, while the strengths alone give poor results, the additional knowledge of the degrees yields accurately reconstructed networks. Information-theoretic criteria rigorously confirm that the degree sequence, as soon as it is non-trivial, is irreducible to the strength sequence. Our results have strong implications for the analysis of motifs and communities and whenever the reconstructed ensemble is required as a null model to detect higher-order patterns

The compositional and evolutionary logic of metabolism

Metabolism displays striking and robust regularities in the forms of modularity and hierarchy, whose composition may be compactly described. This renders metabolic architecture comprehensible as a system, and suggests the order in which layers of that system emerged. Metabolism also serves as the foundation in other hierarchies, at least up to cellular integration including bioenergetics and molecular replication, and trophic ecology. The recapitulation of patterns first seen in metabolism, in these higher levels, suggests metabolism as a source of causation or constraint on many forms of organization in the biosphere. We identify as modules widely reused subsets of chemicals, reactions, or functions, each with a conserved internal structure. At the small molecule substrate level, module boundaries are generally associated with the most complex reaction mechanisms and the most conserved enzymes. Cofactors form a structurally and functionally distinctive control layer over the small-molecule substrate. Complex cofactors are often used at module boundaries of the substrate level, while simpler ones participate in widely used reactions. Cofactor functions thus act as "keys" that incorporate classes of organic reactions within biochemistry. The same modules that organize the compositional diversity of metabolism are argued to have governed long-term evolution. Early evolution of core metabolism, especially carbon-fixation, appears to have required few innovations among a small number of conserved modules, to produce adaptations to simple biogeochemical changes of environment. We demonstrate these features of metabolism at several levels of hierarchy, beginning with the small-molecule substrate and network architecture, continuing with cofactors and key conserved reactions, and culminating in the aggregation of multiple diverse physical and biochemical processes in cells.Comment: 56 pages, 28 figure

Spectral goodness of fit for network models

We introduce a new statistic, 'spectral goodness of fit' (SGOF) to measure how well a network model explains the structure of an observed network. SGOF provides an absolute measure of fit, analogous to the standard R-squared in linear regression. Additionally, as it takes advantage of the properties of the spectrum of the graph Laplacian, it is suitable for comparing network models of diverse functional forms, including both fitted statistical models and algorithmic generative models of networks. After introducing, defining, and providing guidance for interpreting SGOF, we illustrate the properties of the statistic with a number of examples and comparisons to existing techniques. We show that such a spectral approach to assessing model fit fills gaps left by earlier methods and can be widely applied

Mechanisms of change in protein architecture

Proteins are the basic building blocks and functional units in all living organisms. Moreover, differences between species can frequently be explained with differences in their protein complements. Importantly, proteins are often composed of segments, i.e. domains that have a certain level of evolutionary, structural and/or functional independence. The majority of proteins in nature contain two or more domains, and an individual domain can often occur in combinations with different domain partners. In the first part of my thesis, I traced the history of animal gene families and the proteins these genes encode. By this means, I was able to infer events where changes in protein domain architectures took place. This showed that both insertions and deletions of single copy domains preferentially occur at protein termini, but also that changes are more likely to occur after gene duplication than organism speciation. Finally, domains that were most frequently gained were the ones that are related to an increase in organismal complexity, thus underlining the important role of domain shuffling in animal evolution. In the second part of my thesis, I focused on a set of high confidence domain gain events and investigated the evidence for molecular mechanisms that caused these domain gains. In agreement with observations from the first part - that changes preferentially occur at the termini - I have found that the strongest contribution to gains of novel domains in proteins comes from gene fusion through the joining of exons from adjacent genes into a novel gene unit. Two other mechanisms that have been suggested to play a major role in the evolution of animal proteins, retroposition and middle insertions through intronic recombination, have a smaller role in comparison to gene fusions. Since the majority of these domain gains are again observed after gene duplication, this suggests a powerful mechanism for neofunctionalization after gene duplication. iii Finally, in the last part of my thesis, I address a mechanism that increases the number and variety of proteins in an organism – alternative splicing. In particular, I investigate the functional consequences of tissue-specific alternative splicing events. I found that tissue-specific splicing tends to affect exons that encode protein regions without defined secondary or tertiary structure. Importantly, it is known that these disordered regions frequently play a role in protein interactions. In agreement with this, I observed significant enrichment of tissue-specifically encoded protein segments in disordered binding peptides and posttranslationally modified sites. A possible result of the finely regulated alternative splicing of these segments is a tissue-specific rewiring of protein network. In conclusion, both alternative splicing and domain shuffling can increase proteome diversity. However, a protein with a new function can often directly or indirectly shape the functions of other proteins in its environment