Trade-off between Multiple Constraints Enables Simultaneous Formation of Modules and Hubs in Neural Systems

The formation of the complex network architecture of neural systems is subject to multiple structural and functional constraints. Two obvious but apparently contradictory constraints are low wiring cost and high processing efficiency, characterized by short overall wiring length and a small average number of processing steps, respectively. Growing evidence shows that neural networks are results from a trade-off between physical cost and functional value of the topology. However, the relationship between these competing constraints and complex topology is not well understood quantitatively. We explored this relationship systematically by reconstructing two known neural networks, Macaque cortical connectivity and C. elegans neuronal connections, from combinatory optimization of wiring cost and processing efficiency constraints, using a control parameter , and comparing the reconstructed networks to the real networks. We found that in both neural systems, the reconstructed networks derived from the two constraints can reveal some important relations between the spatial layout of nodes and the topological connectivity, and match several properties of the real networks. The reconstructed and real networks had a similar modular organization in a broad range of , resulting from spatial clustering of network nodes. Hubs emerged due to the competition of the two constraints, and their positions were close to, and partly coincided, with the real hubs in a range of values. The degree of nodes was correlated with the density of nodes in their spatial neighborhood in both reconstructed and real networks. Generally, the rebuilt network matched a significant portion of real links, especially short-distant ones. These findings provide clear evidence to support the hypothesis of trade-off between multiple constraints on brain networks. The two constraints of wiring cost and processing efficiency, however, cannot explain all salient features in the real networks. The discrepancy suggests that there are further relevant factors that are not yet captured here.     

Models of cortical networks with long-range patchy projections

The cortex exhibits an intricate vertical and horizontal architecture, the latter often featuring spatially clustered projection patterns, so-called patches. Many network studies of cortical dynamics ignore such spatial structures and assume purely random wiring. Here, we focus on non-random network structures provided by long-range horizontal (patchy) connections that remain inside the gray matter. We investigate how the spatial arrangement of patchy projections influences global network topology and predict its impact on the activity dynamics of the network. Since neuroanatomical data on horizontal projections is rather sparse, we suggest and compare four candidate scenarios of how patchy connections may be established. To identify a set of characteristic network properties that enables us to pin down the differences between the resulting network models, we employ the framework of stochastic graph theory. We find that patchy projections provide an exceptionally efficient way of wiring, as the resulting networks tend to exhibit small-world properties with significantly reduced wiring costs. Furthermore, the eigenvalue spectra, as well as the structure of common in- and output of the networks suggest that different spatial connectivity patterns support distinct types of activity propagation.     

Nonoptimal component placement, but short processing paths, due to long-distance projections in neural systems

It has been suggested that neural systems across several scales of organization show optimal component placement, in which any spatial rearrangement of the components would lead to an increase of total wiring. Using extensive connectivity datasets for diverse neural networks combined with spatial coordinates for network nodes, we applied an optimization algorithm to the network layouts, in order to search for wire-saving component rearrangements. We found that optimized component rearrangements could substantially reduce total wiring length in all tested neural networks. Specifically, total wiring among 95 primate (Macaque) cortical areas could be decreased by 32%, and wiring of neuronal networks in the nematode Caenorhabditis elegans could be reduced by 48% on the global level, and by 49% for neurons within frontal ganglia. Wiring length reductions were possible due to the existence of long-distance projections in neural networks. We explored the role of these projections by comparing the original networks with minimally rewired networks of the same size, which possessed only the shortest possible connections. In the minimally rewired networks, the number of processing steps along the shortest paths between components was significantly increased compared to the original networks. Additional benchmark comparisons also indicated that neural networks are more similar to network layouts that minimize the length of processing paths, rather than wiring length. These findings suggest that neural systems are not exclusively optimized for minimal global wiring, but for a variety of factors including the minimization of processing steps.     

Variability v.s. synchronicity of neuronal activity in local cortical network models with different wiring topologies

Dynamical behavior of a biological neuronal network depends significantly on the spatial pattern of synaptic connections among neurons. While neuronal network dynamics has extensively been studied with simple wiring patterns, such as all-to-all or random synaptic connections, not much is known about the activity of networks with more complicated wiring topologies. Here, we examined how different wiring topologies may influence the response properties of neuronal networks, paying attention to irregular spike firing, which is known as a characteristic of in vivo cortical neurons, and spike synchronicity. We constructed a recurrent network model of realistic neurons and systematically rewired the recurrent synapses to change the network topology, from a localized regular and a “small-world” network topology to a distributed random network topology. Regular and small-world wiring patterns greatly increased the irregularity or the coefficient of variation (Cv) of output spike trains, whereas such an increase was small in random connectivity patterns. For given strength of recurrent synapses, the firing irregularity exhibited monotonous decreases from the regular to the random network topology. By contrast, the spike coherence between an arbitrary neuron pair exhibited a non-monotonous dependence on the topological wiring pattern. More precisely, the wiring pattern to maximize the spike coherence varied with the strength of recurrent synapses. In a certain range of the synaptic strength, the spike coherence was maximal in the small-world network topology, and the long-range connections introduced in this wiring changed the dependence of spike synchrony on the synaptic strength moderately. However, the effects of this network topology were not really special in other properties of network activity. Action Editor: Xiao-Jing Wang     

Measuring Symmetry,Asymmetry and Randomness in Neural Network Connectivity

Cognitive functions are stored in the connectome, the wiring diagram of the brain, which exhibits non-random features, so-called motifs. In this work, we focus on bidirectional, symmetric motifs, i.e. two neurons that project to each other via connections of equal strength, and unidirectional, non-symmetric motifs, i.e. within a pair of neurons only one neuron projects to the other. We hypothesise that such motifs have been shaped via activity dependent synaptic plasticity processes. As a consequence, learning moves the distribution of the synaptic connections away from randomness. Our aim is to provide a global, macroscopic, single parameter characterisation of the statistical occurrence of bidirectional and unidirectional motifs. To this end we define a symmetry measure that does not require any a priori thresholding of the weights or knowledge of their maximal value. We calculate its mean and variance for random uniform or Gaussian distributions, which allows us to introduce a confidence measure of how significantly symmetric or asymmetric a specific configuration is, i.e. how likely it is that the configuration is the result of chance. We demonstrate the discriminatory power of our symmetry measure by inspecting the eigenvalues of different types of connectivity matrices. We show that a Gaussian weight distribution biases the connectivity motifs to more symmetric configurations than a uniform distribution and that introducing a random synaptic pruning, mimicking developmental regulation in synaptogenesis, biases the connectivity motifs to more asymmetric configurations, regardless of the distribution. We expect that our work will benefit the computational modelling community, by providing a systematic way to characterise symmetry and asymmetry in network structures. Further, our symmetry measure will be of use to electrophysiologists that investigate symmetry of network connectivity.     

"Guilt by association" is the exception rather than the rule in gene networks

Gene networks are commonly interpreted as encoding functional information in their connections. An extensively validated principle called guilt by association states that genes which are associated or interacting are more likely to share function. Guilt by association provides the central top-down principle for analyzing gene networks in functional terms or assessing their quality in encoding functional information. In this work, we show that functional information within gene networks is typically concentrated in only a very few interactions whose properties cannot be reliably related to the rest of the network. In effect, the apparent encoding of function within networks has been largely driven by outliers whose behaviour cannot even be generalized to individual genes, let alone to the network at large. While experimentalist-driven analysis of interactions may use prior expert knowledge to focus on the small fraction of critically important data, large-scale computational analyses have typically assumed that high-performance cross-validation in a network is due to a generalizable encoding of function. Because we find that gene function is not systemically encoded in networks, but dependent on specific and critical interactions, we conclude it is necessary to focus on the details of how networks encode function and what information computational analyses use to extract functional meaning. We explore a number of consequences of this and find that network structure itself provides clues as to which connections are critical and that systemic properties, such as scale-free-like behaviour, do not map onto the functional connectivity within networks.     

Resolving Structural Variability in Network Models and the Brain

Large-scale white matter pathways crisscrossing the cortex create a complex pattern of connectivity that underlies human cognitive function. Generative mechanisms for this architecture have been difficult to identify in part because little is known in general about mechanistic drivers of structured networks. Here we contrast network properties derived from diffusion spectrum imaging data of the human brain with 13 synthetic network models chosen to probe the roles of physical network embedding and temporal network growth. We characterize both the empirical and synthetic networks using familiar graph metrics, but presented here in a more complete statistical form, as scatter plots and distributions, to reveal the full range of variability of each measure across scales in the network. We focus specifically on the degree distribution, degree assortativity, hierarchy, topological Rentian scaling, and topological fractal scaling—in addition to several summary statistics, including the mean clustering coefficient, the shortest path-length, and the network diameter. The models are investigated in a progressive, branching sequence, aimed at capturing different elements thought to be important in the brain, and range from simple random and regular networks, to models that incorporate specific growth rules and constraints. We find that synthetic models that constrain the network nodes to be physically embedded in anatomical brain regions tend to produce distributions that are most similar to the corresponding measurements for the brain. We also find that network models hardcoded to display one network property (e.g., assortativity) do not in general simultaneously display a second (e.g., hierarchy). This relative independence of network properties suggests that multiple neurobiological mechanisms might be at play in the development of human brain network architecture. Together, the network models that we develop and employ provide a potentially useful starting point for the statistical inference of brain network structure from neuroimaging data.     

Cliques and cavities in the human connectome

Encoding brain regions and their connections as a network of nodes and edges captures many of the possible paths along which information can be transmitted as humans process and perform complex behaviors. Because cognitive processes involve large, distributed networks of brain areas, principled examinations of multi-node routes within larger connection patterns can offer fundamental insights into the complexities of brain function. Here, we investigate both densely connected groups of nodes that could perform local computations as well as larger patterns of interactions that would allow for parallel processing. Finding such structures necessitates that we move from considering exclusively pairwise interactions to capturing higher order relations, concepts naturally expressed in the language of algebraic topology. These tools can be used to study mesoscale network structures that arise from the arrangement of densely connected substructures called cliques in otherwise sparsely connected brain networks. We detect cliques (all-to-all connected sets of brain regions) in the average structural connectomes of 8 healthy adults scanned in triplicate and discover the presence of more large cliques than expected in null networks constructed via wiring minimization, providing architecture through which brain network can perform rapid, local processing. We then locate topological cavities of different dimensions, around which information may flow in either diverging or converging patterns. These cavities exist consistently across subjects, differ from those observed in null model networks, and – importantly – link regions of early and late evolutionary origin in long loops, underscoring their unique role in controlling brain function. These results offer a first demonstration that techniques from algebraic topology offer a novel perspective on structural connectomics, highlighting loop-like paths as crucial features in the human brain’s structural architecture.     

Quantifying robustness and dissipation cost of yeast cell cycle network: the funneled energy landscape perspectives

We study the origin of robustness of yeast cell cycle cellular network through uncovering its underlying energy landscape. This is realized from the information of the steady-state probabilities by solving a discrete set of kinetic master equations for the network. We discovered that the potential landscape of yeast cell cycle network is funneled toward the global minimum, G1 state. The ratio of the energy gap between G1 and average versus roughness of the landscape termed as robustness ratio (RR) becomes a quantitative measure of the robustness and stability for the network. The funneled landscape is quite robust against random perturbations from the inherent wiring or connections of the network. There exists a global phase transition between the more sensitive response or less self-degradation phase leading to underlying funneled global landscape with large RR, and insensitive response or more self-degradation phase leading to shallower underlying landscape of the network with small RR. Furthermore, we show that the more robust landscape also leads to less dissipation cost of the network. Least dissipation and robust landscape might be a realization of Darwinian principle of natural selection at cellular network level. It may provide an optimal criterion for network wiring connections and design.     

Communication Efficiency and Congestion of Signal Traffic in Large-Scale Brain Networks

The complex connectivity of the cerebral cortex suggests that inter-regional communication is a primary function. Using computational modeling, we show that anatomical connectivity may be a major determinant for global information flow in brain networks. A macaque brain network was implemented as a communication network in which signal units flowed between grey matter nodes along white matter paths. Compared to degree-matched surrogate networks, information flow on the macaque brain network was characterized by higher loss rates, faster transit times and lower throughput, suggesting that neural connectivity may be optimized for speed rather than fidelity. Much of global communication was mediated by a “rich club” of hub regions: a sub-graph comprised of high-degree nodes that are more densely interconnected with each other than predicted by chance. First, macaque communication patterns most closely resembled those observed for a synthetic rich club network, but were less similar to those seen in a synthetic small world network, suggesting that the former is a more fundamental feature of brain network topology. Second, rich club regions attracted the most signal traffic and likewise, connections between rich club regions carried more traffic than connections between non-rich club regions. Third, a number of rich club regions were significantly under-congested, suggesting that macaque connectivity actively shapes information flow, funneling traffic towards some nodes and away from others. Together, our results indicate a critical role of the rich club of hub nodes in dynamic aspects of global brain communication.     

Feedforward architectures driven by inhibitory interactions

Directed information transmission is paramount for many social, physical, and biological systems. For neural systems, scientists have studied this problem under the paradigm of feedforward networks for decades. In most models of feedforward networks, activity is exclusively driven by excitatory neurons and the wiring patterns between them, while inhibitory neurons play only a stabilizing role for the network dynamics. Motivated by recent experimental discoveries of hippocampal circuitry, cortical circuitry, and the diversity of inhibitory neurons throughout the brain, here we illustrate that one can construct such networks even if the connectivity between the excitatory units in the system remains random. This is achieved by endowing inhibitory nodes with a more active role in the network. Our findings demonstrate that apparent feedforward activity can be caused by a much broader network-architectural basis than often assumed.     

A stimulus-dependent connectivity analysis of neuronal networks

We present an analysis of interactions among neurons in stimulus-driven networks that is designed to control for effects from unmeasured neurons. This work builds on previous connectivity analyses that assumed connectivity strength to be constant with respect to the stimulus. Since unmeasured neuron activity can modulate with the stimulus, the effective strength of common input connections from such hidden neurons can also modulate with the stimulus. By explicitly accounting for the resulting stimulus-dependence of effective interactions among measured neurons, we are able to remove ambiguity in the classification of causal interactions that resulted from classification errors in the previous analyses. In this way, we can more reliably distinguish causal connections among measured neurons from common input connections that arise from hidden network nodes. The approach is derived in a general mathematical framework that can be applied to other types of networks. We illustrate the effects of stimulus-dependent connectivity estimates with simulations of neurons responding to a visual stimulus. This research was supported by the National Science Foundation grants DMS-0415409 and DMS-0748417.     

Processing of Feature Selectivity in Cortical Networks with Specific Connectivity

Although non-specific at the onset of eye opening, networks in rodent visual cortex attain a non-random structure after eye opening, with a specific bias for connections between neurons of similar preferred orientations. As orientation selectivity is already present at eye opening, it remains unclear how this specificity in network wiring contributes to feature selectivity. Using large-scale inhibition-dominated spiking networks as a model, we show that feature-specific connectivity leads to a linear amplification of feedforward tuning, consistent with recent electrophysiological single-neuron recordings in rodent neocortex. Our results show that optimal amplification is achieved at an intermediate regime of specific connectivity. In this configuration a moderate increase of pairwise correlations is observed, consistent with recent experimental findings. Furthermore, we observed that feature-specific connectivity leads to the emergence of orientation-selective reverberating activity, and entails pattern completion in network responses. Our theoretical analysis provides a mechanistic understanding of subnetworks’ responses to visual stimuli, and casts light on the regime of operation of sensory cortices in the presence of specific connectivity.     

The impact of sparsity in low-rank recurrent neural networks

Neural population dynamics are often highly coordinated, allowing task-related computations to be understood as neural trajectories through low-dimensional subspaces. How the network connectivity and input structure give rise to such activity can be investigated with the aid of low-rank recurrent neural networks, a recently-developed class of computational models which offer a rich theoretical framework linking the underlying connectivity structure to emergent low-dimensional dynamics. This framework has so far relied on the assumption of all-to-all connectivity, yet cortical networks are known to be highly sparse. Here we investigate the dynamics of low-rank recurrent networks in which the connections are randomly sparsified, which makes the network connectivity formally full-rank. We first analyse the impact of sparsity on the eigenvalue spectrum of low-rank connectivity matrices, and use this to examine the implications for the dynamics. We find that in the presence of sparsity, the eigenspectra in the complex plane consist of a continuous bulk and isolated outliers, a form analogous to the eigenspectra of connectivity matrices composed of a low-rank and a full-rank random component. This analogy allows us to characterise distinct dynamical regimes of the sparsified low-rank network as a function of key network parameters. Altogether, we find that the low-dimensional dynamics induced by low-rank connectivity structure are preserved even at high levels of sparsity, and can therefore support rich and robust computations even in networks sparsified to a biologically-realistic extent.     

Correlations in spiking neuronal networks with distance dependent connections

Can the topology of a recurrent spiking network be inferred from observed activity dynamics? Which statistical parameters of network connectivity can be extracted from firing rates, correlations and related measurable quantities? To approach these questions, we analyze distance dependent correlations of the activity in small-world networks of neurons with current-based synapses derived from a simple ring topology. We find that in particular the distribution of correlation coefficients of subthreshold activity can tell apart random networks from networks with distance dependent connectivity. Such distributions can be estimated by sampling from random pairs. We also demonstrate the crucial role of the weight distribution, most notably the compliance with Dales principle, for the activity dynamics in recurrent networks of different types.     

Self-Organization of Microcircuits in Networks of Spiking Neurons with Plastic Synapses

The synaptic connectivity of cortical networks features an overrepresentation of certain wiring motifs compared to simple random-network models. This structure is shaped, in part, by synaptic plasticity that promotes or suppresses connections between neurons depending on their joint spiking activity. Frequently, theoretical studies focus on how feedforward inputs drive plasticity to create this network structure. We study the complementary scenario of self-organized structure in a recurrent network, with spike timing-dependent plasticity driven by spontaneous dynamics. We develop a self-consistent theory for the evolution of network structure by combining fast spiking covariance with a slow evolution of synaptic weights. Through a finite-size expansion of network dynamics we obtain a low-dimensional set of nonlinear differential equations for the evolution of two-synapse connectivity motifs. With this theory in hand, we explore how the form of the plasticity rule drives the evolution of microcircuits in cortical networks. When potentiation and depression are in approximate balance, synaptic dynamics depend on weighted divergent, convergent, and chain motifs. For additive, Hebbian STDP these motif interactions create instabilities in synaptic dynamics that either promote or suppress the initial network structure. Our work provides a consistent theoretical framework for studying how spiking activity in recurrent networks interacts with synaptic plasticity to determine network structure.     

Assembly rules for protein networks derived from phylogenetic-statistical analysis of whole genomes

Background

We report an analysis of a protein network of functionally linked proteins, identified from a phylogenetic statistical analysis of complete eukaryotic genomes. Phylogenetic methods identify pairs of proteins that co-evolve on a phylogenetic tree, and have been shown to have a high probability of correctly identifying known functional links.

Results

The eukaryotic correlated evolution network we derive displays the familiar power law scaling of connectivity. We introduce the use of explicit phylogenetic methods to reconstruct the ancestral presence or absence of proteins at the interior nodes of a phylogeny of eukaryote species. We find that the connectivity distribution of proteins at the point they arise on the tree and join the network follows a power law, as does the connectivity distribution of proteins at the time they are lost from the network. Proteins resident in the network acquire connections over time, but we find no evidence that 'preferential attachment' – the phenomenon of newly acquired connections in the network being more likely to be made to proteins with large numbers of connections – influences the network structure. We derive a 'variable rate of attachment' model in which proteins vary in their propensity to form network interactions independently of how many connections they have or of the total number of connections in the network, and show how this model can produce apparent power-law scaling without preferential attachment.

Conclusion

A few simple rules can explain the topological structure and evolutionary changes to protein-interaction networks: most change is concentrated in satellite proteins of low connectivity and small phenotypic effect, and proteins differ in their propensity to form attachments. Given these rules of assembly, power law scaled networks naturally emerge from simple principles of selection, yielding protein interaction networks that retain a high-degree of robustness on short time scales and evolvability on longer evolutionary time scales.

     

Influence of Wiring Cost on the Large-Scale Architecture of Human Cortical Connectivity

In the past two decades some fundamental properties of cortical connectivity have been discovered: small-world structure, pronounced hierarchical and modular organisation, and strong core and rich-club structures. A common assumption when interpreting results of this kind is that the observed structural properties are present to enable the brain''s function. However, the brain is also embedded into the limited space of the skull and its wiring has associated developmental and metabolic costs. These basic physical and economic aspects place separate, often conflicting, constraints on the brain''s connectivity, which must be characterized in order to understand the true relationship between brain structure and function. To address this challenge, here we ask which, and to what extent, aspects of the structural organisation of the brain are conserved if we preserve specific spatial and topological properties of the brain but otherwise randomise its connectivity. We perform a comparative analysis of a connectivity map of the cortical connectome both on high- and low-resolutions utilising three different types of surrogate networks: spatially unconstrained (‘random’), connection length preserving (‘spatial’), and connection length optimised (‘reduced’) surrogates. We find that unconstrained randomisation markedly diminishes all investigated architectural properties of cortical connectivity. By contrast, spatial and reduced surrogates largely preserve most properties and, interestingly, often more so in the reduced surrogates. Specifically, our results suggest that the cortical network is less tightly integrated than its spatial constraints would allow, but more strongly segregated than its spatial constraints would necessitate. We additionally find that hierarchical organisation and rich-club structure of the cortical connectivity are largely preserved in spatial and reduced surrogates and hence may be partially attributable to cortical wiring constraints. In contrast, the high modularity and strong s-core of the high-resolution cortical network are significantly stronger than in the surrogates, underlining their potential functional relevance in the brain.     

Functional Brain Networks: Random, “Small World” or Deterministic?

Lately the problem of connectivity in brain networks is being approached frequently by graph theoretical analysis. In several publications based on bivariate estimators of relations between EEG channels authors reported random or “small world” structure of networks. The results of these works often have no relation to other evidence based on imaging, inverse solutions methods, physiological and anatomical data. Herein we try to find reasons for this discrepancy. We point out that EEG signals are very much interdependent, thus bivariate measures applied to them may produce many spurious connections. In fact, they may outnumber the true connections. Giving all connections equal weights, as it is usual in the framework of graph theoretical analysis, further enhances these spurious links. In effect, close to random and disorganized patterns of connections emerge. On the other hand, multivariate connectivity estimators, which are free of the artificial links, show specific, well determined patterns, which are in a very good agreement with other evidence. The modular structure of brain networks may be identified by multivariate estimators based on Granger causality and formalism of assortative mixing. In this way, the strength of coupling may be evaluated quantitatively. During working memory task, by means of multivariate Directed Transfer Function, it was demonstrated that the modules characterized by strong internal bonds exchange the information by weaker connections.