BioSystems 85 (2006) 5564

Small-world connectivity, motif composition, and complexity of fractal neuronal connections

Olaf Sporns
Department of Psychological and Brain Sciences, Indiana University, 1101 East 10th Street, Bloomington, IN 47405, USA Received 8 July 2005; accepted 17 February 2006

Abstract Connection patterns of the cerebral cortex consist of pathways linking neuronal populations across multiple levels of scale, from whole brain regions to local minicolumns. This nested interconnectivity suggests the hypothesis that cortical connections are arranged in fractal or self-similar patterns. We describe a simple procedure to generate fractal connection patterns that aim at capturing the potential self-similarity and hierarchical ordering of neuronal connections. We examine these connection patterns by calculating a broad range of structural measures, including small-world attributes and motif composition, as well as some global measures of functional connectivity, including complexity. As we vary fractal patterns by changing a critical control parameter, we nd strongly correlated changes in several structural and functional measures, suggesting that they emerge together and are mutually linked. Measures obtained from some modeled fractal patterns closely resemble those of real neuroanatomical data sets, supporting the original hypothesis. 2006 Elsevier Ireland Ltd. All rights reserved.
Keywords: Brain connectivity; Complexity; Network motifs; Graph theory; Fractal patterns

1. Introduction Recent advances in neuroinformatics and computational neuroscience have revealed characteristic nonrandom patterns in connection matrices of invertebrates and mammalian cerebral cortex (Sporns et al., 2004). For example, large-scale cortical networks exhibit distinct clusters (Hilgetag et al., 2000a), hierarchical organization (Hilgetag et al., 2000b), a specic composition of structural and functional motifs (Sporns and K otter, 2004), small-world attributes, i.e. high clustering and short path lengths (Sporns et al., 2000; Hilgetag et al., 2000a; Sporns and Zwi, 2004), short wiring length (Cherniak et al., 2004) and high complexity (Sporns et al., 2000; Sporns and Tononi, 2002). Recently, sta-

E-mail address: osporns@indiana.edu.

tistical analyses of connectivity have been extended to the level of single neurons in the cortex (Chklovskii et al., 2002) and in subcortical regions such as the brain stem (Humphries et al., 2006), generally conrming the existence of small-world attributes, found to be associated with conserved wiring length and efcient synchronization (Buzsaki et al., 2004). Studies of patterns of functional connectivity (coherence or correlation) among cortical regions have demonstrated that functional brain networks also exhibit small-world (Salvador et al., 2005; Achard et al., 2006) and scalefree properties (Eguiluz et al., 2005), possibly reecting the underlying structural organization of anatomical connections. In general, it has been suggested that the large-scale organization of anatomical cortical connections may impose important constraints on functional dynamics underlying cognition (Bressler, 1995; Friston, 2002).

0303-2647/$ see front matter 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.biosystems.2006.02.008

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The networks of the cerebral cortex can be characterized at multiple levels of scale, ranging from local neuronal groups, via patterns of intra-areal connections, to entire brain regions, and nally to extended cortical systems (Sporns et al., 2005). Cortical neurons display specic patterns of interconnectivity at each level. Individual neurons within local cortical neighborhoods are more densely interconnected, forming specialized circuits that carry out local processing within neuronal groups or minicolumns (Mountcastle, 1997), each with an approximate diameter of 50 m. These minicolumns are connected within individual cortical areas via tangential or horizontal connections, forming functionally segregated networks spanning several millimeters (Callaway and Katz, 1990; Somogyi et al., 1998; Amirikian and Georgopoulos, 2003). Neuronal groups in different cortical regions are connected via inter-regional pathways, linking areas over several millimeters or centimeters of cortical space. These interregional pathways then form extended cortical systems, such as segregated areas of the cortical visual, auditory and somatosensory systems that are in turn connected between each other through additional long-range pathways (Felleman and Van Essen, 1991). The nested aspect of the connectivity of cortical neurons points toward the possible existence of an underlying fractal, or selfsimilar connection pattern and leads us to hypothesize

that self-similarity is an important organizational feature of cortico-cortical connectivity. In this paper, we explore ways to generate self-similar connection patterns and we analyze and compare their structural and functional properties. In generating these connection patterns, we deliberately chose an approach that is easily parameterized to facilitate formal analysishowever, we are aware that this simplied approach does not capture all that is known about cortical connection patterns at any particular level of scale. Fig. 1A illustrates our approach to generate fractal or self-similar connection matrices that resemble those of brain networks. We begin by generating an isolated elementary group consisting of 2m fully connected units (hierarchical level k = 0). Then, two of these groups are linked by generating connections between them at a given density (k = 1). Then this network is again duplicated and connections are generated between the two resulting subnets (k = 2). This process is repeated until a desired network size N = 2n is reached. At each step the connection density is decreased, resulting in progressively sparser interconnectivity at higher hierarchical levels. Following this procedure, the resulting connection matrices exhibit self-similar (fractal) properties. In this study, the fall-off in density of connections is governed by a single control parameter (see Section 2), which allows us to examine a continuous spectrum

Fig. 1. Construction of fractal, random, and lattice connection matrices. (A) Schematic diagram illustrating the construction of self-similar connection patterns, starting from a single elementary group (k = 0), to a connected couple of groups (k = 1), couples of couples (k = 2), and so forth. (B) Example of a connection matrix constructed with E = 2.0, with connection densities indicated at left, as well as reected by the greyscale of the matrix. (C) Examples of random (rnd), lattice (ltc), fractal (frc), and mapped fractal (mfr) connection matrices, for N = 128, n = 7, m = 3, and E = 2.0. Intra-group connections are indicated in black, inter-group connections are indicated in grey. K = 3065 for all matrices shown.

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of connection matrices ranging from isolated groups to a fully connected network. This paper is about characterizing and comparing the structural and functional characteristics of fractal neuronal connection patterns. After examining examples of structural connection patterns for the existence of smallworld attributes, we examine their motif composition. We then derive the covariance structure of these networks and compute global measures of functional connectivity to allow a comparison of structural and functional measures.
2. Methods 2.1. Generation of fractal connection patterns Fractal connection patterns were generated as sparse matrices with binary directed connections arranged as a fractal set. All fractal connection matrices were of size N = 2n with N2 N entries specifying the interconnections of N units (no selfconnections). In the present study, we varied n between 5 and 9 (in some cases up to n = 12). The generating process for fractal connection matrices operated as follows (Figs. 1 and 2). At the beginning, we generated a single elementary group of 2m units. Units within this group were fully interconnected. Then, two groups were interconnected with a connection density of Ek , with k = 1. Connection density refers to the fraction of all existing (binary) connections out of all possible ones, for a given section of the connection matrix. For example, two groups with

8 units each (m = 3) can be interconnected by maximally 64 connections (in one direction) and if 16 out of these 64 possible connections exist, the corresponding connection density would be 0.25 (E = 4, k = 1). By incrementing k and increasing the size of interconnected sets, larger and larger sets of units became linked with connection weights or densities of Ek , with k = 0, 1, 2, . . ., n m. By setting the parameter E, steeper or shallower connection gradients could be generated. Examples of matrices generated according to this procedure are shown in Fig. 1B and C. Each fractal connection matrix was fully characterized by three parameters: n, m, and E. Most networks shown in this paper have n = 7, m = 3, and 5.0 > E > 1.2. Each network also has a specic total number of connections K, determined by the overall network size n, the group size m, and the density fall-off E (see Fig. 2 for plots of connection density). Two distinct types of fractal patterns were generated, termed fractal (frc) and mapped fractal (mfr). For fractal (frc) patterns, interconnections were assigned randomly, resulting in the absence of any ordered mapping between groups or subnets at any hierarchical level. For mapped fractal (mfr) patterns, interconnections were assigned using the density specied by the control parameter E and the hierarchical level k, but with a Gaussian topographic prole, analogous to a toeplitz matrix with a standard deviation along the diagonal that was proportional to K/2N. Thus, frc and mfr patterns did not differ in terms of the number of density of their connections. However, they differed in their topological arrangement. The frc patterns had random topology every where, while the procedure to generate mfr patterns effectively generated networks con-

Fig. 2. Spectrum of connectivity and connection densities. (A) Tuning of the parameter E yields connection patterns that range from disconnected groups (E ) to fully connected networks (E = 1). (B) Overall connection density increases, as does the ratio of inter-group/intra-group (between/within) connections, as E decreases.

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taining multiple nested mappings between groups and subnets, across all hierarchical levels. Ordered mappings are introduced in frc because of the preferential reciprocal connection of corresponding units along a main topographical axis. This arrangement may be viewed as a simple approximation of topographical mappings found at various levels in the cerebral cortex. All comparisons between frc, mfr, rnd, and ltc networks are carried out for equal n, m, E, and K. Group structure was conserved, only the connection topology of inter-group connections differed between these cases. 2.2. Generation of random connection patterns Random connection patterns (termed rnd) are created by rst generating non-overlapping and fully connected sets of 2m units that are arranged along the main diagonal of the matrix. Then the remaining connections are assigned with equal probability throughout the remaining possible entries of the sizeN matrix. The resulting networks contain elementary groups that are identical to those of their fractal counterparts, but all inter-group connections are homogeneously and randomly distributed. An example matrix is shown in Fig. 1C. 2.3. Generation of lattice connection patterns Ideal one-dimensional lattices (termed ltc) are generated by rst generating elementary groups (as for random networks) and then lling in the remaining connections at or near the main diagonal. An example matrix is shown in Fig. 1C. 2.4. Graph theory measures As measures of structural connectivity, we utilize several graph theoretical methods based on classical digraph theory (Harary, 1968; Chartrand and Lesniak, 1996) as well as methods specically developed for the analysis of small-world networks (Watts and Strogatz, 1998) and motifs (Milo et al., 2002; Sporns and K otter, 2004). Computation of graph theoretical measures of all connection matrices were carried out using Matlab toolboxes (www.indiana.edu/cortex/CCNL.html), described in detail in Sporns (2002) and Sporns and K otter (2004). Small-world attributes measured in this study were path length and clustering coefcient. The characteristic path length of a graph is computed as the average length of the shortest possible paths linking any pair of its nodes, also called the distance between these two nodes. The clustering coefcient captures how many connections are maintained between a nodes neighbors, i.e. the degree to which the nodes neighbors are connected to each other. In digraphs, neighbors of a node are all other nodes that are connected to it, either through an incoming or an outgoing connection. The nodes clustering coefcient is dened as the ratio of actually existing connections among its neighbors and the maximal number of such connections possible. The average of the clustering coefcients

for each node is the clustering coefcient of the graph, here denoted . Scaled path lengths and clustering coefcients were derived as: scaled = scaled = (frc,mfr) (rnd) (frc,mfr) (rnd) (1) (2)

Essentially, scaled path length and clustering coefcient quantify the degree to which these two measures deviate for fractal (frc) or mapped fractal (mfr) architectures relative to equivalent (same N, K, n, m, E) random (rnd) architectures. Generally, small-world architectures are characterized by low values for scaled (path length very similar to random networks) and higher values for scaled (signicantly increased clustering coefcient relative to random networks). To express the smallworld-ness of a network in one parameter, we dene a scaled small-world index, rst introduced by Humphries et al. (2006), as: scaled = scaled scaled (3)

This small-world index should be >1 for any small-world architecture, given that scaled > scaled (and both scaled > 1 and scaled > 1). Following more detailed denitions provided in earlier work (Sporns and K otter, 2004; Milo et al., 2002), a motif is a connected graph or network consisting of M vertices and a set of edges (maximally M2 M, for directed graphs, minimally M 1 with connectedness ensured) forming a sub-graph of a larger network. For each size M there is a limited set of distinct motif classes. In this paper, we consider only M = 3, for which there are 13 distinct motifs classes. We distinguish structural and functional motifs (Sporns and K otter, 2004). A structural motif of size M is comprised of a specic set of M vertices that are linked by edges. It is called a structural motif because a larger network could be structurally assembled from a nite set of such motifs. Functional motifs form a set of sub-graphs of a given structural motif. All such functional motifs consist of the original M vertices of the structural motif to which they belong, but contain only a subset of its edges. We view functional motifs as potential processing modes or effective circuits of a network, while structural motifs refer to anatomical elements or building blocks. Motif composition of a network can be determined using motif-detection algorithms, which enumerate all structural motifs from which functional motifs can then be derived. In this study, we compute the total number of all functional motifs, a measure that was found to take on large values for neurobiological data sets (Sporns and K otter, 2004) and was therefore of particular interest in the context of the present study. The number of functional motifs of size M = 3 corresponds to the total number of all motifs of all 13 motif classes. We then derive a scaled functional motif number, by dividing the functional motif number for fractal networks by that of

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random networks: (frc,mfr) scaled = (rnd) 2.5. Covariance structure and complexity measures

(4)

We take the elementary units of the networks discussed in this paper to be local populations of single neurons, whose activation values are related to a local mean ring rate. For the examples discussed in this paper we used a linear system approach, without performing nonlinear numerical simulations. Given a multi-dimensional Gaussian stochastic process and linear dynamics the covariance matrix COV can be derived analytically from the networks connectivity matrix and the amount of injected uncorrelated noise (Tononi et al., 1994). Under these assumptions the covariance matrix provides all deviations from statistical independence between the elements of the system (i.e. its functional connectivity). Once the covariance matrix is obtained, global statistical measures can be calculated (Tononi et al., 1994). In this paper, we compute the complexity of the networks dynamics, using a measure derived and applied in previous work (Tononi et al., 1998). Complexity captures the extent to which a system is both functionally segregated (small subsets of the system tend to behave independently) and functionally integrated (large subsets tend to behave coherently). We derive complexity C(X) as: C(X) = H (X)
i

of all possible connections are realized, and the connection matrix approaches full connectivity. Thus, by tuning the control parameter E one can model a gradual transition of networks from isolated groups to full connectivity, with fractal patterns in between. Variations in the size of the elementary group m, while n and E remain xed, result in similar connection matrices that are more or less dominated by the elementary groups (not shown here). Fig. 1 shows a comparison of the four main types of connection matrices investigated in this paper: random (rnd), lattice (ltc), fractal (frc) and mapped fractal (mfr), for a single setting of E = 2.0, N = 128, and K = 3065. Note, that for a given value of the control parameter E all types of connection matrices have equal numbers of connections (constant connection density). Fig. 2A shows examples taken from the spectrum of fractal connection matrices for N = 128, m = 3. Connection density increases gradually as E is increased, as does the ratio of inter- to intra-group connections (Fig. 2B). For E < 5.0 all connection matrices are fully connected (data not shown). 3.2. Small-world attributes Small-world attributes (path length and clustering coefcients) of connection patterns of different types (rnd, ltc, frc, mfr) are shown in Fig. 3A, for different settings of the control parameter E. Scaled parameters are plotted in Fig. 3B, revealing a tendency for scaled path lengths to decrease as connection matrices become denser, while scaled clustering coefcients exhibit a marked peak between E = 3 and E = 2 (for N = 128). The scaled small-world index also exhibits a peaked prole, for both frc and mfr connection topologies. Increasing N does not change the shape of this prole and reveals a tendency for maximal small-world indices to converge around E = 2. Thus, small-world attributes of fractal matrices as dened in Section 2.1 are invariant with respect to changes in the overall size of the network. We performed analyses of matrices up to sizes of N = 4096, with peaks of the scaled small-world index at E = 2.10 for frc matrices. Peak E-values decreased exponentially as N increased. However, sample sizes of larger matrices proved to be too small to allow precise quantication of the asymptote in this study. 3.3. Motif composition Fig. 4A displays scaled structural and functional motif numbers for frc and mfr matrices. As found for neurobiological data sets (Sporns and K otter, 2004), structural motif numbers of fractal connection matri-

H (xi |X xi ) (5)

= (N 1)I (X) N I (X xi )

X refers to a system composed of N elements, H(X) to the systems entropy, I(X) to the systems integration (Tononi et al., 1994), and H(xi |X xi ) to the conditional entropy of the element xi , given the complement X xi . As for small-world measures and motif numbers, we derive a scaled measure of complexity expressing the deviation of complexity for fractal connection patterns relative to random control cases: Cscaled = C(frc,mfr) C(rnd) (6)

3. Results 3.1. Comparison of connection patterns Fig. 2 shows examples of fractal connection patterns generated by varying the control parameter E, while maintaining xed n and m. For E = 5.0, the majority of the inter-group connections are made between neighboring groups of units and very few, if any, connections exist between more distant groups. This type of connectivity resembles lattice architectures. For E < 2.0, the connection matrix exhibits denser connections between more distant groups. For E = 1.2, a large proportion out

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Fig. 3. Small-world attributes. (A) Plots of path length and clustering coefcient for 5 < E < 1.2, N = 128, n = 7, m = 3. Grey area indicates the range between random matrices (lower end) and lattice matrices (upper end). Thin line indicates values for frc matrices, thick line indicates mfr matrices (a convention adopted in this and all other plots in the paper). Values are means (N = 100), standard errors are omitted for clarity. (B) Plots of scaled path length scaled (left) and scaled clustering coefcient scaled (right) for frc and mfr networks, with N = 128, n = 7, m = 3. (C) Plots of scaled small-world index scaled for N = 128 (left; N = 128, n = 7, m = 3) and networks of different size (middle and right; N and n vary, m = 3). Note that the peak of the scaled small-world index approaches E 2 as network sizes increase.

ces are decreased relative to those for random matrices, while functional motif numbers are increased. Scaled functional motif number exhibits a peaked prole with a single maximum near E = 2. Fig. 4B shows mean structural motif frequency spectra for random, fractal, and mapped fractal matrices, for E = 2.0, i.e. near the peak of functional motif number.

The motif frequency spectrum for mapped fractal matrices (mfr) shown in Fig. 4B (right) is highly correlated (r2 > 0.9) with motif frequency spectra of neurobiological connection matrices, e.g. those of the mammalian cerebral cortex (cf. data shown in Sporns and K otter, 2004). This high degree of correlation is remarkable, given the many simplifying assumptions that go into the

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Fig. 4. Motif composition. (A) Plots of scaled number of structural motifs (left) and scaled number of functional motifs (right), for motif size M = 3, for frc and mfr networks. Peak for functional motif number is around E 2. (B) Structural motif frequencies for 13 motifs of size M = 3 (see Sporns and K otter, 2004, for motif plots), averaged over N = 10 individual examples of rnd, frc, and mfr networks, E = 2.0, N = 128, n = 7, m = 3. (C) Motifs 9, 12, and 13 (left) and z-scores for motif frequency spectra for 5 < E < 1.2, N = 128, n = 7, m = 3, N = 10 (middle and right). z-Scores are derived via comparisons carried out between frc and rnd (middle) and mfr and rnd (right) networks. Plots show z > 5 on a grey scale, all z 5 are left blank. Note that for mfr networks only motifs 9, 12, and 13 are signicantly (z > 5) increased over rnd networks, over a broad range of E.

construction of mfr matrices. As is the case for actual neurobiological matrices, there is a strong resemblance to regular lattice matrices, with an increased frequency of motif 9 relative to the more compact motifs 12 and 13.

Whether these increased frequencies are statistically signicant is examined in Fig. 4C, which shows corresponding z-scores, allowing an identication of motifs that are signicantly increased (z > 5) in frc and mfr matrices relative to equivalent rnd matrices. All types

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of matrices exhibit degree distributions that are close to Gaussian, thus allowing valid statistical comparisons without replicating exact degree sequences. For E = 2, in frc networks only motifs 12 and 13 (corresponding to full or nearly full 3-node subgraphs) are signicantly increased. In mfr networks, motif 9 is signicantly increased as well. Motifs 9, 12, and 13 were previously shown to be simultaneously increased in several neurobiological data sets (Sporns and K otter, 2004). A separate statistical comparison can be made between fractal matrices and randomized or latticized control cases for which the degree sequences have been preserved. This comparison reveals the same signicant motifs (9, 12, and 13) for comparisons between mfr matrices and randomized/latticized controls (data not shown).

3.4. Complexity Under assumptions of Gaussian statistics and stationarity, linear dynamics allow the direct calculation of covariance matrices for each given connection matrix. Entropy mutual information and complexity can then be derived using standard formulae (see Section 2). Values for complexity of fractal connection matrices can be compared to those of random and lattice matrices. Scaled plots of complexity are shown in Fig. 5A, exhibiting a peaked prole with a single peak near E = 2. As for the small-world index (see Fig. 3C), increasing N does not alter the shape of this prole and the convergence of the location of the peak near E = 2.

Fig. 5. Complexity. (A) Plots of complexity C(X) (Eq. (5), left) and scaled complexity Cscaled (Eq. (6) right) for networks with N = 128, n = 7, m = 3. (B) Plots of scaled complexity for networks of different sizes (all m = 3). Note that the peak of scaled complexity approaches E 2 as the network sizes increase.

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4. Discussion In this paper, we analyzed structural and functional connectivity measures of fractal (self-similar) connection patterns. We introduced a simple approach to generate a spectrum of self-similar connection patterns, with a single control parameter E that governs self-similar distributions of connections among a set of seed groups. We observed that small-world architectures were restricted to a specic and scale-invariant range of this control parameter, with a single peak around a value of E = 2 for large N. We found that two other measures, the scaled number of functional motifs (a second structural measure) and the scaled complexity (a functional measure) exhibited highly similar proles, with single peaks that appeared to coincide with that of the small-world index. We conclude that, at least for the types of connection patterns examined in this paper, specic structural and functional attributes are tightly correlated. Prior work had revealed relationships between several indices of structural or functional connectivity in brain or brain-like networks (Sporns et al., 2000; Sporns, 2004; Sporns and K otter, 2004). Optimization studies showed that maximizing one measure (for example, complexity) often resulted in simultaneous increases in other measures as well (e.g. small-world attributes) and that all of them favored similar global network architectures characterized by two coexisting organizational principles, functional segregation and functional integration (Tononi et al., 1998; Friston, 2002). In this paper, we utilized a simple metric dened by a single control parameter to generate a continuous spectrum of connectivity matrices and we attempted to correlate small-world attributes, motif composition and complexity across this spectrum. Our data reveal a close association of these measures, in particular a peak around E 2 that coincides for small-world index, functional motif number and complexity. Do fractal matrices represent connections patterns with optimal or near-optimal complexity? To address this question we performed analyses in which fractal matrices were gradually degraded by randomly rewiring a fraction of their connections (data not shown). Random rewiring, on average, resulted in lowered complexity, lowered numbers of functional motifs and lowered small-world indices. However, additional gains in complexity can be achieved by redistributing connections while maintaining the overall fractal architecture, as exemplied by the complexity gain in the transition from frc to mfr matrices. This preliminary result argues that fractality is not the only, but possibly one among several structural attributes that might con-

tribute to the emergence of a small-world inside a large network. The present paper provides some initial results regarding the structure of fractal neuronal connectivity patterns, but additional work needs to be done. Other ways to generate fractal or self-similar connection matrices may exist and are not captured in the present exploratory study. While the data presented in this paper are certainly suggestive, the strong association between small-world attributes, functional motif number and complexity has not been analytically proven or demonstrated in a rigorously quantitative manner. However, the strong resemblance of the structural and functional characteristics of mapped fractal connection patterns to those of real neuroanatomical patterns supports the original hypothesis concerning fractal patterning of cortical connections. Further studies are needed to reveal additional complex interrelationship between network structure and function. Acknowledgements The author wishes to thank Karl Friston, Michael Breakspear, Chris Honey and an anonymous reviewer for helpful suggestions and comments. References
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