Spatial Embedding Imposes Constraints on the Network Architectures

of Neural Systems
Jennifer Stiso1,2 and Danielle S. Bassett1,3,4,5,6
1
Department of Bioengineering, School of Engineering and Applied Sciences,
University of Pennsylvania, Philadelphia, PA, 19104
5
Department of Physics & Astronomy, College of Arts and Sciences,
University of Pennsylvania, Philadelphia, PA, 19104
3
Department of Electrical and Systems Engineering, School of Engineering and Applied Sciences,
University of Pennsylvania, Philadelphia, PA, 19104
4
Department of Neurology, Perelman School of Medicine,
University of Pennsylvania, Philadelphia, PA, 19104
2
Neuroscience Graduate Group, Perelman School of Medicine,
University of Pennsylvania, Philadelphia, PA, 19104 and
6
arXiv:1807.04691v1 [q-bio.NC] 12 Jul 2018

To whom correspondence should be addressed: dsb@seas.upenn.edu

A fundamental understanding of the network architecture of the brain is necessary for the further
development of theories explicating circuit function. Recent progress has capitalized on quantitative
tools from network science to parsimoniously describe and predict neural activity and connectiv-
ity across multiple spatial and temporal scales. Perhaps as a historical artifact of its origins in
mathematics or perhaps as a derivative of its initial application to abstract informational systems,
network science provides many methods and summary statistics that address the networks topologi-
cal characteristics with little or no thought to its physical instantiation. Yet, for embedded systems,
physical laws can directly constrain processes of network growth, development, and function, and
an appreciation of those physical laws is therefore critical to an understanding of the system. Re-
cent evidence demonstrates that the constraints imposed by the physical shape and volume of the
brain, and by the mechanical forces at play in its development, have marked effects on the observed
network topology and function. Here, we review the rules imposed by space on the development
of neural networks and show that these rules give rise to a specific set of complex topologies. We
present evidence that these fundamental wiring rules affect the repertoire of neural dynamics that
can emerge from the system, and thereby inform our understanding of network dysfunction in dis-
ease. We also discuss several computational tools, mathematical models, and algorithms that have
proven useful in delineating the effects of spatial embedding on a given networked system and are
important considerations for addressing future problems in network neuroscience. Finally, we out-
line several open questions regarding the network architectures that support circuit function, the
answers to which will require a thorough and honest appraisal of the role of physical space in brain
network anatomy and physiology.

NETWORK TOPOLOGY VERSUS GEOMETRY by studies of regional activation (Box 1).

IN NEURAL SYSTEMS
In contemporary neuroscience, increasing volumes of
data are being brought to bear on the question of how
heterogeneous and distributed interactions between neu-
ral units might give rise to complex behaviors. Such
interactions form characteristic patterns across multiple
spatial scales, spanning from the relatively small scales of
molecules and cells, to the relatively large scales of areas
and lobes [1]. A natural language in which to describe
such interactions is network science, which elegantly rep-
resents interconnected systems as sets of nodes linked by
edges [2]. Intuitively, nodes often represent proteins, neu-
rons, subcortical nuclei, or large cortical areas, and edges
often represent either (i) structural links in the form of
chemical bonds, synapses, or white-matter tracts, or (ii)
functional links in the form of statistical relations be-
tween nodal activity time series. Generally, the resultant
network architecture can be fruitfully studied using tools
from graph theory to obtain mechanistic insights perti-
nent to cognition [3, 4], above and beyond those provided
In particular, several fundamental questions in neuro-
science are quintessentially network questions concern-
ing the physical relationships between functional units.
How does the physical structure of a circuit affect its
function? How does coordinated activity at small spa-
tial scales give rise to emergent phenomena at large spa-
tial scales? How might alterations in neurodevelopmental
processes lead to circuit malfunction in psychiatric disor-
ders? How might pathology spread through cortical and
subcortical tissue giving rise to the well-known clinical
presentations of neurological disease? These questions
collectively highlight the fact that the brain — and its
multiple networks of interacting units — is physically em-
bedded into a fixed three-dimensional enclosure. Natural
consequences of this embedding include diverse physical
drivers of early connection formation and physical con-
straints on the resultant adult network architecture. An
understanding of the system’s constitution and basal dy-
namics therefore require not only approaches to quantify
and predict network topology, but also tools, theories,
and methods to quantify and predict network geometry

and its role in both enabling and constraining system
function.
In this review, we provide evidence to support the no-
tion that a consideration of the brain’s physical embed-
ding will prove critical for a holistic understanding of neu-
ral circuit function. We focus our comments on the utility
of informing this consideration with emerging computa-
tional tools developed for the characterization of spatial
networks. Indeed, while network science was originally
developed in the context of systems devoid of clear spatial
characteristics [5], the field has steadily developed tools
and intuitions for spatially embedded network systems
[6]. In the light of these recent technical developments,
we begin by recounting observations from empirical stud-
ies addressing the question of how brain networks are
embedded into physical space. Next, we discuss the rele-
vance of this spatial embedding for an understanding of
network function and dysfunction. We complement these
empirical discussions with a more technical exposition on
the relevant tools, methods, and statistical approaches to
be considered when analyzing brain networks. Lastly, we
close by outlining a few important future directions in
methodological development and neuroscientific investi-
gation that would benefit from an honest appraisal of the
role of space in neural network architecture and dynam-
ics.
PHYSICAL CONSTRAINTS ON NETWORK
TOPOLOGY AND GEOMETRY
The processes and influences that guide the formation
of structural connections in neural systems are disparate
and varied [7, 8]. Evidence from genetics suggests that
neurons with similar functions as operationalized by sim-
ilar gene expression tend to have more similar connection
profiles than neurons with less similar functions [7, 9, 10].
Of course, it is important to note that some spatial sim-
ilarity of expression profiles is expected due to the in-
fluence of small scale spatial gradients in growth factors
over periods of development [7]. However, evidence from
the Allen Brain Atlas suggests that interareal connec-
tivity profiles in rodent brains are even more correlated
with gene co-expression than expected simply based on
such spatial relationships [9]. This heightened correlation
could be partially explained by observations in mathe-
matical modeling studies that neurons with similar in-
puts (and therefore potentially performing similar func-
tions) tend to have more similar connection profiles than
neurons with dissimilar inputs [11].
Yet, while genetic coding and functional utility each
play important roles, a key challenge lies in summariz-
ing the various constraints on connection formation in
a simple and intuitive theory that can guide future pre-
dictions. One particularly acclaimed candidate mecha-
nism for such a theory is that of physical constraints on
the development, maintenance, and use of connections.
Metabolism related to neural architecture and function
2
is costly, utilizing 20% of the body’s energy, despite com-
prising only 2% of its volume [12, 13]. Even the devel-
opment of axons alone, comprising only a small portion
of cortical tissue, extorts a large material cost [7]. The
existence of these pervasive costs motivated early work
to postulate that wiring minimization is a fundamental
driver of connection formation. Consistent with this hy-
pothesis, the connectomes of multiple species are pre-
dominantly comprised of wires extending over markedly
short distances [13–19], and this observation holds across
different methods of data collection [16, 18, 19].
However, mounting evidence suggests that pressures
for wiring minimization may compete against pressures
for efficient communication [20–22]. Early evidence sup-
porting the role of efficient communication came from the
observation that one can fix the network architecture of
inter-areal projections in the macaque cortex and then
rearrange the location of areas in space to obtain a con-
figuration with significantly (32%) lower wiring cost than
that present in the real system [21]. A similar method
can be used to obtain a configuration of the C. elegans
neuronal connectome with 48% lower wiring cost than
that present in the real system [21]. Interestingly, the
connections whose length is decreased most also tend to
be those that shorten the characteristic path length –
one of many ways to quantify how efficiently a network
can communicate [21, 23]. Consistent observations have
been made in human white matter tractography [20], the
mouse inter-areal connectome [10], and dendritic arbors
[7, 14]. Notably, computational models that instantiate
both constraints on wiring and efficient communication
produce topologies more similar to the true topologies
than models that instantiate a constraint on wiring min-
imization alone [11, 24]. Moreover, models that allow for
changes in this tradeoff over developmental time peri-
ods better fit observed connectome growth patterns than
prior models [25].
It is precisely this balance between wiring minimiza-
tion and communication efficiency that is thought to pro-
duce the complex network topologies observed in neural
systems, along with markedly precise spatial embedding
[24, 26]. To better understand this spatially embedded
topology, it is useful to consider methods that can si-
multaneously (rather than independently) assess topol-
ogy and geometry. One such method that has proven
particularly useful in the study of neural systems from
mice to humans is Rentian scaling, which assesses the
efficiency of a network’s spatial embedding [20, 27–30].
Originally developed in the context of computer circuits,
Rentian scaling describes a power-law scaling relation-
ship between the number of nodes in a volume and the
number of connections crossing the boundary of the vol-
ume [7, 20]. The existence of such a power law relation-
ship with an exponent known as Rent’s exponent is con-
sistent with an efficient spatial embedding of a complex
topology [31, 32]. In turn that efficient spatial embedding
is thought to support a broad repertoire of functional
dynamics. For example, tracts that bridge disparate ar-

eas of cortex to increase communication efficiency despite
greater wiring cost, also critically add to the functional
diversity of the brain in a manner that is distinct from
that predicted by path length alone [33].
REFLECTIONS OF PHYSICAL CONSTRAINTS
IN LOCAL, MESOSCALE, AND GLOBAL
NETWORK TOPOLOGY
Across species, the brain consistently exhibits a set
of topological features at local, meso-, and global scales
that can be relatively simply explained by spatial wiring
rules [34–36]. At the local scale, multiple modalities have
been used to demonstrate that a key conserved topologi-
cal feature is the existence of hubs, or nodes of unexpect-
edly high degree [37, 38]. Such hubs emerge naturally
in computational models in which the location of nodes
are fixed in space, and edges between nodes are rewired
to miminize average wiring length and to maximize topo-
logical efficiency by minimizing the average shortest path
length (Box 1). Interestingly, the number and degree of
hubs varies systematically with the relative importance of
the two constraints [14, 24] (Fig. 1). When wiring min-
imization is not enforced, networks become star graphs
with a single giant hub [14, 24]; when both constraints
are balanced, networks contain several hubs of varying
degrees, consistent with the topology observed in brain
networks [24]. It is notable that such constraints can
be implemented within the natural processes of devel-
opment; for example, in adult C. elegans, hub neurons
have been tracked back to the earliest born neurons in
the embryo, which accumulate a large number of connec-
tions along the normative growth trajectory [26, 39].
At the mesoscale, a key conserved topological feature is
modularity, or the existence of internally dense and exter-
nally sparse communities of nodes [34, 40]. The strength
of modularity in a network is commonly quantified using
a modularity quality index (Box 1). In computational
models, this index obtained under pressures of wiring
minimization and communication efficiency (quantified
with path length) was more similar to that empirically
measured in the connectomes of the macaque and C. el-
egans than to that obtained under either constraint sep-
arately [8, 24]. Again it is notable that such constraints
can be implemented within the natural processes of de-
velopment; for example, in C. elegans, communities form
when many neurons are born in a similar temporal win-
dow, and therefore typically share a common progenitor
type, spatial location, and genetic profile [26, 41]. Spaces
between modules can form cavities or cycles, or intu-
itively holes in the network, that can be identified with
emerging tools from applied algebraic topology (Box 2)
[42]. The locations, prevalence, and weight structure of
these cycles differs markedly between geometric and ran-
dom networks [43, 44], with patterns of functional con-
nectivity among neurons exhibiting characteristics simi-
lar to those observed in spatially constrained geometric
3
networks [45]. It will be interesting in future to gain
a deeper understanding of the relations between cycles
and modules, and their emergence through the spatially
constrained processes of development.
At the global scale, a key conserved topological feature
is small-worldness, or the confluence of unexpectedly high
clustering and short path length (Box 1) [46]. Such an
architecture is thought to be particularly conducive to a
balance between local information processing within the
clusters, and global information transmission across the
topologically long distance connections [47]. Similar to
the existence of hubs, modules, and cavities, small-world
architecture in a network can naturally arise from spa-
tial constraints on wiring [48]. Intuitively, clusters tend
to form in spatially nearby regions in order to minimize
wiring cost, while long distance connections facilitating
efficient communication tend to form only occasionally
due to their elevated wiring cost [49]. In concert with
these empirical observations, computational models that
account for wiring economy produce networks with small-
world architecture reminiscent of that observed in real
neural systems [50]. Collectively, these studies demon-
strate the influence of parsimonious wiring rules on com-
plex network topology. Future work could be directed to
better understand the aspects of connectome topology
that remain unexplained and thus may arise from more
subtle rules [8].
RELEVANCE OF NETWORK GEOMETRY FOR
DYNAMICS AND COGNITION
Pressures for wiring minimization and communica-
tion efficiency can exist alongside developmental pro-
cesses that produce non-isotropically structured organs.
Such processes include migration, elongation, segrega-
tion, folding, and closure that accompany neurulation
resulting in the bilaterally symmetric nervous system
composed of proencephalon, mesencephalon, rhomben-
cephalon, and spinal cord as well as patterning across
multiple overlapping signaling gradients. It is intuitively
possible that such processes could also explain the ob-
served differences in the network topologies of different
sectors of the brain [51, 52], which can impinge on the
functions that those sectors are optimized to perform
(Box 3). Indeed, prior work has noted the co-existence
of complex structural topologies and spatial gradients of
specific function [53], although it has been difficult to
achieve a mechanistic understanding of exactly how the
two relate to one another. One particularly promising
recent line of investigation has proposed the existence of
a set of primary spatial gradients that explain variance
in large-scale connectivity [54, 55]. In both humans and
macaques, the primary axis of variance is bounded on
one end by the transmodal default mode system, and on
the other end by the unimodal sensory systems [55]. No-
tably, this gradient is tightly linked to the geometry of
the network, with the regions located at one end having
 4

β=0 β = .8 β=1
B

Relative Temporal Cost (%)

Relative Spatial Cost (%)

Trade-off Parameter (β)

FIG. 1. Effect of wiring minimization and communication efficiency on network topology. Networks were generated
by modulating the balance between a constraint on wiring (in the figure referred to as a spatial cost) and a constraint on
information routing efficiency (in the figure referred to as a temporal cost). The parameter β, which ranges between 0 and 1,
tunes this balance by weighting spatial cost against temporal cost. When β = 0 only the spatial cost is considered, while when
β = 1 only the temporal cost is considered. (A) Examples of networks at different values of β when only the spatial constraint
exists (left), when only the temporal constraint exists (right), and when the two constraints are balanced (middle). Root nodes
are shown in green and all other nodes are shown in yellow. (B) Spatial costs (blue) and temporal costs (red) vary as a function
of β. This figure was adapted with permission from [14].

maximal spatial distances from the regions located at the
other end [55]. Additionally, the regions located at the
peaks of the transmodal gradient have substantial overlap
with structural hubs in human connectomes [4, 56]. As
discussed earlier, these hub could serve to optimally bal-
ance wiring cost and communication efficiency across the
connectome, in addition to explaining patterns of func-
tional connectivity. Put simply, such evidence supports
the notion that the cortex is fundamentally organized
along a dimension of function from concrete to abstract,
and that dimension manifests clearly in the network’s
spatial embedding.
The diverse spatial location of cortical and subcortical
areas has important implications for the patterns of neu-
ral dynamics that one would expect to observe. Consider,
for example, the patterns of intrinsic activity noted con-
sistently across species, individuals, and imaging modal-
ities [55, 57–59]. While prior work has reported a con-
sistent architecture of correlations between regional time
series [59], the manner in which the across-region activity
pattern at one time point is related to the across-region
activity pattern at other time points is not well under-
stood. Recent work addressing this gap has posited the
existence of so-called lag threads, or spatial similarities
between whole-brain activity patterns at non-zero time
lags [60]. Unexplained by vasculature, the orthogonal
threads are thought to reflect slow, subthreshold changes
in the membrane potential of large neuronal populations
[61], a notion that is supported by subtle changes in
lag thread structure across sleep and during cognitively
demanding tasks [60, 62]. Notably, regions of the de-
fault mode (which coincide with peaks of the transmodal
gradient discussed above) participate in lag thread mo-
tifs, where changes in the activity in one region lead to
changes in the activity of another region more frequently
than expected in an appropriate statistical null model

[58, 59]. The existence of these dependencies is consistent
with time-invariant, possibly structural features of brain
organization producing highly reproducible patterns of
activity.
RELEVANCE OF NETWORK GEOMETRY FOR
DISEASE
The spatial architecture of brain networks not only
impacts our understanding of dynamics and cognition,
but also our understanding of neurological disease and
psychiatric disorders. Mounting evidence suggests that
many diseases and disorders of mental health can be
thought of fruitfully as network disorders, where the
anatomy and physiology of cross-regional communication
can go awry [63, 64]. Intuitively, spatial anisotropies of
developmental processes, spatial specificity of pathology,
and spatial inhomogeneities of drug targets that either
lead to or accompany these disorders can also explain al-
terations in the spatial characteristics of brain networks
[65]. In this section we briefly discuss this correspondence
in epilepsy, a particularly common neurological disease,
and in schizophrenia, a particularly devastating psychi-
atric disorder.
Despite a diverse pathophysiology and a renitent uni-
fying biological mechanism, epilepsy is characterized by
altered network dynamics in the form of seizures that
display spatially consistent patterns. For example, an
ictal period often begins with a marked spatial decor-
relation between distributed brain regions followed by a
period in which abnormally synchronized activity prop-
agates in consistent spatial patterns [66, 67]. In addi-
tion to broad patterns of spatial decorrelation, individ-
ual siezures also show stereotyped patterns of both spi-
ral waves and travelling waves of activity [66, 68–73]. In
silico studies have demonstrated that a simple adaptive
model of synaptically coupled and spatially embedded
excitatory neurons can reproduce many basic features of
these waveforms, including their speed and the size of
the wavefront [70]. Yet, it is worth noting that travel-
ling waves are not unique to epilepsy, but also occur in
healthy human and non-human primates where they are
thought to play a role in transporting task-relevant infor-
mation [71, 74–79]. However, marked differences in wave
propagation in healthy and epileptic cortical tissue sug-
gests that the precise spatial progression is important,
potentially supported by distinct underlying microstruc-
tures [80]. Finally, even interictal dynamics are altered
in epilepsy, as manifest by marked decreases in average
functional connectivity across the brain combined with
local increases in functional connectivity and efficiency
in default mode areas [81–83]. These connectivity pat-
terns have some utility in predicting seizure spread, but
the guiding principles leading to these changes and how
they relate to fine scale patterns of activity remains un-
clear [84].
While its pathophysiology is quite distinct from that
5
implicated in epilepsy, schizophrenia is also a condition
marked by severe network disturbances that have broad
ramifications for cognitive function [22, 85, 86]. Some
of these network alterations appear to selectively affect
connections of certain physical lengths, reflecting an al-
teration in the network’s spatial embedding [87]. Specif-
ically, evidence suggests a reduced hierarchical struc-
ture and increased connection distance in the anatom-
ical connectivity of multimodal cortex in patients with
schizophrenia compared to healthy controls, indicative of
less efficient spatial wiring [85]. Moreover, in functional
brain networks, patients display longer high-weight con-
nections, decreased clustering, and increased topological
efficiency in comparison to healthy controls [87]. The
lack of strong, short distance functional connections is
in line with evidence from animal studies suggesting an
over-pruning of synapses in childhood onset schizophre-
nia [87]. Here, the intuitions gained from a consideration
of the network’s spatial embedding offer important di-
rections for future work in linking non-invasive imaging
phenotypes with invasive biomarkers of neural dysfunc-
tion in disease.
STATISTICS, NULL MODELS, AND
GENERATIVE MODELS
In the previous sections, we outlined developmental
rules for efficient wiring and we discussed the reflections
of these rules in spatial patterns of healthy and diseased
brain dynamics. Collectively, the studies that we
have reviewed motivate the broader use and further
development of sophisticated and easily-implementable
tools for the analysis of a network’s spatial embedding
[88]. Here we outline the current state of the field in
developing effective network statistics, network null
models, and generative network models that account for
spatial embedding.
Network Statistics. A simple way to examine net-
work architecture in the context of spatial embedding
is to incorporate the Euclidean distance of connections
into local, meso-scale, and global statistics [87, 89]. Ar-
guably the simplest local statistics that remain spatially
sensitive are moments of the distribution of edge lengths
in the network, including the mean, variance, skewness,
and kurtosis. One can also compute graph metrics that
have been extended to consider space, such as the physi-
cal network efficiency and the physical edge betweenness
[90]. Intuitively, both begin by defining the length of the
shortest physical (as opposed to topological) path along
network edges between any two nodes. The physical net-
work efficiency then takes the inverse of the harmonic
mean of this length, while the physical edge betweenness
provides the fraction of shortest physical paths between
all node pairs that traverse a given edge [91]. One could
also define a physical clustering coefficient in a similar
manner. Finally, one can assess the system for Rentian
 6

FIG. 2. Spatial distribution of intrinsic neural activity. Principal gradients of functional connectivity calculated in the
structural connections of both humans and macaques. The first two principal gradients explained approximately 40% of the
observed variance. (A) (Left) A scatter plot of the first two principal gradients, with transmodal regions shown in red, visual
regions shown in blue, and sensorimotor regions shown in green. (Right) The same colors are used to show the distribution of
points visualized on a cortical surface. The pattern suggests the existence of a macroscale gradient of connectivity that reflects
the systematic integration of information across different sensory modalities. (B, Left) The minimum geodesic distance (mm)
between each point on the cortical surface and the positive peaks of the first principal gradient. The peaks are shown as white
circles. (B, Right) A scatter plot depicting the relationship between distance and location on the trans- to uni-modal gradient.
Put differently, transmodal regions with high values in the principal gradient are maximally distant from unimodal regions with
low values in the principal gradient. This figure was adapted with permission from [55].

scaling as described earlier, providing information on how
efficiently the complex network topology has been embed-
ded into the physical space [20, 27–30]. In the context
of neural systems, these spatially informed graph statis-
tics can be used to account for the physical nature of
information processing, propagation, and transmission.
Complementing local and global graph statistics is
an assessment of a network’s community structure, a
mesoscale property frequently assessed by considering
the existence and strength of network modules [92].
From that community structure, one can determine the
spatial embedding of communities, for example by as-
sessing their laterality in bilaterally symmetric systems
such as the brain [93–95]. One of the most com-
mon ways to assess community structure is to maxi-
mize a modularity quality function, which identifies as-
sortative modules with dense within-module connectivity
and sparse between-module connectivity [96] (although
see [97] for methods to identify non-assortative commu-
nities). Mechanistically, this algorithm compares the
strength of observed connections between two nodes in a
community to that expected under a given a null model.
The most commonly used null model in this context is
the Newman-Girvan or configuration model, which pre-
serves the strength distribution of the network [96]. How-
ever, this null model operationalizes a purely topological
constraint – the strength distribution – and does not ac-
knowledge any spatial constraints that may exist in the
system. For this reason, many investigators across sci-
entific domains have begun developing alternative null
models that account for physical laws [98] or physical
contraints [99–101] on their system of interest.
In the context of brain networks, it is worth con-
sidering three distinct null models for modularity
maximization that incorporate information about the
physical space of the network’s embedding. First,
one can directly incorporate the wiring minimization
constraint observed in brain networks by defining a null
model with a probability of connection between two
nodes that decays exponentially as a function of distance
[99]. Using this model, one can detect different, and
more spatially distributed modules than those obtained
when one uses the configuration model [99]. Second, one
can employ gravity models [100], which account for the
number of connections expected given a certain distance
(typically a power law or inverse of distance), weighted
by the relative importance of each location (typically
a quantification of the population or size of a given
location) [100, 101]. Third, one can employ radiation
models designed to capture flow of information between
regions, by weighting distance functions by the flux
or flow of each location [101]. Of course, there exists
no single correct null model for community detection
that will suit every question in neuroscience. However,
we propose that many studies could test tighter, more
targeted hypotheses about community structure in brain
networks by using a null model that accounts for the
brain’s spatial nature.
Network Null Models. When considering a network
representation of a neural system, one often computes
a statistical quantitity of interest and then compares
that quantity to that expected in a random network null
model. If the observed quantity is significantly greater
than or less than that expected, one concludes that the
network under study shows meaningful architecture of
potential relevance to the biology. Perhaps the most com-
mon random network null model is that which randomly
permutes the locations of edges in the network while pre-
serving the number of nodes, number of edges, and edge

weight distribution. However, one may also be inter-
ested to determine whether observed statistics are dif-
ferent from what one would expect simply from the spa-
tial embedding or wiring rules of the network [102–104].
To address these questions, one can rewire the observed
network by conditionally swapping two links if the swap
preserves the mean wiring length of the network [103].
By pairing this model with a reduced null model in which
connections are only swapped if they reduce connnection
length, one can assess the role of long distance connec-
tions in the network, which will be preserved in the spa-
tial null but not preserved in the reduced null [103]. In
addition to preserving the mean wiring length, one might
also wish to preserve the full edge length distribution
by, for example, (1) fitting a function to the relation-
ship between the mean and variance of edge weights and
their distances, (2) removing the effect of that relation-
ship from the data, (3) randomly rewiring the network,
and (4) adding the effect back into the rewired network
[102].
To complement insights obtained from edge swapping
algorithms, one can also construct null model networks
by stipulating a wiring rule a priori while fixing the
locations of nodes within the embedded system. In
this vein, studies have fruitfully used null models based
on minimum spanning tree and greedy triangulation
methods [105–107]. A minimum spanning tree is a graph
that connects all of the nodes in a network such that
the sum of the total edge weights is minimal. To extend
this notion to spatial networks, one can preserve the
true geographic locations of all nodes in the empirical
network and compute the minimum spanning tree on
the matrix of Euclidean distances between all node pairs
[91]. Representing the opposite extreme is the greedy
triangulation model, which is particularly relevant for
the study of empirical networks that are planar (lying
along a surface) as opposed to non-planar (lying within
a volume). In the context of neural systems, planar
or planar-like networks are observed in vasculature,
and in thinned models of cortex that either consider a
single lamina or a coarse-grained model collapsing across
laminae [108, 109]. To construct a greedy triangula-
tion null model, one can preserve the true geographic
locations of all nodes in the empirical network and
iteratively connect pairs of nodes in ascending order
of their distance while ensuring that no edges cross.
After constructing such minimally and maximally wired
null models, one can calculate relative measures of
wiring length, physical efficiency, physical betweenness
centrality, and community structure by normalizing the
empirical values by those expected in the two extremes
[91].
Generative Network Models. Generative network
models can be used to test hypotheses about the rules
guiding network growth, development, and evolution
[110]. Often, an ensemble of generative models are con-
structed, and summary graph statistics from the empir-
7
ical network are compared to the statistics of each of
the generative models with the goal of inferring which
wiring rule was most likely to have produced the ob-
served architecture [11, 28, 111]. Evidence from such
studies suggests that spatially embedded models tend to
more accurately reproduce network measures of large-
scale neural systems than models that do not account
for space [28]. One particularly influential study consid-
ered 13 generative models that all incorporated a wiring
probability that increased with distance [111]. Consis-
tent with other work, the authors found that the model
that only included the wiring minimization constraint
was unable to recreate long distance connections of in-
dividual connectomes in humans [8, 11, 111]. Successive
generative models were then added that attempted to
recreate certain aspects of topology in addition to these
geometric constraints [111]. The models that performed
the best were those that preserved homophilic attrac-
tion such that connections preferentially formed between
nodes that had similar connection profiles [111]. Contin-
ued advancement of generative network models, and in-
clusion of additional biological features such as bilateral
symmetry, serves as an exciting approach to test mech-
anistic predictions about how network topology forms in
spatially embedded neural systems.
FUTURE DIRECTIONS
The spatial embedding of the brain is an impor-
tant driver of its connectivity, which in turn directly
constrains neural function and by extension behavior.
Emerging tools from network science can be used to as-
sess this spatial architecture, thereby allowing investiga-
tors to test more specific hypotheses about brain network
structure and dynamics. While we envision that the use
of these tools will significantly expand our understand-
ing, it is also important to acknowledge their limitations.
In particular, the majority of currently available network
tools make the simplifying assumption that all of the re-
lations of interests are strictly dyadic in nature, and ex-
ist between inherently separable components [112]. In
truth, however, features that arise from spatial embed-
ding can also manifest as continuous or overlapping maps
and gradients [53], motivating the use of tools from ap-
plied algebraic topology that can account for non-dyadic
interactions (Box 2). As the field moves forward, we
envision existing and yet-to-be-developed tools for char-
acterizing the spatial embedding of brain networks will
prove critical for our understanding of network processes
underlying cognition, and alterations to those processes
accompanying disease.
 8

FIG. 3. Community structure obtained with spatially embedded and non-embedded null models. (A) A schematic
of a spatially-informed null model. The model expects fewer long distance connections than short distance connections. (B)
A schematic of the anticipated difference between the spatial null model and the Newman-Girvan (NG) null model; spatial
communities will have longer distance connections and not capture clustering of spatially nearby regions. (C) Differences in
the association matrices between the two models. Positive (negative) numbers indicate when two nodes were more likely to
be co-assigned to the same module under the spatial (NG) model. (D) The difference in the participation coefficient between
the spatial and NG models. The participation coefficient quantifies how diverse a node’s connections are across modules. (E)
The difference in spatial spread of modules in both models; the spatially embedded model tends to produce modules that cover
larger distances. This figure was adapted with permission from [99].

BOX 1: SIMPLE NETWORK STATISTICS
In a network representation of the brain, units rang-
ing from neurons or neuronal ensembles to nuclei and
areas are represented as network nodes and unit-to-unit
interactions ranging from physical connections to statis-
tical similarities in activity time series are represented as
network edges. The architecture of the network can be
quantitatively characterized using statistics from graph
theory [113]. Here, we mathematically define some of the
topological statistics mentioned elsewhere in this paper.
• Degree and Strength. The degree of a node is the
number of connections it has. In a binary graph
encoded in the adjacency matrix A, where two re-
gions i and j are connected if Aij = 1, and not
connected
P if Aij = 0, then the degree ki is defined
as ki = i,j∈N Aij , where N is the set of all nodes.
In a weighted graph, where Aij is the strength of
the connection between nodes P i and j, then the
strength si is defined as si = i,j∈N Aij .
• Path Length and Network Efficiency. The term
path length frequently refers to the average length
of the shortest path in a network. The short-
est path between any two nodes is given by the
path requiring the fewest hops. The network ef-
ficiency is given by the inverse of the harmonic
mean of the shortest path length. To be pre-
cise, we can write the path length of node i as
P
1 i∈N,j6=i di,j
P
Li = n i∈N n−1 , where di,j is the short-
est path length between two nodes and n is the
number of nodes.
• Clustering Coefficient. The clustering coefficient
can be used to quantify the fraction of a node’s
neighbors that are also neighbors with each other.
Specifically, the clustering coefficient of node i is
given by Ci = n1 i∈N ki (k2tii−1) , where ti is the
P
number of triangles around node i [46]. The clus-
tering coefficient of the network is the average clus-
tering coefficient of all of its nodes.
• Modularity. While several modularity quality
P func-
tions exist, the most common is Q = ij [Aij −
γPij ]δ(ci cj ), where Q is the modularity quality in-
dex, Pij is the expected number of connections be-
tween node i and node j under a specified null
model, δ() is the Kroenecker delta, and ci indicates
the community assignment of node i. The tuning
parameter γ ranges from (0, ∞) and can be used to
tune the average community size.
BOX 2: APPLIED ALGEBRAIC TOPOLOGY
While graph theory is a powerful and accessible frame-
work for analyzing complex networks, complementary in-
formation can be gained by using different mathematical
9
formalisms. Here, we describe an alternative approach to
studying structure in networks that relies on tools devel-
oped in the field of applied algebraic topology, specifically
persistent homology [115–117]. Persistent homology can
be used to study intrinsically mesoscale structures called
cycles and cliques [118]. Cliques are all-to-all connected
subsets of nodes in a network. The presence of many,
large cliques indicates many highly connected units are
present in the network [119]. Cycles are looped patterns
of cliques which may enclose a cavity, or topological void,
within the network. Cliques and cavities by definition
reside within a binary graph, however one can expand a
weighted network into a sequence of binary graphs via
iterative thresholding [45, 120]. Then using persistent
homology one can track the birth, persistence, and death
of cavities along this sequence which gives a wholistic
insight into the global network (Fig. Box 2, panel A).
In random graphs, the number of births and deaths
across thresholds follows a characteristic pattern [44]. At
high thresholds and low edge density, a few low dimen-
sional cavities exist, while at low thresholds and high
edge density, more high-dimensional cavities exist (Fig.
Box 2, panel B) [44, 121, 122]. Interestingly, geometric
graphs – which can be used to instantiate spatial con-
straints on the topology – show a markedly different dis-
tribution. There are many low dimensional cavities, and
fewer cavities with increasing dimension[43, 44, 121, 123]
(Fig. Box 2, panel C). This general pattern has been
recapitulated in functional networks constructed from
firing of hippocampal neurons, indicating a geometric
rather than random nature to neuronal co-firing [45].
Furthermore, the persistent homology of human connec-
tomes [42] and rat microcircuits [124] is distinct from that
expected in a minimally wired null model. In humans,
the presence of widespread subcortical connections leads
to more cavities being born at high densities [42], while
rat microcircuits display more high dimensional cavities
in general [124]. Further investigation into how wiring
rules shape the topology of neural systems may shed light
on how the brain’s spatial embedding shapes connectivity
across scales and species.
BOX 3: CONTROL THEORY
Network control theory provides a potentially power-
ful approach for modeling neural dynamics [125]. Hail-
ing from physics and engineering, network control theory
characterizes a complex system as composed of nodes
interconnected by edges, and then specifies a model of
network dynamics to determine how external input af-
fects the nodes’ time-varying activity [126]. Most studies
of network control in neural systems stipulate a linear,
time-invariant model of dynamics: ẋ(t) = Ax(t) + Bu(t),
where x is some measure of brain state, A is a struc-
tural connectivity matrix, u is the input into the system
(exogenous stimulation, or endogenous input from other
brain regions), and B selects the control set, or regions
 10

Local Topology Path, distances Module detection,

(degree, clustering) centrality

FIG. 4. Schematic of network measures. (A) An illustration of network space (topology) and physical space (geometry).
The network is embedded into a physical space, indicated by the x- and y-axes. The topological and physical distances between
the nodes are not necessarily related. (B) The network representation enables the calculation of local, mesoscale, and global
features to describe the pattern of connections in topological space (as shown here) as well as the pattern of connections in
physical space (as we describe in the main text). This figure was adapted with permission from [1] and from [114].

to provide input to [127, 128]. Assuming this model of
dynamics, one can calculate the control energy required
to reach specific brain states, which can be used a state
dependent measure of the efficiency of control [129, 130].
Control theory can also posit control metrics that quan-
tify how efficiently a node would drive the brain to vari-
ous states. Two commonly used metrics are average con-
trollability and modal controllability [131]. When every
node is included in the control set, average controllabil-
ity is proportional to the average energy required to drive
the node to any state [132]. Conversely, modal controlla-
bility is high in nodes where a small input will result in
large perturbations to all eigenmodes of the system, and
is interpreted to be high in nodes that can easily drive
the brain to hard-to-reach states [133–135].
If these properties are important for helping the brain
transition between states, one would expect them not
to be randomly distributed across the cortex, but to
be clustered into spatially constrained, functionally rele-
vant systems. More specifically, one might expect func-
tional systems that drive the brain to many accessible
states, such as the default mode system, to have high
average controllability, while regions that drive the brain
to hard-to-reach, cognitively demanding states (executive
control areas) to have high modal controllability. Data
from healthy human adults supports these two hypothe-
ses [133]. Moreover, both average and modal control-
lability increase across development and are correlated
with cognitive performance generally [134] and executive
function specifically [136]. The manner in which network
control tracks individual differences reflects the fact that
the capacity for a network to enact control is dependent
upon its topology [137, 138]. Further efforts are needed
to distill exactly how spatial embedding and wiring con-
straints impinge on that control capacity, and how it is
altered in psychiatric disorders [132] and neurological dis-
ease [139].
BOX 4: OUTSTANDING QUESTIONS
• How do spatially constrained developmental pro-
cesses constrain the formation of cycles in brain
networks?
• What are the aspects of connectome topology that
remain unexplained by wiring minimization or com-
munication efficiency and thus may arise from more
subtle rules?
• How do the structural topologies that arise from
physical growth rules support functional gradients?

A topology with small scale developmental rules?
B erative models of the brain to recapitulate its topol-
C • cycle: In applied algebraic topology, a cycle is
FIG. 5. Applied algebraic topology. (A) An illustration
of thresholding a weighted network across different densities
(ρ). At ρ1 , a cavity of dimension 1 is born (shown in yellow),
which then dies at ρ3 . (B) The characteristic pattern of births
and deaths (called Betti curves) for cycles of dimension 1
(yellow), dimension 2 (red), and dimension 3 (blue) from a
random network. The cliques of each dimension are shown
near each corresponding Betti curve for reference. (C) The
same pattern, but for geometric networks. Different lines of
the same color indicate different dimensions of embedding.
This figure was adapted with permission from [45].
• What is the precise relationship between invari-
ant features of brain activity and the underlying
anatomical structure?
• How does the development of the connectome de-
termine spatial progression of activity through the
cortex in health and disease?
11
• To what extent can we link macro-scale structural
• Can a deeper understanding of connectome devel-
opment be used to help identify new biomarkers for
network diseases?
• What additional rules can be incorporated into gen-
ogy?
• How can frontiers in network science help charac-
terize non-dyadic relationships in the brain?
GLOSSARY
• adjacency matrix: The adjacency matrix of a
graph is an N × N matrix, where N is the number
of nodes. Each element Aij of the matrix gives the
strength of the edge between nodes i and j.
an empty space (or lack of edges) in a graph sur-
rounded by all-to-all connected subgraphs of the
same dimension. The dimension here refers to the
number of nodes included in each all-to-all con-
nected subgraph.
• edge: From the perspective of graph theory, an
edge is a connection between nodes. From the per-
spective of neuroscience, an edge is a statistical de-
pendency (functional) or estimated physical con-
nection (structural) between nodes.
• geometry: The geometry of a network reflects fea-
tures of a graph in the context of physical space.
• hub: A central node in the network, typically hav-
ing many connections.
• node: From the perspective of graph theory, a
node is the unit where edges connect in the graph.
From the perspective of neuroscience, a node is a
brain region, neuron, or protein whose interactions
one wishes to understand.
• topology: The quantification of features of a
graph in the context of space defined by the graph
itself, without respect to any physical embedding.
HIGHLIGHTS
• The physical embedding of neural systems imposes
constraints on the possible patterns of connections
that form, and in turn on the possible repertoire
of functional motifs. Utilizing new tools from net-
work science that account for these constraints can
help researchers understand fundamentals of brain
dynamics in health and disease.

• Prominent, competing rules guiding the forma-
tion of brain networks include the minimization of
wiring cost, and the maximization of communica-
tion efficiency. These competing mechanisms lead
to networks with high local clustering with sparse
long distance connections.
• Recent work suggests that intrinsic functional con-
nectivity varies along dimensions that are tightly
linked to the spatial embedding of the brain and
the topological properties that arise in the pres-
ence of spatial constraints. Similarly, these topo-
logical properties show widespread changes in the
context of the network diseases such as epilepsy and
schizophrenia.
• A rich, and continually growing repertoire of statis-
tics, null models, and generative models exist to aid
researchers in testing focused hypotheses about the
role of physical embedding in observed neural phe-
nomena.
ACKNOWLEDGMENTS
We would like to thank Ann Sizemore for her help with
Box 2: Applied Algebraic Topology. D.S.B. and J.S.
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