Preferential Detachment During Human Brain Development: Age- and Sex-Specific Structural Connectivity in Diffusion Tensor Imaging (DTI) Data

Abstract

Human brain maturation is characterized by the prolonged development of structural and functional properties of large-scale
networks that extends into adulthood. However, it is not clearly understood which features change and which remain stable
over time. Here, we examined structural connectivity based on diffusion tensor imaging (DTI) in 121 participants between 4
and 40 years of age. DTI data were analyzed for small-world parameters, modularity, and the number of fiber tracts at the
level of streamlines. First, our findings showed that the number of fiber tracts, small-world topology, and modular organization
remained largely stable despite a substantial overall decrease in the number of streamlines with age. Second, this decrease
mainly affected fiber tracts that had a large number of streamlines, were short, within modules and within hemispheres; such
connections were affected significantly more often than would be expected given their number of occurrences in the network.
Third, streamline loss occurred earlier in females than in males. In summary, our findings suggest that core properties of
structural brain connectivity, such as the small-world and modular organization, remain stable during brain maturation by
focusing streamline loss to specific types of fiber tracts.

Full text

Preferential Detachment During Human Brain Development: Age- and Sex-Specific
Structural Connectivity in Diffusion Tensor Imaging (DTI) Data
Sol Lim1,2, Cheol E. Han1,3, Peter J. Uhlhaas4,5, 6 and Marcus Kaiser1,2
1
Department of Brain & Cognitive Sciences, Seoul National University, Seoul 151–747, South Korea,
2
School of Computing Science
and Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE1 7RU, UK,
3
Department of Biomedical Engineering,
Korea University, Seoul 136–703, South Korea,
4
Institute of Neuroscience and Psychology, University of Glasgow, Glasgow G12
8QB, UK,
5
Department of Neurophysiology, Max-Planck Institute for Brain Research, 60438 Frankfurt a. M., Germany and
6
Ernst
Strüngmann Institute (ESI) for Neuroscience in Cooperation with Max Planck Society, Deutschordenstr. 46, Frankfurt am Main,
60528, Germany
Address correspondence to Marcus Kaiser, School of Computing Science, Claremont Tower, Newcastle University, Newcastle upon Tyne NE1 7RU,
UK. Email: m.kaiser@ncl.ac.uk
Cheol E. Han, Peter Uhlhaas and Marcus Kaiser shared senior authorship
Human brain maturation is characterized by the prolonged develop-
ment of structural and functional properties of large-scale networks
that extends into adulthood. However, it is not clearly understood
which features change and which remain stable over time. Here, we
examined structural connectivity based on diffusion tensor imaging
(DTI) in 121 participants between 4 and 40 years of age. DTI data
were analyzed for small-world parameters, modularity, and the
number of fiber tracts at the level of streamlines. First, our findings
showed that the number of fiber tracts, small-world topology, and
modular organization remained largely stable despite a substantial
overall decrease in the number of streamlines with age. Second, this
decrease mainly affected fiber tracts that had a large number of
streamlines, were short, within modules and within hemispheres;
such connections were affected significantly more often than would
be expected given their number of occurrences in the network.
Third, streamline loss occurred earlier in females than in males. In
summary, our findings suggest that core properties of structural
brain connectivity, such as the small-world and modular organiz-
ation, remain stable during brain maturation by focusing streamline
loss to specific types of fiber tracts.
Keywords: brain connectivity, connectome, maturation, network analysis,
tractography
Introduction
Human brain development is characterized by a protracted tra-
jectory that extends into adulthood (Benes et al. 1994;Sowell
et al. 1999;Lebel and Beaulieu 2011). Evidence from magnetic
resonance imaging (MRI) has indicated a reduction in gray
matter (GM) volume and thickness across large areas of the
cortex and changes in subcortical structures, which may be at-
tributed to synaptic pruning and ingrowth of white matter
(WM) into the peripheral neuropil (Sowell et al. 1999,2001;
Sowell 2004;Giedd 2008;Giedd and Rapoport 2010). In con-
trast, WM-volume increases with age (Giedd et al. 1997,1999;
Paus et al. 1999;Bartzokis et al. 2001;Sowell 2004;Lenroot
et al. 2007) which could reflect increased myelination of
axonal connections (Sowell et al. 2001;Sowell 2004).
In addition to volume changes, connectivity changes of
axonal fiber bundles have been investigated using diffusion
tensor imaging (DTI). DTI allows the measurement of fiber in-
tegrity through estimates of fractional anisotropy (FA) and mean
diffusivity (MD), which presumably relate to changes in axonal
diameter, density, and myelination (Jones 2010;Jbabdi and
Johansen-Berg 2011). Several studies reported increased FA and
decreased MD values from childhood into adulthood in several
major fiber tracts and brain regions (Faria et al. 2010;Tamnes
et al. 2010;Westlye et al. 2010;Lebel and Beaulieu 2011).
Brain maturation is also accompanied by changes in the top-
ology of structural and functional networks (Fair et al. 2009;
Gong et al. 2009;Hagmann et al. 2010;Yap et al. 2011;Dennis
et al. 2013). Topological features of neural networks that are
now being linked to cognitive performance (Bullmore and
Sporns 2009) concern their small-world and modular organiz-
ation. For small-world network with brain regions or ROIs as
nodes and fiber tracts as edges, there are many connections
between regions mostly located nearby. At the same time, it is
also easy to reach other brain regions far apart in the network
due to the existence of long-range connections or shortcuts
(Watts and Strogatz 1998). Therefore, small-world network
shows high efficiency in facilitating information flow at both the
local and the global scales (Latora and Marchiori 2001,2003).
For example, functional connectivity with high global and local
efficiency correlates with higher intelligence (Li et al. 2009;van
den Heuvel et al. 2009), while disrupted small-world topology
is associated with impaired cognition (Stam et al. 2007;Nir et al.
2012). For a modular organization, large groups of brain
regions can be considered as network modules (or clusters) if
there are relatively more connections within that group than to
the rest of the network (Hilgetag et al. 2000;Meunier et al.
2010). The higher connectivity within modules can segregate
different types of neural information processing while fewer
connections between modules allow for information inte-
gration. This community structure of the brain network incor-
porating and balancing both segregation and integration of
neural processing has been shown to be disrupted in schizo-
phrenia, autism and Alzheimer’s disease. (Alexander-Bloch
et al. 2010;de Haan et al. 2012;Shi et al. 2013).
Small-world and modular organization heavily rely on long-
distance connectivity: long fiber tracts are more likely to
provide shortcuts for reaching other nodes in the network and
are also more likely to link different network modules (Kaiser
and Hilgetag 2006). For example, connections between hemi-
spheres or between the visual and frontolimbic network
module are long distance. By providing shortcuts, long-distance
© The Author 2013.Published by Oxford University Press.
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Cerebral Cortex
doi:10.1093/cercor/bht333
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connections reduce transmission delays and errors, conse-
quently enabling synchronous and more precise information
processing. Conversely, a reduction in long-distance connec-
tivity is well known to impair cognitive ability by adversely af-
fecting efficiency and modularity of a network (Kaiser and
Hilgetag 2004). For instance, patients with Alzheimer’s disease
were shown to lose long-distance projections leading to an in-
crease in functional characteristic path length (Stam et al.
2007). In addition to long-distance connections, intermodule
connections, or fiber tracts linking different modules are also
important to keep the community structure of brain networks
and these also provide shortcuts for communicating with other
functional or structural modules. Reduced between-module
connectivity was strongly associated with cognitive impair-
ment in Alzheimer’s patients (de Haan et al. 2012).
Emerging data suggest that small-world topology and
modular organization in brain networks are already present
during early development (Fan et al. 2011;Yap et al. 2011)and
that these core features of brain networks are retained during
brain maturation despite significant ongoing anatomical
modifications. (Bassett et al. 2008;Fair et al. 2009;Gong et al.
2009;Supekar et al. 2009;Hagmann et al. 2010). Thus, we
hypothesized that certain types of fiber tracts may have been
preferentially affected during development to retain important
topological features during development. These potentially
spared fiber tract types are likely to include long-distance con-
nections but also fiber tracts composed of fewer streamlines
and intermodule fiber tracts. Fiber tracts of the latter 2 types
are often, but not necessarily, also long-distance connections
(Supplementary Material S5 and Fig. S4). Therefore, we ana-
lyzed all 3 types of fiber tracts in relation to topological changes.
To test our hypothesis, we obtained DTI data from a large
cohort of subjects between 4 and 40 years and constructed
streamlines from deterministic tractography to identify fiber
tracts in cortical and subcortical networks. Our results show
that the number of streamlines decreased overall with age
while small-world and modular parameters did not change.
Specifically, our results showed that streamline loss occurred
mostly for fiber tracts composed of more than average number
of streamlines, short and within-module/within-hemisphere
fiber tracts. This focus on certain types of fiber tracts goes
beyond what would be expected by a type’s prevalence within
a network suggesting a preferential detachment of streamlines.
In addition to modifications in cortical fiber tracts, pronounced
changes were observed in subcortical structures, such as basal
ganglia and anterior cingulate cortex (ACC). Finally, streamline
reductions occurred at an earlier age in females than in males,
suggesting sex-specific maturation of connectivity patterns
during human brain maturation.
Materials and Methods
DTI Data
We made use of a public DTI database (http://fcon_1000.projects.nitrc.
org/indi/pro/nki.html) provided by the Nathan Kline Institute (NKI)
(Nooner et al. 2012). DTI data were obtained with a 3 Tesla scanner
(Siemens MAGNETOM TrioTim syngo, Erlangen, Germany). T
1
-weighted
MRI data were obtained with 1 mm isovoxel, FoV 256 mm, TR = 2500 ms,
and TE = 3.5 ms. DTI data were recorded with 2 mm isovoxel, FOV = 256
mm, TR = 10 000 ms, TE = 91 ms, and 64 diffusion directions with b-factor
of 1000 s mm
−2
and 12 b0 images. We included 121 participants between
4and40years.
Data Pre-Processing and Network Construction
We used Freesurfer to obtain surface meshes of the boundary between
GM and WM from T
1
anatomical brain images (http://surfer.nmr.mgh.
harvard.edu) (Fig. 1). After registering surface meshes into the DTI
space, we generated volume regions of interest (ROIs) based on GM
voxels. Freesurfer provides parcellation of 34 anatomical regions of
corticesbasedontheDeskianatlas(Fischl et al. 2004;Desikan et al.
2006) and 7 subcortical regions (Nucleus accumbens, Amygdala,
Caudate, Hippocampus, Pallidum, Putamen, and Thalamus) (Fischl
et al. 2002,2004) for each hemisphere, thus leading to 82 ROIs in
total (See Supplementary Table S5 for full and abbreviated names
of ROIs).
To obtain streamline tractography from eddy current-corrected dif-
fusion tensor images (FSL, http://www.fmrib.ox.ac.uk/fsl/), we used
the fiber assignment by continuous tracking (FACT) algorithm (Mori
and Barker 1999) with 35° of angle threshold through Diffusion toolkit
along with TrackVis (Wang et al. 2007) (Fig. 1). This program gener-
ated the tractography from the center of all voxels (seed voxels) in GM/
WM except ventricles; a single streamline started from the center of
each voxel. Thus, the number of total streamlines never exceeds the
number of seed voxels.
In addition, we also performed tractography with the following par-
ameters: a single tracking per voxel for 45° threshold and 10 random
trackings per voxel for both 35° and 45° thresholds, in total 3 more
cases. These additional analyses were performed to assure that the
results were consistent despite varied tracking parameters (Sup-
plementary Material S6 and Fig. S5).
For network reconstruction, we used the UCLA Multimodal Connec-
tivity Package (UMCP, http://ccn.ucla.edu/wiki/index.php) to obtain
connectivity matrices from the defined and registered ROIs and tracto-
graphy, counting the number of streamlines between all pairs of
defined ROIs. The resulting matrix contains the streamline count
between all pairs of ROIs as its weight. We also computed the average
connection lengths between ROIs (if there is no connection between a
pair, the length was set to zero). The connection length of a streamline
was based on its 3D trajectory.
Network Analysis
Short explanations of network measures are provided here (for
details, cf. Supplementary Material S2). Edge density represents the
proportion of existing connections out of the total number of poten-
tial connections (Kaiser 2011). Note that the weights of individual
edges (streamline count) might change but edge density will remain
the same as long as the total number of edges ( fiber tracts) is un-
changed. Small-world topology can be characterized by high global
and local efficiency (Latora and Marchiori 2001,2003). Global effi-
ciency represents how efficiently neural activity or information is
transferred between any brain regions on average and local efficiency
indicates how well neighbors of a region, or nodes that are directly
connected to that region, are interconnected. Efficiency is greatly
affected by the sparsity of the network (Kaiser 2011); when there are
fewer edges and also even fewer streamlines, efficiency decreases.
Thus, we normalized efficiency with values obtained by 100 ran-
domly rewired networks where randomly selected edges were
exchanged while preserving both degree and strength of each node
(Rubinov and Sporns 2011). Modularity Qrepresents how modular
the network is; higher values of Qindicate that modules are more
segregated with fewer connections between modules. In contrast,
lower Qvalues indicate more connections between modules and thus
represent more distributed organization (Newman 2006). We also
compared the modular membership assignment using the normalized
mutual information (NMI) (Alexander-Bloch, Lambiotte, et al. 2012).
Within-module strength and participation coefficient show local
changes in modular organization. Within-module strength indicates
the degree to which a node is connected to others nodes in the same
module (Guimera and Amaral 2005); high within-module strength
implies that the node is more connected to nodes within the module
in which it participates than the average connectivity of the other
nodes in the module. The participation coefficient indicates how well
the node is connected to all other modules with higher values if
2Preferential Detachment During Human Brain Development •Lim et al.
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many connections of the node are distributed to other modules. We
used Matlab routines from the Brain Connectivity Toolbox (Rubinov
and Sporns 2010).
Edge Group Analysis
We grouped fiber tracts into categories in terms of (a) the number of
streamlines- (thin vs. thick), (b) the length of the streamline trajectory-
(short vs. long), and (c) whether they were within modules (intramo-
dule) or between modules (intermodule) and counted the streamlines
in each group. Then, we examined with general linear model (GLM) if
the number of streamlines in each category changed over age (see Stat-
istical Analysis).
As the spatial (b) and topological (c) properties often overlap but do
not always coincide (Supplementary Material S5 and Fig. S4), we investi-
gated all 3 cases (da Fontoura Costa et al. 2007;Meunier et al. 2010). In
general, short-length and intramodule edges are more numerous than
others. Therefore, largerchanges in those edges would occur for random
selection. Accordingly, we used χ
2
tests to verify any preferential detach-
ment that goes beyond the streamline loss that would be expected based
on the number of fiber tracts of each type. We standardized weights and
lengths for each individual and categorized edge into 2 groups by the
mean of each participant to account for differences in brain volume and
size. For instance, an edge or a fiber tract for a participant is classified as
“thin”when the weight of the fiber tract is less than the average weight
of the participant. Likewise, a fiber tract is considered thick when the
weight is above the average of the participant. The same procedure was
performed to differentiate short and long fiber tracts. Therefore, types of
fiber tracts were distinguished using a subject-specific threshold.
Individual Edge Analysis
In addition to analyzing types of fiber tracts differences, we also exam-
ined changes for individual edges that included the subset of total fiber
tracts that all participants had in common (128 edges, ∼32.3% of the
total number of edges 396 ± 20). Note that the total number of edges
was around 400, which is 12% of the total number of possible connec-
tions (n= 3321). This proportion is consistent with previous evidence
suggesting that the human brain has a sparse connectivity ranging
between 10% and 15% (Kaiser 2011). To analyze individual edges,
each edge with significant age-related changes was mapped to the cor-
responding lobe according to Freesurfer Lobe Mapping (Table 2and
Supplementary Table S4) (http://surfer.nmr.mgh.harvard.edu/fswiki/
CorticalParcellation).
Statistical Analysis
To assess how theoretical graph measures changed during develop-
ment, we used GLM approach (see eqs. 1, 2, and 3). Linear and quadra-
tic effects of age and the interaction between age and gender were
investigated. The quadratic term of age, gender factor, and the inter-
action term between age and gender were dropped and refitted when
the effects were not significant following an F-test as all tested models
were nested. Akaike Information Criterion (AIC) and Bayesian Infor-
mation Criterion (BIC) were also used for model comparison and se-
lecting variables when the F-test alone did not provide a strong
preference for a model. As AIC tends to prefer more complex models
with a larger number of variables compared to BIC (Kadane and Lazar
2004), AIC and the F-test provided consistent results in general. When
the results of the 3 tests conflicted, we chose the most conservative
model with a smaller number of variables. Two-tailed tests were used for
all analyses and tests were regarded as significant with an αlevel of 0.05.
Quadratic age effect was found to be significant in a few fiber tracts but
occurred less frequently than linear cases. We therefore chose to report
age effects of the numbers of streamlines where decrease and increase
could follow a linear or, less often, a nonlinear pattern.
y¼
b
0þ
b
1age þ
b
2sex þeð1Þ
y¼
b
0þ
b
1age þ
b
2sex þ
b
3age sex þeð2Þ
y¼
b
0þ
b
1age þ
b
2sex þ
b
3age2þeð3Þ
where yis measurement, β
0
intercept (bias), β
1
slope over age, β
2
coefficient for sex difference, β
3
coefficient for interaction effect of age
and sex or quadratic age effect, and erepresents errors (noise), which
Figure 1. Overall procedure. From T
1
-weighted images, we generated 82 regions of interests (ROIs, 34 cortical areas and 7 subcortical areas per hemisphere, on the left). From
diffusion tensor images (DTI), we reconstructed streamlines using deterministic tracking (on the right). Combining 2 preprocessing steps, we constructed weighted networks, where
the number of streamlines between any pair of ROIs formed the weight of an edge (fiber tract).
Cerebral Cortex 3
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are independent and identically distributed, having a Gaussian (i.e.,
normal) distribution with mean zero and variance σ².
Through the group analysis of edges (see Edge Group Analysis), we
identified which types of edges were undergoing developmental
changes. Using repeated-measures GLM, we tested whether 2 groups
had different slopes and χ
2
tests were used for verifying the slope
difference of GLM considering the proportion of each group with each
individual network. For individual edge analysis, χ
2
tests, and nodal
properties such as within-module strength and participationcoefficients,
false discovery rate (FDR) procedure was used with a qlevel of 0.05, ad-
justing significance level and confidence intervals (Benjamini and Hoch-
berg 1995;Benjamini et al. 2005;Jung et al. 2011). All statistical tests
were calculated in Matlab R2012b (Mathworks, Inc., Natick, MA, USA)
and R (R Development Core Team 2011) with R packages (Lemon 2006;
Bengtsson 2013;Sarkar 2008;Weisberg and Fox 2011;Suter 2011).
Results
We performed a combined analysis of fiber tracts with network
parameters to examine on-going changes in fiber tracts in
terms of small-world topology and modularity, which may
account for a relationship between topological changes and
modifications in fiber tracts.
We compared developmental changes examining the fol-
lowing features: 1) Overall connectedness: total number of
streamlines, edge density, and thin versus thick connectivity,
2) small-world organization: efficiency and short- versus long-
distance connectivity, 3) modular organization: modularity and
within versus between module connectivity, and 4) local
organization: individual edge analysis.
Age Effect for Both Genders
Connectedness
Streamline count versus edge density. The total number of
streamlines decreased (β
1
=−68.87, t
(118)
=−5.796, P< 0.001,
Fig. 2A) with age; however, edge density remained stable
(t
(118)
= 0.757, P= 0.451, Fig. 2B).
Thick versus thin edges. Edge density or the number of fiber
tracts could be maintained either through new fiber tracts that
make up for lost fiber tracts due to streamline reduction or
through sparing thin edges and therefore retaining existing
fiber tracts while changing only weights for fiber tracts. To test
the latter hypothesis, we tested whether there were differences
in developmental patterns of thick or thin edges (see Edge
Group Analysis).
Streamlines in both thick and thin edges decreased with age
[thick edges: β
1
=−60.184, t
(118)
=−6.195, P<0.001, Fig. 2C;
thin edges: β
1
=−8.685, t
(118)
=−3.27, P= 0.001]. However, the
slopes between thick and thin edges were significantly differ-
ent (repeated-measures GLM, F
1,119
= 40.196, P<10
−8
, Fig. 2C)
with the slope of thick edges showing an ∼8 times steeper
slope than thin edges. This preferential reduction of stream-
lines within thick edges could not be explained by the frequen-
cies of thin and thick fiber tracts (χ
2
test, P<10
−20
).
Small-World Topology and Long-Distance Connectivity
Efficiency and small-world topology. Global and local
efficiency decreased during development (global: β
1
=−0.001,
t
(118)
=−2.496, P= 0.014, Fig. 2D, local: β
1
=−0.019, t
(118)
=
−4.435, P< 0.001, Fig. 2E). Although global and local effi-
ciencies may have been slightly compromised by the loss of
streamlines, small-world features were maintained; global effi-
ciency paralleled that of the rewired network (0.88 ± 0.036,
∼0.9), while local efficiency was much higher (4.06 ± 0.446, ∼4)
than that of the random networks.
Figure 2. Topological and spatial network properties. Fitted lines were drawn when there was a significant age effect (red: female, blue: male). When multiple lines were drawn,
the lines are parallel unless otherwise noted. Black line represents significant age affect without a sex difference. (A) Total number of streamlines, (B) edge density, (C) streamline
count in thick versus thin edges, (E) global efficiency, (F) local efficiency, and (G) streamline count in short versus long streamlines.
4Preferential Detachment During Human Brain Development •Lim et al.
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Short- versus long-distance connectivity. As topological and
spatial organizations are often linked (Kaiser and Hilgetag
2006;da Fontoura Costa et al. 2007;Meunier et al. 2010), we
tested whether the pattern of changes in short- and long-distance
connectivity corresponded to changes in efficiency. From the
preservedsmall-worldtopology,wewouldexpectlongfiber
tracts were likely to be conserved.
Decreasing slopes of the streamline count between short and
long edges were significantly different (F
1, 119
= 44.965, P<10
−9
)
with short-distance connections showing a pronounced reduction
(short: β
1
=−61.515, t
(118)
=−6.773, P<10
−9
,Fig.2F), which was
not solely explained by a higher proportion of short-distance
edges (χ
2
test, P<10
−6
).
Modular Organization
Modularity and module membership assignment. Modularity
did not change with age (t
(118)
=−1.335, P= 0.184, Fig. 3A)and
community structure remained stable during development (Sup-
plementary Table S2 and Fig. S1). Overall modular organization
basedontheNMIdidnotdifferacrossage(P= 0.355), and there
were no significant nodal changes in membership assignment
after multiple comparison correction using FDR (detailed
information cf. Supplementary Material S3).
Within-module strength and participation coefficient. Twenty
of 82 ROIs (24.4%) showed significant changes in within-module
strengths and participation coefficients (FDR corrected). Overall
changes were asymmetric between hemispheres, affecting
homologous ROIs either in the left or right hemisphere. Ten of
the 24 ROIs (42%) characterized by age effects were areas in
subcorticalregions,suchasthebasalganglia,thalamus,and
nucleus accumbens (Table 1). Specifically, within-module
strengths decreased while participation coefficients increased,
indicating that with development connections involving basal
ganglia decreased within its module while connections to the
surrounding modules/regions decreased. In contrast, 8 ROIs
within the ACC and the paralimbic division (Mesulam 2000)were
mainly characterized by increased within-module connectivity
with age.
Within versus between module analysis. Modular membership
and modularity Qstayed relatively stable during development
although there were some ROIs that showed significant
changes in terms of inter- versus intramodules connectivity
(see Within-Module Strength and Participation Coefficient,
Table 1). This can be realized when changes occurred mainly
within modules. The decreasing slopes of streamline count for
intra- and intermodule edges differed (repeated-measures
GLM, F
1,119
= 33.186, P<10
−7
). The reduction of streamlines
occurred within modules (β
1
=−61.25, t
(118)
=−6.321,
P<10
−8
, Fig. 3B) but not between modules (t
(118)
=−1.831,
P= 0.0696, Fig. 3B). This preference was not fully explained by
the higher proportion of intramodule edges (χ
2
test, P<10
−6
).
Figure 3. Modular organization. (A) Modularity Q,(B) Streamline count in within- versus between-module edges, and (C) individual edge analysis (gray: intramodule edges and light
gray: intermodule edges, both without changes over age; red: edges with a decreased streamline count, blue: edges with an increased streamline count; and yellow: edges with
sex-specific changes). When multiple lines were drawn, the lines are parallel unless otherwise noted. A list of all changes is provided in Table 2 for sex-specific changes and
Supplementary Table S4 for age effect.
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Individual Edge Analysis
To identify edge-specific age effects, we investigated 128
edges found in all participants (total number of edges:
396 ± 20), of which 64 edges showed significant age-related
changes. The findings were consistent across different tracto-
graphy parameters (Supplementary Material S6 and Fig. S5).
First, 57 edges (89%) showed developmental changes: 55
edges (86%) showed a reduced number of streamlines while
only 2 (3%) had an increased streamline count (Figs 3Cand
5A, Supplementary Table S4). Reduction of streamlines was
most pronounced in the frontal lobe; increased number of
streamlines only occurred for 2 connections (3%) of cingulate
cortex. These changes for both genders mainly occurred in the
frontal and parietal lobe.
Sex-Specific Age-Related Changes
Unlike developmental changes for both males and females,
only several network properties showed sex-specific develop-
mental changes. While both male and females lost short
streamlines, only female participants were characterized by a
decrease in long streamlines. However, this decrease was less
pronounced than the reduction in short streamlines (β
1
=
−21.229, t
(50)
=−3.372, P= 0.001, Fig. 2F). While global
modular organization (see Modularity and Module Member-
ship Assignment) did not show sex differences, 3 regions of 20
showed sex-specific developmental changes in within-module
strength and participation coefficients (Table 1). In the individ-
ual fiber tract analysis, changes that only affected one gender
occurred in 7 fiber tracts (11%) (Figs 4–6B, Table 2). There
were 4 edges with age effect only in females, and 3 edges only
in males, mostly involving occipital and parietal regions.
Sex Differences Independent of Age
Males had ∼800 more streamlines than females across age
(t
(118)
=−3.949, P<0.001, Fig. 2A) mainly due to larger brain
size.In particular, males had larger number of streamlines
for within-module edges (Supplementary Fig. S2). Although
males showed a substantially larger number of streamlines,
male and female participants demonstrated comparable edge
density (t
(118)
=−0.880, P= 0.381, Fig. 2B) as well as global ef-
ficiency (Global: t
(118)
= 1.598, P= 0.113, Fig. 2D). However,
females showed higher local efficiency than males (Local:
t
(118)
= 2.891, P= 0.005, Fig. 2E). Modularity (t
(118)
=−0.409,
P= 0.684, Fig. 3A) and overall modular organization based on
the NMI also did not differ between genders (P= 0.177). Most
ROIs did not show gender differences in within-module
strength and participation coefficient except 4 ROIs (Table 1).
Discussion
In this study, we investigated changes in structural connectivity
(SC) between ages of 4–40 years from DTI data in cortical and
subcortical regions. Previous studies had shown that the
human brain undergoes vast structural changes involving al-
terations in the topology of structural and functional connec-
tivity. Yet, core properties such as small-world topology and
modular organization were retained throughout development
(Fair et al. 2009;Gong et al. 2009;Supekar et al. 2009;
Hagmann et al. 2010;Dennis et al. 2013). Therefore, we
Table 1
ROIs with age effect in within-module strength (WMS) and participation coefficient (PC)
Increased Decreased Sex-specific
WMS lh.caudalanteriorcingulate (F)
lh.entorhinal (T)
lh.parahippocampal (T)
rh.caudalanteriorcingulate (F)
rh.rostralanteriorcingulate (F)
lh.thalamus
lh.accumbens
rh.putamen ( f > m)
rh.pallidum
lh.putamen
M: decreased
rh.paracentral (F)
M:Increased
PC lh.putamen
lh.pallidum
rh.caudate
rh.putamen (m > f )
rh.pallidum (m > f )
rh.caudalanteriorcingulate (F)
rh.paracentral (F)
rh.posteriorcingulate (P)
lh.medialorbitofrontal (F)
M: increased
rh.insula (m > f )
Note: Basal ganglia showing a more distributed network and anterior cingulate cortex showed a more focused connectivity within its module (bold).
FDR corrected, with a qlevel of 0.05.
F, frontal lobe; P, parietal lobe; T, temporal lobe; O, occipital lobe; lh, left hemisphere; rh, right hemisphere; f, female; m, male.
Table 2
Edges with sex-specific age-related changes
ROI (node) Lobe ROI (node) Lobe Sex Slope FDR-adjusted P
lh.cuneus O lh.pericalcarine O Male 1.035 0.0002
lh.fusiform T lh.lateraloccipital O Female −0.9 0.041
lh.lingual O lh.pericalcarine O Female −0.535 0.041
lh.transversetemporal T lh.insula Male −0.908 0.0002
rh.postcentral P rh.insula Male −0.747 0.001
rh.medialorbitofrontal F rh.rostralanteriorcingulate P Female −0.769 0.0003
rh.precuneus P rh.superiorparietal P Female −1.351 0.023
F:1 P:4 T:2 O:5
Note: Sex-specific developmental changes were asymmetrical compared to the developmental changes for both genders.
The last row gives an overview of how often different lobes participate in these changes. Pvalues were adjusted by FDR with a qlevel of 0.05.
lh, left hemisphere; rh, right hemisphere; m, male; f, female; F, frontal lobe; P, parietal lobe; T, temporal lobe; O, occipital lobe.
6Preferential Detachment During Human Brain Development •Lim et al.
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examined if specific types of fiber tracts were preferentially af-
fected, which might be conducive to conserving major topolo-
gical features. Our results show that small-world features, the
number of fiber tracts, and the modular organization remained
largely stable over age despite a significant reduction of
streamlines in fiber tracts. This reduction preferentially affected
fiber tracts that were relatively short, consisted of more stream-
lines and were within topological modules (Fig. 7A,B). Finally,
streamline loss occurred at an earlier age in females than in
males.
Stable Small-World and Modular Organization with
Preferential Streamline Loss Within Short-Distance,
Thick, and Intramodular Fiber Tracts
We found that fewer long-distance, thin, and intermodular
fiber tracts showed streamline loss than would be expected
given how often such fiber tracts could have been affected by
chance. This preferential streamline loss has several impli-
cations for the stable topological features that we observed.
First, we found that small-world features were retained over
age despite the overall reduction in the number of streamlines.
A significant decrease in many long-distance streamlines
would remove shortcuts and result in larger path lengths and
reduced global efficiency while fewer connections between
neighbors would decrease local clustering and local efficiency,
disrupting small-world features of a brain network. However,
global efficiency stayed comparable with that of rewired net-
works, local efficiency was much higher than in rewired
networks across age, conserving small-world topology (Latora
and Marchiori 2001,2003). We would therefore expect
changes mainly in short-distance connectivity. Indeed, short
streamlines were mostly affected and long-distance connec-
tivity was rather preserved. Relatively conserved streamlines in
long-distance fiber tracts could be achieved by strengthening
long-range pathways while a reduction in the number of
streamlines in short fiber tracts could be due to weakening of
short connections, which is consistent with previous findings
from rs-fMRI and DTI data (Fair et al. 2009;Supekar et al.
2009;Dosenbach et al. 2010;Hagmann et al. 2010).
Second, in line with previous rs-fMRI and DTI studies (Fair
et al. 2009;Hagmann et al. 2010), modularity Qremained
stable over age. We found that the global modular organization
and module membership of ROIs were unchanged with local
changes especially in the basal ganglia. Therefore, local net-
works re-organized their relationships with other community
members while keeping the global community structure
stable. This retained modular organization (Kaiser et al. 2010;
Meunier et al. 2010) might be crucial in keeping the balance
between information integration and the segregation of separ-
ate processing streams (Sporns 2011). Too many connections
between modules would interfere with different processing
demands, for example, leading to interference between visual
and auditory processing. In addition, more intermodule con-
nections would also facilitate activity spreading potentially
leading to large-scale activation as observed during epileptic
seizures (Kaiser et al. 2007;Kaiser and Hilgetag 2010).
Figure 4. Sex-specific developmental changes in individual edge analysis for male (A–C) and for female subjects (D–F), where red edges represent significant decrease, blue
edges indicate significant increases over development, gray edges illustrate the tested edges that all subjects shared in common and the sex-specific changes were emphasized by
the thick edges. (Aand C) Sagittal views of the left hemisphere, (Band D) transverse view, and (Cand F) sagittal views of the right hemisphere, of male and female brains,
respectively. (A) Two edges showed age-related changes; one in the temporal lobe lost streamlines and the other edge in the occipital lobe gained streamlines. (C) An edge in the
parietal lobe lost streamlines. (D). Two edges in the temporal and the occipital lobes lost streamlines. (F) Two edges in the frontal and parietal lobes lost streamlines.
Cerebral Cortex 7
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However, because of the reduction of streamlines in intramo-
dule edges, proportionally intermodule connections increased,
indicating that the brain network became more distributed
rather than modular with age as observed in previous studies,
which was associated with development of advanced cognitive
abilities by enhancing integration of neural processing (Fair
et al. 2009;Supekar et al. 2009;Hagmann et al. 2010).
In summary, we find that long-distance and intermodular
connectivity is largely spared from the ongoing streamline
losses during development, which is potentially beneficial for
the observed stability of small-world and modular connectome
features. Note that as connections between modules are not
necessarily long distance (Kaiser and Hilgetag 2006), we found
that only 47% of intermodular fiber tracts also belong to the
class of long-distance connections. Retaining long-distance
and intermodular fibers indicate that small-world features,
such as the number of processing steps but also the balance
between information integration and large-scale brain activity,
are kept within a critical range during development (Kaiser
and Hilgetag 2006). Preserving this balance is crucial as
changes in long-distance connectivity are a hallmark of
neurodegenerative and neurodevelopmental disorders ranging
from Alzheimer’s disease (Ponten et al. 2007;Stam et al. 2007)
to schizophrenia (Alexander-Bloch, Vértes, et al. 2012). There-
fore, stable topological network features might help to prevent
cognitive deficits in neuropsychiatric disorders.
Another important implication of the reduced number of
streamlines is the relationship to the number of edges within a
network. Changes in streamline count can lead to a reduction
of connections within a network if an edge comprised of few
streamlines loses all its streamlines, thus reducing edge
density. However, edge density did not significantly change
during brain maturation. Therefore, several mechanisms are
conceivable how the number of edges is maintained during de-
velopment. One option is that newly emerging edges cancel
out disappearing edges (equilibrium state), which is biologi-
cally costly by removing already established connections and
unlikely because new connections are established mostly early
in the development. Alternatively, only the weight of an edge
changes (stable state). For the latter case, a reduction of stream-
lines in thin edges, which could result in the loss of the whole
edge, needs to be prohibited. Indeed, we found that thick
Figure 5. Sex-specific developmental changes. (A–G) Scatter plots of streamline count with relevant fitted lines. Red: female, blue: male. Upper panel: The 4 fiber tracts
demonstrating age effects only for females. Lower panel: The 3 fiber tracts displaying age effects only for males. Lh, left hemisphere; rh, right hemisphere. (A) The fiber tract
between lh.fusiform and lh.lateraloccipital showing a reduction of streamline counts only for females. (B). The fiber tract between lh.lingual and lh.pericalcarine with a decreased
number of streamlines for females, (C). rh.medialorbitofrontal–rh.rostralanteriorcingulate, (D)
rh.precuneus-rh.superiorparietal
, (E) The fiber tract between lh. transversetemporal
and lh.insula with a reduced number of streamlines over age only for males, (F) rh.postcentral–rh.insula, (G) lh.cuneus–lh.pericalcarine. The rate of change per year and
corresponding P value is included in the figure and FDR-adjusted P values can be found in Table 2.
8Preferential Detachment During Human Brain Development •Lim et al.
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edges were mostly affected from the decreased streamlines,
thus preserving the structure of the network. This is beneficial,
as reducing thin fibers would necessitate an increase in synap-
tic weights or number of synapses to transmit the same
amount of information. Reducing streamlines for thick fibers,
on the other hand, has only a small effect on activity flow due
to the large number of remaining streamlines.
Preferential Streamline Loss for Frontal and
Subcortical Regions
Changes in individual edges were most pronounced in the
frontal lobe, a brain region that is characterized by protracted
development until the third and fourth decade of life as indi-
cated by ongoing synaptic pruning and myelination (Benes
et al. 1994;Sowell et al. 1999;Shaw et al. 2008;Petanjek et al.
2011). In addition, the fiber tract between putamen and palli-
dum in the basal ganglia for the left hemisphere was character-
ized by a reduced number of streamlines. Previous studies that
examined GM volume (Sowell et al. 1999) also found changes
in GM density in putamen and pallidum in postadolescent
brain development, which are involved in learning and neuro-
development diseases (DeLong et al. 1984;Alexander and
Crutcher 1990;Hokama et al. 1995;Teicher et al. 2000;Ell
et al. 2006;DeLong Mr 2007;de Jong et al. 2008;Farid and
Mahadun 2009). Furthermore, basal ganglia were character-
ized by decreased within-module strengths and increased par-
ticipation coefficients over age. This suggests that connectivity
to within these areas decreased relative to connections to
outside of the basal ganglia, which is consistent with data from
Supekar et al. (2009) who demonstrated that subcortical func-
tional connectivity in children had higher degree and effi-
ciency than in adults.
This reorganization of corticosubcortical connectivity could
be involved in the ongoing changes of cognition and behavior
during development. The basal ganglia involve regions that are
crucially involved in neural circuits relevant for response inhi-
bition and reward modulation. Previous studies have shown
that response inhibition improves significantly with age (Wil-
liams et al. 1999) as well as reward modulation (Gardner and
Steinberg 2005). Unlike for the basal ganglia, the ACC was
characterized by an increased connectivity within its module
with age. This observation is consistent with functional con-
nectivity of ACC that develops a more focal organization with
age (Kelly et al. 2009). ACC has also shown to mature late
through error-related ERPs (Santesso and Segalowitz 2008).
Delayed Streamline Loss for Males
Individual edge analysis revealed sex-specific age effects in the
occipital and parietal lobe but to a much lesser extent in the
frontal lobe. This is consistent with a previous WM study
where mainly the occipital lobe development varied with sex
while the growth trajectory in the frontal lobe was similar for
both genders (Baron-Cohen et al. 2005;Lenroot et al. 2007;
Giedd 2008;Perrin et al. 2009). These results can be explained
if we assume that the same mechanism of preferential stream-
line loss operates at different time-scales in males and females.
Provided that males had a similar developmental curve but
with a shifted peak (Fig. 7C,D), we can explain the sex-specific
changes. As expected from the shifted peak hypothesis
(Fig. 7C,D), the total number of streamlines for males, but not
females, remained stable at an earlier age range (4–28 years,
not shown) while both genders showed streamline reductions
in the age range 4–40 years. This delayed developmental
growth curve in streamline count can be related to later volume
growth peaks for GM and WM in males (Giedd et al. 1997;
Giedd and Rapoport 2010) and earlier myelination for females
(Benes et al. 1994).
Figure 6. Individual edge slopes representing age effect per year with FDR-adjusted confidence intervals. (A) Individual edge age effect for both genders. x-axis: indices of edges,
y-axis: coefficients for age effect per year with FDR-adjusted confidence intervals. The last 2 edges with positive slopes and confidence interval ranges are the edges with an
increased streamline count and the others are the fiber tracts characterized by a decreased number of streamlines. (B) Age-related sex effect. x-axis: indices of edges, First 4 edges
show decreasing rate of streamline count for females and the rest 3 edges displays age effect for males, y-axis: coefficients for age effect per year with FDR-adjusted confidence
intervals.
Cerebral Cortex 9
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We only observed circumscribed sex-differences indepen-
dent of age. Local efficiency was higher for females than males
consistent with Gong and colleagues’finding (Gong et al.
2009) and some ROIs showing higher within-module strength
and lower participation coefficient for females can be related
to higher local efficiency in females. Interestingly, absolute
difference in the number of streamlines between genders was
not uniformly distributed; males exhibited more streamlines
for intramodule edges. This is consistent with the finding that
males and females do not differ in the WM volume growth tra-
jectory in the corpus callosum (Giedd 2008). However, this
means proportionally females have more connections across
hemispheres and between modules (DeLacoste-Utamsing and
Holloway 1982;Davatzikos and Resnick 2002;Allen et al.
2003).
Structural Correlates of Streamline Loss
The observed reduction in the total number of streamlines
could be related to rs-fMRI developmental “system-level
pruning”(Supekar et al. 2009), considering tight coupling
between SC and functional connectivity (Honey et al. 2009,
2010). As Supekar and colleagues suggested for functional
connectivity (Supekar et al. 2009), the decreased number of
streamlines for short and intramodule connections in this
study could be due to weakening of local connections through
synaptic pruning and neuronal rewiring. These local processes
prolong until adulthood and are major factors for anatomical
developmental changes (Benes et al. 1994;Petanjek et al.
2011). The reduction of synapses and corresponding axons or
axon collaterals could potentially also lead to a decreased
number of streamlines within fiber tracts. Owing to technical
limitations of DTI, pruning of dendrites and intracortical con-
nections cannot be detected. However, synaptic pruning in the
prefrontal cortex for intracortical connections (Petanjek et al.
2011) was mainly limited to children at younger ages than in
our study (Petanjek et al. 2008). In contrast, the pruning of
long-distance connection, observable in DTI, occurs in devel-
oping rhesus monkeys, both at earlier and later stages of devel-
opment (LaMantia and Rakic 1990,1994;Luo and O’Leary
2005). Considering both limitations of DTI (Jones and
Leemans 2011) and previous studies (Fair et al. 2009;Supekar
et al. 2009;Dosenbach et al. 2010), changes in corticocortical
and subcorticocortical projections might underlie our results
but further investigations are needed to determine the contri-
butions of these potential biological correlates.
Studies have shown that volume for WM fiber tracts in-
creased with age (Faria et al. 2010;Lebel and Beaulieu 2011)
and continued myelination also leads to an increase in WM
volume, which could explain an increase in total WM volume
while undergoing a possible reduction of fiber tracts. Even
though streamlines were reduced in our study, an increased
myelination might still have taken place but might have been
overshadowed by axonal changes and vice versa. Greater
amounts of myelination would generate higher FA values
(Mädler et al. 2008;Faria et al. 2010), leading to an increase in
Figure 7. (Aand B) The schematic summary of the preferential reduction of thick, short, and within-module streamlines over age. (A) Location of change: 2 ellipses represent left
and right hemispheres and small circles inside hemispheres indicate ROIs. Lines connecting ROIs illustrate fiber tracts between ROIs. Red lines are where the reduction of
streamlines occurred; thick, short or intramodule edges were mostly affected. (B) Magnitude of change: Short, thick, or intramodule edges lost more streamlines than long, thin, or
intermodule edges. x-axis: either long, thin, or intermodule streamline count (SC), y-axis: either short, thick, or intramodule SC. (Cand D) Hypothetical developmental curves for
males (blue) and females (red). (C) For the total streamline count based on the observation of our data (Fig. 2A): a longer lasting and higher peaked increase and a delayed decrease
in males. (D) For individual edges: we observed sex-specific development (Fig. 4C), which can be explained by 3 representative cases: if the 2 curves strongly overlap they show
similar decreasing patterns (case 1), if one of the curves peaks later, one curve shows a decreasing pattern while the other curve is still increasing (case 3) or simply not decreasing
yet (case 2). Therefore, depending on the time scale of the developmental trajectory, males and females may show different patterns.
10 Preferential Detachment During Human Brain Development •Lim et al.
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the number of detected streamlines. For example, even if the
number of axonal projections were reduced the remaining
fibers with an increased myelination could be detected easily
by tractography and compensate the lost fiber tracts, leading to
no changes in the number of streamlines. Thus, the balance
between myelination and axonal pruning may have contribu-
ted to our final results.
The reduction in streamlines with age cannot be attributable
to ongoing changes in the number of seed voxels used for trac-
tography as this number was unaffected by age. Other factors
affecting tractography include axon diameter distributions
(See detailed Discussion Jones 2010;Jones et al. 2013) and
fiber curvature changes. If many fiber tracts became more
curved over age, as DTI normally does not track highly curved
trajectories, the number of streamlines of the fiber tract could
decrease. However, most of the fiber tracts (edges) that we
tested did not change their curvature over age (83%, 106 of
128) only 22 edges (17%) showed changed curvature over de-
velopment. Of these 22, only half showed curvature increase.
For a single edge we find streamline decrease while curvature
increased ruling out curvature as a confounding factor of our
results (See detailed Results and Discussion in Supplementary
Material S4).
Limitations
Even though the current study observes a large dataset, there
are several inherent limitations. First, the subjects were
unequally distributed across ages. Having subjects at ages
between 4 and 40 years may not be optimal for detecting major
changes as small-world and modular features were established
during the first 2 years (Fan et al. 2011;Yap et al. 2011). Our
focus, however, was not the major structural changes but the
continuous development while keeping the network economic
(Vertes et al. 2012) and stable. Second, studies that network ap-
proaches use different definitions for weight and different nor-
malization schemes complicating the comparison between
studies. We used absolute number of streamlines as weights;
however, our results are consistent with previous studies with
slightly different weight definitions (Gong et al. 2009;
Hagmann et al. 2010). Third, our DTI approach, unlike DSI or
HARDI analysis, will not resolve crossing fibers. However, the
shorter recording time of this data are an advantage when
measuring connectivity in children. Modeling through prob-
abilistic tracking with crossing fibers (Behrens et al. 2007;
Jbabdi and Johansen-Berg 2011) would therefore be a future
research direction. Although streamlines do not directly corre-
spond to axonal projections (Jones 2010;Jones et al. 2013), we
found our results were consistent with previous anatomical
studies (Benes et al. 1994;Sowell et al. 1999;Gong et al. 2009;
Perrin et al. 2009).
Conclusions
The human brain undergoes vast structural changes during de-
velopment. Nonetheless, brain networks develop in a way that
preserves its topological (small-world/modular) and spatial
(long-distance connectivity) organization to secure its capability
of integration of information and individual processing of
modules. This present study showed how brain connectivity
changed during development in terms of fiber tracts as well as
global network features. We showed preferential decreases
in the number of streamlines for thick, short-distance, and
within-module/within-hemisphere fiber tracts. These changes
may not necessarily occur at the same time for males and
females; males seem to show a delayed start from the prolonged
development in WM and GM. However, although with different
time courses between genders, the global topological features
ensuring healthy brain development apply to both genders.
Therefore, brain networks maintain their topological stability
during brain development by preferentially modifying structural
connectivity.
Supplementary Material
Supplementary material can be found at: http://www.cercor.oxford-
journals.org/.
Funding
This work was supported by National Research Foundation of
Korea funded by the Ministry of Education, Science and Tech-
nology (R32-10142 to S.L., C.E.H., and M.K.), the National Re-
search Foundation of the Korea government (MSIP NRF,
2010-0028631 to C.E.H.), the Royal Society (RG/2006/R2 to
M.K.), the CARMEN e-Science project (http://www.carmen.org.
uk) funded by EPSRC (EP/E002331/1, EP/K026992/1, EP/
G03950X/1 to M.K.), and Max-Planck Society to P.J.U. Funding
to pay the Open Access publication charges for this article was
provided by EPSRC. Conflict of Interest: None declared.
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