Correspondence of the brains functional architecture

during activation and rest

Stephen M. Smitha,1, Peter T. Foxb, Karla L. Millera, David C. Glahnb,c, P. Mickle Foxb, Clare E. Mackaya, Nicola Filippinia,
Kate E. Watkinsa, Roberto Torod, Angela R. Lairdb, and Christian F. Beckmanna,e
aCentre for Functional MRI of the Brain, University of Oxford, Oxford OX3 9DU, United Kingdom; bResearch Imaging Center, University of Texas
Health Science Center, San Antonio, TX 782229; cOlin Neuropsychiatry Research Center, Institute of Living, Yale University, New Haven, CT 06106;
dHuman Genetics and Cognitive Function, Institut Pasteur, 75724 Paris, France; and eClinical Neuroscience Department, Imperial College London,
London SW7 2AZ, United Kingdom

Edited by Marcus E. Raichle, Washington University School of Medicine, St. Louis, MO, and approved June 12, 2009 (received for review May 13, 2009)

Neural connections, providing the substrate for functional networks, exist whether or not they are functionally active at any
given moment. However, it is not known to what extent brain
regions are continuously interacting when the brain is at rest. In
this work, we identify the major explicit activation networks by
carrying out an image-based activation network analysis of thousands of separate activation maps derived from the BrainMap
database of functional imaging studies, involving nearly 30,000
human subjects. Independently, we extract the major covarying
networks in the resting brain, as imaged with functional magnetic
resonance imaging in 36 subjects at rest. The sets of major brain
networks, and their decompositions into subnetworks, show close
correspondence between the independent analyses of resting and
activation brain dynamics. We conclude that the full repertoire of
functional networks utilized by the brain in action is continuously
and dynamically active even when at rest.
brain connectivity BrainMap FMRI functional connectivity
resting-state networks

pontaneous fluctuations in the brain have been studied with

functional magnetic resonance imaging (FMRI) since it was
first noted that, even with the subject at rest, the FMRI time
series from one part of the motor cortex were temporally
correlated with other parts of the same functional network (1).
Following this, several other networks of correlated temporal
patterns in the resting brain have been identified. These
distinct patterns can be separated from each other from a single
resting FMRI dataset, because, although each has relatively
consistent time courses across its set of involved regions, the
different networks have different temporal characteristics from
each other (24). The networks continue to covary even when
the subject is asleep (5) and under anesthesia (6). Furthermore,
several networks have been found to be spatially consistent
across different subjects (7). Although such resting state networks (RSNs), and related networks of deactivation under task,
have also been investigated in other modalities such as electroencephalography (EEG) (8) and positron emission tomography
(PET) (9), the majority of the research to date has used FMRI.
In addition to offering information about the structure and
function of the healthy brain, the study of RSNs has already been
shown to be of great potential clinical value, providing rich and
sensitive markers of disease (10, 11). Although there has been
concern that some patterns of spatially extended spontaneous
signals may be of nonneural physiological origin (12), these
concerns are increasingly being addressed (13), and it has been
posited that RSNs do reflect functional networks (see an excellent review in ref. 14). However, to date, it has not been shown
to what extent the RSN functional networks match the full set
of functional networks used by the active brain undergoing a
comprehensive set of task types. In this study, we compared
network analyses from 36 subjects resting FMRI data against
the entirety of a large database of activation studies to test the
13040 13045 PNAS August 4, 2009 vol. 106 no. 31

hypothesis that the set of functional networks seen in resting data

closely matches the set derived from thousands of different
activation conditions.
To this end, we have used BrainMap (15, 16), currently the
largest database of FMRI and PET brain activation studies. At
present, 1,600 journal articles are included; at the end of 2007,
this represented 19% of all published imaging studies (17). Each
study typically includes several different task conditions and
contrasts between these; 7,000 functional maps are summarized in terms of the coordinate locations of peaks of activation
(or differential activation between conditions). In addition, a
large amount of study information is included in the database,
including carefully structured, rich descriptive text detailing the
experimental paradigm. Each paradigm is also categorized under
one or more of 66 behavioral domain classifications; these
provide a more simplistic summary of the experimental tasks but
are immediately quantitatively useful. Metaanalysis investigations of such databases often begin by reforming pseudoactivation images from the list of activation peak locations (18, 19).
It is then possible to investigate cooccurrence of different
activation sites across the range of experiments represented in
the database. A previous analysis of activation images from
BrainMap used such an approach to produce an exploratory tool
that allows the user to specify a brain location; the tool then
generates an image showing which other brain locations tend to
coactivate, across all paradigms, with the seed point (20). Here,
we take this further by estimating the primary set of independent
networks of activation that represent the major modes of coactivation across all activation images. We have done this using
independent component analysis (ICA), a powerful data-driven
approach for finding independent patterns in multivariate data.
This allows us to identify the major functional networks in the
brain as estimated from, and hence representative of, a significant proportion of all functional activation studies carried out to
date.
Our ICA-based analyses of BrainMap and the resting FMRI
data were carried out independently of each other. In each case,
we estimated a set of spatial maps and associated time courses
in this fully data-driven (unconstrained) analysis of the major
modes, or networks, of covariance across the brain. In the case
of the resting FMRI data, the time courses correspond to the
average spontaneous fluctuation within the corresponding spatial map, and in the case of BrainMap, time is the experiment
Author contributions: S.M.S., P.T.F., K.L.M., D.C.G., C.E.M., N.F., K.E.W., R.T., A.R.L., and
C.F.B. designed research; S.M.S. and C.F.B. performed research; S.M.S., P.M.F., A.R.L., and
C.F.B. contributed new reagents/analytic tools; S.M.S. analyzed data; and S.M.S. wrote the
paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
1To

whom correspondence should be addressed. E-mail: steve@fmrib.ox.ac.uk.

This article contains supporting information online at www.pnas.org/cgi/content/full/

0905267106/DCSupplemental.

www.pnas.orgcgidoi10.1073pnas.0905267106

RSN

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Fig. 1. Ten well-matched pairs of networks from the 20-component analysis of the 29,671-subject BrainMap activation database and (a completely separate
analysis of) the 36-subject resting FMRI dataset. This figure shows the 3 most informative orthogonal slices for each pair. (Left column of each pair) Resting FMRI
data, shown superimposed on the mean FMRI image from all subjects. (Right column of each pair) Corresponding network from BrainMap, shown superimposed
on the MNI152 standard space template image. The networks were paired automatically by using spatial cross-correlation, with mean r 0.53 (0.25:0.79); the
weakest of these correlations thus has a significance of P 105 (corrected). All ICA spatial maps were converted to z statistic images via a normalized
mixturemodel fit, and then thresholded at Z 3.

ID, so each time point in one components time course describes

how strongly that components spatial map relates to that
particular activation image in BrainMap. Thus, the original data
are decomposed into d networks, in a way that maximizes the
homogeneity of function within each network while maximizing
the heterogeneity between them. If d is increased, a greater
number of networks will be found, accounting for the original
data in a more detailed way; in general, these might be expected
to constitute subnetworks of the lower-d decomposition (although this is not mathematically guaranteed with such an
approach, because the different levels of the functional hierarchy are estimated independently of each other). In this article,
we report results from analyses at 2 levels: first, a network
dimensionality approximately matching many previous RSN
studies (d 20), and, second, using a much greater level of detail
(d 70), low enough to be supported by the resolution of the
datasets but giving 34 times more subnetworks than the lowerdimensional results. With these analyses, at 2 levels of the
functional hierarchy, we investigated the hypothesis that the
major functional networks found in the working brain correspond to the networks of correlated spontaneous fluctuations
observed when the subject is at rest.
Results
Our primary results stem from ICA decompositions of BrainMap and (independently) of the resting FMRI data, at an ICA
dimensionality of 20 components; this matches a common
degree of clustering/splitting previously applied via ICA to
resting FMRI data (4, 7). We compared components between
the resting FMRI and BrainMap datasets through simple spatial
cross-correlation of the ICA spatial maps. Of the 20 components
generated separately from the 2 datasets, 10 maps from each set
Smith et al.

were unambiguously paired between datasets, with a minimum

correlation r 0.25 (P 105, corrected for multiple comparisons across all possible pairings and for spatial smoothness); see
Fig. 1. The remaining maps were either judged to be artifactual,
or of more complex interpretation. See supporting information (SI)
for more detailed images of all maps and their classifications.
To aid interpretation of the components (and to illustrate the
relevance and accuracy of even the simplest form of the experimental descriptions in BrainMap), we extracted the behavioral
domain categorizations from the BrainMap database for each
ICA component shown in Fig. 1. The results (Fig. 2) were found
to be in good agreement with known localization of brain
function. The 10 primary maps correspond to the 8 RSN maps
previously described (4), with the addition of a cerebellar map
and with a splitting of one of the previously reported visual maps
into 2 distinct maps (220 and 320). The 10 maps correspond to
interpretable functional categories and can be considered the
major representative functional networks as derived independently from both activation metaanalysis and resting data. We
describe each of these briefly below. The maps are numbered,
with the subscript 20 to distinguish them from the higherdimensionality 70 decomposition described later. Anatomical
and functional descriptions below were derived with reference to
the underlying standard-space images in conjunction with several atlases (2123).
Maps 120, 220 and 320 (visual) correspond to medial, occipital pole, and lateral visual areas. The explicitly visual behavioral
domains correspond most strongly to these maps, and paradigms
cognitionlanguageorthography and cognitionspace correspond to the occipital pole and lateral visual maps, respectively.
We presume that the orthography correspondence reflects the
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Fig. 2. A mapping of the 10 primary functional networks shown in Fig. 1 onto

the behavioral domains (experimental paradigm classifications) in the
BrainMap database. Each of the BrainMap-derived ICA spatial maps has an
associated experiment-ID time course quantifying its relevance to each of
the original 7,342 BrainMap activation images. Each one of those activation
images is listed, in BrainMap, against 1 or more of 66 possible behavioral
domains. By multiplying the value at each time point by the corresponding
behavioral domain(s) and averaging over all time points (experiments), we can
derive a measure of how strongly each network relates to each behavioral
domain, subject to interpretational caveats regarding such reverse inference (24) (see SI for detail; color scale is arbitrary units). Each row is normalized to have a mean count of 1, to balance for different domains being
represented different numbers of times in the database. Of the original 66
behavioral domains, we show here only those that correspond most strongly
to the 10 maps, for display brevity.

visual nature of stimuli used in these studies (e.g., written-word

forms).
Map 420 (default mode network) includes medial parietal
(precuneus and posterior cingulate), bilateral inferiorlateral
parietal and ventromedial frontal cortex. This is often referred
to as the default mode network (9), and is possibly the most
widely studied RSN in the resting-state FMRI literature. This is
also the network that is most commonly seen as deactivating in
task-based FMRI experiments; hence, one would not expect this
map to correspond strongly to any particular behavioral domain,
because more contrasts associated with any given paradigm will,
on average, be looking for positive activations rather than
deactivations (or negative contrasts). However, there will be
some studies that contain a deactivation contrast, and hence,
we are not surprised that this map is found in our analysis of
BrainMap. Indeed, inspection of the full set of experiments
reveals that this map does indeed correspond in general to
negative contrasts, in particular in cognitive paradigms.
Map 520 (cerebellum) covers the cerebellum. Because of
limited field of view of the MRI acquisitions in some of the
resting FMRI subjects, more inferior parts of the cerebellum are
not included in the multisubject RSN analysis. This corresponds
most strongly to actionexecution and perceptionsomesthesis
pain domains.
Map 620 (sensorimotor) includes supplementary motor
area, sensorimotor cortex, and secondary somatosensory cortex.
This corresponds closely to the activations seen in bimanual
motor tasks and was the first resting state network to be
13042 www.pnas.orgcgidoi10.1073pnas.0905267106

identified in FMRI data (1). This corresponds most strongly to

the actionexecution and perceptionsomesthesis paradigms.
Map 720 (auditory) includes the superior temporal gyrus,
Heschls gyrus, and posterior insular. It includes primary and
association auditory cortices. This corresponds most strongly to
actionexecutionspeech, cognitionlanguagespeech, and perceptionaudition paradigms.
Map 820 (executive control) covers several medialfrontal
areas, including anterior cingulate and paracingulate. This corresponds strongly to several cognition paradigms, as well as
actioninhibition, emotion, and perceptionsomesthesispain.
Maps 920 and 1020 (frontoparietal) cover several frontoparietal areas. These are the only maps to be strongly lateralized,
and are largely leftright mirrors of each other. They correspond
to several cognition/language paradigms. In addition, map 920
corresponds strongly to perceptionsomesthesispain; this is
consistent with the insular areas seen (see SI for more detailed
figures showing all maps). Map 1020 corresponds strongly to
cognitionlanguage paradigms, which is consistent with the
Brocas and Wernickes areas seen in the map (see SI for slices
more clearly showing these areas). Given the known lateralization
of language function, it is not surprising that these (mirrored)
networks have such different behavioral domain associations.
If the brain is thought of as being organized into functionally
distinct (if connected) networks, these can themselves be considered to comprise subnetworks, each with distinct, if related,
function. Hence, one would hope to find interpretable network
decompositions at a range of levels of detail. Although a
thorough investigation into the full hierarchy of functional
networks and subnetworks is outside the scope of this article, we
do include some results from a higher dimensionality than the
20-component results presented above. We generated 70component ICA decompositions of BrainMap and the resting
FMRI data in the hope that we would obtain a richer, more
detailed separation of functional subnetworks that could be related
to both the 20-component results and, at the 70-component level,
between BrainMap and resting FMRI components.
Of the 70-component decompositions, 45 of the resting
FMRI and 60 of the BrainMap components were nonartifactual.
The pairing of components is driven by simple correlation of the
spatial maps, aided by association with the original 20component maps through similarity of component time courses,
i.e., by using functional similarity. This allowed us to unambiguously identify groups of 70-component RSNBrainMap
pairings with 20-component pairings. In Fig. 3, we show 2
examples: 8 well-matched pairs of networks in the visual cortex,
and 2 pairs covering the sensorimotor cortex. There is clear
correspondence between the RSNs and BrainMap components
and clear functional interpretation of the maps.
Maps 1370 show early visual areas (i.e., covering the same
combined area as V1, V2, and V3 combined). In maps 270 and
370 the RSNs are split into 2 components (shown separately in
yellow and blue); the combination of these corresponds well with
the BrainMap maps. Maps RSN-2a,b70 show a right vs. left visual
hemifield distinction, and maps RSN-3a,b70 show an upper vs.
lower visual hemifield distinction. At a dimensionality of 100, the
BrainMap map BM-370 also splits in a similar way. Map 470
corresponds to area V5 (motion), maps 5,670 cover the ventral/
ventrolateral visual stream, and maps 7,870 cover the dorsal
visual stream.
Maps 9,1070 cover the sensorimotor cortex (both precentral
and postcentral gyri, although overlapping the latter more fully).
In the 20-component analyses, this appeared as a single map; at
this more detailed decomposition it splits into lateralized maps
(one shown in red-yellow, the other in blue). The detail of the
splitting is the same in BrainMap and in the resting FMRI data,
even including medial cortical regions and cerebellar areas
Smith et al.

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contralateral to the associated cortical areas, consistent with

known corticocerebellar connectivity (25).
The hierarchical relationship between the 2 analysis levels is
interesting; for example, 120splits into (is most strongly related
to) 170, 570, and 870; 220 into 270 and 370; 320 into 470, 670 and 770.
Hence, in some cases, a lower-dimensional network splits (at
higher dimensionality) into left and right subnetworks, but in the
majority of cases, leftright symmetry is preserved within the
subnetworks, and splitting is into different subfunctions rather
than into left vs. right.
Discussion
We have shown the major covarying functional networks in the
brain, as imaged by FMRI and PET, from thousands of tests of
explicit brain activation conditions in 1,600 functional neuroimaging studies. We have found that most of these are very
similar to the majority of the networks of spontaneous covariation in the resting brain, as imaged by FMRI. The fact that the
set of networks in the 2 domains is highly similar, in at least
two-thirds of the (nonartifactual) extracted network components, implies that the resting brains functional dynamics are
fully utilizing the set of functional networks as exhibited by the
brain over its range of possible tasks. All regions involved in all
functional networks are continuously interacting with each other
when the brain is at rest, with the same functional hierarchy that
controls all brain action and cognition. The set of covarying
networks that can be seen to be paired across the resting and
active domains can be (at the simplest level) interpreted in terms
of the major functional tasks, for example by mapping the
functional networks extracted from BrainMap and resting FMRI
data onto the set of BrainMap behavioral domains.
With an ICA dimensionality of 20, the RSN components found
are almost identical to those found previously with ICA on
different resting FMRI datasets (4, 7). The latter study showed
that these primary RSNs are consistent across different individSmith et al.

uals, providing convincing evidence that, although the quality of

our results (e.g., in terms of spatial detail and signal-to-noise
ratio) is aided by having multiple subjects resting datasets
combined, the close matching of the RSNs onto activation
networks is not an artifact of combining many subjects together;
the set of distinct functional networks is continuously present
and identifiable (given sufficient data quality) in all subjects at
rest.
When extracting a larger number of components from both
BrainMap and resting FMRI data, we probe a different level in
the hierarchy of functional networks and their subnetworks.
With an ICA dimensionality of 70, we find many more subnetworks than in the 20-component analysis but still find close
correspondence between activation networks and resting networks. These subnetworks (obviously a relative term) are, in
general, subsets of the larger networks found at d 20, again
allowing straightforward interpretation of their functional nature. The primary networks split into subnetworks in both active
and resting data in almost identical ways, e.g., into areas of
slightly different function or into left vs. right subnetworks.
(Note, however, that because the brain is a highly complex set of
interconnected functional areas, we do not expect a simple
tree-structure hierarchy to be a perfect model of connectivities
covering all levels of detail, because that would imply acyclic
functional graphs, which is clearly not the case.) There is greater
functional (temporal) correlation between subnetworks within a
primary network than across primary networks. The mappings
found in both domains, and the implied functional hierarchy, will
aid in the development of an objective and rich hierarchical
functional ontology, one that links functional activity types and
spatial localizations in a direct and practically useful way.
Achieving this has been one of the primary purposes of BrainMap, and the work presented here complements progress already made by BrainMap towards functional ontologies.
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Fig. 3. Eight well-matched pairs of networks in visual areas (1 870), and 2 pairs from the sensorimotor areas (9, 1070), from the 70-component analyses of the
BrainMap activation database and the resting FMRI dataset. All Gaussianized ICA maps are thresholded at Z 4 (higher than for the 20-dimensional results for
comparability, because the higher-dimensional analysis, by definition, has reduced ICA residuals).

The quality of the correspondence between the BrainMapderived activation networks and the resting FMRI networks is
particularly compelling given the fundamentally different nature
of the data feeding into these 2 analyses and potential problems
involved in finding a close match. For the resting FMRI analyses,
we have data from just 36 subjects (compared with nearly 30,000
subjects in BrainMap), comprising just a few minutes resting
FMRI data from each. For the BrainMap analyses, the pseudoactivation images have to be created purely from the coordinates
of the peaks of just a few locations in the brain for each activation
condition; the full richness of the original activation maps is not
available currently in BrainMap because of necessary practical
considerations. The spatial extent of the activations in each
pseudoactivation image generated from BrainMap is simply
created by adding a Gaussian of fixed size around every activation peak; this is one reason why we see slightly more spatial
detail in some of the resting FMRI maps (26). Furthermore, the
extent to which different activation paradigms are represented
with different frequencies in BrainMap was not adjusted for in
our decompositions. This introduces an arbitrary factor into the
decompositions, with respect to finding the d strongest components in the data (one could attempt to normalize for different
numbers of different paradigms in the database, but this would
be quite difficult to achieve objectively, and remains to be
elucidated in future work). Finally, the BrainMap database
comprises results from across a broad range of imaging hardware
types, data qualities, analysis software implementations, and task
paradigm specifics. Although every effort is made to reduce the
final spatial activation information to an objective and comparable representation (the peak locations), the experimental and
analytical differences across the 1,600 studies represented in
BrainMap lead to a fundamental heterogeneity of information
and data quality. The fact that the major functional networks
found from the resting and task domains match so closely
indicates that BrainMap has been largely successful in its goal of
objectively representing the brains activation dynamics. On the
other hand, given the above comments (in particular the lack of
normalization of numbers of different paradigms), it is hardly
surprising that approximately one-third of the components
extracted from the rest and active domains do not achieve a clear
1:1 pairing between the domains. These do cover similar overall
spatial extents, i.e., are mostly different linear combinations of
each other; further improvement in objective decompositions
should be attainable in future, which will provide an optimal
integrated decomposition of active and rest data (as opposed to
independent analyses carried out to show the resulting similarities).
Note that the ICA decomposition of the BrainMap data in no
way used the behavioral paradigm information shown in Fig. 1;
the ICA was purely driven by the 7,342 pseudoactivation images,
each of which potentially contains a unique spatial activation
pattern. In the figure, we have utilized only the crudest level of
behavioral information available in BrainMap, but further work
can hope to make much richer use of the more detailed paradigm
descriptions also encoded in the database. The lack of reliance
on behavioral information for our primary analyses is a potential
strength when wanting to find the most natural, data-driven,
representation of the primary networks. This also helps avoid the
problem of reverse inference (24) (the likely one-to-many
mapping from activation location to function) in the core
analysis and may partly explain why our results are so different
from those shown in ref. 19, where paradigm information was
combined with imaging data before decomposition.
The value of resting FMRI data and the analysis of RSNs has
begun to be appreciated. RSNs have already been shown to be
of potential clinical value as rich and sensitive markers of disease
(10, 11). One obvious strength is that multiple functional networks can be tested in a very short scanning session without
having to decide in advance what functional paradigm is most
13044 www.pnas.orgcgidoi10.1073pnas.0905267106

likely to be useful or, indeed, requiring active subject participation. This is particularly important in the clinical setting, where
subjects could range from 10-week-old infants (27) to Alzheimers patients. Our results indicate that the full repertoire of
functional dynamics can be investigated in resting FMRI.
The development of an ontology for functional networks (28)
and their hierarchy is likely to be of interest to nonclinical
neuroscientists to complement other ontologies such as cytoarchitectonic mapping (29) and structural (e.g., lobular) descriptions (30). This work should be able to make contributions in the
development of objective, data-driven ontologies, derived directly from functional brain data, from both the full history of
activation studies and from the spontaneous dynamics in the
resting brain. On a more practical level, although there is
continuing debate as to the value and dangers of functional
localizers, the information that resting data gives us about
functional networks and their localizations encourages the use of
such data and analyses to aid the spatial correspondence (or
labeling) of data, for improved cross-subject analyses in activation studies. Although single-session analyses may not result in
a detailed functional decomposition with the same reliability as
one can achieve with multisubject datasets, it should still be
possible to derive benefit from aligning those networks that are
reliably detectable in single-session data with an appropriate
network template. We intend to supplement the existing set of
complementary brain atlases distributed with FSL (FMRIB
Software Library, www.fmrib.ox.ac.uk/fsl), by using the datasets
and analyses described in this article to generate a set of
functional network maps (such as those shown in Fig. 1) to aid
neuroimaging researchers in the interpretation of their functional and structural imaging studies.
Although we may not be surprised to see temporal coherence
across functional networks when at rest, we might expect such
coherent fluctuations to have minimal amplitude, whereas the
amplitudes seen are of the same order as found under explicit
activation (7). Although we have shown that activation networks
are mirrored in resting data, we must acknowledge that this does
not begin to answer the question of why the brains many regions
continue to function (with large amplitude fluctuations) when
the subject is at rest, and even when the subject is asleep (5) and
under anesthesia (6). There are suggestions of rehearsal, learning consolidation, and future preparation as possible explanations (31), but there is not yet conclusive evidence for any of
these possibilities. However, the results we have presented here
surely provide motivation for further investigations regarding
this fundamental question.
Materials and Methods
Image processing and ICA decompositions were carried out with FSL (32, 33).
Resting FMRI. FMRI time series data from each of 36 healthy adults at rest was
acquired over 6 min. Each subjects dataset was transformed into a standard
coordinate space, and all subjects datasets were concatenated temporally. The
resulting multisubject dataset was fed into ICA, after an initial PCA-based dimensionality reduction to 20 (and, separately, 70) components, to find the most
representative networks of covariation when the brain is at rest (4, 34 38).
BrainMap. We extracted 7,342 activation-peak images from BrainMap (in
standard coordinate space) and applied 12-mm full-width Gaussian blurring
to each, producing extended areas of activation (attempting to mimic the
nature of the original activation images). We applied ICA to this space
experiment-ID dataset, including an initial PCA-based dimensionality reduction to 20 (and, separately, 70) components to find the most representative
functional networks from the entire BrainMap database.
Comparing BrainMap with Resting FMRI. Spatial maps from BrainMap and
resting FMRI were associated with each other primarily via spatial similarity, by
using (Pearson) spatial cross-correlation. See SI for more detail on datasets and
methodology.

Smith et al.

A.R.L. were supported, as part of the Human Brain Project, by National

Institute of Mental Health Grant R01-MH074457-01A1 (P.T.F., principal
investigator).

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Smith et al.

PNAS August 4, 2009 vol. 106 no. 31 13045

NEUROSCIENCE

ACKNOWLEDGMENTS. We are grateful to Holly Bridge and Paul Matthews

for advice. K.L.M. was supported by the Engineering and Physical Sciences
Research Council/Royal Academy of Engineering. P.T.F., P.M.F., R.T., and

Supporting Information
Smith et al. 10.1073/pnas.0905267106
SI Text
BrainMap Activation Experiment Data and Analysis. The BrainMap

database contains the results of a large number of brain activation studies; at the time of our analyses, it contained the results
from 1,687 journal articles. Each study can involve multiple
conditions, for example, comparing finger tapping with rest
and comparing different rates of tapping with each other. The
1,687 studies resulted in 7,342 separate activation images and
between them involved 29,671 human subjects. In the BrainMap
database, the spatial distributions of these activations are represented via the coordinate locations of statistically-significant
local maxima in the activation images. All coordinates are in a
standard brain space, in the case of BrainMap, the Talairach
coordinate system (1). For each activation result, we recreated
a 2-mm-resolution standard space pseudoactivation image by
filling an empty image with points corresponding to the activation coordinates and then convolving this with a Gaussian kernel
of FWHM 12 mm (2). Although the actual spatial extent of the
original activation has not been preserved, this smoothing extent
is a reasonably close match to that applied as data preprocessing
in most FMRI activation studies and is close to the spatial
variability in database coordinate locations as carefully investigated by ref. 3. We tested other spatial smoothing extents from
8- to 15-mm FWHM and found the results not significantly
sensitive to the exact extent.
The resulting 7,342 activation images are concatenated together to produce a 2D dataset, where the first dimension is
space (the 3 spatial dimensions are unwrapped onto 1 dimension), and the second is experiment ID (1:7,342; this dimension
is referred to as time at points in our text, as a convenient
shorthand, and in analogy to the temporal dimension in the
resting FMRI data). For the PCA-based dimensionality reduction (described below) it is necessary for the data to be demeaned; also, as part of the pre-ICA processing, all voxels time
series are normalized to have variance of unity. These 2 practical
data transformations are necessary in order for the PCA and
ICA models to function correctly but do result in the presence
of a few artifactual components in the ICA output. For parts
of standard space involving very few nonzero values in the raw
data (e.g., in voxels that do not correspond to gray matter), the
combination of demeaning (of what was originally positive or
zero data) and the variance normalization of voxels time series
(poorly conditioned and inflated in such voxels) leads to meaningless components. These can be seen below in Results: 20Dimensional Results in Detail and are easily identified and
discarded from further consideration.
The initial spatial maps generated by the principal component
analysis (run before the final ICA) are not generally interpretable; although they span the space of the strongest d covariance components in the database, they are uninterpretably
separated from each other because of the mathematical constraint in PCA that components are orthogonal in space and
time. ICA aims to resolve this problem, by optimizing the
independence of the resulting spatial maps while applying only
a weak constraint on the relationship between any 2 networks
associated time courses; in ICA, time courses only have to be
noncolinear, just as is required for the covariates in a multiple
regression. Indeed, ICA resembles multiple regression, being
different in that the covariates here are estimated from the data.
In effect, the ICA unmixing is applying the central limit
theorem in reverse, utilizing the fact that the optimal (and most
meaningful) identification of components is achieved by miniSmith et al. www.pnas.org/cgi/content/short/0905267106

mizing the mutual statistical dependence between any 2 estimated components. A further strength of an ICA decomposition
is that the ICA model allows any given brain region to be
associated with 1 component, if the regions time series is a
linear combination of the time series of 1 component. This
makes biological sense, because a given point in the brain may
be part of 1 functional network, but in general, such a
representation is not possible with many other (e.g., clusteringbased) approaches to multivariate decompositions. Hence, we
apply ICA to identify the primary independent components in
this data: d spatial maps, each with its own associated experiment
ID time course that describes how strongly that particular map
was relevant to each of the original 7,342 activation maps.
For the ICA decomposition, we used the MELODIC (multivariate exploratory linear optimized decomposition into independent components) tool (4) in the FSL [FMRIB Software
Library (5, 6)] brain image analysis tool set. The ICA spatial
maps are scaled by dividing by the noise standard deviation
image from the residuals of the initial PCA-based dimensionality
estimation and then Gaussianized by fitting a Gaussian-center
-tailed mixture model, with the parameters of the fitted null
Gaussian used to set the background mode to zero and background standard deviation to unity. The final ICA spatial maps
were affine-transformed from BrainMap standard space (Talairach space) into 2-mm MNI152 space. These maps are, at any
given dimensionality d, the d nartifacts most representative
functional networks from the entire BrainMap database.
Resting FMRI Experiment Data and Analysis. The resting-state
FMRI dataset and analysis followed a fairly standard protocol,
albeit with a higher number of subjects than often acquired for
resting state experiments. Thirty-six healthy adult subjects were
imaged (age range 2035 y, mean 28.5 y; 21 male, 15 female)
in a 3T Siemens Trio MRI scanner, using a 12-channel head coil.
Structural brain images were acquired by using a T1-weighted 3D
MPRAGE sequence with whole-head coverage, TR 2.04 s,
TE 4.7 ms, flip angle 8, resolution 1 1 1 mm, total
acquisition time 12 min. These were used purely to aid the
registration of the functional data into a common standard brain
coordinate system (MNI152). Resting FMRI BOLD (blood
oxygenation level-dependent) data were acquired with a standard gradient echo echo-planar-imaging (EPI) acquisition,
TR 2 s, TE 28 ms, flip angle 89, resolution 3 3 3.5
mm, whole-head coverage except for the lowest parts of the
cerebellum in some subjects. The resting FMRI scan lasted 6
min. Ambient light was minimized, and the subjects were
instructed to lie with eyes open, think of nothing in particular,
and not to fall asleep. This dataset is not related to any
experiments contained in BrainMap.
Data preprocessing was carried out with FSL tools. The
following prestatistics processing was applied for each subject:
head motion correction by using MCFLIRT (7); non-brainremoval by using BET (8); spatial smoothing by using a Gaussian
kernel of FWHM 5 mm; grand-mean intensity normalization of
the entire 4D dataset by a single multiplicative factor; high-pass
temporal filtering (subtraction of Gaussian-weighted leastsquares straight-line fitting, with 50.0 s). Registration of each
subjects FMRI data to that subjects high-resolution structural
image was carried out by using FLIRT (7). Registration from the
high-resolution structurals to MNI152 standard space was
achieved by using FLIRT affine registration and then further
refined by using FNIRT nonlinear registration (9, 10).
1 of 10

All subjects 4D FMRI time series data were transformed into

standard space at 2 2 2-mm resolution, by using the
registration transformations derived as described above. All
resulting datasets were concatenated in the temporal dimension,
resulting in a 2D dataset with spatial dimension of size 91
109 91 902,629 and 6,226 time points. ICA was run using
MELODIC at dimensionalities of 20 and 70. In normal usage,
MELODIC estimates the optimal dimensionality of the data;
this aids in achieving ICA convergence stability. However, in this
case, because we were enforcing the dimensionality and, hence,
reducing the likelihood of guaranteed stable convergence, we
ran the ICA unmixing 8 times and combined these analyses (via
a metalevel ICA decomposition fed by all d8 maps) to find the
overall most stable decomposition. The ICA spatial maps were
Gaussianized as described above. The resulting maps are, at a
chosen dimensionality d, the d nartifacts most representative
resting state covarying networks across a large sample of normal
subjects.
Spatial and Functional Associations of the ICA Components. For the

20-component decompositions of the resting FMRI and BrainMap datasets, spatial maps were compared between the 2 sets of
results by using simple Pearson correlation of the unthresholded,
Gaussianized spatial maps. For the 70-component decompositions, maps were again compared/matched between the resting
FMRI and BrainMap results by using spatial correlation, also
related to the 20-component decompositions by using a combination of spatial correlations and functional correlations (i.e.,
also by using ICA time courses). This latter analysis is now
described in more detail.
Let the matrix of spatial cross-correlation values between the
70-component BrainMap and resting FMR I maps be
RS:RSN70BM70. Let the matrix of temporal cross-correlation
values between the 70-component BrainMap and 20-component
BrainMap maps (where the 20-component maps have been
reordered to be consistent between BrainMap and RSNs, according to the pairings found in the 20-component analyses) be
RT:BM70BM20, and the matrix of spatial cross-correlations be
RS:BM70BM20. Likewise, let the matrices of temporal and spatial
correlations from the resting FMRI maps be RT:RSN70RSN20 and
RS:RSN70RSN20. When associating 70-component with 20component maps, we care about both spatial overlap and
functional correspondence and so (because these are normalized
correlations) average the spatial and temporal matrices to give
spatiotemporal correspondence matrices:
RST:BM70BM20 R S:BM70BM20 R T:BM70BM20/2,

[s1]

RST:RSN70RSN20 R S:RSN70RSN20 R T:RSN70RSN20/2.

[s2]
We now associate 70-component maps with the 20-component
maps by combining all of the above spatial and temporal
information and utilizing information from both domains simultaneously to give automated pairings across dimensionalities and
domains:
RRSN70BM20 R S:RSN70BM70 R ST:BM70BM20

[s3]

RRSN70RSN&BM20 R RSN70BM20 . R ST:RSN70RSN20

Schur product,

[s4]

where searches for maxima in the rows of this final matrix,

RRSN70RSN&BM20, map the RSN70 maps onto the reordered (and
matched) 20-component BrainMap-RSN maps. The equivalent
calculation is also made for the BM70 maps, resulting in correspondences across dimensionalities and domains.
Smith et al. www.pnas.org/cgi/content/short/0905267106

Extracting Behavioral Domain Information from BrainMap. To add

functional interpretation to each of the ICA components, we

projected each BrainMap-derived component time course back
onto the original list of 7,342 experimental conditions and,
hence, extracted the corresponding behavioral domain information from the BrainMap database. We now describe this process
in more detail.
We define e 7,342 to be the number of experiments
(different activation conditions in BrainMap) and d to be the
dimensionality of the PCA-reduced dataset (e.g., d 20). The
standard-brain-space image has s 199,191 nonzero voxels.
Hence, the raw BrainMap data matrix Y is of size s e. The PCA
decomposition is
Y USV,

[s5]

where U are the spatial modes, S is a diagonal matrix containing

the singular values (ordered, by convention), and V are the
temporal (experiment ID) modes. To pass on the strongest d
spatial modes to the ICA decomposition, we take the first d
columns from V (corresponding to the d largest singular values),
giving Vd, of size e d, and then calculate
Ud YV dS 1
d ,

[s6]

which is an s d matrix of the top d whitened spatial modes. ICA

is then applied, and the resulting mixing matrix Md is of size d
d; to project this back onto the experiment-ID domain, and
hence onto BrainMap, we need to reuse Vd:
M V d M d.

[s7]

Thus, we have M, an e d matrix whose d columns (one for each

ICA component) describe the weightings of each component for
each of the original activation images. We then extract the b
(behavioral domains) e matrix P from BrainMap and form the
final matrix of domains vs. ICA maps,
Pd PM.

[s8]

We scale each row of Pd to have mean of unity, to normalize for

different numbers of different behavioral domains existing in the
database. This results in the mapping matrix as seen in Fig. 2 in
the main article.
Note that a normalization for the different numbers of
different paradigms (behavioral domains) is not straightforward
to apply to the raw data fed into the PCA/ICA decomposition,
because there will be some functional covariance between the
different paradigms, so it would not be correct to treat every
behavioral domain in the same way (in terms of variance scaling);
however, it would be good to achieve normalization if possible,
to improve the objectivity of the derived maps. With respect
to the reverse inference of ICA spatial maps and experimental-ID-time courses back onto the 66 BrainMap behavioral
domains, we note the warning made in articles such as ref. 11; this
discusses the danger of oversimplistically assigning a limited set
of functions to an activated brain region, on the basis of prior
experiments that activated that region. Our figure is included for
illustrative purposes, and as a sanity check for our spatiotemporal manipulations of the BrainMap data; the fact that we have
presented the back-projection matrix unthresholded directly
relates to the wish for caution in such reverse inference of
function from location. In fact, we could immediately head
toward the (Bayesian) selectivity discussed by Poldrack if we
were to normalize vertically in the matrix, and not just horizontally, as described above.
Results: 20-Dimensional Results in Detail. In this section, we show
more complete images of the 10 main corresponding pairs
2 of 10

presented in Fig. 1 of the main article as well as for all other

components extracted by the 20-dimensional ICA decompositions of BrainMap and the resting FMRI data. We also give more
detailed descriptions of the nonpaired components.
The 10 well-matched pairs of components (maps 11020) are
shown in Figs. S1 and S2. As with all images in this article, the
left side of the brain is shown on the right of the image. All ICA
spatial maps were originally Gaussianized via a normalized
mixture-model fit, and then thresholded at Z 2 for all images
shown in this section. Both datasets are in 2 2 2-mm MNI152
standard space; every third slice is shown here, starting with the
lowest slice at 28 mm in the MNI152 coordinate system.
The weakest spatial correlation in these 10 paired maps is r
0.25 (Pearson). A correction for the number of possible paired
comparisons would be a factor of 20 20 400 (conservative
because not all components are considered to be nonartifactual).
A correction for the spatial degrees of freedom is given via
Gaussian random field theory and empirical smoothness estimation (12, 13); for this data, the number of independent
resels (resolution elements) was found to be 665; we therefore set this conservatively to be 500. Applying Fishers r-to-z
transform by using degrees-of-freedom 500, converting to a P
value and multiplying by 400 to correct for multiple comparisons,
we obtain P 5 106, hence, our statement in the main article
that the weakest pairing corresponds to (at least as small as) P
105 (corrected).
Figs. S3S5 show BrainMap and RSN components that are
plausible functional networks but that did not find a strong and
unambiguous (1:1) mapping between BrainMap and the resting
FMRI data. Each also has some overlap with the 10 main paired
maps, or some combination of these. We have loosely grouped
these maps along with one or more of the paired maps (the latter
being shown in the top part of each of these 3 figures, for
reference), partly on the basis of spatial overlap but also taking
into account functional correspondence. For an RSN, this
means using the temporal correlation between the RSN map in
question and the paired RSN maps; for a BrainMap map, this

means using the experiment-ID correlation between the BrainMap map in question and the paired BrainMap maps.
Fig. S3 shows map BM-1120. This component has clear spatial
overlap with the visual subset of paired components, as well as
functional similarity to the visual subset of BrainMap components. This map includes the parahippocampal gyrus, lateral
occipital cortex, and, possibly, lingual gyrus and primary visual
cortices.
Fig. S4 shows map BM-1220. This component has clear spatial
overlap with the default mode network map 420 as well as
functional similarity to the BrainMap 420 map.
Fig. S5 shows maps RSN-11, 12, 1320 and BM-13, 14, 1520 from
the 20-component ICA decomposition of BrainMap and the
resting FMRI data. These components do not directly match
single maps but do have some spatial overlap with the set of maps
6, 8, 9, 1020 as well as functional similarity.
Fig. S6 shows maps RSN-14, 15, 1620 and BM-16, 17, 1820 from
the 20-component ICA decomposition of BrainMap and the
resting FMRI data. It is not clear whether the resting FMRI
maps are artifactual (e.g., caused by the presence of larger blood
vessels), or valid RSNs. The BrainMap maps are biologically
plausible, corresponding probably to thalamus/caudate, hippocampus/amygdala, and orbitofrontal cortex/anterior insular;
however, the decomposition at this dimensionality did not find
exactly corresponding maps in the resting FMRI data.
Fig. S7 shows clearly artifactual maps from the 20-component
ICA decomposition of BrainMap and the resting FMRI data.
The RSN maps do not lie within gray matter and are caused
by confound factors such as variations in subjects head sizes
(residual after registration to standard space), head motion, and
nonneural physiological fluctuations. ICA has been shown to be
very effective at separating such artifacts into separate components from plausible functional components (14). The BrainMap
components are mathematical artifacts, again not in gray matter,
caused by the temporal variance standardization and data demeaning carried out by the PCA-based initial dimensionality
reduction.

1. Talairach J, Tournoux P (1988) Co-Planar Stereotaxic Atlas of the Human Brain

(Thieme, New York).
2. Turkeltaub P, Eden GF, Jones KM, Zeffiro TA (2002) Meta-analysis of the functional
neuroanatomy of single-word reading: Method and validation. NeuroImage
16(3):765780.
3. Eickhoff SB, et al. (2009) Coordinate-based activation likelihood estimation metaanalysis of neuroimaging data: A random-effects approach based on empirical estimates of spatial uncertainty. Hum Brain Mapp, in press.
4. Beckmann CF, Smith SM (2004) Probabilistic independent component analysis for
functional magnetic resonance imaging. IEEE Trans Med Imag 23(2):137152.
5. Smith SM, et al. et al. (2004) Advances in functional and structural MR image analysis
and implementation as FSL. NeuroImage 23(S1):208 219.
6. Woolrich MW, et al. (2009) Bayesian analysis of neuroimaging data in FSL. NeuroImage
45:S173S186.
7. Jenkinson M, Bannister PR, Brady JM, Smith SM (2002) Improved optimisation for the
robust and accurate linear registration and motion correction of brain images. NeuroImage 17(2):825 841.
8. Smith SM (2002) Fast robust automated brain extraction. Hum Brain Mapp 17(3):143
155.

9. Andersson J, Smith S, Jenkinson M (2007) Non-linear optimisation. Internal Technical

Report TR07JA1, Oxford Centre for Functional Magnetic Resonance Imaging of the
Brain, Department of Clinical Neurology (Oxford Univ, Oxford, UK), available at
www.fmrib.ox.ac.uk/analysis/techrep.
10. Andersson J, Jenkinson M, Smith S (2007) Non-linear registration aka spatial normalisation. Internal Technical Report TR07JA2, Oxford Centre for Functional Magnetic
Resonance Imaging of the Brain, Department of Clinical Neurology (Oxford Univ,
Oxford, UK), available at www.fmrib.ox.ac.uk/analysis/techrep.
11. Poldrack R (2006) Can cognitive processes be inferred from neuroimaging data? Trends
Cognit Sci 10(2):59 63.
12. Jenkinson M (2000) Estimation of smoothness from the residual field. Internal Technical Report TR00MJ3, Oxford Centre for Functional Magnetic Resonance Imaging of
the Brain, Department of Clinical Neurology (Oxford Univ, Oxford, UK).
13. Forman S, et al. (1995) Improved assessment of significant activation in functional
magnetic resonance imaging (fMRI): Use of a cluster-size threshold. Magn Reson Med
33:636 647.
14. Birn R, Murphy K, Bandettini P (2008) The effect of respiration variations on independent component analysis results of resting state connectivity. Hum Brain Mapp 29:740
750.

Smith et al. www.pnas.org/cgi/content/short/0905267106

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Smith et al. www.pnas.org/cgi/content/short/0905267106

4 of 10

Fig. S1. Maps 120 through 520 of the 10 well-matched pairs of networks from the 20-component ICA decomposition of BrainMap and the resting FMRI data. The top row of each pair
is the RSN, and the bottom is the BrainMap network. This figure shows every 3rd axial slice in 2-mm MNI152 standard space, starting with the lowest slice at 28 mm.

Smith et al. www.pnas.org/cgi/content/short/0905267106

5 of 10

Fig. S2.

Maps 620 through 1020 of the 10 well-matched pairs of networks from the 20-component ICA decomposition of BrainMap and the resting FMRI data.

Smith et al. www.pnas.org/cgi/content/short/0905267106

6 of 10

Fig. S3. Map BM-1120 from the 20-component ICA decomposition of BrainMap and the resting FMRI data. This component does not directly match a single map from the resting FMRI
data but does have spatial overlap with the visual subset of paired components as well as functional similarity to the visual subset of BrainMap components.

Smith et al. www.pnas.org/cgi/content/short/0905267106

7 of 10

Fig. S4. Map BM-1220 from the 20-component ICA decomposition of BrainMap and the resting FMRI data. This component does not directly match a single map from the resting FMRI
data but does have clear spatial overlap with the default mode network map 420 as well as functional similarity (according to the experiment-ID ICA time courses) to the BrainMap
420 map.

Smith et al. www.pnas.org/cgi/content/short/0905267106

8 of 10

Fig. S5. Maps RSN-11,12,1320 and BM-13, 14, 1520 from the 20-component ICA decomposition of BrainMap and the resting FMRI data. These components do not directly match
single maps but do have some spatial overlap with the set of maps 6, 8, 9, 1020 as well as functional similarity.

Smith et al. www.pnas.org/cgi/content/short/0905267106

9 of 10

Fig. S6. Maps RSN-14, 15, 1620 and BM-16, 17, 1820 from the 20-component ICA decomposition of BrainMap and the resting FMRI data. It is not clear whether the resting FMRI maps
are artifactual (e.g., caused by the presence of larger blood vessels), or valid RSNs. The BrainMap maps are biologically plausible, corresponding probably to thalamus/caudate,
hippocampus/amygdala, and orbitofrontal cortex/anterior insular; however, the decomposition at this dimensionality did not find exactly corresponding maps in the resting FMRI data.

Smith et al. www.pnas.org/cgi/content/short/0905267106

10 of 10

Fig. S7. Clearly artifactual maps from the 20-component ICA decomposition of BrainMap and the resting FMRI data. The RSN maps are clearly not lying within gray matter and are
caused by confounding factors such as variations in subjects head sizes (residual after registration to standard space), head motion, and nonneural physiological fluctuations. The
BrainMap maps are mathematical artifacts, again not in gray matter, caused by the temporal variance standardization and data demeaning carried out by the PCA-based initial
dimensionality reduction.