Abstract
Background
Graphbased analysis of fMRI data has recently emerged as a promising approach to study brain networks. Based on the assessment of synchronous fMRI activity at separate brain sites, functional connectivity graphs are constructed and analyzed using graphtheoretical concepts. Most previous studies investigated regionlevel graphs, which are computationally inexpensive, but bring along the problem of choosing sensible regions and involve blurring of more detailed information. In contrast, voxellevel graphs provide the finest granularity attainable from the data, enabling analyses at superior spatial resolution. They are, however, associated with considerable computational demands, which can render highresolution analyses infeasible. In response, many existing studies investigating functional connectivity at the voxellevel reduced the computational burden by sacrificing spatial resolution.
Methods
Here, a novel, timeefficient method for graph construction is presented that retains the original spatial resolution. Performance gains are instead achieved through data reduction in the temporal domain based on dichotomization of voxel time series combined with tetrachoric correlation estimation and efficient implementation.
Results
By comparison with graph construction based on Pearson’s r, the technique used by the majority of previous studies, we find that the novel approach produces highly similar results an order of magnitude faster.
Conclusions
Its demonstrated performance makes the proposed approach a sensible and efficient alternative to customary practice. An open source software package containing the created programs is freely available for download.
Keywords:
Functional connectivity; Graph theory; Tetrachoric correlation; Restingstate; fMRIBackground
The functioning of the human brain relies on the interplay and integration of numerous individual units in a complex network. Insights into its topology are thus essential to promote our understanding of the brain in general, as well as its maladaptive states associated with dysfunction and disease. An increasingly popular approach to the analysis of functional brain networks is based on the framework of graph theory [14]. A graph is a mathematical structure designed for modelling pairwise relationships, known as edges, between an assortment of objects, referred to as nodes. In applications to fMRI, the node set is defined as a collection of brain sites, and edges are established by measuring internodal functional connectivity [5] based on the regions’ associated time series. The obtained functional connectivity graph, serving as a simple model of the brain’s functional organization in a complex network, is subsequently examined drawing on a rich collection of graphtheoretical metrics that target various aspects of its topology [6]. Several studies indicate, for instance, that the brain’s functional network conforms to a smallworld architecture [1,2,7,8]. Beyond that, the usefulness of graphbased functional connectivity analyses has been demonstrated in applications to brain development and aging [911], gender differences [12], intellectual performance [13], and neurological disorders, such as Alzheimer’s disease [14,15] or schizophrenia [16,17].
In most previous studies, functional connectivity graphs have been constructed at the level of regions [1,7,10,14,18], meaning that graphical nodes are defined based on a parcellation of the brain into regions of interest (ROI), each consisting of several voxels. Due to the limited number of nodes, such analyses are computationally inexpensive and their results are comparatively easy to visualize and interpret. However, regionlevel nodes involve mixing fMRI time series from the incorporated voxels, thus obliterating more detailed spatial information [4,19]. ROIbased analyses are therefore highly dependent on the quality of the parcellation: If ROI boundaries and actual functional boundaries are inconsistent, the results can be erroneous [20]. Voxellevel analyses, in contrast, are not subject to these limitations, since the parcellation inherent to the original data is used for node definition [8,11,13,15,2123]. Consequently, voxellevel graphs provide a finer model of the brain’s functional network organization, since the original spatial resolution of the fMRI data is preserved [4,24].
Because of the large number of nodes, the construction and analysis of voxellevel graphs can involve considerable computational efforts. In response, the computational burden has often been reduced by sacrificing spatial resolution (using relatively large voxels to begin with or reslicing the data to a lower resolution) thus reducing the number of nodes in the graph [15,2527]. While reduction of spatial resolution is undesirable in general (given that the main advantage of fMRI as compared to other methods such as EEG/MEG is its superior spatial resolution), it can even render a study infeasible, e.g., when investigating very small brain structures or different regions that lie in close proximity to each other. Efficient algorithms and implementations are therefore required in order to take full advantage of the data’s original spatial resolution [24].
Here, we propose a novel approach aiming to increase the computational efficiency of voxellevel graph construction by combining time series dichotomization, tetrachoric correlation estimation, and efficient implementation, while retaining the full spatial resolution of the data. Comparison with conventional graph construction (as carried out in previous studies) shows that the new approach not only produces highly similar results, but also executes an order of magnitude faster.
Methods
This section consists of three parts. We begin with a short introduction to voxellevel functional connectivity graphs and explain their construction from fMRI data. In particular, it is established how time series dichotomization can be combined with tetrachoric correlation estimation to efficiently measure functional connectivity. The second part describes analyses comparing Pearson’s r and the tetrachoric correlation coefficient r_{t} (1) as correlation estimators in the controllable environment of synthetic data, (2) as measures of functional connectivity in the context of graph construction from fMRI data, and (3) with respect to the similarity of graphs resulting from (2). The last part provides implementation details regarding the programs created for this study and assesses their computational performance.
Voxellevel graph construction
Formally, an undirected binary graph is defined as an ordered pair G_{B}=(N,E), comprised of a set of nodes N and a set of pairwise internodal connections, or edges, E. Individual edges are unordered pairs {i,j}, where i,j∈N. G_{B} can be represented by a binary adjacency matrix B^{N×N}=(b_{i,j}), where b_{i,j}∈{0,1}, i,j∈N, and b_{i,j}=1 indicates that {i,j}∈E, i.e., that a connection between the two nodes i and j exists. In order to represent not only the presence or absence of connections but also their strength, a graph can be extended by assigning a weight to each edge.
In applications to fMRI data, graphbased analyses rely on the derivation of a graphical representation of the brain’s functional network, which is then examined in terms of graph theory (Figure 1). Voxellevel functional connectivity graphs are constructed based on individual voxels as nodes, that is, the set of nodes N is a collection of voxels. In the literature, N is often defined as all inbrain voxels, or all gray matter (GM) voxels. Functional connectivity is estimated between all pairs of nodes based on their corresponding time series using a measure of association.
Figure 1. Construction and analysis of voxellevel functional connectivity graphs. Starting with the preprocessed fMRI data, all gray matter voxels are defined as graphical nodes (1). Using their associated time series, pairwise internodal functional connectivity is measured in terms of linear correlation. Typically, this is done using Pearson’s r. Alternatively, one can derive binary time series via medianbased dichotomization and employ tetrachoric correlation estimation (r_{t}). In both cases, the result is a correlation matrix (2) representing the pairwise functional connectivity between nodes. A binary undirected graph, represented by a binary adjacency matrix (3), is obtained via thresholding. Based on the adjacency matrix, graphtheoretical metrics, such as the node degree k, are computed (4).
To construct a binary graph, edges are established by thresholding the functional connectivity estimates: Two nodes are connected by an edge if their functional connectivity exceeds a given threshold. Alternatively, one can take the pairwise functional connectivity matrix as a basis for a weighted graph, thus conserving the strength of individual functional connections between nodes [28]. For simplicity, and in a manner consistent with the majority of previous work on voxellevel functional connectivity graphs, we presently focus on binary graphs for our analysis.
Measuring functional connectivity
In most previous studies investigating voxellevel functional connectivity graphs, internodal functional connectivity is measured using Pearson’s sample correlation coefficient r[2,8,13,15,2127,2931]. When using Pearson correlation as a measure of functional connectivity, it seems sensible to assume bivariate normality with respect to the distribution of pairwise observations arising from each pair of voxel time series. This is because Pearson correlation may be a poor measure of association if the data are not normally distributed [32]. Encouragingly, in a recent study employing regionlevel graphs, data for the most part appeared to meet the assumption of bivariate normality [33].
Assuming bivariate normality between pairs of voxels, an alternative correlation estimator, the tetrachoric correlation coefficient r_{t}[34], can be used instead of r. Given two dichotomous variables x_{d} and y_{d}, r_{t} estimates the correlation of the latent continuousvalued variables x_{c} and y_{c} associated with x_{d} and y_{d}, under the assumption that x_{c} and y_{c} follow a bivariate normal distribution. Thus, if we dichotomize, i.e., binarize, the voxel time series data, r_{t} can be used to estimate the pairwise correlation of the original continuousvalued time series from the dichotomized ones.
Consider two voxels, v and w, and their corresponding time series, s_{v} and s_{w}. Using the medians of s_{v} and s_{w}, i.e.,
By virtue of
Figure 2. Dichotomization and tetrachoric correlation estimation. Consider a sample ((x_{1},y_{1}), (x_{2},y_{2}),…,(x_{T},y_{T})) of size T where (x,y) is distributed according to bivariate normality. Further, let x=x_{1},x_{2},…,x_{T} and y=y_{1},y_{2},…,y_{T} denote the samples from x and y, respectively. Using
The probability masses corresponding to the table’s relative frequencies are equal
to the respective partial volumes belonging to the four quadrants in the xyplane under the curve representing the bivariate normal distribution (Figure 2A). The correlation coefficient r_{t}, for which these partial volumes resemble the relative frequencies in a given table,
is an estimate of the population correlation ρ belonging to the underlying distribution. Since a 2×2 contingency table is uniquely
defined by the marginal probabilities and one joint probability, r_{t} can be found by solving, e.g.,
Given a pair of voxels, we can determine p_{11} from the dichotomized time series and use the relationship r_{t}=− cos(2πp_{11}) in order to obtain r_{t}. As a consequence, r_{t} can be used instead of r to estimate pairwise functional connectivity in the process of graph construction from fMRI data (Figure 1).
Simulations
Building upon the theoretical considerations presented above, we analyzed the characteristics of r_{t} in the controllable environment of synthetic data. More specifically, we assessed its usefulness relative to r in estimating the correlation parameter ρ of bivariate normal populations of known properties.
Data
Bivariate normal populations were generated, such that each of them exhibited a predefined population correlation ρ, where ρ∈{−0.99,−0.98,…, 0,…,0.98,0.99}. Then, 10000 bivariate samples of size T (one sample represents a pair of time series of length T) were randomly drawn from each of the populations. For each sample, r and r_{t} were calculated. Prior to calculating the latter, the data were dichotomized as described above. The entire procedure was conducted separately for two different sample sizes, T=100 and T=300, resulting in two data sets, where the choice of these numbers was guided by the parameters of the real fMRI data we analyzed.
Correlation estimation
For each data set and estimator
Application to fMRI data
Comparative graphbased analyses of restingstate fMRI data were carried out based on r vs. r_{t} as measures of functional connectivity.
Data
MRI data were obtained from the “1000 Functional Connectomes Project” repository [36,37]: We used the “Cambridge” and “Pittsburgh” data sets, contributed by R.L. Buckner and G. Siegle, respectively. These data sets contain restingstate fMRI data from 198 subjects (75 males/123 females, ages: 18–30 years; imaging parameters: TR = 3s, voxel size =3×3×3 mm^{3}, number of slices = 47; number of volumes =119) and 17 subjects (10 males/7 females, ages: 25–54; imaging parameters: TR = 1.5s, voxel size =3.125×3.125×3.2 mm^{3}, number of slices =29; number of volumes =275), respectively. Both data sets also include anatomical scans for each subject.
Preprocessing
Using SPM8 [38] functional data were motioncorrected by alignment to the mean functional image, then anatomical scans were coregistered to the mean functional image and segmented. In order to account for low frequency intensity drifts and high frequency noise, frequencies below 0.01Hz and above 0.1Hz were removed from the voxels time series by bandpass filtering, as is customary for restingstate data [39]. In order to minimize the impact of preprocessing on the data’s correlation structure, we refrained from spatial smoothing and spatial normalization [8,27].
Correlation estimation
Based on r and r_{t} as a measure of functional connectivity, two voxellevel graphs were constructed
for each subject from the two data sets. Nodes were defined as suprathreshold voxels
in the subjectspecific GM probability maps obtained from the segmentation (threshold
θ_{GM}=0.2). To measure internodal functional connectivity, two correlation matrices, C_{r} and
Functional connectivity graphs
Subjectspecific binary functional connectivity graphs, B_{r} and
Node degree maps
In graphbased fMRI functional connectivity analyses, one of the most popular graphtheoretical
metrics is the node degree, or degree centrality, a measure aiming to characterize
the importance of individual nodes in a binary graph. Given a binary graph B, the degree k_{i} of a node i is defined as the number of nodes that are connected to i via an edge, or, more formally,
Here, node degrees k were calculated for all subjectspecific functional connectivity graphs B_{r} and
Implementations
The most timeconsuming step when constructing a graph from fMRI data consists in
the computation of a functional connectivity matrix, which here corresponds to the
computation of a correlation matrix based on r or r_{t}. In the following, the programs created for calculating the voxellevel pairwise
correlation matrices C_{r} and
Calculation of C_{r}
Pearson’s sample correlation coefficient r is calculated for a pair of voxels v and w using
To avoid redundant operations, subexpressions depending on one voxel only are precalculated for all voxels before computing C_{r}.
In order to take advantage of the processor’s cache without the need for explicit knowledge about its size, we adopted a socalled cacheoblivious algorithm[45,46] to compute the correlation matrix, rather than explicit blocking (with a predetermined block size that optimally fits the cache). The core idea is to recursively divide the problem so that the computations are carried out on smaller and smaller blocks of data. Given that the minimum block size is small enough, there is a division step from which on all computations use only data that fits into the processor cache (regardless of its size), thus making optimal use of the cache by localizing the computations. The division scheme we implemented is illustrated in Additional file 1: Figure S1, which shows the first three steps of dividing the upper triangle of the correlation matrix.
Additional file 1. Supporting information.
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In addition, we exploited SSE2 (Streaming SIMD Extensions version 2, where SIMD stands for Single Instruction Multiple Data) and AVX (Advanced Vector eXtensions) instructions (on processors that support them^{c}), which allow for parallelization on a single core by carrying out the same operation on multiple data elements in parallel (also known as vectorized computations). Using SSE2 (AVX), the computation of the numerator of the correlation coefficient can be parallelized by computing four (eight) sums in parallel (if the float data type is used; for double, two and four sums, respectively, can be computed in parallel). The procedure is illustrated in Additional file 1: Figure S2 for SSE2 using float or AVX using double (four sums in parallel).
Calculation of
C
r
t
For each pair of voxels, r_{t} is computed in three steps. First, the bitwise AND operator is applied to the voxels’ associated binary time series. Second, the set
bits in the result are counted to obtain n_{11}. Third, r_{t} is retrieved from a lookup table of the function r_{t}=− cos(2πn_{11}T^{−1}). The table is indexed by n_{11} and contains the corresponding r_{t} values for those values that n_{11} can attain. Depending on T being even or odd, these are
Storing the binary time series in integers of, e.g., 32 bit, 32 points in time can
be processed in parallel, so that the above three steps need to be executed only ⌈T/32⌉ times per pair. Hence, it seems conceivable that the computational cost in terms
of CPU time could be lower for the calculation of
Following the procedure outlined above, two programs, tetracc/32 and tetracc/128 were created. tetracc/32 uses 32 bit integers for storing binary time series and a 16 bit lookup table for bitcounting. tetracc/128 uses __mm128i variables (holding 128 bit each) for time series storage. Using the intrinsics _mm_and_si128 and _mm_popcnt_u64 for bitwise AND and bitcounting, respectively, it is expected to improve over tetracc/32, since more data can be processed in parallel and no extra memory access (lookup table) is needed. While tetracc/32 is platformindependent, tetracc/128 is only applicable on fairly modern CPUs, because _mm_and_si128 and _mm_popcnt_u64 depend on the availability of SSE2 and POPCNT instructions, respectively^{d}.
Parallel versions
For additional performance gains, parallel versions of pcc and tetracc have been implemented using multiple threads. This aspect is, however, beyond the focus of this article, since the resulting benefits relative to singlethreaded programs are expected to be fairly independent of the choice of r versus r_{t} as a measure of internodal functional connectivity.
Performance tests
In order to assess the performance of the programs described above, we compared them to three other programs: Matlab’s builtin function corrcoef, corr from Matlab’s Statistics Toolbox, and IPN_fastCorr, a function from the Matlab toolbox ipnvoxelgraph by X.N. Zuo. Experiments were conducted from within Matlab (R2011b) on a desktop computer with an Intel(R) Core(TM) i73960X CPU (3.30GHz) and 64GB main memory running Linux (Kernel 3.4). The C/MEX routines that are part of our programs were compiled using the GNU C compiler gcc (version 4.7.1, optimization level 3). In order to prevent programs from making use of multiple cores, Matlab was restricted to one CPU core.
Input data sets (S^{V×T}) were generated using pseudorandom numbers of type float. While the length of time series T was fixed at T=200, the number of voxels V was varied between 10000 and 170000 in steps of 10000. The maximum number of voxels,
170000, follows from the fact that storing the resulting matrix (upper triangular
part) requires 53.83 GB (
Results
Correlation estimation
Overall, the correlation estimation from dichotomized data using r_{t} yielded results strongly resembling those obtained through estimation from continuous
data using r. For synthetic data, as expected, r and r_{t} exhibited linear relationships to ρ and also to each other (Figure 3A). Standard deviations (with respect to means per ρbin) were greater for r_{t} than for r, but were reasonably small for both. Peaking at ρ=0 with 0.101 and 0.058 (r), and 0.158 and 0.09 (r_{t}), for T=100 and T=300, respectively, they exhibited a gradual decrease towards the range limits of
ρ. Naturally, deviations from ρ were larger for T=100 than for T=300, because for T=100 each calculated correlation is based on fewer values than for T=300. Close inspection of the mean signed differences MSD(r_{t},ρ) and MSD(r,ρ) revealed a small systematic bias of both r and r_{t} as estimators of ρ (Additional file 1: Figure S3). The expected value of r, E(r), can be approximated by
Figure 3. Comparison of correlation estimatesr andr_{t}. Each composite plot consists of a joint histogram and the corresponding marginal
histograms. Joint probabilities were mapped to grayscale intensities. A: Results for synthetic data. Top row: T=100. Bottom row: T=300. Left and mid column: r vs. ρ and r_{t} vs. ρ, respectively; mean (solid) and mean±STD (dashed) per ρbin shown in red. Right column: r_{t} vs. r; Deming regression line (dashed) shown in orange. B: Results for fMRI data (r_{t} vs. r). Top row: Cambridge data set. Bottom row: Pittsburgh data set. Left and mid column:
Based on correlation matrices C_{r} and
For fMRI data, r_{t} and r followed a linear relationship in both data sets, although there was a slight counterclockwise rotation about the origin as reflected in a slope >1 as opposed to 1 for a perfect relation r_{t}=r (Figure 3B). This suggests only limited deviation from the assumption of pairwise bivariate normality, and, moreover, indicates that r_{t}based graphs closely resemble rbased graphs. Furthermore, the results for the Cambridge data set (T=119) showed a greater variance than those for the Pittsburgh data set (T=275). Since this feature was also observed in the results for the synthetic data sets, we presume that this was caused by the smaller sample size for the calculation of each sample correlation. The overall correlation between r and r_{t} amounted to 0.82 (Cambridge) and 0.85 (Pittsburgh).
Note that the vertical gaps in bin occupation in those histograms involving r_{t} are due to the fact that r_{t} can attain a distinct set of values only, as explained earlier. The number of attainable values, and hence the (potential) performance of r_{t} as an estimator, increases with T.
Node degree
Group average node degree maps from r and r_{t}based binary graphs B_{r} and
Figure 4. Comparison of node degreesk fromr (k_{r}) andr_{t}based (
Performance tests
The most timeconsuming step when constructing a graph from fMRI data consists in the computation of a functional connectivity matrix. We compared the performance of our programs on this task to three other programs: Matlab’s builtin function corrcoef, corr from Matlab’s Statistics Toolbox, and IPN_fastCorr, a function from the Matlab toolbox ipnvoxelgraph by X.N. Zuo. Table 1 shows memory requirements, execution times, and speedups relative to corrcoef which was selected as reference since it is available to any Matlab user out of the box and we therefore assume that it has a higher prevalence than corr or IPN_fastCorr. Figure 5 illustrates the performance in terms of data troughput measured in correlation coefficients per second. This measure does not depend on the performance of a reference program and offers more immediate access to the key results. In this sense, it is complementary to Table 1.
Table 1. Performance comparison for computation of correlation matrices
Figure 5. Performance comparison for computation of correlation matrices. Results are averages from 10 runs on a desktop computer with an Intel(R) Core(TM)
i73960X CPU (3.3GHz) and 64GB main memory. All programs were restricted to one CPU
core. Length of time series T was fixed at T=200. N: number of nodes. The programs corrcoef (Matlab builtin), corr (Matlab Statistics Toolbox), IPN_fastCorr (X.N. Zuo), and pcc (three variants) computed C_{r}, while tetracc (two variants) computed
In line with expectations, execution times increased quadratically with the number of nodes for all programs (Table 1). While pcc’s basic variant (pcc/naive) was considerably slower than corrcoef (speedup 0.31×), its SSE2 and AVXbased variants achieved speedups around 1.34× and 2.08×, respectively. The performance of corr (speedup 1.35×) was comparable to that of pcc/SSE2, while IPN_fastCorr (speedup 1.63×) ranked between pcc/SSE2 and pcc/AVX. The tetracc variants (32 and 128) were considerably faster than all programs computing r with speedups (relative to corrcoef) around 5.7× and 13.5×, respectively.
As an aside, we note that IPN_fastCorr as well as pcc and tetracc scaled better with the number of cores than corrcoef and corr. For example, using 6 cores and a data set of 50000 nodes (T=200), the speedups were 1.16× (corr), 2.46× (IPN_fastCorr), 2.32× (pcc/SSE2), 3.42× (pcc/AVX), 9.44× (tetracc/32), and 20.22× (tetracc/128), compared to corrcoef’s execution time of 18.5 seconds. Using the same data set but only 1 core the respective speedups were 1.35×, 1.63×, 1.33×, 2.08×, 5.7×, and 13.5× as compared to corrcoef’s execution time of 55.9 seconds (Table 1). Thus, the speedup gained by using 6 cores instead of 1 amounts to 4.56× (IPN_fastCorr), 5.29× (pcc/SSE2), 4.98× (pcc/AVX), 4.98× (tetracc/32), and 4.49× (tetracc/128), while corr and corrcoef gain only 2.6× and 3×, respectively.
Note that pcc and tetracc require only half the amount of memory (column 8) that corrcoef, corr, and IPN_fastCorr require (column 2), because they store only half of the symmetric matrix for memory efficiency (Table 1). In addition, corrcoef, corr, and IPN_fastCorr failed with an outofmemory error for input data sets with 90000 or more nodes. We assume that these programs internally use more memory than we expected, since the resulting matrix of correlation coefficients would require less than half of the available memory (90000^{2}·4Byte=30.17GB). Hence, the speedups of the remaining programs compared to corrcoef could not be computed for T≥90000.
Discussion
Graphbased functional connectivity analysis at the level of individual voxels allows for spatially finegrained characterization of functional networks in the human brain. However, with highresolution data sets, such analyses can become infeasible due to the computational demands involved. Most previous studies investigating voxellevel functional connectivity graphs relied on Pearson’s r for estimating internodal functional connectivity [2,8,13,15,2127,2931]. As demonstrated here, the tetrachoric correlation coefficient r_{t} constitutes a timeefficient alternative to r as a measure of functional connectivity.
In order to reduce the computational costs associated with the analysis of voxellevel graphs, previous studies reduced the data’s spatial resolution [15,26,27], spatially restricted the graphical edges incorporated into the analysis [21], or utilized parallel computing [31]. In contrast, efficiency benefits from r_{t}based graph construction are achieved without sacrificing spatial resolution, disregarding graphical edges, or exploiting parallel computing. An open source software package containing the created programs is freely available for download [44]. Note that parallel versions of r and r_{t}based graph construction have been implemented in addition to the sequential ones, thus providing additional efficiency gains that depend on the number of available processors. While this aspect is not the main focus of this article, as the resulting benefits (relative to sequential implementations) can be expected to be fairly independent of the choice of r versus r_{t} as a measure of internodal functional connectivity, the parallel implementations are still included in the software package [44].
Even though the dichotomization procedure (a prerequisite to the computation of r_{t}) entails discarding information in the time domain, important characteristics of the original data appear to be preserved. In applications to artificially generated as well as real fMRI data the new technique proved capable of closely reproducing results obtained in conventional ways. More specifically, the usefulness of the r_{t}based approach was assessed by comparison with r in estimating the correlation parameter ρ of bivariate normal populations of known properties. In this setting, both the bias and standard deviation were greater for r_{t} than for r, but still reasonably small. Thus, r_{t}based correlation estimation yielded results closely resembling those obtained when using r. Beyond that, r and r_{t}based graph construction and node degree computation were carried out for real fMRI data. A strong linear relationship was found between r and r_{t}based correlations indicating that r_{t}based graphs closely resemble rbased graphs, since the graphs are derived from the correlation matrices. In line with this, the spatial distribution of node degrees was highly similar for r and r_{t}based graphs and also in good correspondence with previous work [15,27,31].
As data mining approaches are currently gaining momentum in the neuroimaging community [36,37,49,50], the amount of publicly available experimental data is steadily growing. Consequently, development and implementation of efficient exploratory methods, such as the one presented here, are necessary in order to take full advantage of this wealth of data, especially with respect to connectivity analyses [51]. Fast construction and subsequent analysis of graphs may thus open new avenues for applications, including those within a clinical setting, where the voxellevel approach may be of particular importance. It is worth noting in this context that voxellevel graph construction can operate at the original data resolution, thus avoiding the reduction of the analysis’ spatial sensitivity [4,24]. For example, diseaserelated patterns, once identified, may serve as connectivitybased biomarkers that could aid, guide, or facilitate diagnostics and may increase prediction accuracy with respect to disease occurrence, recurrence, severity, or treatment outcome. Here, again, efficient methods are essential to facilitate assessment of individual patients within a narrow time frame [52]. If combined with efficient tools for subsequent analysis, the presented methods for fast graph construction may also be useful for online evaluation of functional connectivity in the context of realtime fMRI. This would allow for connectivitybased adaptation of experimental stimulation and interaction with the subject, for example, in taskbased fMRI studies, or neurofeedbackbased training. Taken together, we believe that there is a multitude of applications (be them experimental or clinical) that could benefit from the methods presented here, highlighting the growing importance of efficient tools for graphbased analysis of voxellevel connectivity.
Limitations
As illustrated by the results, the accuracy of a correlation estimate naturally increases with the number of data points, i.e., the number of scans. Along the same lines, it has recently been shown that the reliability of functional homogeneity increases with scan duration [53]. For both correlation estimators, it is therefore recommended to avoid a low number of scans (caused, for example, by a short scan duration, or a long TR, or both). Since the deviation from the population correlation ρ is generally higher for r_{t} than for r, a low number of scans will affect r_{t} more severely than r.
The main focus of this work lies with the comparison of r and r_{t} as functional connectivity estimators. To reduce the impact of preprocessing on the data’s correlation structure prior to this comparison, we limited the preprocessing of the fMRI data to a minimum. The effect of additional preprocessing steps, or a different preprocessing pipeline altogether, on the robustness of the proposed methods should be subject of future research. Unpublished results from our group indicate, however, that the comparability of r and r_{t} remains essentially consistent.
Conclusions
Voxellevel graphs allow for spatially finegrained analyses of functional connectivity networks. In order to reduce the considerable computational demands involved, many previous studies reduced the spatial resolution of the data. Here, a new method for graph construction—exploiting time series dichotomization and tetrachoric correlation estimation—was devised, efficiently implemented, and compared to the conventional approach based on continuousvalued data and Pearson’s r. In applications to artificially generated as well as real fMRI data the new technique proved capable of producing highly similar results. Through efficient bitbased implementation adapted to the dichotomized data the novel method runs an order of magnitude faster while the original spatial resolution of the data is retained. Hence, its demonstrated performance, not only in producing consistent results, but in obtaining them substantially faster, makes the new approach a sensible and economical alternative to customary practice. An open source software package containing the created programs is freely available for download [44].
Endnotes
^{a} Deming regression is a linear regression method that accounts for errors in both variables.
^{b} International Consortium for Brain Mapping.
^{c} SSE2 was introduced by Intel with the Pentium 4. It is also supported by AMD CPUs starting with the Athlon 64. AVX is supported starting with the Sandy Bridge (Intel) and Bulldozer (AMD) microarchitectures.
^{d}POPCNT became available starting with the Nehalem (Intel) and Barcelona (AMD) microarchitectures.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
KL conceived of the study and carried out the data analyses with conceptual input from MG, CMS, and CB. KL and CB created the software package and carried out the performance tests. KL drafted the manuscript. MG, CMS, RK, and CB edited the manuscript. All authors read and approved the final manuscript.
Acknowledgements
The authors would like to thank Sarah Donohue, Joseph Harris, Martin von Kurnatowski, Christian Moewes, and Mircea Ariel Schoenfeld for their support.
This work was supported by Deutsche Forschungsgemeinschaft SFB 779 (A11) and STSM grant 9059 of COST Action IC0702.
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