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Co-activation pattern (CAP) analysis is a frame-wise analytical approach that disentangles the different functional brain networks that interact with a user-defined seed region. While fruitful applications in various clinical settings have been demonstrated, there is not yet any centralised, publicly accessible resource to facilitate the deployment of the technique. + +Here, we release a working version of a toolbox for CAP analysis, which includes all steps of the analytical pipeline, introduces new methodological developments that build on already existing concepts, and enables a facilitated inspection of CAPs and resulting metrics of brain dynamics. Our toolbox can be downloaded at \url{https://c4science.ch/source/CAP_Toolbox.git}. + +In addition, to illustrate the usefulness of our pipeline, we describe an application to the study of human cognition. CAPs are constructed from a right dorsolateral prefrontal cortex seed, and in a separate subject population with matched fMRI volumes, we successfully (R=0.59) predict a behavioural measure of continuous attentional performance from metrics characterising CAP dynamics. + \end{abstract} + +\begin{keyword} +dynamic functional connectivity \sep frame-wise analysis \sep co-activation pattern analysis \sep task-positive network \sep attention \sep continuous performance \sep toolbox +\end{keyword} + +\end{frontmatter} + + +%%%% Introduction +\section{Introduction} + +Functional magnetic resonance imaging (fMRI) has enabled to track temporal changes in activity levels at the whole-brain scale by means of the blood oxygenation level-dependent (BOLD) contrast, a proxy for neural activation~\citep{Logothetis2001}. In addition to more traditional task-based studies in which BOLD changes are mapped to a paradigm of interest~\citep{Friston1994}, the characterisation of statistical interdependence between remote brain locations (termed \textit{functional connectivity}~\citep{Friston1994b}) in the resting-state, and the concomitant definition of large-scale \textit{resting-state brain networks} (RSNs), has been a popular endeavour~\citep{Biswal1995,Fox2005,Damoiseaux2006,Power2011}, with great benefits for the understanding of cognition and disease~\citep{VanDenHeuvel2010,Greicius2008,Fox2010}. + +Over the past years, it has become increasingly appreciated that cross-regional relationships do not remain static over the course of a full scanning session~\citep{Chang2010}: instead, a given area rearranges its interactions along time, in ways that have been addressed with very diverse analytical tools (see~\citet{Preti2017} for an exhaustive review of the \textit{dynamic functional connectivity} field). + +In one family of approaches that has been developed, it is assumed that only few salient time points contain the information of interest that shapes whole-brain correlational relationships; selecting only these frames, by means of a seed-based thresholding process, already enables to derive accurate RSN maps, even if as little as 10\% of data points is retained~\citep{Tagliazucchi2012b}. The analysis then moves from a second-order correlation-based characterisation to a first-order activation viewpoint, and reduces computational load, a desirable feat in light of the numerous large-scale acquisition initiatives embraced by the fMRI community~\citep{VanEssen2013,Nooner2012,Holmes2015}. + +Building on this point-process analysis concept, and inspired by the dynamic viewpoint on resting-state brain function,~\citet{Liu2013} hypothesised that at different moments in time, the seed region of interest would display distinct interactions with the rest of the brain. A k-means clustering step was thus appended to frame selection, so that fMRI volumes with a large enough seed activity would be partitioned into a limited set of \textit{co-activation patterns} (CAPs). + +Since then, co-activation pattern analysis has started to gain momentum as a potent tool to reveal functional brain dynamics subtleties: analyses taking the posterior cingulate cortex (PCC) as a seed revealed alterations of spatial intensity level and occurrence in specific CAPs~\cite{Amico2014,DiPerri2018}, while in adolescent depression,~\citet{Kaiser2019} showed that the time spent in a specific frontoinsular-default network CAP positively correlated with symptoms severity. CAP analysis also enabled to track the renormalisation of CAP occurrences in patients with essential tremor following surgical intervention~\citep{Tuleasca2019}. + +In parallel to clinical applications, the technical details of the approach have also been addressed, in terms of retaining activation versus deactivation time points~\citep{Di2013}, extending the approach to the whole brain~\citep{Liu2013b}, designing novel metrics of interest~\citep{Chen2015}, or constraining the extent of spatial overlap across CAPs~\citep{Zhuang2018}. For more details, the reader is pointed at the recent review of~\citet{Liu2018}. + +Here, we wish to further foster the development of CAP analysis by releasing a dedicated toolbox, which enables to easily navigate through the steps of the analytical pipeline through a graphical user interface, and also offers additional technical developments regarding frame selection and metrics computation. While the mathematical underpinnings of CAP analysis are relatively straightforward, we hope that providing such a resource will encourage practitioners to embrace the method. + +Further, to exemplify the use of our toolbox, we also describe an application of CAP analysis in the yet unaddressed setting of predicting cognitive skills: in a battery of healthy individuals, we show that continuous performance in a visual attention and vigilance task correlates with the expression profile of task-positive network (TPN) CAPs. + +%%%% Materials and Methods +\section{Materials and Methods} + +\subsection{Co-activation pattern analysis theory} + +Let us consider the data matrix $\mathbf{X_s}\in \mathbb{R}^{V \times T}$ for subject $s$, where $V$ is the number of voxels to consider in the analysis and $T$ the number of time points. Each voxel-wise time course is temporally z-scored, so that $\mu_i=\frac{\sum_{t=1}^{T}X_{s}(i,t)}{T}=0$ and $\sigma_i=\sqrt{\frac{\sum_{t=1}^{T}(X_{s}(i,t)-\mu_i)^2}{T-1}}=1$ for all $i=1,2,\cdots,V$. + +Co-activation pattern analysis requires the definition of a seed region, whose interactions with the rest of the brain will be probed. Formally, a set of voxels $\mathcal{S}$ that one wishes to consider is specified, and a time point $t$ of the seed activation time course is then given by: +\begin{equation*} +S_{s}(t) = \frac{\sum_i\in\mathcal{S} X_{s}(i,t)}{|\mathcal{S}|}\quad\text{for all}\quad t\in 1,2,\cdots,T. +\end{equation*} + +Only time points when the seed time course takes sufficiently extreme values (denoting significant seed (de)activation) are considered. Let the activation threshold $T$; we then construct the set $\mathcal{T}_s$ of time points that satisfy $S_{s}(t)>T$ (if we wish to consider solely activation moments) or $S_{s}(t)